FIELD OF THE INVENTION
The present invention relates to α1aa 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 a disease or disorder mediated through α1a and/or α1d adrenergic receptor.
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. Process for the preparation of the disclosed compounds, as well as, pharmaceutical composition containing the disclosed compounds, and the methods of treating benign prostatic hyperplasia or related symptoms thereof.
BACKGROUND OF THE INVENTION
Benign prostatic hyperplasia (BPH) is a condition, which develops in elderly males and refers to the benign overgrowth of the stromal and epithelial elements of the prostate with aging. The symptoms of BPH vary, but the most common ones involve changes or problems with urination, such as hesitant, interrupted, weak stream or urgency and leaking or dribbling or more frequent urination, especially at night. Consequences of BPH can involve hypertrophy of bladder smooth muscle, a decompensated bladder and an increased incidence of urinary tract infection.
There are two components of BPH. static and a dynamic component. The static component is due to enlargement of the prostate gland, which may result in compression of the urethra and obstruction to the flow of the urine from the bladder. The dynamic component is due to increased smooth muscle tone of the bladder neck and prostate itself and is regulated by a -1 adrenergic receptor.
Currently, the most effective treatment for BPH is the surgical procedure of transurethral resection of the prostate (TURP), since it removes the obstructing tissue (C. Chappie's Br. Med. Journal 304: 1198-1199. 1992). It is a treatment, which is directed to the static and dynamic components of the BPH. However this surgical treatment is associated with rates of mortality (1%) and adverse event (incontinence 2-4%) infection 5-10 %. and
impotence 5-10%. A noninvasive alternative treatment is therefore highly desirable. There are some drug therapies, which address the static component of this condition. Administration of finasteride is one such therapy, which is indicated for the treatment of symptomatic BPH. This drug is a competitive inhibitor of the enzyme 5 α-reductase that is responsible for the conversion of testosterone to dihydrotestosterone in the prostate gland. Dihydrotestosterone appears to be the major mitogen for prostate growth, and agents, which inhibit 5-α reductase reduce the size of the prostate and improve urine flow through the prostatic urethra. Although finasteride is a potent 5-α reductase inhibitor and causes a marked decrease in serum and tissue concentrations of dihydrotestosterone. it is moderately effective in the treatment of symptomatic BPH. The effects of finasteride take 6-12 months to become evident and for many men the clinical development is minimal.
The dynamic component of BPH has been addressed by the use of adrenergic receptor blocking agents, which act by decreasing the smooth muscle tone within the prostate gland. A variety of α1a AR antagonists, for example,terazosin, doxazosin, prazosin, alfuzosin and tamulosin have been investigated for the treatment of symptomatic bladder outlet obstruction due to BPH. However, these drugs are associated with vascular side effects (e.g. postural hypertention. syncope, dizziness, headache etc) due to lack of selectivity of action between prostatic and vascular α1 adrenoceptor. There are several lines of evidence to suggest that selectivity for α1a adrenoceptor over α1b adrenoceptor will result in relative lack of vascular side effects, thus lead to a better tolerability. Mice deficient in α1b adrenoreceptors show diminished blood pressure response to phenylephrine injection compared to homozygous controls (Decreased blood pressure response in mice deficient of α1b adrenergic receptor. (Proc Natl Acad Sci USA 1997.94.11589-11594). In-vivo studies in healthy subjects comparison of α1a /α1d selective antagonists (for example, tamsulosin) or α1a selective antagonists (for example, urapidil) with non selective antagonists (for example.doxazosin. prazosin, or terazosin) under a variety of experimental conditions (e.g. involving the administration of exogenous agonist or release of endogenous agonist by cold stimulation) in several vascular beds including the skin circulation in finger tips, the dorsal hand vein, or with total peripheral resistance have been reported. (Eur J Clin Pharmacol. 1996. 49. 371-375; Naunyn Schmiedeberg's Arch Pharmacol 1996. 354. 557-561; Jpn J
Pharmacol 1999. 80. 209-215; Br J Clin Pharmacol 1999. 47. 67-74). These studies have reported that an antagonist with high affinity for α1a, or α1a/α1d can cause some degree of vasodilation but that it is much smaller than with non-subtype-selective α1a adrenoceptor antagonist. Further, there is increased vascular α1b adrenoceptor expression in elderly patients and thus α1a/α1d selective agents with selectivity over α1b adrenoceptor subtype would be of particular importance in benign prostatic hyperplasia, which is generally a disease of old age. Antagonism of both α1aadrenoceptor and α1d adrenoceptor is important to relieve lower urinary tract symptoms especially associated (suggestive of) with BPH. Targeting α1a adrenoceptor with antagonists is important in relaxing prostate smooth muscle and relieving bladder outlet obstruction whereas α1d adrenoceptor antagonism is important to target irritative symptoms.
Over the past decade, there has been an intensive search for selective α1a adrenoceptor antagonists for benign prostatic hyperplasia, which would avoid the cardiovascular side effects, associated with currently used drugs. Many selective antagonist have been described by Hieble et al in Exp opin Invest Drugs; 6. 367-387 (1997) and by Kenny et al.. in J. Med. Chem.; 40. 1293-1325 (1995). Structure activity relationships in many of these structural series have been studied in details and numerous highly selective compounds have been identified. There are many description in the literature about the pharmacological activities associated with phenyl piperazines, Eur. J. Med. Chem. -Chimica Therapeutica. 12. 173-176 (1977). describes substituted trifluorometyl phenyl piperazines having cyclo-imido alkyl side chains shown below.
(Formula Removed)
Other related compounds which have been prepared as anxiolytic, neuroleptic, 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. Bult; 39 (9). 2288-2300 (1991).Kitaro et al; JP 02-
235865 (1990).Ishizumi et al; US 4,598.078 (1086).Newet. al; J. Med. Chem. 29. 1476-1482(1986).Shigeru et. al; JP 60-204784 (1985).New et al. US 4.524. 206 (1985).Korgaonkar et al; J. Indian Chem. Soc. 60. 874-876 (1983).
However, none of the above mentioned references disclose or suggest the ai subtype selectivity profile of the compounds disclosed therein and thus their usefulness in the treatment of symptoms of benign prostate hyperplasia did not arise.
The synthesis of l-(4-arylpiperazin-l-yl)-w-[N- (a. 0)-dicarboximido)]-alkanes useful as uro-selective ai-adrenoceptor blockers are disclosed in US patent Nos. 6.083,950. 6.090,809. 6.410.735, 6.420.559, 6,420.366. WO 00/05206. US patent appl. 2002/0156085 and WO 02/44151. These compounds had good α1-adrenergic blocking activity and selectivity.
Other reports describing selective α1a adrenoceptor antagonists are US 6,376,503. US 6,319.932. US 6.339.090. EP 711757. WO 99/42448, WO 99/42445. WO 98/57940. WO 98/57632. WO 98/30560 WO 97/23462. WO 03/084928 and WO 03/084541all these patents are incorporated by reference herein in their entirety.
SUMMARY OF THE INVENTION
The present invention provides α1a and/or α1d adrenergic receptor antagonists, which can be used for treatment of benign prostatic hyperplasia (BPH) or related symptoms thereof or lower urinary tract symptoms (LUTS) with or without BPH. and process for the synthesis of these compounds.
Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers. diastereomers, polymorphs or N-oxide of these compounds having the same type of activity are also provided.
Pharmaceutical composition containing the disclosed compounds, and which may also contain pharmaceutically acceptable carrier, excipients or diluents, which can be used for the treatment of BPH or related symptoms thereof or LUTS with or without BPH.
Other objects will be set forth in accompanying description, which follows and in the part will be apparent from the description or may be learnt by the practice of the invention.
In accordance with one aspect, there are provided compounds having the structure of Formula I. as shown in accompanied drawing, and its pharmaceutically acceptable salts.
pharmaceutically acceptable solvates, enantiomers. diastereomers, N-oxides, prodrugs, polymorphs or metabolites, wherein: A can represent
(Formula Removed)
wherein:
R.2. R3. R4 and R5 can independently represent
o hydrogen
o alkyl
o phenyl R6 can represent
o hydrogen
o alkyl
o phenyl
o hydroxy
o alkoxy — can represent optional single bond R7 and R8 can independently represent
o hydrogen
o alkyl
o f=CH2 (wherein ■ is the point of attachment)
o alkynyl
o cycloalkyl
o halogen
o hydroxy
o aryl
o acetoxy
o heterocycle
o R12 Q (CH2)-M wherein m can be an integer 0 to 3
R12 can represent
• alkyl
• alkenyl
• alkynyl
• cycloalkyl
• cycloalkenyl
• aryl
• heterocycle Q can represent

• oxygen
• sulphur
• carbonyl
• carboxylic
• wherein
(Formula Removed)
W can represent
♦ no atom
♦ carbonyl
♦ carboxylic
♦ amide
R13 can represent
♦ hydrogen
♦ alkyl
♦ cycloalkyl
♦ aryl
♦ heterocycle
R7 and R8 together can represent
o cycloalkyl
o cycloalkenyl
o bicyclic alkyl
o bicyclic alkenyl
o aryl
o heterocycle
o(Formula Removed)
wherein Z is CO or SO
R9 and R10 can independently represent
o hydrogen
o hydroxy
o alkoxy
o acetyl
o acetyloxy R11 can represent
o hydrogen
o alkyl
o alkenyl
o alkynyl
o cycloalkyl
o aryl
o heterocycle X can represent -CO, -CS or -CHY wherein: Y can represent
• hydrogen
• hydroxy
• halogen
• alkoxy
• haloalkoxy R can represent
o alkyl
o alkenyl
o alkynyl
o cycloalkyl
o aryl
o heterocycle
ith the proviso that
(a) when A is J^ .X is -CH2- and R11 is hydrogen then R7 is hydrogen or =CH2 or alkyl with the further provisio that when R7 is alkyl and R8 is R 12 NH-, then R12 is substituted alkyl wherein the substituents are selected from aryl or heterocyclyl
when A is (Formula Removed)
(b) and X is -CH2-. R7 = R8 = R9 =R10 =hydrogen or halogen.
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 α1a and/or α1d adrenergic receptor, comprising administering to a patient, a therapeutically effective amount of a compound disclosed herein.
In accordance with a third aspect, there is provided a method for the treatment of a patient suffering from benign prostatic hyperplasia (BPH) and related symptoms, comprising administering to a patient, a therapeutically effective amount of a compound disclosed herein.
In accordance with a fourth aspect, there is provided a method for the treatment of a patient suffering from lower urinary tract symptoms (LUTS) with or without BPH. LUTS may include, for example, irritative symptoms, for example, frequent urination, urgent urination, nocturia and unstable bladder contractions, obstructive symptoms, for example, hesitancy, poor stream, prolong urination, and feelings of incomplete emptying, comprising administering to a patient, a therapeutically effective amount of a compound disclosed herein.
In accordance with a fifth aspect, there is provided a process for the preparation of the compounds described herein.
In accordance with a sixth aspect, there is provided a method for the treatment of a patient suffering from BPH or LUTS with or without BPH. comprising administering to a patient, a therapeutically effective amount of a compound (or composition) described herein in combination with a bladder selective muscarinic receptor antagonist.
In accordance with a seventh aspect, there is provided a method for the treatment of a patient suffering from BPH or LUTS with or without BPH, comprising administering to a
patient, a therapeutically effective amount of a compound (or composition) described herein in combination with a testosterone 5 a -reductase inhibitor.
In accordance with a eighth aspect, there is provided a method for the treatment of a patient suffering from BPH or LUTS with or without BPH, comprising administering to a patient, a therapeutically effective amount of a compound (or composition) described herein in combination with a bladder selective muscarinic receptor antagonist and optionally included testosterone 5 a reductase inhibitor.
Receptor binding and in vitro functional assay studies described below indicated that the compounds disclosed herein possess selective and potent α1a adrenoceptor antagonistic activity over the α1b and/or α1d 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 disclosed compounds demonstrated manifest selectivity for prostatic tissues in comparison to known compounds. Additionally, the disclosed compounds can be used for relaxing lower urinary tract tissues and thus alleviating irritative symptoms in-patient. Therefore, the present invention provides pharmaceutical compositions for treatment of a disease or disorder mediated through α1a adrenoceptor. Moreover, the disclosed compounds of the present invention can also be used for treatment of lower urinary tract symptoms. Compounds and compositions described herein can be administered orally, parenterally. subcutaneously. transdermally or topically.
The following definitions apply to terms as used herein.
The term "alkyl" refers to straight or branched saturated hydrocarbon having one to six carbon atom (s). One or more hydrogen atom (s) of said alkyl can optionally be replaced by alkenyl, alkynyl. halogen, hydroxy, cycloalkyl. cycloalkenyl, aryl, heterocyclyl or-NR14R15, wherein R14 and R15 are selected from hydrogen and alkyl. Examples of alkyl include, but are not limited to. methyl, ethyl, propyl, isopropyl and butyl, and the like.
The term "alkenyl or alkynyl'* stands for unsaturated hydrocarbon having two to six carbon atoms. One or more hydrogen of said alkenyl or alkynyl can be replaced by halogen. Examples of alkenyl and alkynyl include, but are not limited to. ethylene, propylene, ethynyl and propynyl, and the like.
The term "cycloalkyl" refers to saturated carbocyclic ring having three to seven carbon atoms. Examples of cycloalkyl include, but are not limited to. cyclopropyl. cyclobutyl and cyclopentyl. and the like.
The term "cycloalkenyr refers to unsaturated carbocyclic ring having three to seven carbon atoms. Examples of cycloalkenyl include, but are not limited to, cyclopropenyl and cyclobutenyl, and the like.
The said "cycloalkyl" or "cycloalkenyl" may optionally be substituted with alkyl. halogen or hydroxy.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "aryl" stands for an aromatic radical having 6 to 14 carbon atoms. Examples of aryl include, but are not limited to. phenyl, napthyl. anthryl and biphenyl. and the like.
The term "heterocycle" refers to non-aromatic or aromatic ring system having one or more heteroatom (s) wherein the said hetero atom (s) is/ are selected from the group comprising of nitrogen, sulphur and oxygen and the ring system includes mono, bi or tricyclic. Examples of heterocycles include, but not limited to, azetidinyl, benzimidazolyl. 1,4-benzodioxanyl, 1.3-benzodioxolyl. benzoxazolyl. benzothiazolyl. benzothieenyl, dihydroimidazolyl. dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, furyl. homopiperidinyl. imidazolyl. imidazolinyl. imidazolidinyl. indolinyl, indolyl. isoquinolinyl. isothiazolidinyl. isothiazolyl. isoxazolidinyl. isoxazolyl. morpholinyl, napthyridinyl, oxazolidinyl. oxazolyl. piperazinyl, piperidinyl, pyrazinyl, pyrazolinyl, pyridyl, pyrimidinyl. pyrrolidinyl, pyrrolinyl. pyrrolyl, quinolinyl. tetrahydrofuranyl. tetrahydropyranyl. thiazolidinyl. thiazolyl. and thienyl, and the like.
The said aryl and heterocycle may optionally be substituted with one or more substituent(s) independently selected from the group consisting of halogen, hydroxy, nitro. mercapto. cyano. alkyl. haloalkyl. alkoxy. haloalkoxy, thioalkyl. cycloalkoxy. -NR R , -CONR'R2, -COOR2. -CONHR2. -OCOR2. -COR2, -NHS02R2 and -S02NHR2 wherein R1 and R" are independently selected from hydrogen or alkyl.
The term "alkoxy or cycloalkoxy" stands for a radical represented by Formula O-alkyl and O-cycloalkyl wherein alkyl and cycloalkyl are the same as defined above.
Examples of alkoxy or cycloalkoxy include, but are not limited to. methoxy. ethoxy. propoxy, isopropoxy, cyclopentyloxy, and the like.
The term "thioalkyl" refers to S-alkyl wherein alkyl is the same as defined above.
The term "haloalkyl" stands for alkyl radical in which one or more hydrogen atom(s) is/are replaced by halogen atom(s). Examples of haloalkyl include, but are not limited to. trifluoromethyl. trifluoroethyl, tribromomethyl, chloro difluoro ethyl, and the like.
The term ""haloalkoxy" refers to O-haloalkyl wherein haloalkyl is the same as defined above. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy. trifluoroethoxy. chloro difluoro ethoxy. tetrafluoropropoxy and the like.
The present invention also includes within its scope prodrugs of these agents. In general, such prodrugs will be functional derivatives of these compounds, which are readily convertible in vivo into the required compound. Conventional procedure for the selection and preparation of suitable prodrug derivatives are described, for example, in "design of prodrugs", ed. H Bundgaard and, Elsevier, 1985.
The present invention also includes metabolites, which become active upon introduction into the biological system.
The compounds of the invention possess two chiral centers, they may. therefore, exist as enantiomers and diastereomers. It is to be understood that all such isomers and racemic mixtures therefore are encompassed within the scope of the present invention.
The crystalline or amorphous forms of compounds disclosed herein may exist as polymorphs and as such are intended to be included in the present invention.
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 following the reaction sequences as shown in Schemes I. II. III. IV. V. VI. VII. VIII and IX of the accompanied drawings. Scheme I
The compound of Formula VII can be prepared according to Scheme I. as shown in the accompanied drawings. Thus, reacting a compound of Formula II with 2-chloromethyl oxirane to give a compound of Formula III (wherein A is same as defined earlier), which on reaction with hydrochloric acid gives a compound of Formula IV. which on oxidation gives a compound of Formula V. which on reaction with a compound of Formula VI gives a compound of Formula VII (wherein R is same as defined earlier), which can then be further, converted to pharmaceutically acceptable salt using the methods well known to one ordinary skilled in art.
The reaction of a compound of Formula II with 2-chloromethyl-oxirane to give a compound of Formula III can be carried out in a solvent, for example, acetone, methyl ethyl ketone, diisopropyl ketone, tetrahydrofuran. dimethylformamide or dimethylsulfoxide.
The reaction of a compound of Formula II with 2-chloromethyl-oxirane can be carried out in the presence of an inorganic base, for example, barium carbonate, cesium carbonate, calcium carbonate, sodium carbonate, potassium carbonate or sodium bicarbonate.
The reaction of a compound of Formula III with hydrochloric acid to give a compound of Formula IV can be carried out in a solvent, for example, ethanol. methanol, isopropanol. ethyl acetate or tetrahydrofuran.
The oxidation of a compound of Formula IV to give a compound of Formula V can be carried out in a solvent, for example, chloroform, methanol, acetone, dichloromethane. acetonitrile or tetrahydrofuran.
The oxidation of a compound of Formula IV to give a compound of Formula V can be carried out in the presence of an oxidizing agent, for example, pyridinium dichromate or pyridinium chlorochromate.
The reaction of a compound of Formula V with a compound of Formula VI to give a compound of Formula VII can be carried out in a solvent, for example, acetonitrile. acetone, tetrahydrofuran. dimethylformamide. dimethylsulfoxide or toluene.
The reaction of a compound of Formula V with a compound of Formula VI can be carried out in the presence of an inorganic base, for example, barium carbonate, cesium carbonate, calcium carbonate, sodium carbonate, potassium carbonate or sodium bicarbonate. Scheme II
The compounds of Formula VII and IX can be prepared according to Scheme II. as shown in the accompanied drawings. Thus, reacting a compound of Formula III with a compound of Formula VI to give a compound of Formula VIII (wherein A and R are the same as defined earlier), which on,
(a) oxidation gives a compound of Formula VII.
(b) fluorination gives a compound of Formula IX.
The compounds of Formula VII and IX can then be further converted to pharmaceutically acceptable salt using the methods well known to one ordinary skilled in art.
The reaction of a compound of Formula III with a compound of Formula VI to give a compound of Formula VIII can be carried out in a solvent, for example, acetonitrile, acetone, ethanol, tetrahydrofuran, cyclohexane, dimethylformamide. dimethylsulfoxide. toluene or methylethylketone.
The reaction of a compound of Formula III with a compound of Formula VI can be carried out in the presence of a base, for example, potassium carbonate, sodium carbonate, calcium carbonate, barium carbonate, sodium bicarbonate, triethyl amine, trimethyl amine or sodium hydride.
The fluorination of a compound of Formula VIII to give a compound of Formula IX can be carried out in the presence of a fluorinating agent, for example, diethylamino sulphur trifluoride or tris (dimethylamino)sulphur(trimethyl silyl) difluoride.
The fluorination of a compound of Formula VIII to give a compound of Formula IX can be carried out in a solvent, for example, chloroform, dichloromethane, tetrahydrofuran or acetonitrile.
The oxidation of a compound of Formula VIII to give a compound of Formula VII can be carried out in a solvent, for example, chloroform, methanol, acetone, dichloromethane. acetonitrile or tetrahydrofuran.
The oxidation of a compound of Formula VIII to give a compound of Formula VII can be carried out in the presence of an oxidizing agent, for example, pyridinium dichromate or pyridinium chlorochromate. Scheme III
The compound of Formula XII can be prepared according to Scheme III. as shown in the accompanied drawings. Thus, alkylating a compound of Formula II with a compound of Formula X to give a compound of Formula XI (wherein hal is a halogen and A is the same as defined earlier), which on reaction with a compound of Formula VI gives a compound of XII (wherein R is the same as defined earlier), which can then be further converted to pharmaceutically acceptable salt using the methods well known to one ordinary skilled in art.
The alkylation of a compound of Formula II with a compound of Formula X to give a compound of Formula XI can be carried out in a solvent, for example, acetone, methyl ethylketone. diisopropyl ketone, tetrahydrofuran. dimethylformamide or dimethylsulfoxide.
The alkylation of a compound of Formula II with a compound of Formula X can be carried out in the presence of an inorganic base, for example, potassium carbonate, barium carbonate, cesium carbonate, calcium carbonate, sodium carbonate or sodium bicarbonate and an organic or inorganic halide. for example, tetrabutyl ammonium chloride, tetrabutyl ammonium bromide or potassium iodide.
The reaction of a compound of Formula XI with a compound of Formula VI to give a compound of Formula XII can be carried out in a solvent, for example, acetonitrile. ethanol. butanol. dichloromethane. dimethylformamide or dimethylsulfoxide.
The reaction of a compound of Formula XI with a compound of Formula VI can be carried out in the presence of an inorganic base, for example, potassium carbonate, barium carbonate, cesium carbonate, calcium carbonate, sodium carbonate or sodium bicarbonate. Scheme IV
The compound of Formula XVI can be prepared according to Scheme IV. as shown in the accompanied drawings. Thus, reacting a compound of Formula VI with acrylonitrile
to give a compound of Formula XIII (wherein R is the same as defined earlier), which on reduction gives a compound of Formula XIV, which on reaction with a compound of Formula XV gives a compound of Formula XVI (wherein R7, R8 and R11 are the same as defined earlier), which can then be further, converted to pharmaceutically acceptable salt using the methods well known to one ordinary skilled in art.
The reaction of a compound of Formula VI with acrylonitrile to give a compound of Formula XIII can be carried out in an alcoholic solvent, for example, methanol, ethanol. propanol or n-butanol.
The reduction of a compound of Formula XIII to give a compound of Formula XIV can be carried out in the presence of a reducing agent, for example, palladium on carbon and hydrogen or raney nickel and hydrogen and ammonia in an alcoholic solvent, for example, methanol, ethanol. propanol or n-butanol.
The reaction of a compound of Formula XIV with a compound of Formula XV to give a compound of Formula XVI can be carried out in a solvent, for example, toluene, tetrahydrofuran. acetonitrile or xylene. Scheme V
The compounds of Formula XIX and XXII can be prepared according to Scheme V. as shown in the accompanied drawings. Thus, reacting a compound of Formula XVII with
(a) 1-acetoxy-1.3-butadiene to give a compound of Formula XVIII. which on hydrolysis gives a compound of Formula XIX ( wherein R is the same as defined earlier).
(b) 1.4 -diacetoxy-1.3-butadiene to give a compound of Formula XX. which on hydrolysis gives a compound of Formula XXI. which on reduction gives a compound of Formula XXII ( wherein R is the same as defined earlier).
The compounds of Formula XIX and XXII can then be further converted to pharmaceutically acceptable salt using the methods well known to one ordinary skilled in art.
The reaction of a compound of Formula XVII with 1-acetoxy-1.3-butadiene and 1.4 -diacetoxy-1.3-butadiene to give a compounds of Formula XVIII and XX. respectively can be carried out in a solvent, for example, toluene, benzene or xylene.
The hydrolysis of compounds of Formula XVIII and XX to give compounds of Formula XIX and XXI, respectively can be carried out in the presence of hydrochloric acid in an alcoholic solvent, for example, methanol, ethanol. propanol or n-butanol.
The reduction of a compound of Formula XXI to give a compound of Formula XXII can be carried out in the presence of a reducing agent, for example, palladium on carbon and hydrogen or raney nickel and hydrogen and ammonia in an alcoholic solvent, for example, methanol, ethanol. propanol or n-butanol. Scheme VI
The compound of Formula XXV can be prepared according to Scheme VI. as shown in the accompanied drawings. Thus, reacting isoindole-1.3-dione with 2-chloromethyl oxirane to give 2-oxiranylmethyl-isoindole-l .3-dione. which on reaction with a compound of Formula VI gives a compound of Formula XXIII ( wherein R is the same as defined earlier).which on reaction with hydrazine hydrate gives a compound of Formula XXIV, which on reaction with a compound of Formula XV gives a compound of Formula XXV (wherein R7. R8 and R11 are the same as defined earlier), which can then be further converted to pharmaceutically acceptable salt using the methods well known to one ordinary skilled in art.
The reaction of isoindole-1, 3-dione with 2-chloromethyl-oxirane to give 2-oxiranylmethyl-isoindole-1, 3-dione can be carried out in a solvent, for example, acetone, methyl ethyl ketone, diisopropyl ketone, tetrahydrofuran. dimethylformamide or dimethylsulfoxide.
The reaction of isoindole-1.3-dione with 2-chloromethyl-oxirane to give 2-oxiranylmethyl-isoindole-1.3-dione can be carried out in the presence of an inorganic base, for example, barium carbonate, cesium carbonate, calcium carbonate, sodium carbonate, potassium carbonate or sodium bicarbonate.
The reaction of 2-oxiranylmethyl-isoindole-l. 3-dione with a compound of Formula VI to give a compound of Formula XXIII can be carried out in an organic solvent, for example, acetonitrile. ethanol. butanol. tetrahydrofuran. dimethylsulphoxide. dimethylformamide or dichloromethane.
The reaction of a compound of Formula XXIII with hydrazine hydrate to give a compound of Formula XXIV can be carried out in a solvent, for example, acetonitrile.
ethanol, butanol. tetrahydrofuran, dimethylsulphoxide. dimethylformamide or dichloromethane.
The reaction of a compound of Formula XXIV with a compound of Formula XV to give a compound of Formula XXV can be carried out in a solvent, for example, acetonitrile. acetone, tetrahydrofuran, dimethylformamide. dimethylsulfoxide or toluene. Scheme VII
The compounds of Formula XXVII. XXIX and XXX can be prepared according to Scheme VII. as shown in the accompanied drawings. Thus
(a) reacting a compound of Formula XXVI with a methylating agent, for example, trimethyl sulphoxinium iodide to give a compound of Formula XXVII ( wherein X is the same as defined earlier).
(b) reducing a compound of Formula XXVI to give a compound of Formula XXIX ( wherein X is the same as defined earlier).
(c) reacting a compound of Formula XXVI with a compound of Formula XXVIII ( wherein X. R12 and R13 are the same as defined earlier) to give a compound of Formula XXX.
The compounds of Formula XXVII. XXIX and XXX can then be further converted to pharmaceutically acceptable salt using the methods well known to the ordinary skilled in the art.
The reaction of a compound of Formula XXVI with a methylating agent to give a compound of Formula XXVII can be carried out in a solvent, for example, acetonitrile. acetone, tetrahydrofuran. dimethylformamide, dimethylsulfoxide or toluene.
The reduction of a compound of Formula XXVI to give a compound of Formula XXIX can be carried out in the presence of a reducing agent, for example, palladium on carbon and hydrogen or raney nickel and hydrogen and ammonia, in an alcoholic solvent, for example, methanol, ethanol. propanol or n-butanol.
The reaction of a compound of Formula XXVI with a compound of Formula XXVIII to give a compound of Formula XXX can be carried out in a solvent, for example, chloroform, methanol, acetone, dichloromethane. acetonitrile or tetrahydrofuran. Scheme VIII
The compounds of Formula XXXV and XXXVI can be prepared according to Scheme VIII, as shown in the accompanied drawings. Thus, reacting a compound of Formula XXXI with tetra hydro phthalimide to give a compound of Formula XXXII (wherein X and R are the same as defined earlier), which on
(a) oxidation gives a compound of Formula XXXIII. which on reaction with diethyl amino sulphur trifluoride gives a compound of Formula XXXIV , which on further reaction with diethyl amino sulphur trifluoride gives a compound of Formula XXXV. (b) reduction gives a compound of Formula XXXVI.
The compounds of Formula XXXV and XXXVI which can then be further converted to pharmaceutically acceptable salt using the methods well known to one ordinary skilled in art.
The reaction of a compound of Formula XXXI with tetra hydro phthalimide to give a compound of Formula XXXII can be carried out in a solvent, for example, acetonitrile. acetone, tetrahydrofuran. dimethylformamide, dimethylsulfoxide or toluene.
The oxidation of a compound of Formula XXXII to give a compound of Formula XXXIII can be carried out in an alcoholic solvent, for example, methanol, ethanol. propanol or n-butanol in the presence of an oxidizing agent, for example, potassium permanganate.
The reaction of a compound of Formula XXXIII with diethyl amino sulphur trifluoride to give a compound of Formula XXXIV can be carried out in a solvent, for example, chloroform, dichloromethane. tetrahydrofuran or acetonitrile.
The reaction of a compound of Formula XXXIV with diethyl amino sulphur trifluoride to give a compound of Formula XXXV can be carried out in a solvent, for example, chloroform, dichloromethane. tetrahydrofuran or acetonitrile.
The reduction of a compound of Formula XXXII to give a compound of Formula XXXVI can be carried out in the presence of a reducing agent, for example, palladium on carbon and hydrogen or raney nickel and hydrogen in an alcoholic solvent, for example, methanol, ethanol. propanol or n-butanol. Scheme IX
The compounds of Formula XL and XLI can be prepared according to Scheme IX. as shown in the accompanied drawings. Thus, reaction of a compound of Formula XXXVII (wherein hal is a halogen) with a peroxy acid, for example, m-chloroperbenzoic acid gives a
compound of Formula XXXVIII. which on reaction with a compound of Formula VI gives a compound of Formula XXXIX (wherein R is the same as defined earlier), which on.
(a) reduction gives a compound of Formula XL.
(b) fluorination gives a compound of Formula XLI
The compounds of Formula XL and XLI can then be further converted to pharmaceutically acceptable salt using the methods well known to one ordinary skilled in art.
The reaction of a compound of Formula XXXVII with a peroxyacid to give a compound of Formula XXXVIII can be carried out in a solvent, for example, chloroform, methanol, acetone, dichloromethane. acetonitrile or tetrahydrofuran.
The reaction of a compound of Formula XXXVIII with a compound of Formula VI to give a compound of Formula XXXIX can be carried out in a solvent, for example, acetonitrile, ethanol. butanol. halogenated solvents, tetrahydrofuran. dimethylformamide or dimethylsulfoxide.
The reaction of a compound of Formula XXXVIII with a compound of Formula VI can be carried out in the presence of an inorganic base, for example, potassium carbonate, barium carbonate, cesium carbonate, calcium carbonate, sodium carbonate or sodium bicarbonate.
The reduction of a compound of Formula XXXIX to give a compound of Formula XL can be carried out in the presence of a reducing agent, for example, palladium on carbon and hydrogen or raney nickel and hydrogen in a solvent, for example, chloroform, methanol, acetone, dichloromethane. acetonitrile or tetrahydrofuran.
The fluorination of a compound of Formula XXXIX to give a compound of Formula
XLI can be carried out in the presence of a fluorinating agent, for example, diethylamino
sulphur trifluoride ortris (dimethylamino)sulphur(trimethyl silyl) difluoride
in a solvent, for example, chloroform, dichloromethane. tetrahydrofuran or acetonitrile.
An illustrative list of compounds of the invention are listed below (also shown in Table I):
-2-(2-Hydroxy-3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl)-hexahydro-isoindole-1.3-dione (Compound No. 1)
-2-{2-Hydroxy-3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl!-hexahydro-isoindole-1.3-dione hydrochloride salt (Compound No. 2)
-2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-2-oxo-propyl)-hexahydroisoindole-1.3-dione (Compound No. 3)
-2- {3-[4-(2-Isopropoxy-phenyl)-piperazin-1 -yl] -2-oxo-propyl ] -hexahydroisoindole-1,3-dione hydrochloride salt (Compound No. 4)
-2-(3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-2-oxo-propyl)-3a.4,7,7a-tetrahydro-isoindole-1.3-dione (Compound No. 5)
-2-(3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-2-oxo-propyl]-3a.4.7.7a-tetrahydro-isoindole-1.3-dione hydrochloride salt (Compound No. 6)
-2-{(S)-2-Hydroxy-3-{4-[2-(2.2,2-trifluoro-ethoxy)-phenyl]-piperazin-l-ylj-propyl)-3a.4.7.7a-tetrahydro-isoindole-1.3-dione (Compound No. 7)
-2-j(S)-2-Hydroxy-3-{4-[2-(2.2.2-trifluoro-ethoxy)-phenyl]-piperazin-l-yl)-propyl)-3a.4.7.7a-tetrahydro-isoindole-1.3-dione hydrochloride salt (Compound No. 8)
-2-(2-Hydroxy-3-(4-[2-(2.2.3.3-tetrafluoro-propoxy)-phenyl]-piperazin-l-ylj-propyl)-3a.4.7.7a-tetrahydro-isoindole-l,3-dione (Compound No. 9)
-2-(2-Hydroxy-3-{4-[2-(2.2.3.3-tetrafluoro-propoxy)-phenyl]-piperazin-l-ylj-propyl)-3a.4.7.7a-tetrahydro-isoindole-l,3-dione hydrochloride salt (Compound No. 10)
-2-{2-Hydroxy-3-[4-(2-isopropoxy-4-nitro-phenyl)-piperazin-l-yl]-propyl)-3a.4.7,7a-tetrahydro-isoindole-l,3-dione (Compound No. 11)
-2-{2-Hydroxy-3-[4-(2-isopropoxy-4-nitro-phenyl)-piperazin-l-yl]-propyl}-3a.4.7.7a-tetrahydro-isoindole-l,3-dione hydrochloride salt (Compound No. 12)
-2-{2-Fluoro-3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl)-3a.4,7,7a-tetrahydro-isoindole-1.3-dione (Compound No. 13)
-2-{2-Fluoro-3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl)-3a.4,7.7a-tetrahydro-isoindole-1.3-dione hydrochloride salt (Compound No. 14)
-Acetic acid 2-{3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl)-l,3-dioxo-2.3.3a.4.7.7a-hexahydro-lH-inden-4-yl ester (Compound No. 15)
-Acetic acid 2-{3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl}-1.3-dioxo-2.3.3a.4.7.7a-hexahydro-lH-inden-4-yl ester hydrochloride salt (Compound No. 16)
-4-Hydroxy-2- {3-[4-(2-methoxy-phen\ 1 )-piperazin-1 -yl] -propyl J -3a.4.7.7a-tetrahydro-isoindole-1.3-dione (Compound No. 17)
-4-Hydroxy-2-{3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl}-3a,4.7,7a-tetrahydro-isoindole-1.3-dione hydrochloride salt (Compound No. 18)
-2- (3-[4-(2-Methoxy-phenyl)-piperazin-1 -yl]-2-oxo-propyl J -3a.4.7.7a-tetrahydro-isoindole-1.3-dione (Compound No. 19)
-2-{3-[4-(2-Methoxy-phenyl)-piperazin-1 -yl]-2-oxo-propyl J -3a.4.7„7a-tetrahydro-isoindole-l,3-dione hydrochloride salt (Compound No. 20)
-2-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-2-oxo-propyl}-3a,4,7,7a-tetrahydro-isoindole-1,3-dione (Compound No. 21)
-2-{2-Oxo-3-[4-(2-propoxy-phenyl)-piperazin-l-yl]-propyl}-3a.4.7.7a-tetrahydro-isoindole-1.3-dione (Compound No. 22)
-2- {2-Oxo-3- [4-(2-propoxy-phenyl)-piperazin-l -yl]-propyl j -3a. 4.7.7a-tetrahydro-
isoindole-1. 3-dione hydrochloride salt (Compound No. 23)
-2- {3-[4-(4-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-2-oxo-propyl}-3a.4.7.7a-tetrahydro-isoindole-1.3-dione (Compound No. 24)
-2-{3-[4-(4-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-2-oxo-propyl]-3a.4.7,7a-tetrahydro-isoindole-1,3-dione hydrochloride salt (Compound No. 25)
-2- {3-[4-(2-Isopropoxy-phenyl)-piperazin-1 -yl]-2-oxo-propyl} -isoindole-1.3-dione (Compound No. 26)
-2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-2-oxo-propyl}-isoindole-1.3-dione hydrochloride salt (Compound No. 27)
-2-(2-Oxo-3-{4-[2-(2.2.2-trifluoro-ethoxy)-phenyl]-piperazin-l-ylj-propyl)-3a.4.7,7a-tetrahydro-isoindole-1.3-dione (Compound No. 28)
-2-(2-Oxo-3-{4-[2-(2,2,2-trifluoro-ethoxy)-phenyl]-piperazin-l-yl]-propyl)-3a.4.7,7a-tetrahydro-isoindole-1.3-dione hydrochloride salt (Compound No. 29)
-6-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-2-oxo-hexahydro-1.3-dioxa-2-lambda*4*-thia-6-aza-s-indacene-5,7-dione (Compound No. 30)
-6-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl ]-2-oxo-hexahydro-1.3-dioxa-2-lambda*4*-thia-6-aza-s-indacene-5,7-dione hydrochloride salt (Compound No. 31)
-l-[2-Oxo-3-(4-phenyl-piperazin-l-yl)-propyl]-pyrrolidine-2,5-dione (Compound No. 32)
-l-(3-[4-{4-Fluoro-phenylj-piperazin-l-yl]-2-oxo-propyl}-3-phenyl-piperidine-2.6-dione (Compound No. 33)
-3.4-Dimethyl-1 - [ 2-oxo-3-[4-(2-trifluoromethyl-phenyl)-piperazin-1 -yl] -propyl j -pyrrole-2,5-dione (Compound No. 34)
-l-{2-Fluoro-3-[4-(4-fluorophenyl)piperazin-l-yl]-propyl}-pipridine-2,6-dione (Compound
No. 35)
-l-(2-Fluoro-3-{4-[2-(2.2.2-trifluoro-ethoxy)-phenyl]-piperazin-l-yl) propyl )-3.4-dimethylpyrrole-2,5-dione (Compound No. 36)
-l-(3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-2-hydroxy-propyl)-3-cyclopropylamino-4-methyl-pyrrolidine-2.5-dione ( Compound No. 37)
-l-(3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-2-hydroxy-propyl}-3-cyclopropylamino-4-methyl-pyrrolidine-2.5-dione hydrochloride salt ( Compound No. 38)
-l-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-hydroxy-propyl]-3-cyclopropylamino-4-methyl-pyrrolidine-2.5-dione( Compound No. 39)
-l-(3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-hydroxy-propyl]-3-cyclopropylamino-4-methyl-pyrrolidine-2.5-dione hydrochloride salt( Compound No. 40)
-l-[3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-hydroxy-propyl}-3-cyclopropylaminomethyl-pyrrolidine-2.5-dione( Compound No. 41)
-l-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-hydroxy-propyl}-3-cyclopropylaminomethyl-pyrrolidine-2.5-dione hydrochloride salt( Compound No. 42)
-2-{3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl]-5,6-dihydroxy-hexahydro-isoindole-l,3-dione( Compound No. 43)
-2-»3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl]-5.6-dihydroxy-hexahydro-isoindole-l,3-dione hydrochloride salt( Compound No. 44) -l-(3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-hydroxy-propyl}-3-methyl-4-methylamino-pyrrolidine-2,5-dione( Compound No. 45)
-l-(3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-hydroxy-propyl}-3-methyl-4-methylamino-pyrrolidine-2.5-dione hydrochloride salt( Compound No. 46)
-l-[3-[4-(2-Methoxy-5-methyl-phenyl)-piperazin-l-yl]-propyl)-piperidine-2,6-dione( Compound No. 47)
-l-^3-[4-(2-Methoxy-5-methyl-phenyl)-piperazin-l-yl]-propyl]-piperidine-2.6-dione hydrochloride salt( Compound No. 48)
-5.6-Dihydroxy-2-(3-[4-(2-methoxy-5-methyl-phenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-l,3-dione( Compound No. 49)
-5.6-Dihydroxy-2-(3-[4-(2-methoxy-5-methyl-phenyl)-piperazin-l-yl] -propyl j-hexahydro-isoindole-1.3-dione hydrochloride salt( Compound No. 50)
-l-(3-[4-[5-Fluoro-2-(2.2,2-trifluoro-ethoxy)-phenyl]-piperazin-l-ylj-propyl)-piperidine-2,6-dione( Compound No. 51)
-l-(3-{4-[5-Fluoro-2-(2,2.2-trifluoro-ethoxy)-phenyl]-piperazin-l-yl]-propyl)-piperidine-2.6-dione hydrochloride salt( Compound No. 52)
-2-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl}-5.6-dihydroxy-hexahydro-isoindole-l,3-dione( Compound No. 53)
-2-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-1.3-dione hydrochloride salt( Compound No. 54)
-3-{3-[4-(3-Fluoro-2-methoxy-phenyl)-piperazin-l-yl]-propyl)-l-methyl-3-aza-bicyclo [3.1.0]hexane-2.4-dione( Compound No. 55)
-3-{3-[4-(3-Fluoro-2-methoxy-phenyl)-piperazin-l-yl]-propyl)-l-methyl-3-aza-bicyclo [3.1.0]hexane-2.4-dione hydrochloride salt( Compound No. 56)
-3-! 3-[4-(5-Fluoro-2-methoxy-phenyl)-piperazin-1-yl]-propyl J -1-methyl-3-aza-bicyclo [3.1.0]hexane-2.4-dione( Compound No. 57)
-3-{3-[4-(5-Fluoro-2-methoxy-phenyl)-piperazin-l-yl]-propyl!-l-methyl-3-aza-bicyclo [3.1.0]hexane-2.4-dione hydrochloride salt( Compound No. 58)
-3-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl}-l-methyl-3-aza-bicyclo [3.1.0]hexane-2.4-dione( Compound No. 59)
-3-{3-[4-(2-Cyclopentyloxy-phenyi)-piperazin-l-yl]-propyl}-l-methyl-3-aza-bicyclo [3.1.0]hexane-2.4-dione hydrochloride salt( Compound No. 60)
-5-Fluoro-6-hydroxy-2-{2-hydroxy-3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-l,3-dione( Compound No. 61)
-5-Fluoro-6-hydroxy-2-{2-hydroxy-3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-l,3-dione hydrochloride salt( Compound No. 62)
-3-(3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl)-l-methyl-3-aza-bicyclo [3.1.0]hexane-2,4-dione( Compound No. 63)
-3-(3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-l-methyl-3-aza-bicyclo [3.1.0]hexane-2,4-dione hydrochloride salt( Compound No. 64)
-5-Fluoro-6-hydroxy-2-{3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1.3-dione( Compound No. 65)
-5-Fluoro-6-hydroxy-2- (3-[4-(2-isopropoxy-phenyl)-piperazin-l -yl]-propyl] -hexahydro-isoindole-l,3-dione hydrochloride salt( Compound No. 66)
-2- {3 -[4-(2-Cyclopentyloxy-phenyl)-piperazin-1 -yl] -2-hydroxy-propyl} -hexahydro-isoindole-l,3-dione( Compound No. 67)
-2-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-l,3-dione hydrochloride salt( Compound No. 68)
-5-Hydroxy-2-{3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl}-hexahydro-isioindole-l,3-dione( Compound No. 69)
-5-Hydroxy-2-{3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl}-hexahydro-isioindole-l,3-dione hydrochloride salt( Compound No. 70)
-2-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione( Compound No. 71)
-2-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione hydrochloride salt( Compound No. 72)
-2-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione( Compound No. 73)
-2- (3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl] -propyl} -5-hydroxy-hexahydro-isoindole-1.3-dione hydrochloride salt( Compound No. 74)
-2-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione( Compound No. 75)
-2-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione hydrochloride salt( Compound No. 76)
-2-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-oxo-propyl}-3a,4,7,7a-tetrahydro-isoindole-1.3-dione( Compound No. 77)
-2- (3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-1 -yl]-2-oxo-propyl) -3a.4.7,7a-tetrahydro-isoindole-1.3-dione hydrochloride salt( Compound No. 78)
-2-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-1.3-dione( Compound No. 79)
-2-{3-[4-(2-Cydopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-hydroxy-propyl)-hexahydro-isoindole-l,3-dione hydrochloride salt( Compound No. 80)
-5-Fluoro-2-{3-[4-(5-fluoro-2-methoxy-phenyl)-piperazin-l-yl]-propyl)-6-hydroxy-hexahydro-isoindole-l,3-dione( Compound No. 81)
-5-Fluoro-2- {3-[4-(5-fluoro-2-methoxy-phenyl)-piperazin-1 -yl]-propyl J -6-hydroxy-hexahydro-isoindole-1.3-dione hydrochloride salt( Compound No. 82)
-2-{3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl)-5-hydroxy-hexahydro-isoindole-l,3-dione( Compound No. 83)
-2-{3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-1.3-dione hydrochloride salt( Compound No. 84)
-5-Fluoro-2-[3-[4-(5-fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-1.3-dione( Compound No. 85)
-5-Fluoro-2-{3-[4-(5-fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl]-6-hydroxy-hexahydro-isoindole-l,3-dione hydrochloride salt( Compound No. 86)
-1 - {3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-1 -yl] -2-hydroxy-propyl ] -piperidine-2.6-dione( Compound No. 87)
-1- j3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl] -2-hydroxy-propyl j-piperidine-2.6-dione hydrochloride salt( Compound No. 88)
-l-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-hydroxy-propyl!-piperidine-2.6-dione( Compound No. 89)
-l-(3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-hydroxy-propyl}-piperidine-2.6-dione hydrochloride salt( Compound No. 90)
-Acetic acid 7-acetoxy-2- {3-[4-(5-fluoro-2-isopropoxy-phenyl)-piperazin-1 -yl]-propyl j -1.3-dioxo-2.3.3a.4.7.7a-hexahydro-lH-isoindol-4-yl ester( Compound No. 91)
-Acetic acid 7-acetoxy-2- {3-[4-(5-fluoro-2-isopropoxy-phenyl)-piperazin-1 -yl]-propyl {-1.3-dioxo-2.3.3a.4.7.7a-hexahydro-lH-isoindol-4-yl ester hydrochloride salt( Compound No. 92)
-Acetic acid 7-acetoxy-2-{3-[4-(2-cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl]-l,3-dioxo-2.3,3a.4.7.7a-hexahydro-lH-isoindol-4-ylester( Compound No. 93)
-Acetic acid 7-acetoxy-2-(3-[4-(2-cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl J -1.3-dioxo-2,3,3a.4,7.7a-hexahydro-1 H-isoindol-4-ylester hydrochloride salt( Compound No. 94)
-2-{3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-4.7-dihydroxy-3a.4,7. 7a-tetrahydro-isoindole-l,3-dione( Compound No. 95)
-2-(3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl)-4,7-dihydroxy-3a,4.7, 7a-tetrahydro-isoindole-l,3-dione hydrochloride salt( Compound No. 96)
-1 - j 3-[4-(5-Fluoro-2-propoxy-phenyl)-piperazin-1 -yl]-propyl j -piperidine-2.6-dione( Compound No. 97)
-l-{3-[4-(5-Fluoro-2-propoxy-phenyl)-piperazin-l-yl]-propyl)-piperidine-2.6-dione hydrochloride salt( Compound No. 98)
-l-(3-[4-(5-Fluoro-2-propoxy-phenyl)-piperazin-l-yl]-2-hydroxy-propyl)-piperidine-2.6-dione( Compound No. 99)
-l-{3-[4-(5-Fluoro-2-propoxy-phenyl)-piperazin-l-yl]-2-hydroxy-propyl)-piperidine-2,6-dione hydrochloride salt( Compound No. 100)
-2-(3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl)-5.6-dihydroxy-hexahydro-isoindole-l,3-dione( Compound No. 101)
-2-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl)-5.6-dihydroxy-hexahydro-isoindole-l,3-dione hydrochloride salt( Compound No. 102)
-2-(3-[4-(5-Fluoro-2-propoxy-phenyl)-piperazin-l-yl]-propyl)-5.6-dihydroxy-hexahydro-isoindole-1.3-dione( Compound No. 103)
-2-(3-[4-(5-Fluoro-2-propoxy-phenyl)-piperazin-l-yl]-propyl]-5.6-dihydroxy-hexahydro-isoindole-1.3-dione hydrochloride salt( Compound No. 104)
-2-(3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-1.3-dione( Compound No. 105)
-2-(3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-l,3-dione hydrochloride salt( Compound No. 106)
-2-(3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-l,3-dione( Compound No. 107)
-2-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-,3-dione hydrochloride salt( Compound No. 108)
-3-Cyclopropylaminomethyl-l-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl}-pyrrolidine-2.5-dione( Compound No. 109)
-3-Cyclopropylaminomethyl-l-(2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl}-pyrrolidine-2,5-dione hydrochloride salt( Compound No.l 10)
-3-Cyclopropylaminomethyl-l-(2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl] -4-methyl-pyrrolidine-2,5-dione( Compound No. Ill)
-3-Cyclopropylaminomethyl-l-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl)-4-methyl-pyrrolidine-2.5-dione hydrochloride salt( Compound No. 112)
-3-Cyclobutylaminomethyl-1 - [2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1 -yl]-propyl}-pyrrolidine-2,5-dione( Compound No. 113)
-3-Cyclobutylaminomethyl-l-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl]-pyrrolidine-2,5-dione hydrochloride salt( Compound No. 114)
-l-{2-Hydroxy-3-[4-(2-methoxy-phen\i)-piperazin-l-yl]-propyl}-3-methyl-pyrrolidine-2.5-dione( Compound No. 115)
-l-{2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl]-3-methyl-pyrrolidine-2.5-dione hydrochloride salt( Compound No. 116)
-2- [3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l -yl]-propyl J -4,7-dihydroxy-3a.4.7.7a-tetrahydro-isoindole-l,3-dione ( Compound No. 117)
-2-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl}-4,7-dihydroxy-3a.4.7.7a-tetrahydro-isoindole-1.3-dione hydrochloride salt ( Compound No. 118)
-2- J 3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-1 -yl]-2-oxo-propyl j -5.6-dihydroxy-hexahydro-isoindole-l,3-dione( Compound No. 119)
-2-!3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-oxo-propyl}-5.6-dihydroxy-hexahydro-isoindole-l,3-dione hydrochloride salt( Compound No. 120)
-2-(3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-2-oxo-propyl}-5.6-dihydroxy-hexahydro-isoindole-1.3-dione( Compound No. 121)
-2-(3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-2-oxo-propyl}-5.6-dihydroxy-hexahydro-isoindole-l,3-dione hydrochloride salt( Compound No. 122)
-2-!3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5.6-dihydroxy-hexahydro-isoindole-1.3-dione( Compound No. 123)
-2-{3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5.6-dihydroxy-hexahydro-isoindole-l,3-dione hydrochloride salt( Compound No. 124)
-2-(3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-1.3-dione( Compound No. 125)
-2-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-1.3-dione hydrochloride salt ( Compound No. 126)
-l-(3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl)-piperidine-2,6-dione( Compound No. 127)
-1 - (3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-1 -yl]-propyl J -piperidine-2.6-dione hydrochloride salt( Compound No. 128)
-l-{3-[4-(3-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl)-piperidine-2.6-dione( Compound No. 129)
-l-{3-[4-(3-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl)-piperidine-2.6-dione hydrochloride salt( Compound No. 130)
-1 - {3-[4-(3-Fluoro-2-methoxy-phenyl)-piperazin-1 -yl]-propyl} -piperidine-2.6-dione( Compound No. 131)
-l-(3-[4-(3-Fluoro-2-methoxy-phenyl)-piperazin-l-yl]-propyl}-piperidine-2.6-dione hydrochloride salt( Compound No. 132)
-l-{3-[4-(3-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3-methylene-pyrrolidine-2.5-dione( Compound No. 133)
-l-(3-[4-(3-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3-methylene-pyrrolidine-2.5-dione hydrochloride salt( Compound No. 134)
-l-!3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl)-3-methylene-pyrrolidine-2„5-dione( Compound No. 135)
-l-{3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3-methylene-pyrrolidine-2.5-dione hydrochloride salt ( Compound No. 136)
-l-(3-[4-(5-Fluoro-2-(2,2,3.3-tetrafluoro-propoxy)-phenyl]-piperazin-l-ylj-propyl)-piperidine-2.6-dione( Compound No. 137)
-l-(3-[4-(5-Fluoro-2-(2,2.3,3-tetrafluoro-propoxy)-phenyl]-piperazin-l-yl)-propyl)-piperidine-2.6-dione hydrochloride salt( Compound No. 138)
-l-[3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl)-3-methyl-4-(l-phenyl-ethylamino)-pyrrolidine-2.5-dione( Compound No. 139)
-1 - (3-[4-(2-Methoxy-phenyl)-piperazin-1 -yl]-propyl )-3-methyl-4-( 1 -phenyl-ethylamino)-pyrrolidine-2,5-dione hydrochloride salt( Compound No. 140)
-l-{3-[4-(5-Fluoro-2-trifluoromethoxy-phenyl)-piperazin-l-yl]-propyl)-piperidine-2.6-dione( Compound No. 141)
-l-j3-[4-(5-Fluoro-2-trifluoromethoxy-phenyl)-piperazin-l-yl]-propyl)-piperidine-2.6-dione hydrochloride salt( Compound No. 142)
-Acetic acid 7-acetoxy-2- (3-[4-(2-ethoxy-phenyl)-piperazin-1 -yl]-propyl)-1,3-dioxo-2,3.3a,4.7,7a-hexahydro-lH-isoindol-4-yl ester( Compound No. 143)
-Acetic acid 7-acetoxy-2-{3-[4-(2-ethoxy-phenyl)-piperazin-l-yl]-propyl)-1.3-dioxo-2.3.3a.4.7,7a-hexahydro-lH-isoindol-4-yl ester hydrochloride salt( Compound No. 144)
-2-{3-[4-(2-Ethoxy-phenyl)-piperazin-l-yl]-propyl)-4.7-dihydroxy-3a,4,7,7a-tetrahydro-isoindole-1.3-dione( Compound No. 145)
-2-{3-[4-(2-Ethoxy-phenyl)-piperazin-l-yl]-propyl)-4.7-dihydroxy-3a,4.7.7a-tetrahydro-isoindole-l,3-dione hydrochloride salt( Compound No. 146)
-3-Cyclopropylamino-l-{3-[4-(2-ethoxy-phenyl)-piperazin-l-yl]-propyl}-pyrrolidine-2.5-dione( Compound No. 147)
-3-Cyclopropylamino-l-{3-[4-(2-ethoxy-phenyl)-piperazin-l-yl]-propyl)-pyrrolidine-2.5-dione hydrochloride salt( Compound No. 148)
-Acetic acid 7-acetoxy-2-(3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl)-1.3-dioxo-2.3.3a.4.7.7a-hexahydro-lH-isoindol-4-yl ester( Compound No. 149)
-Acetic acid 7-acetoxy-2-{3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl)-l,3-dioxo-2.3.3a,4.7.7a-hexahydro-lH-isoindol-4-yl ester hydrochloride salt( Compound No. 150)
-l-[3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl)-3-cyclopropylamino-pyrrolidine-2.5-dione( Compound No. 151)
-l-[3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl)-3-cyclopropylamino-pyrrolidine-2.5-dione hydrochloride salt( Compound No. 152)
-4.7-Dihydroxy-2-{3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl)-3a,4,,7a-tetrahydro-isoindole-1.3-dione( Compound No. 153)
-4.7-Dihydroxy-2-(3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl)-3a.4,7,7a-tetrahydro-isoindole-1.3-dione hydrochloride salt( Compound No. 154)
-Acetic acid 7-acetoxy-2-{3-[4-(2-cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl)-1.3-dioxo-2,3.3a.4.7.7a-hexahydro-lH-isoindol-4-yl ester( Compound No. 155)
-Acetic acid 7-acetoxy-2- {3-[4-(2-cyclopentyloxy-phenyl)-piperazin-1 -yl]-propyl)-1.3-dioxo-2.3.3a.4.7.7a-hexahydro-lH-isoindol-4-yl ester hydrochloride salt ( Compound No. 156)
-2-(3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl)-4,7-dihydroxy-hexahydro-isoindole-1.3-dione( Compound No. 157)
-2-(3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl)-4.7-dihydroxy-hexahydro-isoindole-1.3-dione hydrochloride salt( Compound No. 158)
-2-(3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl}-4.7-dihydroxy-3a.4.7,7a-tetrahydro-isoindole-l,3-dione( Compound No. 159)
-2- j 3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-1 -yl]-propyl j -4,7-dihydroxy-3a.4.7.7a-tetrahydro-isoindole-1.3-dione hydrochloride salt ( Compound No. 160)
-3-Methylene-l-[3-(4-0-tolyl-piperazin-l-yl)-propyl]-pyrrolidine-2.5-dione(Compound No. 161)
-3-Methylene-l-[3-(4-0-tolyl-piperazin-l-yl)-propyl]-pyrrolidine-2.5-dione hydrochloride salt( Compound No. 162)
-l-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl)-3-methyl-4-[(thiophen-2-ylmethyl)-amino]-pyrrolidine-2, 5-dione (Compound No. 163)
-l-(3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl)-3-methyl-4-[(thiophen-2-ylmethyl)-amino]-pyrrolidine-2.5-dione hydrochloride salt( Compound No. 164)
-l-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl)-3-methylene-pyrrolidine-2.5-dione( Compound No. 165)
-l-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl)-3-methylene-pyrrolidine-2.5-dione hydrochloride salt( Compound No. 166)
-l-{3-[4-(5-Fluoro-2-methoxy-pheny])-piperazin-l-yl]-propyl)-3.3.4-trimethyl-pyrrolidine-2,5-dione( Compound No. 167)
-l-{3-[4-(5-Fluoro-2-methoxy-phenyl)-piperazin-l-yl]-propyl}-3.3.4-trimethyl-pyrrolidine-2.5-dione hydrochloride salt( Compound No. 168)
-l-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl)-piperidine-2.6-dione( Compound No. 169)
-l-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl}-piperidine-2,6-dione hydrochloride salt( Compound No. 170) Table 1

(Table Removed)
The compounds described herein are basic and form organic or inorganic acid addition salts, which are within the scope of sound medical judgement 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 composition. These salts may be prepared by the useful 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 neutral solution of the resulting salt is subjected to rotary evaporation under diminished pressure 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 with the solvent, and dried.
Alternatively, the solvent is stripped of completely to obtain the desired salt. These salts are often preferred for use in formulating the therapeutic composition of the invention because they are crystalline and relatively more stable and water-soluble.
The compounds described herein have got pharmacological activity, therefore may be administered to an animal for treatment orally, parenterally, topically, rectally. internasally. subcutaneously or by transdermally. The pharmaceutical compositions of the present invention comprise a pharmaceutical!}' effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers.
The term "pharmaceutically acceptable carriers" is intended to include non-toxic, inert solid, semi-solid or liquid filter, diluent, encapsulating material or formulation auxiliary of any type.
Solid form preparation for oral administrations, include capsules, tablets, pills, powder, granules cathets and suppository. For solid form preparation, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate, dicalcium phosphate and/or a filler or extenders such as starch, lactose, sucrose, glucose, mannitol and silicic acid; binders, for example, carboxymethylcellulose. alginates, gelatins, polyvinylpyrolidinone. sucrose, acacia; disintegrating agents .for example.a agar-agar, calcium carbonate, potato starch, alginic acid, certain silicates and sodium carbonate, absorption accelators .for example.quaternary ammonium compounds; wetting agents .for example.cetyl alcohol, glycerol, monostearate; adsorbents .for example,kaolin; lubricants .for example.talc. calcium stearate. magnesium stearate. solid polyethyleneglycol. sodium lauryl sulphate and mixture thereof.
In case of capsules, tablets, pills, the dosage form may also comprise buffering agents.
The solid preparation of tablets, capsules, pills, granules can be prepared with coating and shells, for example, enteric coating and other coatings well known in the pharmaceutical formulating art.
Liquid form preparation for oral administration includes pharmaceutically acceptable emulsions, solution, suspensions, syrups and elixirs. For liquid form preparation, the active compound is mixed with water or other solvent, solubilizing agents and emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate. propylene glycol. 1.3-butylene glycol, dimefhylformamide. oils (for example, 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, for example, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents and perfuming agents.
Injectable preparations, for example, 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 a compound of the present invention include ointments, pastes, creams, lotions, gel. powders, solutions, spray.
inhα1ants or patches. The active compound is admixed under sterile condition with a pharmaceutically acceptable carrier and any needed preservative or buffer as may be required. Ophthalmic formulation, eardrops, eye ointments, powder and solution are also contemplated as being within the scope of this invention.
The pharmaceutical preparation may be in unit dosage form. In such form, the preparation may be subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be packaged preparation, the package containing discrete capsules, powders, in vials or ampoules and ointments, capsules, cachet, tablet, gel cream itself or it can be the appropriate number of any of there packaged forms.
The formulation of the present invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known to the art.
The dosages of the compounds described herein, bladder selective muscarinic receptor antagonist and 5 a reductase inhibitor are adjusted when combined to achieve desired effects. As those skilled in the art will appreciate, dosages of the compounds described herein, bladder selective muscarinic receptor antagonist and 5 a reductase inhibitor may be independently optimized and combined to achieve a synergistic result wherein the pathology is reduced more than it would be if either agent were used alone. In accordance with the method of this invention, the individual component of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
Examples set forth below demonstrates the general synthetic procedure for the preparation of the representative compounds. The examples are provided to illustrate particular aspect of the disclosure and do not constrain the scope of the present invention as defined by the claims.
Experimental details
EXAMPLE 1
Preparation of 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-2-oxo-propyl]-3a.4,7.7a-
tetrahydro-isoindole-1.3-dione hydrochloride salt (Compound No. 6)
Step 1: Preparation of 2-oxiranylmethyl-3a.4,7,7a-tetra hydro-isoindole-1,3-dione
A solution of cis-1.2.3.6-tetrahydrophthalimide (5 gm. 32.89 mmol), epichlorohydrin
(6.0 gm. 65.7 mmol). and potassium carbonate (9.0 gm. 65.7 mmol) in methyl ethyl ketone
(30 ml) was refluxed. After completion of the reaction, the reaction mixture was filtered
through G-4. washed with methyl ethyl ketone. Filtrate was concentrated to yield the thick
residue. To it was added water, extracted with ethyl acetate, dried over anhydrous sodium
sulphate and concentrated to yield the crude product. The crude product was purified on
silica gel column using dichloromefhane as eluent.
Yield: 5.0 g (74%)
Step 2: Preparation of 2-(3-chloro-2-hydroxy-propyl)-3a.4,7.7a-tetrahydro-isoindole-1.3-dione
To a solution of 2-oxiranylmethyl-3a. 4.7.7a-tetra hydro-isoindole-1. 3-dione (4.0
gm. 19.23 mmol) in ethanol was added ethanolic hydrochloride and reaction mixture stirred.
It was then neutralized with sodium bicarbonate. Inorganics were then filtered, washed with
ethanol. Filtrate was concentrate to yield the desired compound.
Yield: 4.2 g (89.36%)
Step 3: Preparation of 2-(3-chloro-2-oxo-propyl)-3a. 4.7.7a-tetrahydro-isoindole-l. 3-dione To a solution of 2-(3-chloro-2-hydroxy-propyl)-3a. 4,7.7a-tetrahydro-isoindole-l. 3-
dione (2.0 gm. 8.17 mmole) in dichloromethane was added pyridinium chlorochromate (3.5
g. 16.35 mmole) and reaction mixture refluxed. After completion of the reaction, the
reaction mass filtered through celite pad. washed with dichloromethane. Filtrate thus
obtained was concentrated to give the crude product. It was then purified on silica gel
column using dichloromethane-methanol as eluent.
Yield: 1.5 g (75%)
Step 4: Preparation of 2-J3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-2-oxo-propyl}-3a.4.7.7a-tetrahydro-isoindole-l,3-dione
A solution of 2-(3-chloro-2-oxo-propyl)-3a. 4.7.7a-tetrahydro-isoindole-l. 3-dione
(1.0 gm. 4 mmole). 2-isopropoxyphenyl piperazine (0.91 gm. 4 mmole). potassium
carbonate (0.57 gm. 4 mmole) in dimethylformamide was heated. Reaction was quenched
by adding water, extracted with ethyl acetate. Organic layer was dried over anhydrous
sodium sulphate and concentrated to yield the crude product. It was then purified on silica gel column using dichloromethane-methanol as eluent. Yield: 1.2 gm (69%)
The following compound was prepared following the above procedure
Compound No. 21: 2-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazn-l-yl]-2-oxo-propyl}-3a.4.7.7a-tetrahydro-isoindole-1.3-dione
IR(KBr): 1703.9 cm"1
1H NMR (300 MHz, DMSO-d6): δ 1.61-1.74 (m, 8H). 2.23-2.27 (m. 2H). 2.37-2.42 (m, 2H).
3.04 (brs, 2H). 3.18-3.47 (m. 8H), 4.50 (s. 2H). 4.62-4.65 (brs. 2H). 4.83 (brs, 1H), 5.88
(brs. 2H). 6.87-7.00 (m. 4H). 10.5 (brs. 1H).
Mass (m/z): 452.3 (M++l)
The following compounds are prepared similarly
Compound No. 32: l-[2-Oxo-3-(4-phenyi-piperazin-l-yl)-propyl]-pyrrolidine-2.5-dione
Compound No. 33: 1 - [3-[4- {4-Fluoro-phenyl} -piperazin-1 -yl]-2-oxo-propyl j -3-phenyl-piperidine-2.6-dione
Compound No. 34: 3,4-Dimethyl-l-(2-oxo-3-[4-(2-trifluoromethyl-phenyl)-piperazin-l-yl]-propyl) -pyrrole-2.5-dione
Step 5: Preparation of 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-2-oxo-propyl}-3a.4.7.7a-tetrahydro-isoindole-l,3-dione hydrochloride salt
To a solution of 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-2-oxo-propyl}-3a.4.7.7a-tetrahydro-isoindole-l.3-dione (0.5 gm. 1 mmole) in isopropyl alcohol was added isopropyl alcohol - hydrochloride at 10-15 C and the reaction mixture was stirred for about 1 hr. Solid . thus, precipitated was filtered, dried and weighed. Yield : 0.45gm (83%) IR(KBr): 1746.7. 1705.0 cm"1
1H NMR (300 MHz. DMSO-d6): δ 1.26-1.28 (d. 6H). 2.22-2.26 (d. 2H). 2.36-2.41 (d. 2H). 3.05-3.47 (m. 10H). 4.49-4.64 (m. 5H). 5.89 (brs. 2H). 6.90-6.95 (m. 4H). 10.40 (brs, 1H). Mass (m/z): 426(M++1)
The following compounds were prepared following the above procedure
Compound No. 20: 2-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-2-oxo-propyl)-3a, 4.7.7a-tetrahydro-isoindole-1, 3-dione hydrochloride salt
IR(KBr): 1707.4 cm"1
1H NMR (300 MHz. DMSO-d6): δ 2.22-2.27 (m. 2H). 2.36-2.42 (m. 2H). 3.05-3.17 (m. 2H). 3.25-3.36 (m, 8H). 3.78 (s. 3H). 4.49-4.59 (m, 4H). 5.89 (brs. 2H). 6.90-7.02 (m. 4H). 10.60 (brs. 1H). Mass(m/z): 398.3 (M++l)
Compound No. 23: 2-{2-Oxo-3- [4-(2-propoxy-phenyl)-piperazin-l-yl]-propyl}-3a. 4.7.7a-tetrahydro-isoindole-1. 3-dione hydrochloride salt
IR(KBr): 1704.7 cm"1
1H NMR (300 MHz. DMSO-d6): δ 0.99-1.04 (t. 3H). 1.71-1.80 (m. 2H). 2.23-2.27 (m. 2H). 2.37-2.42 (m. 2H). 3.08 (m. 2H). 3.17-3.48 (m, 8H). 3.91-3.95 (m. 2H). 4.50 (s. 2H), 4.63 (s. 2H). 5.89 (brs. 2H). 6.86-7.02 (m. 4H). 10.65 (brs. 1H). Mass (m/z): 426.5 (M++l)
Compound No. 25: 2-(3-[4-(4-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-2-oxo-propyl}-3a. 4.7.7a-tetrahydro-isoindole-l. 3-dione hydrochloride salt
IR(KBr): 1707.5 cm"1
1H NMR (300 MHz. DMSO-d6): δ 1.27-1.29 (d. 6H). 2.22-2.27 (m. 2H). 2.36-2.41 (m. 2H). 3.06 (brs. 2H). 3.25-3.38 (m. 8H), 4.49-4.66 (m. 5H). 5.88-5.89 (d. 2H). 6.67-6.68 (m. 1H). 6.85-6.89 (m. 3H). 10.80 (brs. 1H). Mass (m/z): 444.3 (M++l)
Compound No. 27: 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-2-oxo-propyl}-isoindole-1.3-dione hydrochloride salt
IR(KBr): 1727.1 cm"1
1H NMR (300 MHz, DMSO-d6): δ 1.27-1.29 (d. 6H). 3.10-3.49 (m. 8H). 4.59-4.65 (m. 1H). 4.74 (s. 4H). 6.88-6.98 (m. 4H). 7.89-7.97 (m. 4H). 10.87 (brs, 1H).
Mass (m/z): 422.5 (M++l)
Compound No. 29: 2-(2-0.\o-3- [4-[2-(2.2.2-trifluoro-ethoxy)-phenyl]-piperazin-l -yl]-propyl)-3a.4.7.7a-tetrahydro-isoindole-1.3-dione hydrochloride salt
IR(KBr): 1704.2 cm"1
1H NMR (300 MHz. DMSO-d6): δ 2.22-2.41 (m. 4H). 3.10-3.31 (m. 10H). 4.48 (brs. 2H). 4.61 (brs. 2H). 4.68-4.77 (m. 2H). 5.88 (s. 2H). 7.01-7.04 (m. 2H), 10.50 (brs, 1H). Mass (m/z): 466.5 (M++l)
EXAMPLE 2
Preparation of 2-{2-Hydroxy-3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-
hexahydro-isoindole-1.3-dione hydrochloride salt (Compound No. 2)
Step 1: Preparation of 2-(2-Hydroxy-3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl]-3a.4.7.7a-tetrahydro-isoindole-1.3-dione hydrochloride salt
A solution of 2-oxiramylmethyl-3a,4.7.7a-tetrahydroisoindole-1.3-dione (4.0 gm. 19.2 mmole). 2-isopropoxyphenyl piperazine monohydrochloride (4.9 g. 19.2 mmole). potassium carbonate (5.3 gm, 38.4 mmole) in dimethylformamide was heated. Reaction was quenched by adding water, extracted with ethyl acetate, dried over anhydrous sodium sulphate and concentrated to yield the crude product. The crude product was purified on silica gel column using dichloromethane-methanol as eluent. Yield: 7.0 gm (85%)
Step 2: Preparation of 2-(2-Hydroxy-3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1.3-dione hydrochloride salt
A solution of 2-{2-Hydroxy-3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl!-3a.4.7.7a-tetrahydro-isoindole-1.3-dione (2.0 g. 4.6 mmole). palladium-Carbon on hydrogen in methanol was hydrogenated. After completion of the reaction, the reaction mass filtered through celite pad. washed with methanol, filtrate was concentrated to give the required compound. Yield: 1.9 gm (95%) IR(KBr): 1699.0. 1671.2 cm"1
1H NMR (300 MHz. CDC13): δ 1.33-1.35 (d. 6H). 1.46 (brs. 4H). 1.84-1.85 (m. 4H). 2.43-2.46 (m. 2H). 2.60-2.63 (m, 2H). 2.80-2.85 (m. 4H). 3.10 (brs. 4H). 3.53-3.68 (m. 2H). 4.01-4.04 (m, 1H). 4.56-4.60 (m. 1H). 6.84-6.92 (m. 4H). 9.96 (brs. 1H). Mass (m/z): 430.1 (M++l)
The following compounds were prepared following the above procedure
Compound No. 8: 2-{(S)-2-Hydroxy-3-!4-[2-(2,2.2-trifluoro-ethoxy)-phenyl]-piperazin-l-yl}-propyl)-3a.4.7,7a-tetrahydro-isoindole-1.3-dione hydrochloride salt
IR(KBr): 1697.4 cm"1
1H NMR (300 MHz, DMSO-d6): δ 2.21-2.25 (d. 2H), 2.44-2.56 (d. 2H), 3.02-3.20 (m. 8H). 3.37-3.63 (m. 6H). 4.16 (m, 1H). 4.63-4.72 (m. 2H). 5.89 (brs. 2H). 7.01-7.05 (m. 4H). 10.42 (brs, 1H). Mass (m/z): 468.2 (M++l)
Compound No. 10: 2-(2-Hydroxy-3-{4-[2-(2.2.3.3-tetrafluoro-propoxy)-phenyl]-piperazin-1 -yl {-propyl)-3a.4.7.7a-tetrahydro-isoindole-l ,3-dione hydrochloride salt
IR(KBr): 1695.3 cm"1
1H NMR (300 MHz. DMSO-d6): δ 2.19-2.24 (m. 2H). 2.36-2.41 (m. 2H), 3.01-3.16 (m. 8H). 3.41-3.50 (m. 6H). 3.62-3.65 (m, 1H). 4.20 (m, 1H). 4.54-4.63 (m. 2H), 5.88 (brs, 2H). 6.49-6.68 (m, 1H). 7.01-7.08 (m. 4H). 10.14 (brs. 1H). Mass (m/z): δ00.3. (M++l)
Compound No. 12: 2-{2-Hydroxy-3-[4-(2-isopropoxy-4-nitro-phenyl)-piperazin-l-yl]-propyl) -3a,4.7.7a-tetrahydro-isoindole-l ,3-dione hydrochloride salt
IR(KBr): 1697.4 cm"1
1H NMR (300 MHz. CDCl3): δ 1.41-1.43 (d. 6H). 2.01 (m. 2H). 2.20-2.25 (m. 2H). 3.16 (m.
6H). 3.46-3.49 (m. 6H), 4.01 (m. 2H). 4.71 (m. 2H). 5.89 (brs. 2H). 6.97 (d. 1H). 7.71 (s.
1H). 7.83 (brs. 1H). 11.40 (brs. 1H).
Mass (m/z): 472.7 (M++l)
Compound No. 68: 2-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-2-hydroxy-propyl}-
hexahydro-isoindole-1.3-dione hydrochloride salt
IR(KBr): 1701.9 cm"1
1H NMR (300 MHz, CDC13): δ 1.446 (s. 4H). 1.668-2.008 (m. 12H). 2.981-3.153 (m. 4H). 3.447 (s. 6H). 3.524-3.586 (m. 2H). 3.677-3.722 (q. 2H). 4.541 (s. 1H). 4.713-4.806 (d. 2H). 6.842-7.004 (m. 4H). Mass (m/z): 456(M++1)
Compound No. 80: 2-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-1.3-dione hydrochloride salt
IR(KBr): 1701cm"1
1H NMR (300 MHz. CDC13): δ 1.456-1.860(m. 16H). 2.922-2.969(d. 4H). 3.223-3.356(d. 8H). 3.532-3.671(m. 2H). 4.415(s, 1H). 4.738(s. 2H). 6.623-6.762 (m, 3H). Mass (m/z): 474 (M++l)
Compound No. 88: l-[3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-2-hydroxy-propyl}-piperidine-2,6-dione hydrochloride salt
IR(KBr): 1653.3 cm"1
1H NMR (300 MHz, CDC13): δ 1.31-1.33 (d. 6H). 1.96-2.00 (t, 2H), 2.66-2.71(t. 4H). 3.26
(s. 3H). 3.48-3.66 (t. 9H). 4.04-4.06 (d. 2H). 4.44-4.50 (m. 1H). 6.63-6.69 (m.3H).
Mass (m/z): 408 (M++l)
Compound No. 90: l-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-hydroxy-propyl}-piperidine-2,6-dione hydrochloride salt
IR(KBr): 1668.2 cm"1
1H NMR (300 MHz. CDCI3): δ 1.65-1.98 (m. 11H). 2.72 (s. 3H). 2.81(s. 1H). 3.51-3.94(m.
12H). 4.03-4.09(m. 1H). 4.73(s. 1H). 6.63- 6.77(m. 3H).
Mass (m/z): 767 (M++l)
Compound No. 100: l-{3-[4-(5-Fluoro-2-propoxy-phenyl)-piperazin-l-yl]-2-hydroxy-propyl)-piperidine-2,6-dione hydrochloride salt
IR(KBr): 1659.3 cm"1
1H NMR (300 MHz, CDC13): δ 1.021-1.071 (t. 3H). 1.797-1.867 (m. 2H). 1.980-2.022 (t.
2H). 2.690-2.764 (q. 4H). 3.132-3.159 (t. 2H). 3.493(s, 6H). 3.763-3.825(q, 2H).3.894-
3.938(t.2H).4.010-4.077(m.2H).4.534-4.548(d.lH).6.657-6.791(m.3H).
Mass (m/z): 408 (M++l)
Example 3
Preparation of 2-{3-[4-(2-CycIopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-oxo-propyl}-3a.4.7.7a-tetrahydro-isoindole-l,3-dione hydrochloride salt ( Compound No. 78)
Step 1: Preparation of 2-(3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-oxo-propyl] -3a.4.7.7a-tetrahydro-isoindole-l .3-dione
To a clear solution of 2-(3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-
hydroxy-propyl}-3a.4.7,7a-tetrahydro-isoindole-1.3-dione (1.0 gm. 0.00212 mol) in
dichloromethane (20 ml) was added pyridinium chlorochromate (0.915 gm. 0.00425 mol)
and reaction mixture stirred at room temperature for about 2 hours then refluxed further for
about 4 hours. Reaction mixture was filtered through celite pad, washed with
dichloromethane; combined filtrate was concentrated to yield the crude product which was
then purified on a column of silica gel (60-120 mesh) to afford the desired compound.
Yield: 0.3 gm (30%)
Step 2: Preparation of 2-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-oxo-propyl ] -3a.4,7.7a-tetrahydro-isoindole-1,3-dione hydrochloride salt
The hydrochloride salt of l-(3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-hydroxy-propyl}-piperidine-2,6-dione was prepared following the previously disclosed procedure. Yield: 0.8 gm (80%) IR(KBr): 1703.2 cm"1
1H NMR (300 MHz. CDC13): δ 1.659-1.854 (m.8H). 2.255-2.301(d.2H),2.569-2.616 (d.2H). 3.223(s,2H).3.469-3.513 (d. 8H).4.458(s.lH). 4.529(s.2H).4.744 (s.lH).5.940 (s.2H), 6.654-6.794 (m,4H).
Mass (m/z): 470 (M++l)
The following compound was prepared following the above procedure
Compound No.4: 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-2-oxo-propyl}-
hexahydroisoindole-l,3-dione hydrochloride salt
IR(KBr): 1707 cm"1
1H NMR (300 MHz. DMSO-d6): δ 1.26-1.28 (d. 6H). 1.35-1.41 (m. 4H). 1.71-1.75 (m. 4H).
3.05 (m. 2H). 3.36-3.48 (m. 8H), 4.50 (brs. 2H). 4.57-4.64 (m. 2H). 6.90-6.96 (m. 4H).
10.70 (brs. 1H).
Mass (m/z): 428.1 (M++l)
EXAMPLE 4
Preparation of 2-J2-Fluoro-3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a,4,7.7a-tetrahydro-isoindole-l,3-dione hydrochloride salt (Compound No. 14)
Step 1: Preparation of 2-{2-Fluoro-3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a.4,7.7a-tetrahydro-isoindole-l,3-dione
To a solution of 2-(2-Hydroxy-3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl]-3a.4.7.7a-tetrahydro-isoindole-l,3-dione (1 gm. 2.3 mmole) in dichloromethane was added diethyl amino sulphur trifluoride (0.754 g. 4.6 mmole). After completion of the reaction, water was added and extracted with dichloromethane. Organic layer was dried over anhydrous sodium sulphate and concentrated to yield the crude product. The compound was purified on silica gel column using dichloromethane-methanol. Yield: 0.410 gm (41%)
The following compounds are prepared similarly
Compound No. 35: 1-{2-Fluoro-3-[4-(4-fluorophenyl)piperazin-l-yl]-propyl}-piperidine-2.6-dione
Compound No. 36: l-(2-Fluoro-3-[4-[2-(2.2.2-trifluoro-ethoxy)-phenyl]-piperazin-l-yl}propyl)-3.4-dimethylpyrrole-2.5-dione
Step 2: Preparation of 2-{2-Fluoro-3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl)-3a.4.7„7a-tetrahydro-isoindole-l,3-dione hydrochloride salt
The hydrochloride salt of 2-(2-Fluoro-3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a.4,7.7a-tetrahydro-isoindole-1.3-dione was prepared following the previously disclosed procedure. Yield : 0.385gm (89%) IR(KBr): 1709.2 cm"1
1H NMR (300 MHz. CDC13): δ 1.58 (d. 6H), 2.22-2.26 (m. 2H), 2.59-2.64 (m. 2H). 3.43-3.49 (m. 2H). 3.69-4.24 (m. 8H). 4.85-5.10 (m, 6H). 5.91 (brs. 2H). 7.01-7.43 (m. 3H). 8.18-8.19 (m. 1H). Mass (m/z): 430 (M++l)
Example 5
Preparation of 2-(3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl}-5.6-dihvdroxy-hexahydro-isoindole-l,3-dione hydrochloride salt( Compound No. 102)

Step 1; Preparation of 2-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl]-5.6-dihydroxy-hexahydro-isoindole-1,3-dione
To a clear solution of 2-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl]-3a.4,7.7a-tetrahydro-isoindole-1.3-dione(1.0 gm. 0.002) in ethanol (20 ml) was added potassium permanganate solution (0.417 gm. 0.0026, in water 5 ml) dropwise at 0-5°C. The reaction mixture was stirred at room temperature for about 6-8 hours. After completion of the reaction, it was filtered through celite pad. washed with ethanol .Filtrate thus obtained was concentrated to yield the crude product which was then purified by column chromatography. Yield: 0.51 gm (47%)
Step 2: Preparation of 2-(3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl}-5.6-dihydroxy-hexahydro-isoindole-l .3-dione hydrochloride salt
The hydrochloride salt of 2-(3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-
yl]-propyl]-5.6-dihydroxy-hexahydro-isoindole-l.3-dione was prepared following the
previously disclosed procedure.
Yield: 0.6 gm (56%)
IR(KBr): 1697.7 cm"1
1H NMR (300 MHz. CDC13): δ 1.67-1.77 (m. 10H). 1.84-1.89 (t. 4H). 3.15 (s. 6H). 3.36 (s.
2H). 3.47-3.58 (m. 6H). 3.82 (s. 2H). 4.72 (s. 1H). 6.62-6.77 (m. 3H).
The following compounds were prepared by following the above procedure
Compound No. 44: 2-(3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-5.6-
dihydroxy-hexahydro-isoindole-1.3-dione hydrochloride salt
1H NMR (300 MHz. CDCl3): δ 1.11-1.37 (m. 6H). 1.84-1.94 (m. 6H). 3.05-3.13 (d. 6H).
3.47 (s. 6H), 3.79 (s, 2H). 4.06-4.08 (d. 1H). 4.49-4.5l(lH.d). 4.72-4.75 (d. 3H). 6.62-6.71
(m. 3H).
Mass(m/z): 464(M++1)
Compound No. 50: 5,6-Dihydroxy-2-!3-[4-(2-methoxy-5-methyl-phenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1.3-dione hydrochloride salt
IR(KBr): 1699 cm"1
Mass (m/z): 432 (M++l)
Compound No. 54: 2-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl]-5.6-dihydroxy-hexahydro-isoindole-l,3-dione hydrochloride salt
1H NMR (300 MHz, CDCl3): δ 1.263-1.885 (m. 8H). 2.137-2.177 (t. 4H). 3.077-3.131 (t.5H). 3.322-3.366 (t, 2H). 3.509-3.168 (m. 6H). 3.726-3.746 (t. 2H), 3.944 (s. 6H), 4.808-4.836 (m. 1H). 6.869-7.036 (m. 4H).
Mass (m/z): 472 (M++l)
Compound No. 76: 2-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-2-oxo-propyl}-5.6-dihydroxy-hexahydro-isoindole-1,3-dione hydrochloride salt
IR(KBr): 1704.4 cm"1
1H NMR (300 MHz, CDC13): δ 1.588-2.008 (m.8H). 2.162 (s.4H). 3.213 (s,3H). 3.446-3.516
(q.6H), 3.793 (s.4 H),4.616-4.732 (d.6H), 6.810-6.947(m;4H).
Mass (m/z): 486 (M++l)
Compound No. 104: 2-{3-[4-(5-Fluoro-2-propoxy-phenyl)-piperazin-l-yl]-propyl]-5.6-dihydroxy-hexahydro-isoindole-1.3-dione hydrochloride salt
IR(KBr): 1697.3 cm"1
1H NMR (300 MHz. CDC13): δ 1.036-1.086 (t. 3 H). 1.185-1.255 (m. 4H), 1.812-1.880 (m. 4H). 1.944 (s. 2H). 3.030-3.061 (t. 4 H). 3.446-3.516 (m. 10H). 3.569-3.661(m. 1H), 3.906-3.927 (d. 2H). 4.080 (s. 1H). 6.601-6.774 (m. 3H). Mass (m/z): 464.58 (M++l)
Compound No. 120: 2- {3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-oxo-propyl J -5,6-dihydroxy-hexahydro-isoindole-l .3-dione hydrochloride salt
IR(KBr): 1704.9 cm"1
Mass (m/z): δ04(M++1)
Compound No. 122: 2-{3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-2-oxo-
propyl)-5,6-dihydroxy-hexahydro-isoindole-l.3-dione hydrochloride salt
IR(KBr): 1706.4 cm"1
Mass (m/z): 478(M++1)
Compound No. 124: 2-{3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l -yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-l .3-dione hydrochloride salt
IR(KBr): 1699.3 cm'1
Mass (m/z): 480 (M++l)
Compound No. 126: 2-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-
hydroxy-propyl) -5.6-dihydroxy-hexahydro-isoindole-l .3-dione hydrochloride salt
IR(KBr): 1699.1cm"1
Mass (m/z): δ06(M++1)
Example 6
Preparation of 6-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl]-2-oxo-hexahydro-1.3-dioxa-2-lambda*4*-thia-6-aza-s-indacene-5,7-dione hydrochloride salt (Compound No. 31)
Step 1: Preparation of 6-(3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl]-2-oxo-hexahydro-1.3-dioxa-2-lambda*4*-thia-6-aza-s-indacene-5.7-dione
To a solution 5.6-Dihydroxy-2- J3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-
propy! ]-hexahydro- isoindole-1. 3 -dione (0.5gm. 0.001 mol) (prepared according to
example 5) in dichloromethane (5ml) was added diethyl amino sulphur trifluoride (0.18gm.
0.001mol) dropwise at 0-5 °C and reaction mixture was stirred for about 4hrs. After
completion of the reaction, it was quenched by adding water (15ml). Reaction mixture
extracted with dichloromethane (2x10ml). combined organic layer were dried over
anhydrous sodium sulphate and concentrated. The crude product thus obtained was purified
on a column of silica gel (60-120 mesh) using dichloromethane:methanol as eluent to yield
the desired product.
Step 2: Preparation of 6-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-2-oxo-hexahydro-1 „3-dioxa-2-lambda*4*-thia-6-aza-s-indacene-5,7-dione hydrochloride salt
The hydrochloride salt of 6-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl)-2-
oxo-hexahydro-1.3-dioxa-2-lambda*4*-thia-6-aza-s-indacene-5.7-dione was prepared
following the previously disclosed procedure.
Yield: 0.5 gm (85%)
IR(KBr): 1700.1 cm"'
1H NMR (300 MHz, CDC13): δ 1.37-1.38 (d. 6H). 2.18-2.54 (m. 6H). 3.02-3.08 (m. 4H). 3.29 (m. 2H). 3.45-3.69 (m. 8H). 4.61 (m. 1H). 5.03-5.08 (m, 1H), 5.28-5.31 (m. 1H). 6.87-7.24 (m.4H). 12.42 (brs. 1H).
Mass (m/z): 492.2 (M++l)
Example 7
Preparation of l-[3-[4-(5-Fluoro-2-methoxy-phenyl)-piperazin-l-yl]-propyl] -3.3.4-trimethyl-pyrrolidine-2,5-dione hydrochloride salt( Compound No. 168)
Step 1: Preparation of 3-[4-(5-fluoro-2-methoxyphenyl) piperazin-1-yl] propionitrile
To a solution of l-(5-fluoro-2-methoxy phenyl) piperazine (2.0gm. 0.009mol) in
methanol (25 ml) was added acrylonitrile (1 .Ogm. 0.018 mol) under stirring at room
temperature. The reaction mixture was stirred for about 3-4 hours. After completion of the
reaction, reaction mass was concentrated on buchi to yield the desired product.
Yield: 2.2 gm (88%)
Step 2: Preparation of 3-[4-(5-fluoro-2-methoxyphenyl) piperazin-1-yl] propylamine
To a solution of 3-[4-(5-fluoro-2-methoxyphenyl) piperazin-1-yl] propionitrile (2
gm. 0.0076mol) in methanol-ammonia (20 ml) was added palladium-carbon (10%) w/w of
compound prepared in step 1 and reaction mixture was hydrogenated at 55-60 psi for about
4-5 hours. After this, reaction mixture was filtered through celite pad. washed with
methanol; filtrate thus obtained was concentrated to yield the desired product.
Yield: 2.0 gm (99%)
Step 3: Preparation of l-{3-[4-(5-Fluoro-2-methoxy-phenyl)-piperazin-l-yl]-propyl)- 3.3.4-trimethyl -pyrrole-2,5-dione
A solution of 3-[4-(5-fluoro-2-methoyphenyl) piperazin-1-yl] propylamine 1.0gm.
0.0037mol) and 3,3.4-trimethyl dihydro furan-2,5-dione (0.53 gm. 0.00376 mole) in toluene
(15 ml) was refluxed for 1 hour. The reaction mixture was concentrated to yield the crude
product, which was purified on a column of silica gel (100-120 mesh) using
dichloromethane:.methanol as eluent.
Yield: 1.2gm(82%)
Step 4: Preparation of l-{3-[4-(5-Fluoro-2-methoxy-phenyl)-piperazin-l-yl]-propyl)- 3.3.4-trimethyl -pyrrole-2.5-dione hydrochloride salt
The hydrochloride salt of l-(3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl)- 3.3,4-trimethy -pyrrole-2,5-dione was prepared following the previously disclosed procedure.
Yield: 0.8gm (85%)
IR(KBr)= 1692.6 cm"1
H1 NMR (300 MHz, CDC13)δ: 1.163-1.253 (6H. m). 1.332-1.351 (3H, d). 2.239 (2H. s),
2.611-2.678 (1H. m). 3.167 (2H. s). 3.620-3.655 (6H, d). 3.997 (5H. s). 4.633 (2H. s). 6.946-
7.696 (3H. m).
Mass (m/z)= 392 (M++l)
Example 8
Preparation of 1 - (3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-1 -yl]-propyl} -3-
methylene-pyrrolidine-2.5-dione hydrochloride salt ( Compound No. 136)
Step 1: Preparation of l-(3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl)-3-methylene-pyrrolidine-2,5-dione
A solution of 3-[4-(5-fluoro-2-isopropoxyphenyl) piperazin-1-yl] propyl amine
(1.0gm, 0.0034 mol) and itaconic anhydride (0.38 gm. 0.0034 mole) in toluene (15 ml) was
refluxed for 1 hour. It was followed by concentration of the reaction mixture to a crude
residue, which is purified by column chromatography.
Yield: 0.700 gm (54%)
Step 2: Preparation of l-(3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3-methylene-pyrrolidine-2.5-dione hydrochloride salt
The hydrochloride salt of l-(3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-
propyl)-3-methylene-pyrrolidine-2,5-dione was prepared following the previously disclosed
procedure.
Yield: 0.5gm (90%)
H1 NMR (300 MHz, CDCl3)δ: 1.23-1.25 (6H. d). 2.10 (2H. s). 2.27-2.34 (2H. q). 3.03-3.08
(4H. t), 3.47-3.68 (8H, m). 4.48-4.52 (1H. t). 6.36 (2H. s). 6.62-6.80 (3H. m)
Mass (m/z)= 390 (M++l)
The following compounds were prepared following the above procedure
Compound No. 134: l-{3-[4-(3-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3-methylene-pyrrolidine-2.5-dione hydrochloride salt
IR(KBr): 1711.5 cm"1
1H NMR (300 MHz, CDCl3)δ: 1.185-1.364 (6H. m). 2.009-2.099 (2H. m). 2.188 (2H, s),
2.940 (3H. s). 3.130 (3H. s). 3.374-3.721 (7H, m). 4.461-4.521 (1H. q), 6.352-6.357 (1H. s).
6.668-6.984 (3H. m)
Mass (m/z)= 390.7 (M++l)
Compound No. 162: 3-Methylene-l-[3-(4-0-tolyl-piperazin-l-yl)-propyl]-pyrrolidine-2.5-dione hydrochloride salt
Compound No. 166: l-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl}-3-methylene-pyrrolidine-2.5-dione hydrochloride salt
IR KBr): 1706.7 cm"1
Mass (m/z): 398 (M++l)
Example 9
Preparation of 1 - {3-[4-(2-Methoxy-phenyl)-piperazin-1 -yl]-propyl)-3-methyl-4-( 1 -phenyl-ethylamino)-pyiTolidine-2.5-dione hydrochloride salt( Compound No. 140)
Step 1 Preparation of l-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl)-3-methyl-4-(l-phenyl-ethylamino)-pyrrolidine-2.5-dione
To a solution of l-{3-[4-(2-Methoxy -phenyl)-piperazin-l-yl]-propyl)-3-methyl-
pyrrole-2,5-dione (0.5 gm. 0.001mol) in methanol was added equimolar quantity of 1-
phenylethyl amine 0.2lgm. 0.0017 mol) and reaction mixture stirred at room temperature for
about 10-12 hours. The reaction mixture was concentrated to yield the crude product which
was then purified on a column of silica gel (100-120 mesh) using dichloromethane:methanol
as eluent.
Yield: 0.6 gm (89%)
Step 2: Preparation of l-(3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl)-3-methyl-4-(l-phenyl-ethylamino)-pyrrolidine-2.5-dione hydrochloride salt
The hydrochloride salt of l-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl)-3-
methyl-4-(l-phenyl-ethylamino)-pyrrolidine-2.5-dione was prepared following the
previously disclosed procedure.
Yield: 0.5gm (85%)
IR(DCM): 1690.8 cm"1
Mass (m/z): 465 (M++l)
The following compounds were prepared following the above procedure
Compound No. 148: 3-Cyclopropylamino-l-{3-[4-(2-ethoxy-phenyl)-piperazin-l-\iJ-propyl}-pyrrolidine-2,5-dione hydrochloride salt
IR(KBr): 1707.3 cm"'
Mass (m/z): 401 (M++l)
Compound No. 152: l-(3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl)-3-
cyclopropylamino-pyrrolidine-2.5-dione hydrochloride salt
IR(KBr): 1713.3 cm"1
Mass(m/z):441(M++l)
Compound No. 164: l-(3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl)-3-methyl-4-
[(thiophen-2-ylmethyl)-amino]-pyrrolidine-2,5-dione hydrochloride salt
IR(KBr): 1701.5 cm"1
Mass (m/z): 457 (M++l)
Example 10
Preparation of l-{3-[4-(2-Methoxy-5-methyl-phenyl)-piperazin-l-yl]-propyl}-piperidine-2.6-dione hydrochloride salt( Compound No. 48)
Step 1 Preparation of l-(3-bromopropyl)-piperidine-2.6-dione
A mixture of piperidine-2, 6-dione (2 gm. 0.017 mole), 1.3-dibromopropane (5.3 gm.
0.026 mole), potassium carbonate (4.88 gm. 0.035 mole) and tetrabutylammonium iodide
0.13 gm. 0.0035 mole) in acetone (20 mL) was stirred at 40°C for about 8 hours. Inorganics
were filtered, washed with acetone, solvent thus obtained was removed under pressure and
the residue was suspended in water. The aqueous solution was extracted with ethyl acetate.
The organic layer was washed with water, dried over anhydrous sodium sulphate and
evaporated in vacuo to give the crude product. The crude product was purified on silica gel
(60-120 mesh) column using dichloromethane as eluent to yield the product.
Yield: 3.1 gm (76%)
Step 2: Preparation of l-(3-{4-[2-(2-methoxy-5-mefhyl)-phenyl]- piperazin-1-yl J propyl) -piperidine-2.6-dione
A mixture of l-(3-bromopropyl)-piperidine-2.6-dione (2 gm. 0.0085 mole), anhydrous potassium carbonate (2.36 gm. 0.0017mole) and 2-methoxy-5-methyl phenyl piperazine (1.76gm. 0.0085mole) in dimethylformamide (20 ml) was heated at 75-78 UC for about 6-8 hours. The reaction mixture was quenched by adding water (60 ml), extracted with
ethyl acetate, concentrated and purified on silica gel (60-120 mesh) column using dichloromethane and methanol as eluent to yield the product.
Yield: 2.2 gm (72%)
Step 3: Preparation of l-(3-{4-[2-(2-methoxy-5-methyl)-phenyl]- piperazin-1-yl]propyl) -piperidine-2,6-dione hydrochloride salt
The hydrochloride salt of l-(3-{4-[2-(2-methoxy-5-methyl)-phenyl]- piperazin-1-yl} propyl) -piperidine-2.6-dione was prepared following the previously disclosed procedure. Yield: 0.6gm (87%) IR(KBr): 1668.8 cm"1
Mass (m/z): 360 (M++l)
The following compounds were prepared similarly
Compound No. 52: l-(3-[4-[5-Fluoro-2-(2.2,2-trifluoro-ethoxy)-phenyl]-piperazin-l-ylj-propyl)-piperidine-2.6-dione hydrochloride salt
IR(KBr): 1669.9 cm"1
Mass (m/z): 432 (M++l)
Compound No. 98: l-{3-[4-(5-Fluoro-2-propoxy-phenyl)-piperazin-l-yl]-propyl)-piperidine-2,6-dione hydrochloride salt
IR(KBr)= 1671.8 cm"1
1H NMR (300 MHz, CDC13)8: 1.02-1.07 (3H. t). 1.96-2.00 (2H. t). 2.16-2.21 (2H. t). 2.68-
2.72 (6H, t). 3.02-3.07 (6H. t). 3.52 (6H. s). 3.88-3.94 (4H. m). 6.63-6.79 (3H. m).
Mass (m/z )= 392 (M++l)
Compound No. 128: l-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl!-piperidine-2.6-dione hydrochloride salt
IR(KBr)= 1673.9 cm"1
1H NMR (300 MHz. CDC13)δ: 1.69-2.01 (10H, m). 2.19 (2H, s). 2.68-2.72 (4H. t), 3.02-3.05
(4H. d). 3.51 (6H. s). 3.88-3.92 (2H. t). 4.75 (1H. s). 6.61-6.79 (3H. m)
Mass (m/z)= 418 (M++l)
Compound No. 130: l-[3-[4-(3-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-prop\l}-piperidine-2.6-dione hydrochloride salt
IR(KBr)= 1698.8 cm"1

1H NMR (300 MHz. CDC13)δ: 1.20-1.30 (6H, dd). 1.99-2.01 (2H. d). 2.21 (2H. s). 2.68-2.72
(4H. t). 2.92-3.07 (4H, d). 3.47-3.59 (6H. t), 3.90 (2H. s). 4.44-4.50 (1H, m). 6.68-6.99 (3H.
m)
Mass (m/z)= 392.8 (M++l)
Compound No. 132: l-{3-[4-(3-Fluoro-2-methoxy-phenyl)-piperazin-l-yl]-propyl}-piperidine-2.6-dione hydrochloride salt
IR(KBr): 1669.6 cm"1
1H NMR (300 MHz, CDC13)δ: 1.96-2.03 (2H. q). 2.17-2.24 (2H, q). 2.68-2.72 (4H. t). 3.03-
3.09 (4H, t). 3.55 (6H. s). 3.88-3.90 (5H. d). 6.68-6.96 (3H. m)
Mass (m/z)= 364 (M++l)
Compound No. 138: l-{3-[4-(5-Fluoro-2-(2.2.3,3-tetrafluoro-propoxy)-phenyl]-piperazin-l-yl}-propyl)-piperidine-2.6-dione hydrochloride salt
IR(KBr): 1688.7 cm"1
Mass (m/z): 464 (M++l)
Compound No. 142: l-(3-[4-(5-Fluoro-2-trifluoromethoxy-phenyl)-piperazin-l-yl]-propyl)-piperidine-2.6-dione hydrochloride salt
IR(KBr): 1703 cm"1
Mass (m/z): 400 (M++l)
Compound No. 170: 1 - {3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-1 -yl]-propyl} -piperidine-2.6-dione hydrochloride salt IR(KBr): 1673.1 cm"1
1H NMR (300 MHz, CDC13)δ: 1.631-1.730 (10H. m). 2.010 (2H. s), 2.683-2.726 (4H. t).
3.014-3.041 (4H. d). 3.494 (6H. s). 3.882-3.925 (2H. t). 4.799-4.817 (1H, t). 6.841-7.014
(4H. m)
Mass (m/z)= 400 (M++l)
Example 11
Preparation of 3-(3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl]-l-methyl-3-aza-bicyclo [3.1.0]hexane-2.4-dione hydrochloride salt( Compound No. 64)
Step 1: Preparation of 3-{3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl)-l-methyl-3-aza-bicyclo [3.1.0]hexane-2.4-dione
To a suspension of sodium hydride (0.037 gm, 0.0015 mol) in dimethylsulphoxide
(15 ml) was added trimethyl sulphoxonium iodide (0.34 gm, 0.0015 mol) in lots at room
temperature. It was followed by addition of a solution of l-{3-[4-(5-Fluoro-2-isopropoxy-
phenyl)-piperazin-l-yl]-propyl)-3-methyl-pyrrole-2.5-dione (0.5 gm. 0.0013 mol) in
dimethylsulphoxide (5 ml) to the reaction mixture at 10-15°C. Reaction mixture was stirred
for about 10-15 minutes. Reaction was quenched by adding water (30 ml) to it; extracted
with ethyl acetate; combined organic layers were concentrated to yield the crude product
which was then purified by column chromatography.
Yield: 0.25gm (48%)
Step 2: Preparation of 3-{3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl!-l-methyl-3-aza-bicyclo [3.1.0]hexane-2.4-dione hydrochloride salt
The hydrochloride salt of 3-{3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl]-l-methyl-3-aza-bicyclo [3.1.0]hexane-2.4-dione was prepared following the previously disclosed procedure. Yield: 0.190 gm (37%) IR(KBr): 1704 cm"1
Mass (m/z): 404 (M++l)
The following compounds were prepared by following above procedure
Compound No. 56: 3-{3-[4-(3-Fluoro-2-methoxy-phenyl)-piperazin-l-yl]-propyl)-l-methyl-3-aza-bicyclo [3.1.0]hexane-2.4-dione hydrochloride salt
IR(KBr): 1613.8 cm"1
Mass (m/z): 376(M++1)
Compound No. 58: 3-(3-[4-(5-Fluoro-2-methoxy-phenyl)-piperazin-l-yl]-propyl)-l-methyl-3-aza-bicyclo [3.1.0]hexane-2,4-dione hydrochloride salt
IR(KBr): 1650.3 cm"1
Mass (m/z): 376(M"+1)
Compound No. 60: 3-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl}-l-methyl-3-aza-bicyclo [3.1.0]hexane-2.4-dione hydrochloride salt
IR(KBr): 1617 cm"1
Mass (m/z): 412(M++1)
Example 12
Preparation of 2-(3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-1.3-dione hydrochloride salt ( Compound No. 108)
Step 1: Preparation of 4-(3-chloropropyl) tetrahydro-laH-oxireno [fj isoindole-3, 5 (2H, 4H)-dione
To a solution of 2-(3-chloropropyl)-3a. 4.7.7a-tetrahydroisoindole-l. 3-dione (1.0
gm. 0.0037 mole) in dichloromethane (l0mL) was added equimolar quantity of
metachloroperbenzoic acid (1.33 gm of 50%. 0.0037mole) in dichloromethane at 0-5 C. The
reaction mixture was stirred for about 6-8 hours. Reaction mixture was poured into ice-cold
potassium carbonate solution (5%) and concentrated.
Yield : 0.8 gm .75%
Step 2: Preparation of 4-{3-[4-(2-cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl{-hexahydro-l-oxa-4-aza-cyclopropa[f]indene-3.5-dione
A suspension of 4-(3-chloropropyl)tetrahydro-laH-oxireno[f]isoindole-3.5 (2H.4H)-
dione (0.5 gm. 0.002 mol). l-(5-fluoro-2-cyclopentyloxyphenyl) piperazine (0.49 gm.
0.0018 mol). anhydrous potassium carbonate (0.567 gm. 0.004 mol) and potassium iodide
(0.007 gm. 0.00004 mole) in dimethylformamide (20 ml) was heated at 50-55°C for about
24 hours. Reaction was quenched by adding water to it; extracted with ethyl acetate;
combined organic layer dried over anhydrous sodium sulphate and concentrated to yield the
crude product. It was then purified on a column of silica gel (60-120 mesh) using
dichloromethane: methanol as eluent.
Yield: 0.6 gm. 62%
Step 3: Preparation of 2-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-1.3-dione
To the solution of 4-{3-[4-(2-cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl}-hexahydro-l-oxa-4-aza-cyclopropa[fjindene-3.5-dione (0.5 gm. 0.001 mol) in dichloromethane (15 ml) was added diethyl amino sulphur trifluoride (0.26 gm. 0.0016 mol) dropwise under stirring at 0-5°C. The reaction mixture was further stirred at room temperature for about 2-3 hours. After the completion of the reaction, it was quenched by adding dilute solution of sodium bicarbonate; extracted with dichloromethane; combined
organic layer concentrated to yield the crude product. It was then purified on a column of
silica gel (60-120 mesh) using dichloromethane:methanol as eluent to yield the product.
Step 4: Preparation of 2-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-l 3-dione hydrochloride salt
The hydrochloride salt of 2-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl)-5-fluoro-6-hydroxy-hexahydro-isoindole-l.3-dione was prepared following the previously disclosed procedure. Yield: 0.100 gm (19%) IR(KBr): 1638 cm"1
Mass (m/z): 492 (M++l)
The following compounds were prepared b> following the above procedure
Compound No. 66: 5-Fluoro-6-hydroxy-2-{3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl ] -hexahydro-isoindole-1.3-dione hydrochloride salt
IR(KBr): 1613 cm"1
Mass (m/z): 448 (M++l)
Compound No. 82: 5-Fluoro-2-{3-[4-(5-fluoro-2-methoxy-phenyl)-piperazin-l-yl]-propyl}-
6-hydroxy-hexahydro-isoindole-l,3-dione hydrochloride salt
IR(KBr): 1687 cm"1
Mass (m/z): 438 (M++l)
Compound No. 86: 5-Fluoro-2-(3-[4-(5-fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl J -6-hydroxy-hexahydro-isoindole-1.3-dione hydrochloride salt
IR(KBr): 1709 cm"'
Mass (m/z): 467 (M++l)
Compound No. 106: 2-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl]-5-fluoro-6-hydroxy-hexahydro-isoindole-l.3-dione hydrochloride salt
IR(KBr): 1703 cm"1
Mass (m/z): 474 (M++l)
Example 13
Preparation of 2-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-prop\iJ-5-hydroxy-hexahydro-isoindole-1.3-dione hydrochloride salt( Compound No. 72)
Step 1: Preparation of 2-{3-[4-(2-CycIopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-1.3-dione
To a solution of 4-{3-[4-(2-cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl}-
hexahydro-l-oxa-4-aza-cyclopropa[f]indene-3,5-dione (1.0 gm, 0.002 mol) in methanol (20
ml) was added palladium-carbon (0.5 gm) and resulting mixture was hydrogenated at 55-
60°C psi for about 24 hours. After completion of the reaction, it was filtered through celite
pad. washed with methanol; combined filtrate was concentrated to yield the crude product.
which was purified by column chromatography.
Step 2: Preparation of 2-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l.3-dione hydrochloride salt
The hydrochloride salt of 2-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l.3-dione was prepared following the previously disclosed procedure. Yield: 0.200 gm. 20% IR(KBr): 1696.9 cm"1
1H NMR (300 MHz, CDC13): δ 1.69-1.92(m. 12H). 2.18-2.22 (m. 4H). 2.91-2.92 (d. 4H). 3.47-3.67 (m. 11H), 4.17 (s. 1H). 4.72-4.75 (q. 1H). 6.59-6.76 (m. 3H).
Mass (m/z): 474 (M++l)
The following compounds were prepared by following the above procedure
Compound No. 70: 5-Hydroxy-2-{3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl}-hexahydro-isioindole-1,3-dione hydrochloride salt
IR(KBr): 1697.3 cm"1
1H NMR (300 MHz. CDCI3): δ 1.21-2.37 (m. 13H). 2.92 (s, 2H). 3.33 (s. 1H). 3.47-3.69 (m. 7H). 3.93 (s. 3H). 4.20 (s. 1H). 6.93-7.26 (m. 4H)
Mass (m/z): 402 (M++l)
Compound No. 74: 2-(3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl]-5-hydroxy-hexahydro-isoindole-1.3-dione hydrochloride salt
IR(KBr): 1693.7 cm"1
1H NMR (300 MHz. CDCI3): δ 1.66-2.17(m. 16H). 2.90-2.91 (d. 4H), 3.09 (s. 4H). 3.36 (s. 4H).3.55-3.65 (dd.3H). 4.12 (s. 1H). 4.80-4.82 (t. 1H). 6.83-7.00 (m. 4H). Mass (m/z): 456 (M++l)
Compound No. 84: 2-{3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-1.3-dione hydrochloride salt
IR(KBr): 1706 cm"1
Mass(m/z):448(M++l)
Example 14
Preparation of 4-Hydroxy-2-(3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl]-3a.4.7.7a-tetrahydro-isoindole-1,3-dione hydrochloride salt (Compound No. 18)
Step 1: Preparation of 4-Hydroxy-2-{3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl )-3a.4.7.7a-tetrahydro-isoindole-1.3-dione
A solution of l-{3-[4-(2-methoxyphenyl) piperazin -1-yl] propyl) pyrrole-2, 5-dione (lgm. 0.003mole (prepared as in example 7) and 1-acetoxy-l. 3-butadiene (0.34 gm, 0.003mole) in toluene was refluxed for about 3-4 hours. The reaction mixture was concentrated under vacuum and to the thick residue, thus, obtained was added mixture of methanol - hydrochloric acid (5N, 20 ml) at 10 —15 ° C and the reaction mixture was stirred for about 4-6 hours. Solid sodium bicarbonate was added in lots till the mixture became neutral. Inorganics were filtered through celite pad, washed with methanol and concentrated to yield the crude product. It was purified on silica gel (60-120 mesh) column using dichloromethane and methanol as eluent to yield the product. Yield : 0.8gm (88%)
Step 2: Preparation of 4-Hydroxy-2-{3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl}-3a.4,7.7a-tetrahydro-isoindole-l.3-dione hydrochloride salt
The hydrochloride salt of 4-Hydroxy-2-[3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl]-3a.4.7.7a-tetraydro-isoindole-l.3-dione was prepared following the previously disclosed procedure. Yield: 0.6gm (75%) lR(KBr)cm"': 1693.9

1H NMR (300 MHz, CDCl3): δ 2.04 (2H. m). 2.34-2.49 (2H, m). 3.07-3.18 (2H. m), 3.31
(2H.m).3.35-3.65 (10H,m).3.82-3.86 (4H.brs). 6.00-6.05 (2H,d). 6.86-7.20(4H.m).
12.80(lH.brs)
Mass(m/z): 400.4 (M++ 1)
The following compounds were prepared by following above procedure
Compound No. 16: Acetic acid 2-{3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl}-1.3-dioxo-2,3.3a,4.7,7a-hexahydro-lH-inden-4-yl ester hydrochloride salt
IR(KBr): 1736.9. 1696.8 cm"1
1H NMR (300 MHz, CDC13): δ 2.09 (s. 3H). 2.27-2.39 (m, 3H). 2.67-2.72 (d. 1H), 3.07-3.20 (m. 5H). 3.53-3.65 (m, 9H). 3.89 (s. 3H), 5.41 (brs. 1H). 6.06 (brs. 2H). 6.89-6.94 (m, 2H). 7.09-7.11 (m. 2H). 12.83 (brs. 1H). Mass (m/z): 442.4 (M++l)
Compound No. 92: Acetic acid 7-acetoxy-2-{3-[4-(5-fluoro-2-isopropoxy-phenyl)-
piperazin-l-yl]-propyl]-1.3-dioxo-2,3.3a.4.7.7a-hexahydro-lH-isoindol-4-yl ester
hydrochloride salt
IR(KBr): 1700.8 cm"1
1H NMR (300 MHz. CDC13): δ 1.48-1.50 (d. 6H). 2.06 (s. 3H). 3.12 (s. 2H). 3.65 (s. 8H). 3.96 (s, 2H), 4.43 (s, 2H). 4.67 (s. 1H). 5.42 (s, 2H). 6.19 (s. 2H). 6.69-7.61 (m. 3H). Mass (m/z): δ46 (M++l)
Compound No. 94: Acetic acid 7-acetoxy-2-[3-[4-(2-cyclopentyloxy-5-fluoro-phenyl)-piperazin-1 -yl]-propyl j -1.3-dioxo-2.3.3a.4.7.7a-hexahydro-1 H-isoindol-4-ylester hydrochloride salt 1H NMR (300 MHz. CDC13): δ 1.260-1.494 (8H. m). 2.130 (6H. s). 2.213-2.226 (2H. d).
3.136 (2H.s). 3.655 (8H.m).3.938 (2H. s). 4.391 (2H,s). 4.675(lH.s). 5.428(2H.s),
6.190(2H,s).6.961 -7.600(3H.m).
Mass (m/z): δ72 (M++ 1)
Compound No. 96: 2-(3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-4.7-dihydroxy-3a.4.7. 7a-tetrahydro-isoindole-1.3-dione hydrochloride salt
1H NMR (300 MHz, CDCI3): δ 1.19-1.33 (6H, m). 1.70 (2H. s). 2.37 (2H. s). 3.01-3.18 (6H.d). 3.47-3.52 (6H.t).3.72 (2H. s). 4.47-4.49 (lH,d). 4. 75(2H.s). 6.48(2H.s). 6.61-6.80 (3H.m).
.Mass (m/z): 464 (M++ 1)
Compound No. 118: 2-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl)-4.7-dihydroxy-3a.4,7,7a-tetrahydro-isoindole-1.3-dione hydrochloride salt
1H NMR (300 MHz, CDC13): δ 1.25-1.43 (8H. m). 2.31-2.34 (2H. d), 3.06-3.73 (14H. m).
4.49 (lH.s), 4.74 (2H.s).6.49 (2H, s). 6.49-6.80 (3H,m).
Compound No. 144: Acetic acid 7-acetoxy-2-{3-[4-(2-ethoxy-phenyl)-piperazin-l-yl]-propyl)-l,3-dioxo-2.3.3a,4.7.7a-hexahydro-lH-isoindol-4-yl ester hydrochloride salt
IR(KBr): 1731.9 cm"1
Mass (m/z): 514 (M++l)
Compound No. 146: 2-j3-[4-(2-Ethoxy-phenyl)-piperazin-l-yl]-propyl)-4.7-dihydroxy-3a.4.7.7a-tetrahydro-isoindole-1.3-dione hydrochloride salt
IR(KBr): 1704.3 cm'1
Mass (m/z): 430 (M++l)
Compound No. 150: Acetic acid 7-acetoxy-2-(3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl)-l,3-dioxo-2,3.3a.4.7.7a-hexahydro-lH-isoindol-4-yl ester hydrochloride salt
IR(KBr): 1693 cm"1
Mass (m/z): 500 (M++l)
Compound No. 154: 4.7-Dihydroxy-2-{3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl)-3a.4.7,7a-tetrahydro-isoindole-1.3-dione hydrochloride salt
IR(KBr): 1695.8 cm"1
Mass (m/z): 416 (M++l)
Compound No. 156: Acetic acid 7-acetoxy-2-[3-[4-(2-cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl)-1.3-dioxo-2.3.3a.4.7.7a-hexahydro-lH-isoindol-4-yl ester hydrochloride salt IR(KBr): 1704 cm"1
Mass (m/z) : 554(M++1)
Compound No. 160: 2-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl]-4.7-dihydroxy-3a.4.7.7a-tetrahydro-isoindole-l .3-dione hydrochloride salt
IR(KBr): 1713 cm"1
Mass (m/z): 470 (M++l)
Example 15
Preparation of l-!3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-2-hydroxy-propyl}-3-cyclopropylamino-4-methyl-pyrrolidine-2.5-dione hydrochloride salt ( Compound No. 38)
Step 1: Preparation of 2-{3-[4-(2-cyclopentyloxy-phenyl)-piperazine-l-yl]-2-hydroxy-propyl) -isoindole-1,3-dione
A mixture of 2-oxiranylmethyl-isoindole-1.3-dione (2.0 gm. 0.0098mole) ( prepared as in example 1) and 2-cyclopentyloxy phenyl piperazine (2.6gm.0.0098mol) in alcohol (20 ml) was refluxed for about 4-5 hours. Reaction mixture was concentrated on buchi and resulting mass was purified by column chromatography. Yield: 4.0gm (86%) Step 2: Preparation of l-amino-3-[4-(2-cyclopentyloxy-phenyl)-piperazin-l-ylj-propan-2-ol
To a solution of 2-{3-[4-(2-cyclopentyloxy-phenyl)-piperazine-l-yl]-2-hydroxy-
propyl)-isoindole-1,3-dione (1.0g, 0.0022 mol) in alcohol (15 ml) was added hydrazine
hydrate (0.134g. 0.0026 mol) and reaction mixture refluxed for about 1 hour. Reaction
mixture was cooled, solid thus precipitated was filtered, washed with chilled alcohol; filtrate
thus obtained was concentrated to yield the desired product.
Yield: 0.64gm (90%)
Step 3: Preparation of l-{3-[4-(2-cyclopentyloxy-phenyl)-piperazin-l-yl]-2-hydroxy-propyl ] -3-methyl-pyrrole-2.5-dione
A mixture of l-amino-3-[4-(2-cyclopentyloxy-phenyl)-piperazin-l-yl]-propan-2-ol
(0.5gm. 0.0016 mol) and citaconic anhydride (0.18gm. 0.0016 mol) in toluene was refluxed
for about 1 hour. Reaction mixture was concentrated on buchi and thick residue thus
obtained was purified by column chromatography.
Yield: 0.52gm ( 80%)
Step 4: Preparation of l-{3-[4-(2-cyclopentyloxy-phenyl)-piperazin-l-yl]-2-hydroxy-propyl)-3-cyclopropylamino-4-methyl-pyrrolidine-2.5-dione
To a solution of l-{3-[4-(2-cyclopentyloxy-phenyl)-piperazin-l-yl]-2-hydroxy-propyl}-3-methyl-pyrrole-2.5-dione (0.5gm. 0.0012 mol) in methanol (15 ml) was added cyclopropylamine (0.083gm. 0.0015 mol) and reaction mixture was stirred at room temperature for about 10-12 hours. Reaction mixture was concentrated; the resulting residue was concentrated and purified by column chromatography.
Yield: 0.4gm ( 70%)
Step 5: Preparation of l-[3-[4-(2-cyclopentyloxy-phenyl)-piperazin-l-yl]-2-hydroxy-propyl} -3-cyclopropylamino-4-methyl-pyrrolidine-2.5-dione hydrochloride salt
The hydrochloride salt of l-{3-[4-(2-cyclopentyloxy-phenyl)-piperazin-l-yl]-2-hydroxy-propyl}-3-cyclopropylamino-4-methyl-pyrrolidine-2.5-dione was prepared following the previously disclosed procedure. Yield: 0.35gm (85%) IR(KBr): 1699.6 cm"1
Mass (m/z): 471 (M++l)
The following compounds were prepared by following above procedure
Compound No. 40: l-(3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-hydroxy-propyl)-3-cyclopropylamino-4-methyl-pyrrolidine-2.5-dione hydrochloride salt
IR(KBr): 1682.7 cm"1
Mass (m/z): 489 (M++l)
Compound No. 42: l-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-hydroxy-propyl)-3-methyl-4-methylamino-pyrrolidine-2,5-dione hydrochloride salt
IR(KBr): 1693 cm"1
Mass (m/z): 489 (M++l)
Compound No. 46: l-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-hydroxy-propylJ -3-methyl-4-methylamino-pyrrolidine-2.5-dione hydrochloride salt
IR(KBr): 1704.6 cm"1
Mass (m/z): 463 (M++l)
m.p. : 176-181°C
Compound No. 110: 3-Cyclopropylaminomethyi-l-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-propyl)-4-methyl-pyrrolidine-2.5-dione hydrochloride salt
IR(KBr): 1657 cm"1
Mass (m/z): 417 (M++l)
Compound No. 112: 3-Cyclopropylaminomethyl-l-j2-hydroxy-3-[4-(2-mefhoxy-phenyl)-piperazin-1 -yl]-propyl j -4-methyl-pyrrolidine-2,5-dione hydrochloride salt
IR(KBr): 1625 cm"1
Mass (m/z): 417 (M++l)
Compound No. 114: 3-Cyclobutylaminomethyl-l-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propylj -pyrrolidine-2.5-dione hydrochloride salt
IR(KBr): 1704 cm"1
Mass (m/z): 431 (M++l)
Example 16
Preparation of l-{2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl}-3-methyl-pyrrolidine-2.5-dione hydrochloride salt ( Compound No. 116)
Step 1: Preparation of l-{2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl]-3-methyl-pyrroIidine-2.5-dione
To a clear solution of l-{2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-
propyl}-3-methyl-pyrrole-2.5-dione (0.8gm. 0.0022 mol) methanol (15 ml) was added of
Pd-C(0.4gm) and reaction mixture was hydrogenated at 40-45 psi for 1 hour. Reaction
mixture was filtered through celite pad: washed with methanol; filtrate was concentrated to
yield the desired product.
Yield: 0.8gm (99%)
Step 2: Preparation of l-(2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl)-3-methyl-pyrrolidine-2.5-dione hydrochloride salt
The hydrochloride salt of l-{2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-
propyl!-3-methyl-pyrrolidine-2.5-dione was prepared following the previously disclosed
procedure.
Yield: 0.72g (90%)
IR(KBr): 1693 cm"1
Mass (m/z): 362(M++1)
The following compound was prepared similarly
Compound No. 158: 2-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl)-4.7-dihydroxy-hexahydro-isoindole-l,3-dione hydrochloride salt
IR(KBr): 1703 cm"1
Mass (m/z): 472 (M++l)
Example 17
Preparation of 5-Fluoro-6-hydroxy-2-[2-hydroxy-3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-l,3-dione hydrochloride salt( Compound No. 62)
Step 1: Preparation of 2-{2-hydroxy-3[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl]-3a,4.7.7a-tetrahydro-isoindole-1.3-dione
A mixture of l-amino-3-[4-(2-isopropoxyphenyl)piperazin-l-yl]propan-2-ol (0.7 gm.
0.0023 mole) and tetrahydrophthalic anhydride (0.36gm. 0.0024 mol) in toluene (15 ml) was
refluxed for about 1 hour. The reaction mixture was concentrated and crude product was
purified anhydrous column chromatography.
Yield :0.9gm (90%)
Step 2: Preparation of 5,6-dihydroxy- 2-{2-hydroxy-3[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl) -hexahydro-isoindole-1,3-dione
To a solution of 2-{2-hydroxy-3[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-
3a.4.7.7a-tetrahydro-isoindole-l.3-dione (1.0gm. 0.0023mole) in ethanol (20 ml) was added
potassium permanganate solution (0.44gm. 0.0028 mole) ad 0-5°C. The reaction mixture
was stirred for about 6-8 hours. After completion of the reaction, it was filtered through
celite pad; washed with ethanol; combined filtrate was concentrated; crude product was
purified by column purification.
Yield: 0.54gm. 50%
Step 3: Preparation of 5-Fluoro-6-hydroxy-2-{2-hydroxy-3-[4-(2-isopropoxy-phenyl)-piperazin-1-yl]-propyl) -hexahydro-isoindole-1,3-dione
To a solution of 5.6-dihydroxy- 2-[2-hydroxy-3[4-(2-isopropoxy-phenyl)-piperazin-
l-yl]-propyl}-hexahydro-isoindole-1.3-dione (1.0gm. 0.0022mole) in dichloromethane (10
ml) was added diethylaminosulphurtrifluoride (0.422gm. 0.0026mole) at 0-5°C and reaction
mixture stirred for 2-3 hours. Reaction mixture was quenched by adding water (20 ml) to it;
extracted with dichloromethane; organic layer was concentrated; the crude product was
purified by column separation.
Yield: .25gm (25%)
Step 4: Preparation of 5-Fluoro-6-hydroxy-2-{2-hydroxy-3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl J -hexahydro-isoindole-1,3-dione hydrochloride salt
The hydrochloride salt of 2-(3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl)-4,7-dihydroxy-hexahydro-isoindole-l, 3-dione was prepared following the previously disclosed procedure. Yield: 0.22g (90%) IR(KBr): 1699.2 cm"'
Mass (m/z): 464 (M++l) Pharmacological testing
Receptor Binding Assay
Receptor binding assays were performed using native α1 adrenoceptors. The affinity of different compounds for α1a and α1b adrenoceptor subtypes was evaluated by studing their ability to displace specific [JH]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 "Pochard 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 hydrochloric acid 50 mM. sodium chloride 100 mM, 10 mM ethylene diamine tetra acetic acid pH 7.4). The tissues were homogenized in 10 volumes of buffer (Tris HC1 50 mM. NaCl 100 mM. EDTA 10 mM. pH 7.4). The homogenate was filtered through two layers of wet guaze and filtrate was centrifuged at 500g for 10 min. The supernatant was subsequently centrifuged at 40, OOOg for 45 min. The pellet thus obtained was resuspended in the same volume of assay buffer (Tris HC1 50 mM, EDTA 5 mM. pH 7.4) and were stored at -70 °C until the time of assay.
The membrane homogenates (150-250 µg protein) were incubated in 250 ul of assay buffer (Tris HC1 50 mM. EDTA 5 mM. pH 7.4) at 24-25 "C for I hour. Non-specific binding was determined in the presence of 300 nM prazosin. The incubation was terminated by vaccum filtration over GF/B fibre filters. The filters were then washed with ice cold 50 mM Tris HC1 buffer (pH 7.4). The filtermats were dried and bounded radioactivity retained on filters was counted. The IC50 and Kd were estimated by using the non-linear curve-fitting program using G pad prism software. The value of inhibition constant Ki was calculated from competitive binding studies by using Cheng and Prusoff equation (Cheng and Prusoff.
Biochem Pharmacol, 1973. 22:3099-3108). Ki = IC50 /(1+L/Kd) where L is the
concentration of [3H] prazosin used in the particular experiment. The pKi value for aia is 6.4
or more and for α1b is less than 5 or more.
In vitro functional studies
In vitro oi|a Adrenoceptor selectivity
In order to study selectivity of action of the present compounds towards different α1a adrenoreceptor subtypes, the ability of these compounds to antagonize α1a adrenoreceptor agonist induced contractile response of aorta (α1d), prostate (α1a) and spleen ( α1b,) was studied. Aorta, prostate and spleen tissue were isolated from thipentane anaesthetized (* 300 mg/Kg) male wistar rats. Isolated tissues were mounted in organ bath containing Krebs Henseleit buffer of the following composition (mM): sodium chloride (NaCl) 118; potassium chloride (KG) 4.7; calcium chloride (CaCl2) 2.5; magnesium sulphate hepta hydrate (MgSO4. 7H2O) 1.2; sodium bicarbonate (NaHCO3) 25; potassium dihydrogen phosphate (KH2PO4) 1.2; glucose 11.1. Buffer was maintained at 37 C and aerated with a mixture of 95% oxygen (O2) and 5% carbon dioxide (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 hour. At the end of equilibration period, concentration response curves to norepinephrine (aorta) and phenylepinephrine (spleen and prostate) were obtained in the absence and presence of the tested compound (at concentration of 0.1. 1 and 10 µM). The pKb value for α1a is 8.7 or more, for α1b is 7.44 or more and for α1d is 8.23 or more.

We claim:
1. A compound having the structure of Formula I. as shown in the accompanied drawings, and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers. N-oxides. prodrugs, polymorphs or metabolites wherein: A represents
(Formula Removed)
wherein:
R2. R3. R4 and R5 independently represent
o hydrogen
o alkyl
o phenyl R6 represents
o hydrogen
o alkyl
o phenyl
o hydroxy
o alkoxy — represents optional single bond R7 and R8 independently represent
o hydrogen
o alkyl
o z=CH2 (wherein ■ is the point of attachment)
o alkynyl
o cycloalkyl
o halogen
o hydroxy
o aryl
o acetoxy
o heterocycle
o R12-Q-(CH2)m- wherein m represents an integer 0 to 3
R12 represents
• alkyl
• alkenyl
• alkynyl
• cycloalkyl
• cyclo alkenyl
• aryl
• heterocycle Q represents

• oxygen
• sulphur
• carbonyl
• carboxylic
• | wherein
R|3
W represents
♦ no atom
♦ carbonyl
♦ carboxylic
♦ amide
R13 represents
♦ hydrogen
♦ alkyl
♦ cycloalkyl
♦ aryl
♦ heterocycle
R7 and R8 together represent o cycloalkyl o cyclo alkenyl o bicyclic alkyl
o bicyclic alkenyl
o aryl
o heterocycle
o wherein Z is CO or SO
R9 and R10 independently represent
o hydrogen
o hydroxy
o alkoxy
o acetyl
o acetyloxy R11 represents
o hydrogen
o alkyl
o alkenyl
o alkynyl
o cycloalkyl
o aryl
o heterocycle X represents -CO. -CS or -CHY wherein Y represents
• hydrogen
• hydroxy
• halogen
• alkoxy
• haloalkoxy R represents
o alkyl
o alkenyl
o alkynyl
o cycloalkyl
o aryl
o heterocycle, with the proviso
that when A is (Formula Removed)
(a) ,X is -CH2- and R11 is hydrogen then R7 is hydrogen or s=CH2 or alkyl with the further provisio that when R7 is alkyl and R8 is R 12 NH-, then R12 is substituted alkyl wherein the substituents are selected from aryl or heterocyclyl
when A is (Formula Removed)
(b) ,and X is -CH2-. R7 = R8 - R9 =R10 hydrogen or halogen.
2. A compound according to claim 1 wherein A(Formula Removed)
wherein R7, R8 ,R9 .R10 and --
are the same as defined in claim 1.
3.A compound according to claim 1 wherein A is selected from:
4. A compound according to claim 1 wherein A is K wherein R2. R3. R4. R5 and R6 are
the same as defined in claim 1. (Formula Removed)

5.. A compound according to claim 1 wherein A is
6. A compound according to claim 1 wherein A iswherein R6. R7 and R8 are the same as defined in claim1.
7. A compound according to claim 1 wherein A is
(Formula Removed)
8. A compound according to claim 1 wherein A is(Formula Removed)
wherein R7. R8. R11 andare the
same as defined in claim 1.
9. A compound according to claim 1 wherein A is selected from(Formula Removed)

10. A compound according to claim 1 wherein X is selected from -CHOH. CO. -CH2-. -CHF.
11. A compound according to claim 1 wherein R is phenyl optionally substituted wherein optional substituent(s) is/ are selected from nitro. alkyl. alkoxy. halogen and haloalkoxy.
12. A compound according to claim 1 wherein R is selected from 2-methoxy phenyl. 3-fluoro-2-methoxy phenyl, 5-fluoro-2-methoxy phenyl. 4-fluoro-2-methoxyphenyl. 2-methoxy-5-methyl phenyl. 2-n-propoxyphenyl. 5-fluoro2-n-propoxyphenyl. 2-ethoxy phenyl. 2-isopropoxy phenyl. 4-fluoro-2-isopropoxyphenyl, 4-nitro-2-isopropoxyphenyl. 3-fluoro-2-isopropoxy phenyl. 5-fluoro-2-isopropoxy phenyl. 2-cyclopentoxy-5-fluoro phenyl. 2-cyclopentoxy phenyl. O-tolyl, 2-trifluoroethoxy phenyl. 5-fluoro-2-trifluoromethoxy phenyl and 2-(2.2.3.3-tetrafluoropropoxy) phenyl.
13. A compound, which is:
-2-2-Hydroxy-3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propylj-hexahydro-isoindole-1.3-dione (Compound No. 1)
-2- (3-[4-(2-Isopropoxy-phenyl)-piperazin-1 -yl]-2-oxo-propyl} -hexahydroisoindole-1.3-dione (Compound No. 3)
-2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-2-oxo-propyl)-3a.4.7.7a-tetrahydro-isoindole-1.3-dione (Compound No. 5)
-2-((S)-2-Hydroxy-3-(4-[2-(2.2.2-trifluoro-ethoxy)-phenyl]-piperazin-l-ylj-propyl)-3a.4.7.7a-tetrahydro-isoindole-1.3-dione (Compound No. 7)
-2-(2-Hydroxy-3- (4-[2-(2,2.3.3-tetrafluoro-propoxy)-phenyl]-piperazin-1 -yl J -propyl)-3a.4,7.7a-tetrahydro-isoindole-l,3-dione (Compound No. 9)
-2-{2-Hydroxy-3-[4-(2-isopropoxy-4-nitro-phenyl)-piperazin-l-yl]-propylj-3a.4,7,7a-tetrahydro-isoindole-1.3-dione (Compound No. 11)
-2-}2-Fluoro-3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl)-3a,4.7.7a-tetrahydro-isoindole-1.3-dione (Compound No. 13)
-Acetic acid 2-{3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl)-1.3-dioxo-2.3,3a.4,7.7a-hexahydro-lH-inden-4-yl ester (Compound No. 15)
-4-Hydroxy-2-{3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propylj-3a,4,7.7a-tetrahydro-isoindole-1.3-dione (Compound No. 17)
-2-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-2-oxo-propylj-3a.4.7.7a-tetrahydro-isoindole-1.3-dione (Compound No. 19)
-2-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-2-oxo-propyl)-3a,4.7.7a-tetrahydro-isoindole-l,3-dione (Compound No. 21)
-2-{2-Oxo-3-[4-(2-propoxy-phenyl)-piperazin-l-yl]-propylj-3a.4.7.7a-tetrahydro-isoindole-1.3-dione (Compound No. 22)
-2- ( 3-[4-(4-Fluoro-2-isopropoxy-phenyl )-piperazin-1 -yl]-2-oxo-propyl} -3a.4.7.7a-tetrahydro-isoindole-l,3-dione (Compound No. 24)
-2-{3-[4-(2-lsopropoxy-phenyl)-piperazin-l-yl]-2-oxo-propyl)-isoindole-1.3-dione (Compound No. 26)
-2-(2-Oxo-3-[4-[2-(2,2.2-tritluoro-ethoxy)-phenyl]-piperazin-l-yl}-propyl)-3a.4.7.7a-tetrahydro-isoindole-1.3-dione (Compound No. 28)
-6-(3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-2-oxo-hexahydro-1.3-dioxa-2-lambda*4*-thia-6-aza-s-indacene-5,7-dione (Compound No. 30)
-1 - (3-[4-(2-Cyclopentyloxy-phenyl )-piperazin-1 -yl]-2-hydroxy-propyl}-3-cyclopropylamino-4-methyl-pyrrolidine-2.5-dione ( Compound No. 37)
-l-{3-[4-(2-Cyclopentyloxy-5-fluoro-phen>i)-piperazin-l-yl]-2-hydroxy-propylj-3-cyclopropylamino-4-methyl-pyrrolidine-2.5-dione( Compound No. 39)
-1 - [ 3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl )-piperazin-1 -yl]-2-hydroxy-propyl} -3-cyclopropylaminomethyl-pyrrolidine-2.5-dione( Compound No. 41)
-2-{3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl)-5.6-dihydroxy-hexahydro-isoindole-l,3-dione( Compound No. 43)
-l-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-hydroxy-propyI}-3-methyl-4-methylamino-pyrrolidine-2.5-dione( Compound No. 45)
-l-{3-[4-(2-Methoxy-5-methyl-phenyl)-piperazin-l-yl]-propylj-piperidine-2.6-dione( Compound No. 47)
-5.6-Dihydroxy-2-[3-[4-(2-methoxy-5-methyl-phenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1.3-dione( Compound No. 49)
-l-(3-{4-[5-Fluoro-2-(2.2,2-trifluoro-ethoxy)-phenyl]-piperazin-l-ylj-propyl)-piperidine-2.6-dione( Compound No. 51)
-2-!3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl)-5.6-dihydroxy-hexahydro-isoindole-1.3-dione( Compound No. 53)
-3- {3-[4-(3-Fluoro-2-methoxy-phenyl)-piperazin-1 -yl]-propyl)-1 -methyl-3-aza-bicyclo [3.1.0]hexane-2.4-dione( Compound No. 55)
-3-{3-[4-(5-Fluoro-2-methoxy-phenyl)-piperazin-l-yl]-propyl]-l-methyl-3-aza-bicyclo [3.1.0]hexane-2.4-dione( Compound No. 57)
-3- {3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-1 -yl]-propyl j -1 -methyl-3-aza-bicyclo [3.1.0]hexane-2.4-dione( Compound No. 59)
-5-Fluoro-6-hydroxy-2-J2-hydroxy-3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1.3-dione( Compound No. 61)
-3- {3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-1 -yl]-propyl}-1 -methyl-3-aza-bicyclo [3.1.0]hexane-2.4-dione( Compound No. 63)
-5-Fluoro-6-hydroxy-2-(3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl{-hexahydro-isoindole-l,3-dione( Compound No. 65)
-2-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-1.3-dione( Compound No. 67)
-5-Hydroxy-2-{3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl)-hexahydro-isioindole-1.3-dione( Compound No. 69)
-2-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propylj-5-hydroxy-hexahydro-isoindole-l,3-dione( Compound No. 71)
-2- (3-[4-(2-Cyclopentyloxy-phenyl )-piperazin-1 -yll]-propyl } -5-hydroxy-hexahydro-isoindole-1.3-dione( Compound No. 73)
-2-(3-[4-(2-Cyclopentyloxy-phenyI)-piperazin-l-yI]-2-oxo-propylj-5,6-dihydroxy-hexahydro-isoindole-l,3-dione( Compound No. 75)
-2-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-oxo-propyl)-3a.4.7,7a-tetrahydro-isoindole-l,3-dione( Compound No. 77)
-2- (3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-1 -yl]-2-hydroxy-propyl j -hexahydro-isoindole-1.3-dione( Compound No. 79)
-5-Fluoro-2- {3-[4-(5-fluoro-2-methoxy-phenyl )-piperazin-1 -yl]-propyl} -6-hydroxy-hexahydro-isoindole-1.3-dione( Compound No. 81)
-2-[3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindo!e-l,3-dione( Compound No. 83)
-5-Fluoro-2-{3-[4-(5-fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-1.3-dione( Compound No. 85)
-l-!3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-2-hydroxy-propyl!-piperidine-2.6-dione( Compound No. 87)
-l-(3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-hydroxy-propyl}-piperidine-2.6-dione( Compound No. 89)
-Acetic acid 7-acetoxy-2- {3-[4-(5-fluoro-2-isopropoxy-phenyl)-piperazin-1 -yl]-propyl j -1.3-dioxo-2.3.3a.4.7,7a-hexahydro-lH-isoindol-4-yl ester( Compound No. 91)
-Acetic acid 7-acetoxy-2- (3-[4-(2-cyclopentyloxy-5-fluoro-phenyl)-piperazin-l -yl]-propyl]-1.3-dioxo-2,3,3a.4.7.7a-hexahydro-lH-isoindol-4-ylester( Compound No. 93)
-2-[3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-4.7-dihydroxy-3a,4.7, 7a-tetrahydro-isoindole-l,3-dione( Compound No. 95)
-l-(3-[4-(5-Fluoro-2-propoxy-phenyl)-piperazin-l-yl]-propylj-piperidine-2.6-dione( Compound No. 97)
-l-(3-[4-(5-Fluoro-2-propoxy-phenyl)-piperazin-l-yl]-2-hydroxy-propyl)-piperidine-2.6-dione( Compound No. 99)
-2-(3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propylj-5.6-dihydroxy-hexahydro-isoindole-l,3-dione( Compound No. 101)
-2-{3-[4-(5-Fluoro-2-propoxy-phenyl)-piperazin-l-yl]-propyl}-5.6-dihydroxy-hexahydi"o-isoindole-l,3-dione( Compound No. 103)
-2-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl)-5-fluoro-6-hydroxy-hexahydro-isoindole-l,3-dione( Compound No. 105)
-2-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-1.3-dione( Compound No. 107)
-3-Cyclopropylaminomethyl-1 - {2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1 -yl]-propyl}-pyrrolidine-2,5-dione( Compound No. 109)
-3-Cyclopropylaminomethyl-l-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl}-4-methyl-pyrrolidine-2.5-dione( Compound No. 1ll)
-3-Cyclobutylaminomethyl-l-[2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propylj-pyrrolidine-2.5-dione( Compound No. 113)
-l-{2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl)-3-methyl-pyrrolidine-2.5-dione( Compound No. 115)
-2- J 3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-1 -yl]-propyl}-4.7-dihydroxy-3a.4.7.7a-tetrahydro-isoindole-1.3-dione ( Compound No. 117)
-2-(3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-oxo-propylj-5.6-dihydroxy-hexahydro-isoindole-l,3-dione( Compound No. 119)
-2-{3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-2-oxo-propyl}-5.6-dihydroxy-hexahydro-isoindole-l,3-dione( Compound No. 121)
-2-{3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5.6-dihydroxy-hexahydro-isoindole-1.3-dione( Compound No. 123)
-2- {3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-1 -yl]-2-hydroxy-propyl} -5.6-dihydroxy-hexahydro-isoindole-l,3-dione( Compound No. 125)
-1- {3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l -yl] -propyl j-piperidine-2.6-dione( Compound No. 127)
-1 - J 3-[4-(3-Fluoro-2-isopropoxy-phenyl )-piperazin-1 -yl]-propyl j -piperidine-2.6-dione( Compound No. 129)
-l-[3-[4-(3-Fluoro-2-methoxy-phenyl)-piperazin-l-yl]-propylj-piperidine-2,6-dione( Compound No. 131)
-l-{3-[4-(3-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propylj-3-methylene-pyrrolidine-2.5-dione( Compound No. 133)
-l-{3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl)-3-methylene-pyrrolidine-2.5-dione( Compound No. 135)
-l-(3-[4-(5-Fluoro-2-(2,2.3.3-tetrafluoro-propoxy)-phenyl]-piperazin-l-ylj-propyl)-piperidine-2.6-dione( Compound No. 137)
-l-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl)-3-methyl-4-(l-phenyl-ethylamino)-pyrrolidine-2.5-dione( Compound No. 139)
-l-(3-[4-(5-Fluoro-2-trifluoromedioxy-phenyl)-piperazin-l-yl]-propyl)-piperidine-2,6-dione( Compound No. 141)
-Acetic acid 7-acetoxy-2-(3-[4-(2-ethoxy-phenyl)-piperazin-l-yl]-propyl)-l,3-dioxo-2.3.3a.4.7,7a-hexahydro-lH-isoindol-4-yl ester( Compound No. 143)
-2-{3-[4-(2-Edioxy-phenyl)-piperazin-l-yl]-propyl)-4,7-dihydroxy-3a.4.7.7a-tetrahydro-isoindole-1.3-dione( Compound No. 145)
-3-Cyclopropylamino-l-S3-[4-(2-ethoxy-phenyl)-piperazin-l-yl]-propyl}-pyrrolidine-2.5-dione( Compound No. 147)
-Acetic acid 7-acetoxy-2- j3-[4-(2-methoxy-phenyl)-piperazin-l -yl]-propyl)-l ,3-dioxo-2.3.3a.4.7,7a-hexahydro-lH-isoindol-4-yl ester( Compound No. 149)
-l-(3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl)-3-cyclopropylamino-pyrrolidine-2.5-dione( Compound No. 151)
-4.7-Dihydroxy-2-{3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl)-3a,4.7,7a-tetrahydro-isoindole-1.3-dione( Compound No. 153)
-Acetic acid 7-acetoxy-2- {3-[4-(2-cyclopentyloxy-phenyl)-piperazin-1 -yl]-propyl)-1.3-dioxo-2.3,3a.4.7.7a-hexahydro-lH-isoindol-4-yl ester( Compound No. 155)
-2-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl)-4.7-dihydroxy-hexahydro-isoindole-1.3-dione( Compound No. 157)
-2-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propylj-4,7-dihydroxy-3a.4.7.7a-tetrahydro-isoindole-1.3-dione( Compound No. 159)
-3-Methylene-l-[3-(4-0-tolyl-piperazin-l-yl)-prop>i]-pyiTolidine-2.5-dione(Compound No. 161)
-l-[3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl)-3-methyl-4-[(thiophen-2-ylmethyl)-amino]-pyrrolidine-2.5-dione( Compound No. 163)
-l-(3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl}-3-methylene-pyrrolidine-2.5-dione( Compound No. 165)
-l-(3-[4-(5-Fluoro-2-methoxy-phenyl)-piperazin-l-yl]-propyli-3.3.4-trimethyl-pyrrolidine-2.5-dione( Compound No. 167)
-1-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl}-piperidine-2.6-dione( Compound No. 169)
and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates.
enantiomers, diastereomers, N-oxides, prodrugs, polymorphs or metabolites.
14. A compound, which is:
-2-(2-Hydroxy-3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propylj-hexahydro-isoindole-1.3-dione hydrochloride salt (Compound No. 2)
-2-(3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-2-oxo-propyl]-hexahydroisoindole-1.3-dione hydrochloride salt (Compound No. 4)
-2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-2-oxo-propyl)-3a,4.7,7a-tetrahydro-isoindole-1.3-dione hydrochloride salt (Compound No. 6)
-2-{(S)-2-Hydroxy-3-{4-[2-(2.2.2-trifluoro-ethoxy)-phenyl]-piperazin-l-yl)-propyl)-3a.4.7.7a-tetrahydro-isoindole-1.3-dione hydrochloride salt (Compound No. 8)
-2-(2-Hydroxy-3-(4-[2-(2.2.3.3-tetrafluoro-propoxy)-phenyl]-piperazin-l-yl!-propyl )-3a.4.7.7a-tetrahydro-isoindole-1.3-dione hydrochloride salt (Compound No. 10)
-2- (2-Hydroxy-3-[4-(2-isopropoxy-4-nitro-phenyl )-piperazin-1 -yl]-propyl j -3a.4.7.7a-tetrahydro-isoindole-1.3-dione hydrochloride salt (Compound No. 12)
-2- [2-Fluoro-3-[4-(2-isopropoxy-phenyl)-piperazin-l -yl]-propyl}-3a.4.7,7a-tetrahydro-isoindole-1.3-dione hydrochloride salt (Compound No. 14)
-Acetic acid 2-{3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl)-1.3-dioxo-2.3.3a.4.7.7a-hexahydro-lH-inden-4-yl ester hydrochloride salt (Compound No. 16)
-4-Hydroxy-2-(3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propylj-3a.4.7,7a-tetrahydro-isoindole-1.3-dione hydrochloride salt (Compound No. 18)
-2- (3-[4-(2-Methoxy-phenyl)-piperazin-1 -yl}-2-oxo-propyl} -3a,4.7.7a-tetrahydro-isoindole-l,3-dione hydrochloride salt (Compound No. 20)
-2-(2-0x0-3- [4-(2-propoxy-phenyl)-piperazin-l-yl]-propyl}-3a. 4.7.7a-tetrahydro-isoindole-1. 3-dione hydrochloride salt (Compound No. 23)
-2-(3-[4-(4-Fluoro-2-isopropoxy-phenyl)-piperazin-l-ylJ-2-oxo-propyl}-3a,4.7.7a-tetrahydro-isoindole-l,3-dione hydrochloride salt (Compound No. 25)
-2- (3-[4-(2-Isopropoxy-phenyl)-piperazin-1 -yl]-2-oxo-propyl) -isoindole-1,3-dione hydrochloride salt (Compound No. 27)
-2-(2-Oxo-3-{4-[2-(2,2,2-trifluoro-ethoxy)-phenyl]-piperazin-l-ylj-propyl)-3a.4,7,7a-tetrahydro-isoindole-1,3-dione hydrochloride salt (Compound No. 29)
-6- (3-[4-(2-Isopropoxy-phenyl)-piperazin-1 -yl]-propyl}-2-oxo-hexahydro-l ,3-dioxa-2-lambda*4*-thia-6-aza-s-indacene-5,7-dione hydrochloride salt (Compound No. 31)
-1 - {3-[4-( 2-Cyclopentyloxy-phenyl)-piperazin-1 -yl]-2-hydroxy-propyl j -3-cyclopropylamino-4-methyl-pyrrolidine-2.5-dione hydrochloride salt ( Compound No. 38)
-1 - (3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-1 -yl]-2-hydroxy-propyl) -3-cyclopropylamino-4-methyl-pyrrolidine-2,5-dione hydrochloride salt( Compound No. 40)
-l-p-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-hydroxy-propyl}-3-cyclopropylaminomethyl-pyrrolidine-2.5-dione hydrochloride salt( Compound No. 42)
-2-{3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl)-5.6-dihydroxy-hexahydro-isoindole-1.3-dione hydrochloride salt( Compound No. 44)
-l-(3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-hydroxy-propyl]-3-methyl-4-methylamino-pyrrolidine-2,5-dione hydrochloride salt( Compound No. 46)
-1 - (3-[4-(2-Methoxy-5-methyl-phenyl)-piperazin-1-yl]-propyl)-piperidine-2.6-dione hydrochloride salt( Compound No. 48)
-5.6-Dihydroxy-2-{3-[4-(2-methoxy-5-methyl-phenyl)-piperazin-l-yl]-propyl]-hexahydro-isoindole-1.3-dione hydrochloride salt( Compound No. 50)
-l-(3- j4-[5-Fluoro-2-(2.2.2-trifluoro-ethoxy)-phenyl]-piperazin-l-ylj-propyl )-piperidine-2.6-dione hydrochloride salt( Compound No. 52)
-2-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl}-5.6-dihydroxy-hexahydro-isoindole-1,3-dione hydrochloride salt( Compound No. 54)
-3-!3-[4-(3-Fluoro-2-methoxy-phenyl)-piperazin-l-yl]-propyl)-l-methyl-3-aza-bicyclo [3.1.0]hexane-2.4-dione hydrochloride salt( Compound No. 56)
-3-{3-[4-(5-Fluoro-2-methoxy-phenyl)-piperazin-l-yl]-propyl}-l-methyl-3-aza-bicyclo [3.1.0]hexane-2.4-dione hydrochloride salt( Compound No. 58)
-3-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl}-l-methyl-3-aza-bicyclo [3.1.0]hexane-2.4-dione hydrochloride salt( Compound No. 60)
-5-Fluoro-6-hydroxy-2-{2-hydroxy-3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-l,3-dione hydrochloride salt( Compound No. 62)
-3-(3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl)-l-methyl-3-aza-bicyclo [3.1.0]hexane-2.4-dione hydrochloride salt( Compound No. 64)
-5-Fluoro-6-hydroxy-2-{3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1.3-dione hydrochloride salt( Compound No. 66)
-2-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yi]-2-hydroxy-propyl}-hexahydro-isoindole-l,3-dione hydrochloride salt( Compound No. 68)
-5-Hydroxy-2-(3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl}-hexahydro-isioindole-1.3-dione hydrochloride salt( Compound No. 70)
-2- (3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-1 -yl]-propyl) -5-hydroxy-hexahydro-isoindole-1.3-dione hydrochloride salt( Compound No. 72)
-2- {3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l -yl]-propyl ] -5-hydroxy-hexahydro-isoindole-l,3-dione hydrochloride salt( Compound No. 74)
-2-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-1.3-dione hydrochloride salt( Compound No. 76)
-2-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-oxo-propyl)-3a.4.7,7a-tetrahydro-isoindole-1.3-dione hydrochloride salt( Compound No. 78)
-2-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-l,3-dione hydrochloride salt( Compound No. 80)
-5-Fluoro-2-[3-[4-(5-fluoro-2-methoxy-phenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-1.3-dione hydrochloride salt( Compound No. 82)
-2-{3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-ylJ-propyl!-5-hydroxy-hexahydro-isoindole-1.3-dione hydrochloride salt( Compound No. 84)
-5-Fluoro-2-[3-[4-(5-fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-1.3-dione hydrochloride salt( Compound No. 86)
-l-{3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-ylJ-2-hydroxy-propyl}-piperidine-2.6-dione hydrochloride salt( Compound No. 88)
-l-(3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-hydroxy-propyl}-piperidine-2.6-dione hydrochloride salt( Compound No. 90)
-Acetic acid 7-acetoxy-2- (3-[4-(5-fIuoro-2-isopropoxy-phenyl)-piperazin-l -yl]-propyl j -1.3-dioxo-23.3a 4,7,7a-hexahydro-lH-isoindol-4-yl ester hydrochloride salt( Compound
No. 92)
-Acetic acid 7-acetoxy-2-{3-[4-(2-cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl} -1,3-dioxo-2,3.3a.4,7.7a-hexahydro-1 H-isoindol-4-ylester hydrochloride salt( Compound No. 94)
-2-{3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-4.7-dihydroxy-3a,4,7. 7a-tetrahydro-isoindole-l,3-dione hydrochloride salt( Compound No. 96)
-l-!3-[4-(5-Fluoro-2-propoxy-phenyl)-piperazin-l-yl]-propyl}-piperidine-2.6-dione hydrochloride salt( Compound No. 98)
-l-(3-[4-(5-Fluoro-2-propoxy-phenyl)-piperazin-l-yl]-2-hydroxy-propyl)-piperidine-2.6-dione hydrochloride salt( Compound No. 100)
-2-(3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl)-5,6-dihydroxy-hexahydro-isoindole-l,3-dione hydrochloride salt( Compound No. 102)
-2-{3-[4-(5-Fluoro-2-propoxy-phenyl)-piperazin-l-yl]-propyl}-5.6-dihydroxy-hexahydro-isoindole-l,3-dione hydrochloride salt( Compound No. 104)
-2-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-1.3-dione hydrochloride salt( Compound No. 106)
-2-|3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-1.3-dione hydrochloride salt( Compound No. 108)
-3-Cyclopropylaminomethyl-l-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl)-pyrrolidine-2.5-dione hydrochloride salt( Compound No.l 10)
-3-Cyclopropylaminomethyl-l-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl}-4-methyl-pyrrolidine-2.5-dione hydrochloride salt( Compound No. 112)
-3-Cyclobutylaminomethyl-l-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl j-pyrrolidine-2.5-dione hydrochloride salt( Compound No. 114)
-1 - (2-Hydroxy-3-[4-(2-methoxy-phenyl)-piperazin-1 -yl]-propyl}-3-methyl-pyrrolidine-2.5-dione hydrochloride salt( Compound No. 116)
-2-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl}-4,7-dihydroxy-3a.4.7.7a-tetrahydro-isoindole-1.3-dione hydrochloride salt ( Compound No. 118)
-2-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-1.3-dione hydrochloride salt( Compound No. 120)
-2-{3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-2-oxo-propyl}-5.6-dihydroxy-hexahydro-isoindole-1.3-dione hydrochloride salt( Compound No. 122)
-2-{3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5.6-dihydroxy-hexahydro-isoindole-1.3-dione hydrochloride salt( Compound No. 124)
-2-(3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-2-hydroxy-propyl]-5.6-dihydroxy-hexahydro-isoindole-l,3-dione hydrochloride salt ( Compound No. 126)
-l-{3-[4-(2-Cyclopentyloxy-5-fluoro-phenyl)-piperazin-l-yl]-propyl}-piperidine-2,6-dione hydrochloride salt( Compound No. 128)
-l-{3-[4-(3-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl]-piperidine-2.6-dione hydrochloride salt( Compound No. 130)
-l-(3-[4-(3-Fluoro-2-methoxy-phenyl)-piperazin-l-yl]-propyl}-piperidine-2.6-dione hydrochloride salt( Compound No. 132)
-1 - (3-[4-(3-Fluoro-2-isopropoxy-phenyl )-piperazin-1 -yl] -propyl}-3-methylene-pyrrolidine-2.5-dione hydrochloride salt( Compound No. 134)
-l-(3-[4-(5-Fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]-propyl)-3-methylene-pyrrolidine-2.5-dione hydrochloride salt ( Compound No. 136)
-l-{3-[4-(5-Fluoro-2-(2,2.3.3-tetrafluoro-propoxy)-phenyl]-piperazin-l-ylj-propyl)-piperidine-2,6-dione hydrochloride salt( Compound No. 138)
-1 - {3-[4-( 2-Methoxy-phenyl )-piperazin-1 -yl]-propyl )-3-methyl-4-( 1 -phenyl-ethylamino)-pyrrolidine-2.5-dione hydrochloride salt( Compound No. 140)
-l-(3-[4-(5-Fluoro-2-trifluoroinethoxy-phenyl)-piperazin-l-yl]-propyl)-piperidine-2,6-dione hydrochloride salt( Compound No. 142)
-Acetic acid 7-acetoxy-2-{3-[4-(2-ethoxy-phenyl)-piperazin-l-yl]-propyl)-l,3-dioxo-2.3.3a.4,7,7a-hexahydro-lH-isoindol-4-yl ester hydrochloride salt( Compound No. 144)
-2-{3-[4-(2-Ethoxy-phenyl)-piperazin-l-yl]-propyl)-4.7-dihydroxy-3a.4,7,7a-tetrahydro-isoindole-1.3-dione hydrochloride salt( Compound No. 146)
-3-Cyclopropylamino-1 - (3-[4-(2-ethoxy-phenyl)-piperazin-1 -yl]-propyl j -pyrrolidine-2.5-dione hydrochloride salt( Compound No. 148)
-Acetic acid 7-acetoxy-2-{3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl)-l,3-dioxo-2,3.3a,4.7,7a-hexahydro-lH-isoindol-4-yl ester hydrochloride salt( Compound No. 150)
-l-{3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl)-3-cyclopropylamino-pyrrolidine-2.5-dione hydrochloride salt( Compound No. 152)
-4.7-Dihydroxy-2-{3-[4-(2-methoxy-phenyl)-piperazin-l-yl]-propyl)-3a,4.7.7a-tetrahydro-isoindole-1.3-dione hydrochloride salt( Compound No. 154)
-Acetic acid 7-acetoxy-2-{3-[4-(2-cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl)-1.3-dioxo-2.3,3a.4.7.7a-hexahydro-lH-isoindol-4-yl ester hydrochloride salt ( Compound No. 156)
-2- [3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-1 -yl]-propyl)-4.7-dihydroxy-hexahydro-isoindole-l,3-dione hydrochloride salt( Compound No. 158)
-2-(3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl}-4.7-dihydroxy-3a,4.7.7a-tetrahydro-isoindole-l,3-dione hydrochloride salt ( Compound No. 160)
-3-Methylene-1 -[3-(4-0-tolyl-piperazin-1 -yl)-propyl]-pyrrolidine-2.5-dione hydrochloride salt( Compound No. 162)
-1 - [ 3-[4-(2-Methoxy-phenyl)-piperazin-1 -yl]-propyl )-3-methyl-4-[(thiophen-2-ylmethyl)-amino]-pyrrolidine-2.5-dione hydrochloride salt( Compound No. 164)
-l-(3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-propyl}-3-methylene-pyrrolidine-2.5-dione hydrochloride salt( Compound No. 166)
-l-(3-[4-(5-Fluoro-2-methoxy-phenyl)-piperazin-l-yl]-propyl}-3,3.4-trimethyl-pyrrolidine-2,5-dione hydrochloride salt( Compound No. 168)
-1 - (3-[4-(2-Cyclopentyloxy-phenyl)-piperazin-1 -yl]-propyl j -piperidine-2,6-dione hydrochloride salt( Compound No. 170).
15. 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.
16. A method for treatment of a patient suffering from a disease or disorder mediated
through α1a and/or α1d adrenergic receptor, comprising administering to said patient a
therapeutically effective amount of a compound of any one of the claims 1-14.
17. A method for treatment of a patient suffering from disease or disorder mediated through
α1a and/or α1d adrenergic receptor, comprising administering to said patient a therapeutically
effective amount of a pharmaceutical composition according to claim 15.
18. The method according to claim 16 or 17 wherein a disease or disorder is benign prostatic hyperplasia.
19. The method according to claim 16 or 17 wherein compound causes minimal fall or no fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.
20. A process for the preparation of a compound of Formula VII. as shown in Scheme I of the accompanied drawings and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers. N-oxides. prodrugs, polymorphs or metabolites wherein:
A represents
(Formula Removed)
wherein:
R2. R3. R.4 and R5 independently represent
o hydrogen
o alkyl
o phenyl R.6 represents
o hydrogen
o alkyl
o phenyl
o hydroxy
o alkoxy — represents optional single bond R7 and R8 independently represent
o hydrogen
o alkyl
o 5=CH2 (wherein ■ is the point of attachment)
o alkynyl
o cycloalkyl
o halogen
o hydroxy
o aryl
o acetoxy
o heterocycle
o R12 Q (CH2)m-wherein m represents an integer 0 to 3
R12 represents
• alkyl
• alkenyl
• alkynyl
• cycloalkyl
• cyclo alkenyl
• aryl
• heterocycle Q represents

• oxygen
• sulphur
• carbonyl
• carboxylic
• (Formula Removed)
wherein
W represents
♦ no atom
♦ carbonyl
♦ carboxylic
♦ amide

R13 represents
♦ hydrogen
♦ alky]
♦ cycloalkyl
♦ aryl
♦ heterocycle R7 and R8 together represent
o cycloalkyl
o cyclo alkenyl
o bicyclic alkyl
o bicyclic alkenyl
o aryl
o heterocycle
o wherein Z is CO or SO
R9 and R10 independently represent
o hydrogen
o hydroxy
o alkoxy
o acetyl
o acetyloxy Rn represents
o hydrogen
o alkyl
o alkenyl
o alkynyl
o cycloalkyl
o aryl
o heterocycle R represents o alkyl
o alkenyl
o alkynyl
o cycloalkyl
o aryl
o heterocycle. comprising :
reacting a compound of Formula II with 2-chloromethyl-oxirane to give a compound of Formula III (wherein A is the same as defined earlier), which on reaction with hydrochloric acid gives a compound of Formula IV. which on oxidation gives a compound of Formula V. which is finally treated with a compound of Formula VI (wherein R is the same as defined earlier) to give a compound of Formula VII as shown in the accompanied drawings.
21. The process according to claim 20 wherein the reaction of a compound of Formula II with 2-chloromethyl-oxirane to give a compound of Formula III is carried out in a solvent selected from the group consisting of acetone, methyl ethyl ketone, diisopropyl ketone, tetrahydrofuran. dimethylformamide and dimethylsulfoxide.
22. The process according to claim 20 wherein the reaction of a compound of Formula II with 2-chloromethyl-oxirane is carried out in the presence of an inorganic base selected from the group consisting of barium carbonate, cesium carbonate, calcium carbonate, sodium carbonate, potassium carbonate and sodium bicarbonate.
23. The process according to claim 20 wherein the reaction of a compound of Formula III with hydrochloric acid to give a compound of Formula IV is carried out in a solvent selected from the group consisting of ethanol. methanol, isopropanol. ethyl acetate and tetrahydrofuran.
24. The process according to claim 20 wherein the oxidation of a compound of Formula IV to give a compound of Formula V is carried out in a solvent selected from the group consisting of chloroform, methanol, acetone, dichloromethane. acetonitrile and tetrahydrofuran.
25. The process according to claim 20 wherein the oxidation of a compound of Formula IV to give a compound of Formula V is carried out in the presence of an oxidizing agent
selected from the group consisting of pyridinium dichromate and pyridinium chlorochromate.
26. The process according to claim 20 wherein the reaction of a compound of Formula V with a compound of Formula VI to give a compound of Formula VII is carried out in a solvent selected from the group consisting of acetonitrile. acetone, tetrahydrofuran. dimethylforrnamide, dimethylsulfoxide and toluene.
27. The process according to claim 20 wherein the reaction of a compound of Formula V with a compound of Formula VI is carried out in the presence of an inorganic base selected from the group consisting of barium carbonate, cesium carbonate, calcium carbonate, sodium carbonate, potassium carbonate and sodium bicarbonate.
28. A process for the preparation of a compound of Formula VIII. as shown in Scheme II of the accompanied drawings, its pharmaceutical!}' acceptable salts, pharmaceutically acceptable solvates, enantiomers. diastereomers. N-oxides, prodrugs, polymorphs or metabolites wherein:
A represents
(Formula Removed)
wherein:
R.2. R3. R4 and R5 independently represent
o hydrogen
o alkyl
o phenyl R(l represents
o hydrogen
o alkyl
o phenyl
o hydroxy
o alkoxy — represents optional single bond R7 and R8 independently represent
o hydrogen
o alkyl
o s=CH2 ( wherein ■ is the point of attachment)
o alkynyl
o cycloalkyl
o halogen
o hydroxy
o aryl
o acetoxy
o heterocycle
o R12 Q (CH2)m- wherein m represents an integer 0 to 3
R12 represents
• alkyl
• alkenyl
• alkynyl
• cycloalkyl
• cyclo alkenyl
• aryl
• heterocycle Q represents

• oxygen
• sulphur
• carbonyl
• carboxylic
• | wherein
Rl3
W represents
♦ no atom
♦ carbonyl
♦ carboxylic
♦> amide
R13 represents
♦ hydrogen
♦ alkyl
♦ cycloalkyl
♦ aryl
♦ heterocycle R7 and R8 together represent
o cycloalkyl
o cyclo alkenyl
o bicyclic alkyl
o bicyclic alkenyl
o aryl
o heterocycle
o(Formula Removed)
wherein Z is CO or SO
R9 and R10 independently represent
o hydrogen
o hydroxy
o alkoxy
o acetyl
o acetyloxy R11 represents
o hydrogen
o alkyl
o alkenyl
o alkynyl
o cycloalkyl
o aryl
o heterocycle R represents o alkyl
o alkenyl
o alkynyl
o cycloalkyl
o aryl
o heterocycle. which comprises:
reacting a compound of Formula III with a compound of Formula VI to give a compound of Formula VIII (wherein A and R are the same as defined earlier) as shown in the accompanied drawings.
29.The process according to claim 28 wherein the reaction of a compound of Formula III with a compound of Formula VI to give a compound of Formula VIII is carried out in a solvent selected from the group consisting of acetonitrile. acetone, ethanol. tetrahydrofuran. cyclohexane. dimethylformamide. dimethylsulfoxide. toluene and methylethylketone.
30. The process according to claim 28 wherein the reaction of a compound of Formula III with a compound of Formula VI is carried out in the presence of a base selected from the group consisting of potassium carbonate, sodium carbonate, calcium carbonate, barium carbonate, sodium bicarbonate, triethyl amine, trimethyl amine and sodium hydride.
31. A process for the preparation of a compound of Formula VII. as shown in Scheme II of the accompanied drawings, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers. diastereomers, N-oxides. prodrugs, polymorphs or metabolites wherein:
A represents
(Formula Removed)
wherein:
R.2. R3. R4 and R5 independently represent
o hydrogen
o alkyl
o phenyl R6 represents
o hydrogen
o alkyl
o phenyl
o hydroxy
o alkoxy — represents optional single bond R7 and R8 independently represent
o hydrogen
o alkyl
o s=CH2 (wherein ■ is the point of attachment)
o alkynyl
o cycloalkyl
o halogen
o hydroxy
o aryl
o acetoxy
o heterocycle
o R12 -Q-(CH2)m- wherein m represents an integer 0 to 3
R12 represents
• alkyl
• alkenyl
• alkynyl
• cycloalkyl
• cyclo alkenyl
• aryl
• heterocycle Q represents

• oxygen
• sulphur
• carbonyl
• carboxylic
• (Formula Removed)
wherein
R|3
W represents
♦ no atom
♦ carbonyl
♦ carboxylic
♦ amide
R13 represents
♦ hydrogen
♦ alkyl
♦ cycloalkyl
♦ aryl
♦ heterocycle R7 and R8 together represent
o cycloalkyl
o cyclo alkenyl
o bicyclic alkyl
o bicyclic alkenyl
o aryl
o heterocycle
o (Formula Removed)
wherein Z is CO or SO
R9 and R10 independently represent
o hydrogen
o hydroxy
o alkoxy
o acetyl
o acetyloxy R11 represents
o hydrogen
o alkyl
alkenyl o alkynyl o cycloalkyl o aryl
o heterocycle R represents o alkyl o alkenyl o alkynyl o cycloalkyl o aryl
o heterocycle. which comprises:
oxidising a compound of Formula VIII (wherein A and R are the same as defined earlier) to give a compound of Formula VII. as shown in the accompanied drawings.
32. The process according to claim 31 wherein the oxidation of a compound of Formula VIII to give a compound of Formula VII is carried out in a solvent selected from the group consisting of chloroform, methanol, acetone, dichloromethane. acetonitrile and tetrahydrofuran.
33. The process according to claim 31 wherein the oxidation of a compound of Formula VIII to give a compound of Formula VII is carried out in the presence of an oxidizing agent selected from the group consisting of pyridinium dichromate and pyridinium chlorochromate.
34. A process for the preparation of a compound of Formula IX. as shown in the Scheme II
of the accompanied drawings and its pharmaceutically acceptable salts, pharmaceutically
acceptable solvates, enantiomers. diastereomers. N-oxides, prodrugs, polymorphs or
metabolites wherein:
A represents (Formula Removed)

or wherein:
R2.. R3. R4 and R5 independently represent
o hydrogen
o alkyl
o phenyl R6, represents
o hydrogen
o alkyl
o phenyl
o hydroxy
o alkoxy — represents optional single bond R7 and R8 independently represent
o hydrogen
o alkyl
o =CH2 (wherein ■ is the point of attachment)
o alkynyl
o cycloalkyi
o halogen
o hydroxy
o aryl
o acetoxy
o heterocycle
o R12 Q (CH2) m wherein m represents an integer 0 to 3
R12 represents
• alkyl
• alkenyl
• alkynyl
• cycloalkyi
• cyclo alkenyl
• aryl
• heterocycle

Q represents
• oxygen
• sulphur
• carbonyl
• carboxylic
• y wherein
R|3
W represents
♦ no atom
♦ carbonyl
♦ carboxylic
♦ amide Ri3 represents
♦ hydrogen
♦ alkyl
♦ cycloalkyl
♦ aryl
♦ heterocycle R7 and Rs together represent
o cycloalkyl
o cyclo alkenyl
o bicyclic alkyl
o bicyclic alkenyl
o aryl
o heterocycle
o wherein Z is CO or SO(Formula Removed)

R9 and R10 independently represent o hydrogen o hydroxy o alkoxy
acetyl o acetyloxy R11 represents o hydrogen o alkyl o alkenyl o alkynyl o cycloalkyl o aryl
o heterocycle R represents o alkyl o alkenyl o alkynyl o cycloalkyl o aryl
o heterocycle, which comprises:
fluorinating a compound of Formula VIII (wherein A and R are the same as defined earlier) to give a compound of Formula IX , as shown in the accompanied drawings.
35. The process according to claim 34 wherein the fluorination of a compound of Formula VIII to give a compound of Formula IX is carried out in the presence of a fluorinating agent selected from the group consisting of diethylamino sulphur trifluoride and tris (dimethylamino)sulphur(trirnethyl silyl) difluoride.
36. The process according to claim 34 wherein the fluorination of a compound of Formula VIII to give a compound of Formula IX is carried out in a solvent selected from the group consisting of chloroform, dichloromethane. tetrahydrofuran and acetonitrile.
37. A process for the preparation of a compound of Formula XII. as shown in Scheme III of the accompanied drawings, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers. diastereomers, N-oxides, prodrugs, polymorphs or metabolites wherein:
A represents
(Formula Removed)
wherein:
R2 R3. R4 and R5 independently represent
o hydrogen
o alkyl
o phenyl R6 represents
o hydrogen
o alkyi
o phenyl
o hydroxy
o alkoxy — represents optional single bond R7 and R,s independently represent
o hydrogen
o alkyl
o 5=CH2 (wherein, is the point of attachment)
o alkynyl
o cycloalkyl
o halogen
o hydroxy
o aryl
o acetoxy
o heterocycle
o R12-Q (CH2)m wherein m represents an integer 0 to 3
R12 represents
• alkyl
• alkenyl
• alkynyl
• cycloalkyl
• cyclo alkenyl
• aryl
• heterocycle Q represents

• oxygen
• sulphur
• carbonyl
• carboxylic
• I wherein
R|3
W represents
♦ no atom
♦ carbonyl
♦ carboxylic
♦ amide R13 represents

♦ hydrogen
♦ alkyi
♦ cycloalkyl
♦ aryl
<♦ heterocycle R7 and R8 together represent o cycloalkyl o cyclo alkenyl o bicyclic alkyi o bicyclic alkenyl o aryl
o heterocycle o(Formula Removed)
wherein Z is CO or SO
R9 and R10 independently represent o hydrogen o hydroxy o alkoxy o acetyl o acetyloxy R11 represents o hydrogen o alkyl o alkenyl o alkynyl o cycloalkyl o aryl
o heterocycle R represents
o alkyl
o alkenyl
o alkynyl
o cycloalkyl
o aryl
o heterocycle. with the proviso that
when A is(Formula Removed)
(a) .X is -CFF- and R| i is hydrogen then R7 is hydrogen or ^=CH2 or alkyl with the further provisio that when R7 is alkyl and Rx is R 12 NH-. then R12 is substituted alkyl wherein the substituents are selected from aryl or heterocyclyl
when A is(Formula Removed)
(b) and X is-CH2-. R7 = R8 = R9 =R10 ^hydrogen or halogen, which comprises:'"
alkylating a compound of Formula II with a compound of Formula X to give a compound of Formula XI (wherein hal is a halogen and A is the same as defined earlier), which on reaction with a compound of Formula VI gives a compound of XII (wherein R is the same as defined earlier). as shown in the accompanied drawings.
38. The process according to claim 37 wherein the alkylation of a compound of Formula II
with a compound of Formula X to give a compound of Formula XI is carried out in a solvent
selected from the group consisting of acetone, methyl ethylketone, diisopropyl ketone,
tetrahydrofuran. dimethylformamide and dimethylsulfoxide.
39. The process according to claim 37 wherein the alkylation of a compound of Formula II with a compound of Formula X is carried out in the presence of an inorganic base selected from the group consisting of potassium carbonate, barium carbonate, cesium carbonate, calcium carbonate, sodium carbonate and sodium bicarbonate and an organic and inorganic halide selected from the group consisting of tetrabutyl ammonium chloride, tetrabutyl ammonium bromide and potassium iodide.
40. The process according to claim 37 wherein the reaction of a compound of Formula XI with a compound of Formula VI to give a compound of Formula XII is carried out in a solvent selected from the group consisting of acetonitrile. ethanol. butanol. dichloromethane. dimethylformamide and dimethylsulfoxide.
41. The process according to claim 37 wherein the reaction of a compound of Formula XI with a compound of Formula VI is carried out in the presence of an inorganic base selected from the group consisting of potassium carbonate, barium carbonate, cesium carbonate, calcium carbonate, sodium carbonate and sodium bicarbonate.
42. A process for the preparation of a compound of Formula XVI, as shown in Scheme IV of the accompanied drawings, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers. diastereomers. N-oxides. prodrugs, polymorphs or metabolites wherein:
R.7 and R8 independently represent o hydrogen o alkyl
o ! CH2 (wherein, is the point of attachment) o alkynyl o cycloalkyl o halogen o hydroxy o aryl

o acetoxy o heterocycle
o R12 Q (CH2)m- wherein m represents an integer 0 to 3
R12 represents
• alkyl
• alkenyl
• alkynyl
• cycloalkyl
• cyclo alkenyl
• aryl
• heterocycle Q represents

• oxygen
• sulphur
• carbonyl
• carboxylic
• —N W wherein
W represents
♦ no atom
♦ carbonyl
♦ carboxylic
♦ amide R13 represents

♦ hydrogen
♦ alkyl
♦ cycloalkyl
♦ aryl
♦ heterocycle
R7 and R8 together represent
o cycloalkyl
o cyclo alkenyl
o bicyclic alkyl
o bicyclic alkenyl
o aryl
o heterocycle
o (Formula Removed)
wherein Z is CO or SO
R11 represents o hydrogen o alkyl o alkenyl o alkynyl o cycloalkyl o aryl
o heterocycle R represents o alkyl o alkenyl o alkynyl o cycloalkyl o aryl
o heterocycle, with the proviso that when R11 is hydrogen then R7 is hydrogen or t=CH2 or alkyl with the further provisio that when R7 is alkyl and R8 is R 12NH-. then R12 is substituted alkyl wherein the substituents are selected from aryl or heterocyclyl, which comprises:
reacting a compound of Formula VI with acrylonitrile to give a compound of Formula XIII (wherein R is the same as defined earlier), which on reduction gives a compound of Formula XIV. which on reaction with a compound of Formula XV gives a compound of Formula XVI (wherein R7.R8 and R11 are the same as defined earlier) as shown in the accompanied drawings.
43. The process according to claim 42 wherein the reaction of a compound of Formula VI with acrylonitrile to give a compound of Formula XIII is carried out in an alcoholic solvent selected from the group consisting of methanol, ethanol. propanol and n-butanol.
44. The process according to claim 42 wherein the reduction of a compound of Formula XIII to give a compound of Formula XIV is carried out in the presence of a reducing agent selected from the group consisting of palladium on carbon and hydrogen and raney nickel and hydrogen and ammonia.
45. The process according to claim 42 wherein the reduction of a compound of Formula XIII to give a compound of Formula XIV is carried out in an alcoholic solvent selected from the group consisting of methanol, ethanol. propanol and n-butanol.
46. The process according to claim 42 wherein reaction of a compound of Formula XIV with a compound of Formula XV to give a compound of Formula XVI is carried out in a solvent selected from the group consisting of toluene, tetrahydrofuran. acetonitrile and xylene.
47. A process for the preparation of a compound of Formula XVIII. as shown in Scheme V of the accompanied drawings, its pharmaceutical!}' acceptable salts, pharmaceutically acceptable solvates, enantiomers. diastereomers. N-oxides, prodrugs, polymorphs or metabolites wherein:
R represents
o alkyl
o alkenyl
o alkynyl
o cycloalkyl
o aryl
o heterocycle. which comprises:
reacting a compound of Formula XVII with l-acetoxy-1.3-butadiene gives a compound of Formula XVIII ( wherein R is the same as defined earlier) ,as shown in the accompanied drawings.
48. The process according to claim 47 wherein the reaction of a compound of Formula
XVII with l-acetoxy-l,3-butadiene to give a compound of Formula XVIII is carried out in a
solvent selected from the group consisting of toluene, benzene and xylene.
49. A process for the preparation of a compound of Formula XIX. as shown in Scheme V of
the accompanied drawings, its pharmaceutically acceptable salts, pharmaceutically
acceptable solvates, enantiomers, diastereomers. N-oxides, prodrugs, polymorphs or
metabolites wherein:
R represents
o alkyl
o alkenyl
o alkynyl
o cycloalkyl
o aryl
o heterocycle. which comprises:
hyrolysing a compound of Formula XVIII to give a compound of Formula XIX (wherein R is the same as defined earlier), as shown in the accompanied drawings.
50. The process according to claim 49 wherein the hydrolysis of acompound of Formula
XVIII to give a compound of Formula XIX is carried out in the presence of hydrochloric
acid.
51. The process according to claim 49 wherein the hydrolysis of compound of Formula XVIII to give a compound of Formula XIX is carried out in an alcoholic solvent selected from the group consisting of methanol, ethanol. propanol and n-butanol.
52. A process for the preparation of a compound of Formula XX. as shown in Scheme V of the accompanied drawings, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers. N-oxides, prodrugs, polymorphs or metabolites wherein:
R represents o alkyl o alkenyl o alkynyl
o cycloalkyl
o aryl
o heterocycle, which comprises:
reacting a compound of Formula XVII with 1.4 -diacetoxy-l,3-butadiene to give a compound of Formula XX ( wherein R is the same as defined earlier) as shown in the accompanied drawings.
53. The process according to claim 52 wherein the reaction of a compound of Formula
XVII with 1,4 -diacetoxy-1.3-butadiene to give a compound of Formula XX is carried out in
a solvent selected from the group consisting of toluene, benzene and xylene.
54. A process for the preparation of a compound of Formula XXI, as shown in Scheme V of
the accompanied drawings, its pharmaceutically acceptable salts, pharmaceutically
acceptable solvates, enantiomers, diastereomers. N-oxides, prodrugs, polymorphs or
metabolites wherein:
R represents
o alkyl
o alkenyl
o alkynyl
o cycloalkyl
o aryl
o heterocycle. which comprises:
hydolysing a compound of Formula XX to give a compound of Formula XXI ( wherein R is the same as defined earlier) as shown in the accompanied drawings.
55. The process according to claim 54 wherein the hydrolysis of a compound of Formula XX to give a compound of Formula XXI is carried out in the presence of hydrochloric acid.
56. The process according to claim 54 wherein the hydrolysis of a compound of Formula XX to give a compound of Formula XXI is carried out in an alcoholic solvent selected from the group consisting of methanol, ethanol. propanol and n-butanol.
57. A process for the preparation of a compound of Formula XXII. as shown in Scheme V of the accompanied drawings, its pharmaceutically acceptable salts, pharmaceutically
acceptable solvates, enantiomers. diastereomers, N-oxides. prodrugs, polymorphs or metabolites wherein: R represents
o alkyl
o alkenyl
o alkynyl
o cycloalkyl
o aryl
o heterocycle. which comprises:
reducing a compound of Formula XXI to give a compound of Formula XXII ( wherein R is the same as defined earlier) as shown in the accompanied drawings.
58. The process according to claim 57 wherein the reduction of a compound of Formula XXI to give a compound of Formula XXII is carried out in the presence of a reducing agent selected from the group consisting of palladium on carbon and hydrogen and raney nickel and hydrogen and ammonia.
59. The process according to claim 57 wherein the reduction of a compound of Formula XXI to give a compound of Formula XXII is carried out in an alcoholic solvent selected from the group consisting of methanol, ethanol, propanol and n-butanol.
60. A process for the preparation of a compound of Formula XXV. as shown in Scheme VI of the accompanied drawings, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers. diastereomers, N-oxides. prodrugs, polymorphs or metabolites wherein:
R7 and R8 independently represent o hydrogen o alkyl
o f=CH2 (wherein, is the point of attachment) o alkynyl o cycloalkyl o halogen o hydroxy
o aryl o acetoxy o heterocycle
o R12-Q-(CH2)M-wherein m represents an integer 0 to 3
R12 represents
• alkyl
• alkenyl
• alkynyl
• cycloalkyl
• cycloalkenyl
• aryl
• heterocycle Q represents

• oxygen
• sulphur
• carbonyl
• carboxylic
•—N—W wherein
W represents
♦ no atom
♦ carbonyl
♦ carboxylic
♦ amide R13 represents

♦ hydrogen
♦ alkyl
♦ cycloalkyl
♦ aryl
♦ heterocycle
R7 and R8 together represent
o cycloalkyl
o cycloalkenyl
o bicyclic alkyl
o bicyclic alkenyl
o aryl
o heterocycle
o (Formula Removed)
wherein Z is CO or SO
R11 represents o hydrogen o alkyl o alkenyl o alkynyl o cycloalkyl o aryl
o heterocycle R represents o alkyl o alkenyl o alkynyl o cycloalkyl o aryl
o heterocycle. which comprises:
reacting isoindole-1.3-dione with 2-chloromethyl oxirane to give 2-oxiranylmethyl-isoindole-l,3-dione. which on reaction with a compound of Formula VI, gives a compound of Formula XXIII ( wherein R is the same as defined earlier), which on reaction with hydrazine hydrate gives a compound of Formula XXIV. which on reaction with a compound of Formula XV gives a compound of Formula XXV (wherein R7. R8 and R11 are the same as defined earlier) as shown in the accompanied drawings.
61.The process according to claim 60 wherein the reaction of isoindole-1. 3-dione with 2-chloromethyl-oxirane to give 2-oxiranylmethyl-isoindole-l. 3-dione is carried out in a solvent selected from the group consisting of acetone, methyl ethyl ketone, diisopropyl ketone, tetrahydrofuran, dimethylformamide and dimethylsulfoxide.
62. The process according to claim 60 wherein the reaction of isoindole-1,3-dione with 2-chloromethyl-oxirane to give 2-oxiranylmethyl-isoindole-l.3-dione is carried out in the presence of an inorganic base selected from the group consisting of barium carbonate, cesium carbonate, calcium carbonate, sodium carbonate, potassium carbonate and sodium bicarbonate.
63. The process according to claim 60 wherein the reaction of 2-oxiranylmethyl-isoindole-l. 3-dione with a compound of Formula VI to give a compound of Formula XXIII is carried out in an organic solvent selected from the group consisting of acetonitrile. ethanol, butanol. tetrahydrofuran. dimethylsulphoxide, dimethylformamide and dichloromethane.
64. The process according to claim 60 wherein the reaction of a compound of Formula
XXIII with hydrazine hydrate to give a compound of Formula XXIV is carried out in a
solvent selected from the group consisting of acetonitrile. ethanol. butanol, tetrahydrofuran.
dimethylsulphoxide, dimethylformamide and dichloromethane.
65. The process according to claim 60 wherein the reaction of a compound of Formula
XXIV with a compound of Formula XV to give a compound of Formula XXV is carried out
in a solvent selected from the group consisting of acetonitrile, acetone, tetrahydrofuran.
dimethylformamide. dimethylsulfoxide and toluene.
66. A process for the preparation of a compound of Formula XXVII. as shown in Scheme
VII of the accompanied drawings, its pharmaceutically acceptable salts, pharmaceutically
acceptable solvates, enantiomers, diastereomers. N-oxides. prodrugs, polymorphs or
metabolites wherein:
X represents -CO. -CS or - CHY wherein : Y represents
• hydrogen
• hydroxy
• halogen
• alkoxy
• haloalkoxy
R represents
o alkyl
o alkenyl
o alkynyl
o cycloalkyl
o aryl
o heterocycle, which comprises:
reacting a compound of Formula XXVI with a methylating agent selected as trimethyl sulphoxinium iodide to give a compound of Formula XXVII ( wherein X and R are the same as defined earlier) as shown in the accompanied drawings.
67. The process according to claim 66 wherein the reaction of a compound of Formula XXVI with a methylating agent to give a compound of Formula XXVII is carried out in a solvent selected from the group consisting of acetonitrile. acetone, tetrahydrofuran. dimethylformamide. dimethylsulfoxide and toluene.
68. A process for the preparation of a compound of Formula XXIX. as shown in Scheme VII of the accompanied drawings, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers. diastereomers, N-oxides. prodrugs, polymorphs or metabolites wherein:
X represents -CO. -CS or - CHY wherein : Y represents
• hydrogen
• hydroxy
• halogen
• alkoxy
• haloalkoxy R represents
o alkyl o alkenyl o alkynyl
o cycloalkyl
o aryl
o heterocycle. which comprises:
reducing a compound of Formula XXVI to give a compound of Formula XXIX ( wherein R and X are the same as defined earlier) as shown in the accompanied drawings. 69. The process according to claim 68 wherein the reduction of a compound of Formula XXVI to give a compound of Formula XXIX is carried out in the presence of a reducing agent selected from the group consisting of palladium on carbon and hydrogen and raney nickel and hydrogen and ammonia.
70 .The process according to claim 68 wherein the reduction of a compound of Formula XXVI to give a compound of Formula XXIX is carried out in an alcoholic solvent selected from the group consisting of methanol, ethanol. propanol and n-butanol. 71. A process for the preparation of a compound of Formula XXX, as shown in Scheme VII of the accompanied drawings, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers. diastereomers, N-oxides, prodrugs, polymorphs or metabolites wherein:
X represents -CO. -CS or - CHY wherein: Y represents
• hydrogen
• hydroxy
• halogen
• alkoxy
• haloalkoxy R12 represents

• alkyl
• alkenyl
• alkynyl
• cycloalkyl
• cycloalkenyl
• aryl
• heterocycle R13 represents
♦ hydrogen
♦ alkyl
♦ cycloalkyl
♦ aryl
♦ heterocycle R represents
o alkyl
o alkenyl
o alkynyl
o cycloalkyl
o aryl
o heterocycle. with the proviso that when X is - CH2 - . then R12 is substituted alkyl wherein the substituents are selected from aryl or heterocyclyl. which comprises:
reacting a compound of Formula XXVI with a compound of Formula XXVIII to give a compound of Formula XXX (wherein R12 and R13 are the same as defined earlier) as shown in the accompanied drawings.
72. The process according to claim 71 wherein the reaction of a compound of Formula XXVI with a compound of Formula XXVIII to give a compound of Formula XXX is carried out in a solvent selected from the group consisting of chloroform, methanol, acetone, dichloromethane. acetonitrile and tetrahydrofuran.
73. A process for the preparation of a compound of Formula XXXIII. as shown in Scheme VIII of the accompanied drawings, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers. diastereomers, N-oxides. prodrugs, polymorphs or metabolites wherein:
X represents -CO, -CS or - CHY wherein: Y represents • hydrogen
• hydroxy
• halogen
• alkoxy
• haloalkoxy R represents
o alkyl
o alkenyl
o alkynyl
o cycloalkyl
o aryl
o heterocycle. which comprises:
reacting a compound of Formula XXXI with tetra hydro phthalimide to give a compound of Formula XXXII. which on oxidation gives a compound of Formula XXXIII (wherein X and R are the same as defined earlier) as shown in the accompanied drawings.
74. The process according to claim 73 wherein the reaction of a compound of Formula
XXXI with tetra hydro phthalimide to give a compound of Formula XXXII is carried out in
a solvent selected from the group consisting of acetonitrile, acetone, tetrahydrofuran.
dimethylformamide. dimethylsulfoxide and toluene.
75. The process according to claim 73 wherein the oxidation of a compound of Formula
XXXII to give a compound of Formula XXXIII is carried out in an alcoholic solvent
selected from the group consisting of methanol, ethanol, propanol and n-butanol.
76. The process according to claim 73 wherein the oxidation of a compound of Formula XXXII to give a compound of Formula XXXIII is carried out in the presence of potassium permanganate.
77. A process for the preparation of a compound of Formula XXXIV as shown in Scheme VIII of the accompanied drawings, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers. diastereomers. N-oxides. prodrugs, polymorphs or metabolites wherein:
X represents -CO. -CS or -CHY wherein: Y represents
• hydrogen
• hydroxy
• halogen
• alkoxy
• haloalkoxy R represents
o alkyl
o alkenyl
o alkynyl
o cycloalkyl
o aryl
o heterocycle. which comprises:
reacting a compound of Formula XXXIII with diethyl amino sulphur trifluoride to give a compound of Formula XXXIV ( wherein X and R are the same as defined earlier) as shown in the accompanied drawings.
78. The process according to claim 77 wherein the reaction of a compound of Formula XXXIII with diethyl amino sulphur trifluoride to give a compound of Formula XXXIV is carried out in a solvent selected from the group consisting of chloroform, dichloromethane. tetrahydrofuran and acetonitrile.
79. A process for the preparation of a compound of Formula XXXV. as shown in Scheme VIII of the accompanied drawings, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers. diastereomers. N-oxides. prodrugs, polymorphs or metabolites wherein:
X represents -CO. -CS or -CHY wherein: Y represents
• hydrogen
• hydroxy
• halogen
• alkoxy
• haloalkoxy
R represents
o alkyl
o alkenyl
o alkynyl
o cycloalkyl
o aryl
o heterocycle, which comprises:
reacting a compound of Formula XXXIV with diethyl amino sulphur trifluoride to give a compound of Formula XXXV ( wherein X and R are the same as defined earlier), as shown in the accompanied drawings.
80. The process according to claim 79 wherein the reaction of a compound of Formula XXXIV with diethyl amino sulphur trifluoride to give a compound of Formula XXXV is carried out in a solvent selected from the group consisting of chloroform, dichloromethane. tetrahydrofuran and acetonitrile.
81. A process for the preparation of a compound of Formula XXXVI. as shown in Scheme VIII of the accompanied drawings, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers. diastereomers. N-oxides. prodrugs, polymorphs or metabolites wherein:
X represents -CO. -CS or - CHY wherein: Y represents
• hydrogen
• hydroxy
• halogen
• alkoxy
• haloalkoxy R represents
o alkyl o alkenyl o alkynyl o cycloalkyl
o aryl
o heterocycle, which comprises:
reducing a compound of Formula XXXII to give a compound of Formula XXXVI ( wherein X and R are the same as defined earlier) as shown in the accompanied drawings.
82. The process according to claim 81 wherein the reduction of a compound of Formula XXXII to give a compound of Formula XXXVI is carried out in the presence of a reducing agent selected from the group consisting of palladium on carbon and hydrogen and raney nickel and hydrogen.
83. The process according to claim 81 wherein the reduction of a compound of Formula XXXII to give a compound of Formula XXXVI is carried out in an alcoholic solvent selected from the group consisting of methanol, ethanol. propanol and n-butanol.
84. A process for the preparation of a compound of Formula XL. as shown in Scheme IX of the accompanied drawings, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers. diastereomers, N-oxides, prodrugs, polymorphs or metabolites wherein:
R represents
o alkyl
o alkenyl
o alkynyl
o cycloalkyl
o aryl
o heterocycle. which comprises:
reacting a compound of Formula XXXVII with a peroxy acid selected as m-chloroperbenzoic acid to give a compound of Formula XXXVIII (wherein hal is a halogen), which on reaction with a compound of Formula VI gives a compound of Formula XXXIX (wherein R is the same as defined earlier), which on reduction gives a compound of Formula XL. as shown in the accompanied drawings.
85. The process according to claim 84 wherein the reaction of a compound of Formula
XXXVII with a peroxyacid to give a compound of Formula XXXVIII is carried out in a
solvent selected from the group consisting of chloroform, methanol, acetone, dichloromethane. acetonitrile and tetrahydrofuran.
86. The process according to claim 84 wherein the reaction of a compound of Formula XXXVIII with a compound of Formula VI to give a compound of Formula XXXIX is carried out in a solvent selected from the group consisting of acetonitrile. ethanol. butanol. halogenated solvents, tetrahydrofuran. dimethylformamide and dimethylsulfoxide.
87. The process according to claim 84 wherein the reaction of a compound of Formula
XXXVIII with a compound of Formula VI is carried out in the presence of an inorganic base
selected from the group consisting of potassium carbonate, barium carbonate, cesium
carbonate, calcium carbonate, sodium carbonate and sodium bicarbonate.
88. The process according to claim 84 wherein the reduction of a compound of Formula
XXXIX to give a compound of Formula XL is carried out in the presence of a reducing
agent selected from the group consisting of palladium on carbon and hydrogen and raney
nickel and hydrogen
89. The process according to claim 84 wherein the reduction of a compound of Formula XXXIX to give a compound of Formula XL is carried out in a solvent selected from the group consisting of chloroform, methanol, acetone, dichloromethane. acetonitrile and tetrahydrofuran.
90. A process for the preparation of a compound of Formula XLI, as shown in Scheme IX of the accompanied drawings, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers. N-oxides. prodrugs, polymorphs or metabolites wherein:
R represents
o alkyl
o alkenyl
o alkynyl
o cycloalkyl
o aryl
o heterocycle. which comprises:
fluorinating a compound of Formula XXXIX (wherein R is the same as defined earlier) to give a compound of Formula XLI, as shown in the accompanied drawings.
91. The process according to claim 90 wherein the fluorination of a compound of Formula
XXXIX to give a compound of Formula XLI is carried out in the presence of a fluorinating
agent selected from the group consisting of diethylamino sulphur trifluoride and tris
(dimethylamino)sulphur(trimethyl silyl) difluoride.
92. The process according to claim 90 wherein the fluorination of a compound of Formula
XXXIX to give a compound of Formula XLI is carried out in a solvent selected from the
group consisting of chloroform, dichloromethane. tetrahydrofuran and acetonitrile.
93. The processes for the preparation of compounds of Formulae VII, VIII. IX. XII. XVI.
XVIII. XIX. XX. XXI. XXII. XXV. XXVII, XXIX. XXX. XXXIII, XXXIV. XXXV.
XXXVI, XL and XLI. substantially as herein described and illustrated by example herein.