Title of Invention	"A PROCESS FOR THE PREPARATION OF NOVEL 1-(4-ARYL/HETEROARYLPIPERAZIN/PIPERIDIN-1-YL)-N-(QUINOLOXY-6/7/8-YL/4-(UN)SUBSTITUTED-PYRROLIDIN-2-OXO-1-YL) ALKANES/ALKANONES AND THEIR SALTS USEFUL AS POTENTIAL THERAPEUTIC AGENT"
Abstract	A process for the preparation of 1-(4-aryl/heteroarylpiperazin/piperidin-1-yl)-n-(quinoloxy-6/7/8-yl/4-(un)substituted-pyrrolidin-2-oxo-1-yl) alkanes/alkanones and their salts: The novel 10(4-aryl/heteroarylpiperazin/piperidin-1 -yl)n-(quinoloxy-6/7/8-yl/4-(un)substituted pyrrolidin-2-oxo-1-yl)alkanes/alkanones prepared by the process of the present invention having formula III wherein R represents groups like quinoloxy -6/7/8-yl,4-(un)substituted-pyrrolidin-2-oxo-1-yl, R1 represents group like aryl and heteroaryl, Z=N/CR2(R2=H, OH, COCH3), X=O/H2, n=2-5. These compounds have antiischemic, anti-inflammatory, anxiolytic anft/or antihypertensive activities and would be useful for the treatment of ischemia, inflammation, hypertension and other related CVS and CMS disorders.

Title of Invention

"A PROCESS FOR THE PREPARATION OF NOVEL 1-(4-ARYL/HETEROARYLPIPERAZIN/PIPERIDIN-1-YL)-N-(QUINOLOXY-6/7/8-YL/4-(UN)SUBSTITUTED-PYRROLIDIN-2-OXO-1-YL) ALKANES/ALKANONES AND THEIR SALTS USEFUL AS POTENTIAL THERAPEUTIC AGENT"

Abstract

A process for the preparation of 1-(4-aryl/heteroarylpiperazin/piperidin-1-yl)-n-(quinoloxy-6/7/8-yl/4-(un)substituted-pyrrolidin-2-oxo-1-yl) alkanes/alkanones and their salts: The novel 10(4-aryl/heteroarylpiperazin/piperidin-1 -yl)n-(quinoloxy-6/7/8-yl/4-(un)substituted pyrrolidin-2-oxo-1-yl)alkanes/alkanones prepared by the process of the present invention having formula III wherein R represents groups like quinoloxy -6/7/8-yl,4-(un)substituted-pyrrolidin-2-oxo-1-yl, R1 represents group like aryl and heteroaryl, Z=N/CR2(R2=H, OH, COCH3), X=O/H2, n=2-5. These compounds have antiischemic, anti-inflammatory, anxiolytic anft/or antihypertensive activities and would be useful for the treatment of ischemia, inflammation, hypertension and other related CVS and CMS disorders.

Full Text	The invention particularly relates to a process tor the synthesis of novel l-(4-aryl/heteroaryl- piperazin/piperidin-1-yl)-n-(quinoloxy-6/7/8-y!/4-(un)substituted-pyrrolidin-2-oxo-l- yl)alkanes/alkanones and their salts as potential antiischemic, antiinflammatory and antihypertensive agents useful for the treatment of ischemia, inflammation, hypertension and other related CVS and CNS disorders. The novel l-(4-aryl/heteroarylpiperazin/piperidin-l-yl)-n-(quinoloxy-6/7/8-yl/4-(un)substituted pyrrolidin-2-oxo-l-yl)alkanes/alkanones prepared by the process of the present invention having formula III as shown in the drawing accompanying this specification, where R represents groups like quinoloxy-6/7/8-yl, 4-(un)substituted-pyrrolidin-2-oxo-l-yl, R1 represents group like aryl and heteroaryl, Z=N/CR: (R^H, OH, COCH3), X=O/H2, n=2-5. These compounds have antiischemic, antiinflammatory, anxiolytic and/or antihypertensive activities and would be useful for the treatment of ischemia, inflammation, hypertension and other related CVS and CNS disorders. The main objective of the present invention is to provide novel l-(4-aryl/heteroarylpiperazin/ piperidin- 1 -yl)n-(quinoloxy-6/7/8-yl/ 4-(un)substituted-pyrrolidin-2-oxo- 1 -yi)alkanes/alkanones and their salts/a process for the synthesis of the compounds of the formula III as defined above which would be useful for disease conditions amenable to treatment with agents acting against ischemia,inflammation, hypertension and other related CVS and CNS disorders. The compounds of the present invention may be prepared by the methods well known with art and familiar to a well versed synthetic organic chemist. The process used for the preparation of the compounds of the formula III according to the present inventions are illustrated in the reaction scheme as shown in the accompanying drawing. Accordingly the present invention provides novel l-(4-aryl/heteroarylpiperazin/piperidin-l-yl)-n-(quinoloxy-6/7/8-yl/4-(un)substituted-pyrrolidin-2-oxo-l-yl)alkanes/ alkanones and their salts of the formula given below. (Formula Removed) wherein R represents groups like quinoloxy-6/7/8-yl, 4-(un)substituted-pyrro!idin-2-oxo-l-yl, R' represents group like phenyl, halophenyl, alkylphenyl, alkoxyphenyl, trifluoromethylphenyl, heteroaryl such as pyridyl etc., Z=N/CR2 (R2=H, OH, COCH3), X=0/H2, n=2-5 Accordingly the present invention provides a process for the preparation of 1-(4-aryl/heteroarylpiperazin/piperidin-1-yl) - n - ( quinoloxy-6/7/8-yl/4- (un)substituted pyrrolidin - 2 - oxo - 1-yl)alkanes/alkanones and their salts useful as therapeutic agent and having the formula III as shown in the drawing accompanying this specification, wherein R represents groups such as quinoloxy-6/7/8-yi,4-(un)substituted -pyrrolidin-2-one-1-yl; R1 represents group such as phenyl, halophenyl, alkylphenyl, alkoxyphenyl, pyridyl, trifluorophenyl; n=2-5; X=O/H2 and Z=N/CR2 (R2 = H, OH, COCH3) which comprises condensing of a compound of the formula 1 comprising a group selected from 1-chloro-n-(quinoloxy-6/7/8-yl/4-(un)substituted-pyrroltdin-2-oxo-1-yl)-alkanes/alkan-2-ones with 4-(aryl/heteroaryl)piperazin/piperidin-1-yl of formula II, wherein the meaning of R,R1, n, X,Z is as above, in the presence of a base and an organic solvent as defined herein, in presence of a catalyst as described herein at temperature ranging 80°C-130°C, to produce the corresponding 1-(4-aryl/heteroarylpiperazin/piperidin-1-yl)-n-(quinoloxy - 6/7/ 8 - yl / 4 - (un) substituted - pyrrolidin - 2 - oxo - 1 -yl)alkanes/alkanones of formula III, purifying the products by conventional methods such as herein described, converting free base compounds of formula III into their corresponding salts by known methods. In an embodiment of the present invention the bases used may be such as potassium or sodium carbonate, potassium or sodium bicarbonate , potassium hydroxide. In another embodiment of the present invention the solvents used may be such as acetone, toluene, dimethyl formamide. In yet another embodiment of the present invention the reaction may be catalyzed by the addition of the catalyst such as potassium or sodium iodide, tetrabutylammonium iodide. In a feature of the invention the free bas ecompounds of formula 111 may be converted to the salts such as hydrochloride. The method comprises condensing 1-chloro-n-(quinoloxy-6/7/8-yl/4-(un)substituted pyrrolidin-2-oxo-1-yljalkanes/alkanones of the formula I with (4-aryl/heteroaryl)piperazine/piperidine of the formula II in the presence of bases like potassium or sodium carbonate, potassium or sodium bicarbonate or powdered potassium hydroxide and suitable solvent such as acetone , toluene or dimethylformide at temperatures ranging upto 130°C for a period varying between 6-36 hours to produce the corresponding 1-( 4- aryl/ heteroarylpiperazin/piperidin -1- )- n -( quinoloxy- 6/7/8-yl/4-(un)substituted pyrrolidin-2-oxo-l-yl)alkanes/alkanones of the formula III where R represents groups like quinoloxy-6/7/8-yl, 4-(un)substituted pyrrolidin-2-oxo-l-yl; R1 represents group like phenyl, halophenyl, alkylphenyl, alkoxyphenyl, trifluoromethylphenyl, heteroaryl such as pyridyl etc.; Z=N/CR2 (R2=H, OH, COCH3); XO/H2 n=2-5. The reaction may be facilitated and reaction time can be decreased by adding catalyst like sodium/potassium iodide or tetrabutyl ammonium iodide. In the above synthesis, where specific bases, solvents etc. are mentioned, it is to be understood that the other bases, solvents may be used. Similarly, the reaction temperature and duration of the reaction may be adjusted according to the desired results. Preferred compounds according to the invention and capable of being produced by the reaction sequences described above are given below. (Formula Removed) wherein R represents groups like quinoloxy-6/7/8-yl, 4-(un)substituted-pyrrolidin-2-oxo-l-yl, R1 represents group like phenyl, halophenyl, alkylphenyl, alkoxyphenyl, trifluoromethylphenyl, heteroaryl such as pyridyl etc., Z=N/CR2 (R2=H, OH, COCH3), X=O/H2, n=2-5. The preferred compounds of formula in prepared by the process of present invention are as follows. 1-[4-(4-Fluorophenyi)piperazin-l-yl]-3-(pyrrolidin-2-oxo-l-yI)propan-3-one of the formula III where n=3, X=O, Z=N, R= CAN-2-O, R'=C6H4-4-F 1-[4-(4-FluorophenyI)piperazin-l-yl]-3-[4-(4-chlorophenyI)pyrrolidin-2-oxo-l-ylJpropane of the formula III where n-3, X=H2, Z=N, R= C4H5N-2-O-4-C6H4-4-Cl, R'=C6H4-4-F l-[4-(4-FIuorophenyI)piperazin-l-yI]-3-[4-{3,4-dimethoxyphenyI)pyrrolidin-2-oxo-l-yl]propane of the formula III where n=3, X=H2, Z=N, R=C4HsN-2-O-4-C6H3-3,4-(OCH3)2, R1=C6H4-4-F l-[4-(4-FIuorophenyI)piperazin-l-yIJ-2-(pyrrolidin-2-oxo-l-yl)ethan-2-one of the formula III where n=2, X=O, Z=N, R= C4H6N-2-O, R1=C6H4-4-F l-[4-(2-m ethoxyphenyI)piperazin-l-yl]-3-(pyrrolidin-2-oxo-l-yl)propan-3-one of the formula m where n=3, X=O, Z=N, R= C4H6N-2-O , R'=C6H4-2-OCH3 l-[4-(Trifluoromethylphenyl)piperazin-l-yl]-3-{pyrrolidin-2-oxo-l-yI)propan-3-one of the formula III where n=3, X=O, Z=N, R= C4H6N-2-O ,R1=C6H4-4-CF3 l-[4-(3,4 -Dichlorophenyl)piperazin-l-yl]-3-(pyrrolidin-2-oxo-l-yl)propan-3-one of the formula m where n=3, X=O, Z=N, R= C4H6N-2-O , R1=C6H33,4-C1 2 l-[4-(2-Chlorophenyl)piperazin-l-yl]-3-(pyrroIidin-2-oxo-l-yl)propan-3-one of the formula III where n=3, X=O, Z=N, R= C4H6N-2-O , R'=C6H4-2-CI 1-[4-(2-Methoxyphenyl)piperazin-l-yI]-2-{pyrroIidin-2-oxo-l- yI)ethan-2-one of the formula III where n=2, X=O, Z=N, R= C4H6N-2-O, R1=C6H4-2-OCH3 l-[4-(3,4-DichlorophenyI)piperazin-l-yl]-2-(pyrrolidin-2-oxo-l- yl)ethan-2-one of the formula III where n=2, X=O, Z=N, R= C4H6N-2-O R1=C6H4-3,4-Cl 2 l-[4-(2-ChlorophenyI)piperazin-l-yI]-2-(pyrroLidin-2-oxo-l-yl)ethan-2-one of the formula III where n=2, X=O, Z=N, R= C4H6N-2-O, R1=H2-Z-CI l-[4-(3-TrifluoromethylphenyI)piperazin-l-yl]-2-(pyrrolidin-2-oxo-l-yl)ethan-2-one of the formula III where n=2, X=O, Z=N, R= C4H6N-2-O, R'=C6H4-3-CF3 l-[4-(Phenyl)piperazin-l-yI]-2-(pyrrolidin-2-oxo-l-yl)ethan-2-one of the formula III where n=2, X=O, Z=N, R= C4H4N-2-O, R1=C6H5 l-[4-(4-Chlorophenylpipernzin-l-yl]-2-(pyrro!idin-2-oxo-l-yl)ethan-2-one of the formula III where n=2, X=O, Z=N, R= C6H6N-N-2-O , R1=C6H4-4-Cl l-[4-(4-ChlorophenyIpiperazin-l-yl]-4-(pyrrolidin-2-oxo-l-yl)butan-4-one of the formula III where n=4, X=O, Z=N, R= C4H6N-2-O R'=C6H4--4-Cl l-[4-(3-trifluoromethylphenyl)piperazin-l-yl]-3-(quinoloxy-8-yl)propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO, R1=CsH4-3-CF3 l-[4-(3-chIorophenyl)piperazin-l-yl]-3-(quinoloxy-8-yI) propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO,Rl=C6H4-4-Cl 1-[4-{2-ChlorophenyI)piperazin-l-yl]-4-{quinoIoxy-7-yI)butaneof the formula III where n=4, X=H2, Z=N, R= C9H6NO,R1=C6H4-2-Cl I-[4-(4-hydroxy-4-phenyI)piperidin-l-yl)-4-(quinoIoxy-7-yl)butane of the formula III where n=4, X=H2, Z=C, R= C9H4NO, Rl=C6Hs, R2=OH 1-[4-(4-Hydroxy-4-phenyl)piperidin-l-yI-3-{quinoIoxy-8-yl)propane of the formula III where n=3, X=H2, Z=C, R= C9H6NO, R1C6H, , R2=OH l-[4-(4-ethylphenyl)piperazin-l-yl]-3-(quinoloxy-8-yI)propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO, R1=C6H4-4-C2H5 1-[4-{2-PyridyI)piperazin-l-y3]-3-(quinoIoxy-8-yl)propaneof the formula III where n=4, X=H2, Z=N, R= !-[4-(3-MethyIphenyI)piperazin-l-yI]-3-{quinoIoxy-8-yl)propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO,, R'=C6H4-3-CH3 !-{4-(3,4-diraethoxyphenyl)piperazin-l-yl]-3-{quinoloxy-&-yJ) propane of the formula III where n=3, X=H2, Z=N, R= CsH^NO, R}=C6Hr3t4-(OCH3)2 l-[4-(4-Chloro-2-methylphenyl)piperazin-l-yl]-3-(quinoloxy-8-yI) propane of the formula III where n=3, X=H2, Z^=N, R= C9H6NO, R1=C4H3-2-CH3 -4-Cl l-[4-(3-trifluoromethyl)phenylpiperazin-l-ylJ-3-(quinoloxy-7-yl) propane of the formula III where n=3, X=H2, Z=N, R= C,H4NO, R1=C6H4-3-CF3 I-[4-(3-trifluoromethyIphenyl)piperazin-l-yl]-3-(quinoloxy-6-yl) propane of the formula HI where n=3, X=H2, Z=N, R= C,H6NO, R1=C6H4-3-CF3 l-[4-(3-methoxyphenyl)piperazin-l-yl]-3-(quinoloxy-8-yl) propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO, R1=C6H4-3-OCH3 1-[4-{2-methoxyphenyl)piperazin-l-yI]-3-(quinoIoxy-8-yl) propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO, Rl=C6H42-OCH3 1-[4-{4-fluorophenyI)piperazin-l-yl]-3-(qumoloxy-7-yl) propane of the formula III where n=3, X=H2, Z=N, R= C,H6NO, R1=C6H4-4-F l-[4-(2-methoxyphenyI)piperazin-l-yl]-3-(quinoIoxy-7-y\|) propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO, R'=C6H4-2-OCH3 1-[4-{2-chIorophenyl)piperazin-l-yI]-3-(quinoIoxy-7-yI) propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO, R1=C6H4-2-CI l-[4-(4-hydroxy-4-phenyl)piperidine-l- yl]-3-(quinoloxy-7-yl) propane of the formula III where n=3, X=H2, Z=C, R= C9H6NO, Rl=C6H5, R2= OH 1-[4-(2-methoxyphenyI)piperazin-l-yl]-4-{quinoloxy-7-yl) butane of the formula III where n=4, X=H2, Z=N, R= C9H6NO, R1=C6H4-2-OCH3 1-[4-(2-chlorophenyI)piperazin-l-yI]-5-(quinoloxy-7-yl) pentane of the formula III where n=5, X=H2, Z=N, R= C9H6NO, RJ=C6H4-2-CI l-[4-(4-FluorophenyI)piperazin-l-yl]-3-(quinoloxy-7-yl)propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO, R'=C6H4-4-F l-[4-(2-pyridyl)piperazin-l-yl]-3-{quinoloxy-7-yl)propane of the formula III where n=3, X=H2, Z=N, R= C,H6NO, R1=C5H5N l-[4-(2-Methyl-4-chIorophenyl)piperazin-l-yl]-3-(quinoloxy-7-yl)propane of the formula III where n=3, X=H2, Z=N, R= C,H6NO, RI=C6H3-2-CH3 -4-C1 l-[4-(3,4-dichlorophenyl)piperazin-l-yl]-3-(quinoloxy-7-yl)propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO, R1=- l-[4-(4-Methoxyphenyl)piperazin-1-yL)-3-(quInoloxy-7-yS)propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO, R'=C6H4-4-OCH3 1-[4-(4-Chlorophenyl)piperazin-l-yl]-3-(qu!noIoxy-7-yI)propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO, R'=C6H4-4-Cl l-[4-(4-AcetyI-4-phenyl)piperidin-l-yl]-3-(quinoloxy-7-yl)propane of the formula III where n=3, X=H2, Z=N, R= C,H6NO, Rl=C6H5 , R2=COCH3 1-[4-{3-ChIorophenyl)piperazin-l-yl]-3-(quuioIoxy-7-yl) propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO, R'=C6H4-3-Cl 1-[4-{3-MethylphenyI)piperazin-l-yI]-3-(quinoIoxy-7-yl) propane of the formula III where n=3, X=H2, Z=N, R= C,H6NO, Rl=C6H4-3-CH3 l-[4-(2-Chlorophenyl)piperazin-l-yl]-3-(quinoloxy-6-yl) propane of the formula III where n=3, X=H2, Z=N, R= C,H6NO, Rl=C6R4-2-Cl l-[4-(4-ChIorophenyl)piperazin-l-yl]-3-{quinoloxy-6-yl) propane of the formula III where n=3, X=H2, Z=N, R= , Rl=C6H4-4-Cl l-(4-Hydroxy-4-phenylpiperidin-l-yIJ-3-{quinoIoxy-6-yl) propane of the formula HI where n=3, X=H2, Z=C, R= CsH^NO, R1-C6H5, R2=OH 1-[4-{3-Methylphenyl)piperazin-l-yI]-3-(quinoloxy-6-yI) propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO, R1=C6H4-3-CH3 1-[4-(2-Pyridyl)piperazin-l-yI]-3-(quinoloxy-6-yI)propane of the formula III where n=3, X=H , Z=N, R= C9H6NO, R1=C5H5N 1-{4-{2-Ethylphenyl)piperazin-l-yl]-3-(quinoloxy-6-yl) propane of the formula III where n=3, X=H2, Z=N, R= C,H6NO, R1=HC6H4-2-C2H5. 1-[4-(4-Methoxyphenyl)piperazin-l-ylJ-3-(quinoloxy-6-yI) propane of the formula III where n=3, X=H2, Z=N, R= C9H6O, R1=C6H4-4-OCH3 l-l4-(2-Methoxyphenyl)piperazin-l-yl]-3-(quinoIoxy-6-yl) propane of the formula HI where n=3, X=H2, Z=N, R- C9H6NO, R1=C6H4-2-OCH3. PharmacologicaS Acdvitics : The compounds of invention show marked anti-ischemic/cardioprotective activity with few of them showing mild hypotensive activity and can be used as therapeutic agents in disease arising out of ischemia such as myocardial ischemia. Angina Pectoris myocardial infarction, any cardiac surgical intervention renal ischemia, stroke and trauma. Some of the compounds have also shown antiinflammatory activity and can be used as therapeutic agents in diseases arising out of inflammatory disorders like rheumatism, arthretis etc. Cardioprotective Activities: The most important and intersting observations is cardioprotective/anti-ischemic activity against myocardial stunning at a much smaller dose. Isolated perfused rat heart preparation (Langendorff) were allowed to equilibriate for 30 min. before subjecting to 45 min. of global ischemia followed by 30 min. reperfusion period. Compounds under test were administered during reperfusion period at a concentration of 10 nM. The recovery of mechanical function (start of heart beat) with treated group was much earlier than control group. The incidence of reperfusion induced arrhythmia was either reduced or absent with test compounds when compared with control. Results are given in Table No. 1. 2. Effect on blood pressure, heart rate, respiration and on standard vasopressor and vasopressor responses. Pentobarbitone sodium (40 mg/kg i.p.) Anaesthetized cats of either sex weight 2.5-4.0 kg body weight were used for this study. Majority of them were normotensive but three of them were naturally hypertensive (basal mean arterial blood pressure > 160 mm Hg). Results are summarised in Table No. 2. 3. Antiinfiammatory Activity: Some of these compounds were screened for Anti-inflammatory activity using Carrageenin induced paw oedema in rats in a dose of 100 µmol.p.o.and compared with Ibuprofen (l00µmoI.p.o.). p.o.). Results are summarised in Table No. 3. Table 1: Isolated perfused rat heart preparation No flow - 45'(Global ischemia) Dose -10 nM (Given at the time of reperfusion) (Table Removed) ** = Mild Hypotensive, * = Weak Hypotensive. Table 2: CVS data of the compounds (Table Removed) Tr = Transient, Pt ND= Not Done, - = = Potentiation, J = Fall in blood pressure, f = Rise in blood pressure ; No Effect, R= Reversal, D= Decrease. Table 3 : Antiinflammatory activity of the compounds. (Table Removed) The following examples are given below to illustrate the details of the invention and should not be construed to limit the scope of the present invention. Example 1: l-[4-(4-Fluorophenyl)piperazin-l-yI]-3-(pyrrolidin-2-oxo-l-yl)propan-3-one A mixture of l-chloro-3-(pyrrolidin-2-oxo-l-yl)propan-3-one (0.52 g, 0.003 mol), l-(4-fluorophenyl)-piperazine (0.54 g, 0.003 mol) and K2CO3 (0.42 g) in dry DMF (20 ml) was heated at 90°C for 10 hours. It was diluted with water (50 ml), extracted with chloroform (3x30 mi), the combined chloroform extracts were washed with water (3x20 ml), dried (Na2SO4), concentrated and purified by column chromatography on silica gel column using ethyl acetate as eluant. It was and crystalized with hexane-ether. Yield 0.50 g(53%), m.p. 104C FTIR (KBr, cm'1): 3460, 2932,2824,1738, 1694, 1512, 1242, 820;'H-NMR (CDC13): 5 (ppm) 2.04(qn, 2H, J=7.72 Hz, 4-CH2 (pyrrolidone)), 2.56-2.69(m, 6H, 3-CH2 (pyrrolidone), N(CH2)2), 2.80(1, 2H, J=7.5 Hz, COCH2), 3.09-3.20(m, 6H, N(CH2)2, N-CH2), 3.82(t, 2H, J=7.3 Hz, 5-CH2 (pyrrolidone)), 6.82-7.00(m, 4H, ArH); MS: m/z 319 (M+) Example 2: l-[4-(4-FIuorophenyl)piperazin-l-yI}-3-[4-(4-chlorophenyI)-pyrrolidin-2-oxo-l-yl]propane A mixture of l-chloro-3-[4-(4-chlorophenyl)-pyrrolidin-2-oxo-l-yl)propane (0.27 g, 0.001 mol), l-(4-fluorophenyl)piperazine (0.18 g, 0.001 mol) and K2CO3 (0.14 g) in dry DMF (20 ml) was heated at 1200C for 12 hours. It was diluted with water (50 ml), extracted with chloroform (3x30 ml), the combined chloroform extracts were washed with water (3x20 ml), dried (NaSO4), concentrated and purified by column chromatography on silica gel column using MeOH (2%) in CHC13as eluant. It was characterized as its dihydrochloride. Yield 0.22 g (53%), m.p. 1860C. FT1R (KBr, cm-1): 3466, 2943, 2822, 2785, 1682, 1501, 3234, 1163, 1092, 1015, 825, 754;'H-NMR (CDC1,): 8 (ppm) 1.78(qn, 2H, J=7.32 Hz, CH2), 2.38-2.46(m, 3H, 4-CH & 3-CH2 (pyrrolidone)), 2.53-2.62(m, 4H, N(CH2)2), 3.09-3.14(m, 4H, N(CH2)2), 3.36-3.43(m, 4H, N-CH2), 3.73-3.78(m, 2H, 5-CH, (pyrrolidone)), 6.85-7.00(m, 4H, ArH), 7.13-7.33(m, 4H, ArH); MS: m/z 415 (NT). Example 3: 1-[4-{4-FIuorophenyl)piperazin-l-yl]-3-[4-(3,4-dimethoxyphenyl)-pyrrolidin-2-oxo-l-yllpropane A mixture of l-chloro-3-[4-(3,4-dimethoxyphenyl)-pyrrolidin-2-oxo-l-yl]propane (0.30 g, 0.001 mol), l-(4-fluorophenyl)piperazine (0.18 g, 0.001 mol) and K2CO3 (0.14 g) in dry xylene (30 ml) was heated at 1400C for 15 hours. It was diluted with water (60 ml), extracted with chloroform (3x30 ml), the combined chloroform extracts were washed with water (3x30 ml), dried (Na2O4), concentrated and purified by column chromatography on silica gel column using MeOH (2.5%) in CHC13 as eluant. It was characterized as its dihydrochloride. Yield 0.25 g (57%), m.p. 1410C FT1R (KBr, cm'1): 3381,3022,2920,1576,1215,759;'H-NMR (CDC13): o (ppm) 1.75-1.82(m, 4H, CH2,3~CH2 (pyrrolidone)), 2.39-2.47(m, 2H, CH2-N), 2.57-2.62(m, 4H, N(CH2)2), 2.75-2.79(m, 1H, 4-CH (pyrrolidone)), 3.09-3.14(m, 4H, N(CH2)2), 3.36-3.43(m, 4H, N- CH^ 5-CH2(pyrrolidone)), 3.87(s, 6H, 2(OCH3)), 6.72-7.00(m, 7H, ArH); MS: m/z 438 (M4-3). Example 4: l-[4-(4-Fluorophenyl)piperazin-l-yIj-2-(pyrroIidin-2-oxo-l-yl)ethan-2-one A mixture of l-chloro-2-{pyrrolidin-2-oxo-l-yl)ethan-2-one (0.54 g, 0.0034 mol), l-(4-fluorophenyi)-piperazine (0.54 g, 0.003 mol) and K2CO3 (0.22 g) and Nal (0.05 g) in dry DMF (7 ml) was heated at 80°C for 18 hours. It was diluted with water (20 ml), extracted with ethylacetate (3x50 ml), the combined ethylacetate extract was washed with water (3x30 ml), dried (Na2SO4, concentrated and purified by column chromatography on silica gel column using ethylacetate as eluant. Yield 0.50 g (50%), m.p. 1240C. FTIR (KBr, cm'1): 3454,3052, 2966, 2906, 2826, 1734, 1694, 1512, 1242, 824; 'H-NMR (CDC13): 5 (ppm) 2.08(qn, 2H, J=7.26 Hz, 4-CH2 (pyrrolidone)), 2.61(t, 2H, J-7.88 Hz, 3-CH2 (pyrrolidone)), 2.76-2.81(m, 4H, N(CH2)2), 3.16-3.20(m, 4H, NfCH^), 3.80-3.87(m, 4H, COCH2 & 5-CH2 (pyrrolidone)), 6.84-7,02(m, 4H, ArH); MS; m/z 305 (M4). Example 5: 1-{4-(2-Methoxyphenyl)piperazin-l-yl]-3-(pyrrolidin-2-oxo-l-yl)propan-3-one A mixture of 3-chloro-3-(pyrrolidin-2-oxo-l-yl)propan-3-one (0.52 g, 0.003 mol), l-(2-methoxy-phenyl)piperazine (0.57 g, 0.003 mol) and K2O3(0.42 g) and Nal (0.02 g) in dry DMF (10 ml) was heated at 180°C for 30 hours. It was diluted with water (40 ml), extracted with chloroform (3x30 ml), the combined chloroform extract was washed with water (3x20 ml), dried (Na2S04), concentrated and purified by column chromatography on silica gel column using ethylacetate as eluant. It was characterized as its dihydrochloride. Yield 0.54 g (54%), m.p. 1500C. FTIR (KBr, cm-1 '): 3390, 2954, 1740, 1678, 1594, 1500, 1246, 746;1H-NMR (CDC13): 5 (ppm) 2.02-2.08(m, 2H, 4-CH2 (pyrrolidone)), 2.56-2.61(m, 2H, 3-CH2 (pyrrolidone)), 2.83-2.88(m, 2H, CH2), 2.94-2.97(m, 2H, CH2-N), 3.12-3.23(m, 8H, 2 x N-(CH2)2), 3.78-3.88(m, 5H, OCH3 & 5-CH2(pyrrolidone)), 6.84-7.03(m, 4H, ArH), MS: m/z 331 (M+). Example 6: l-[4-(TrifluoromethyJphenyl)piperazin-l-ylJ-3-(pyrrolidin-2-oxo-l-yI)propan-3-one A mixture of l-chloro-3-(pyrrolidin-2-oxo-l-yl)propan-3-one (0.52 g, 0.003 mol), l-(3-trifluoro-methylphenyl)piperazine (0.73 g, 0.003 mol), Na2CO3 (0.31 g, 0.003 mol) and Nal (0.02 g) in dry acetone (50 ml) was refluxed on water bath for 40 hours. Reaction mixture was filtered, concentrated and purified by column chromatography on silica gel column using ethylacetate as eluant. It was characterized as its dihydrochloride. Yield 0.58 g (53%), m.p. 155 0C. FTIR (KBr, cm -1): 3370,2922, 1674,1338, 1138;'H-NMR (CDC13): 6 (ppm) 2.04-2.08(m, 2H, 4-CH2 (pyrrolidone)), 2.39(bs, 4H, COCH2, 3-CH2 (pyrrolidone)), 2.57-2.95(m, 6H, N(CH2)2 & CH2-N), 3.14-3.27(m, 4H, N(CH2)2), 3.82(t, 2H, J=7.14 Hz, 5-CH2(pyrrolidone)), 6.97-7.16(m, 2H, ArH), 7.30-7.51(m, 2H, ArH); MS: m/z 369 (M+). Example 7: 1-[4-(3,4-Dichlorophenyl)piperazin-l-yI]-3-(pyrroIidin-2-oxo-l-yl)propan-3-one A mixture of l-chloro-3-(pyrrolidin-2-oxo-l-yl)propan-3-one (0.35 g, 0.002 mol), l-(3,4-dichloro-phenyl)piperazine (0.46 g, 0.002 mol) and K2O3(0.26 g) and Nal (0.02 g) in dry DMF (25 ml) was heated at 100°C for 8 hours. The reaction mixture was diluted with water (50 ml), extracted with ethylacetate (3x30 ml), the combined ethylacetate extract was washed with water (3x30 ml), dried (Na2S04), concentrated and purified by column chromatography on silica gel column using MeOH (2%) in ethylacetate as eluant. It was characterized as its dihydrochloride. Yield 0.25 g (34%), m.p. 156°C. FTIR (KBr, cm'1): 3418, 3022, 1714, 1592, 1224, 758;'H-NMR (CDCI3): 5 (ppm) 2.00-2.ll(m, 2H, 4-CH2 (pyrrolidone)), 2.57-2.67(m, 6H, 3-CH2(pyrrolidone) & N(CH2)2), 2.76-2.88(m, 2H, COCH2), 3.12- 3.19(m, 6H, CH2-N & N(CH2)2), 3.82(t, 2H, J=7.12 Hz, 5-CH2 (pyrrolidone)), 6.69-6.76(m, 1H, ArH), 6.93-6.98(m, 1H, ArH), 7.23-7.33(m, 1H, ArH); MS: m/z 370 (MO. Example 8: l-\|4-(2-ChIorophenyl)piperazin-l-yl]-3-(pyrro!idin-2-oxo-l-yl)propan-3-one A mixture of l-chloro-3-(pyrrolidin-2-oxo-l-yl)propan-3-one (0.35 g, 0.002 mol), l-(2-chlorophenyl)-piperazine (0.39 g, 0.002 mol) and K2CO3 (0.26 g) and Nal (0.02 g) in dry DMF (25 ml) was heated at 90°C for 10 hours. The reaction mixture was diluted with water (40 ml), extracted with ethylacetate (3x30 ml), the combined ethylacetate extract was washed with water (3x30 ml), dried (Na2SO4), concentrated and purified by column chromatography on silica gel column using 1% MeOH in ethylacetate as eluant. It was characterized as its dihydrochloride. Yield 0.30 g (45%), m.p. 160°C. FTIR (KBr, cm'1): 3462,2948,2822,1738,1690,1592, 1244,760;'H-NMR (CDC1,): δ (ppm) 2.04(qn, 2H, J=7.24 Hz, 4-CH2 (pyrrolidone)), 2.61(t, 2H, J=8.04 Hz, 3-CH, (pyrrolidone)), 2.71-2.73(m, 4H, l N(CH)2, 2.79-2.88(m, 2H, COCH2), 3.06-3.21(m, 6H, N(CH2)2 & CH2-N), 3.82(t, 2H, J=7.06 Hz, 5-CH2 (pyrrolidone)), 7.01(dd, 2H, J=1.54 & 8.08 Hz, ArH), 7.20(d, 1H, J=7.22 Hz, ArH), 7.34(dd, 1H, J=1.46 & 7.78 Hz, ArH); MS: m/z 335 (Mf). Example 9: l-[4-(2-MethoxyphenyI)piperazin-l-yI]-2-(pyrrolidin-2-oxo-l-yI)ethan-2-one A mixture of l-chloro-2-(pyrrolidin-2-oxo-l-yl)ethan-2-one (0.54 g, 0.0034 mol), l-(2-methoxy-phenyl)piperazine (0.71 g, 0.0037 mol), K2CO, (0.42 g) and Nal (0.06 g) in dry DMF (10 ml) was heated at 90T: for 15 hours. It was diluted with water (20 ml), extracted with ethylacetate (3x30 ml). The combined ethylacetate extract was washed with water (3x20 ml), dried (Na2SO4) and concentrated to give an oil which was purified by column chromatography on silica gel using ethylacetate as eluant. Yield 0.25 g (25%), oil. FTIR (Neat, cm'1): 3372, 2948, 2830, 1676, 1598, 1302, 1240, 754;'H-NMR (CDC13): δ (ppm) 1.99-2.02(m, 2H, 4-CH2 (pyrrolidone)), 2.80-2.84(m, 2H, 3-CH2 (pyrrolidone)), 2.98-3.13(m, 4H, N(CH2)2), 3.30-3.50(m, 4H, N(CH2)2), 3.72-3.81(m, 7H, OCH3, N-CH2, 5-CH, (pyrrolidone)), 6.77-7.02(m, 4H, ArH); MS: m/z 317 (M'). Example 10: l-[4-(3,4-DichIorophenyl)piperazin-l-yl]-2-(pyrrolidin-2-oxo-l-yl)ethan-2-one A mixture of l-chloro-2(pyrrolidin-2-oxo-l-yl)ethan-2-one (0.54 g, 0.0034 mol), 1 -(3,4-dichloro-phenyl)piperazine dihydrochlonde (0.98 g, 0.0037 mol), dry k2co3(0.53 g) and Nal (0.06 g) in dry DMF (5 ml) was heated at 100°C for 12 hours. It was diluted with water (40 ml) and crude solid obtained was purified by column chromatography on silica gel using ethylacetate as eluant. It was crystalized with ether hcxane. Yield 0.65 g (55%), m.p. 1520C. FTIR (KBr, cm'1): 3448,2840, 1698, 1594, 1480, 1240, 808;'H-NMR (CDC13): 8 (ppm) 2.08(qn, 2H, J=7.28 Hz, 4-CH2 (pyrrolidone)), 2.61(1,2H, J=8.12 Hz, 3-CH2(pyrrolidone)), 2.75-2.80(m,4H, N(CH2)2, 3.21-3.25(m, 4H, N(CH2)2), 3.68-3.87(m, 4H, 5-CH2 (pyrrolidone) & N-CH,), 6.73(dd, 1H, J=2.68 & 8.76 Hz, ArH), 6.95(s, 1H, ArH), 7.24-7.28(m, 1H, ArH); MS: m/z 356 (M+). Example 11: l-[4-(2-ChLorophenyl)piperazin-l-ylj-2-(pyrroIidin-2-oxo-l-yl)ethan-2-one A mixture of l-chLoro-2-(pyrrolidin-2-oxo-l-yl)ethan-2-one (0.54 g, 0.0034 mol), l-(2-chlorophenyl)-piperazine monohydrochloride (0.86 g, 0.0037 mol), dry K2CO3 ,(0.53 g) and Nal (0.02 g) in acetone (50 ml) was refluxed at 80°C for 36 hours. Reaction mixture was filtered, concentrated to give an 011 which was purified by column chromatography on silica gel using ethylacetate as eluant. Yield 0.20 g (19%), oil. FTIR (Neat, cm' '): 3352, 3014, 2828, 1740, 1700, 1594, 1226, 758; H-NMR (CDC13): 8 (ppm) 2.05(m, 2H, 4-CH2 (pyrrolidone)), 2.54(t, 2H, J=8.0 Hz, 3-CH2 (pyrrolidone)), 2.80-2.85(m, 4H, N(CH2)2), 3.09-3.17(m, 4H, N(CH2)2), 3.80-3.87(m, 4H, 5-CH2 (pyrrolidone)) & N-CH2), 6.96- 7.08(m, 2H, ArH), 7.18-7.37(m, 2H, ArH); MS: m/z321 (M+). Example 12: l-[4-(3-Trifluoromethylphenyl)piperazin-l-yl]-2-(pyrroIidin-2-oxo-l-yI)ethan-2-one A mixture of l-chloro-2-(pyrrolidin-2-oxo-l-yl)ethan-2-one (0.48 g, 0.003 mol), l-(3-trifluoromethyl-phenyl)piperazine (0.76 g, 0.0033 mol), K2CO3 (0.42 g) and Nal (0.06 g) in dry DMF (5 ml) was heated at 90°C for 16 hours. It was diluted with water (20 ml). The resultant solid was recrystallized with ethylacetate. Yield 0.45 g (43%), m.p. 1050C. FTIR (KBr, cm'1): 3436,2830, 1722,1608,1328, 1162, 956;'H-NMR (CDC13): 5 (ppm) 2.09(qn, 2H, J=7.66 Hz, 4-CH2 (pyrrolidone)), 2.61(t, 2H, J=8.12 Hz, 3-CH2 (pyrrolidone)), 2.82-2.86(m, 4H, N(CH )2)i2 3.30-3.34(m, 4H, N(CH ) ),2 2 3.80-3.87(m, 4H, 5-CH2 (pyrrolidone) & NCH2), 7.05-7.38(m, 4H, ArH); MS: m/z 355 (M4). Example 13: l-[4-(PhenyI)piperazin-l-yI]-2-(pyrrolidin-2-oxo-l-yl)ethan-2-one A mixture of l-chloro-2-(pyrrolidin-2-oxo-l-yl)ethan-2-one (0.48 g, 0.003 mol), phenylpiperazine (0.54 g, 0.0033 mol), Na2CO3 (0.32 g) and Nal (0.04 g) in dry DMF (5 ml) was heated at 90°C for 12 hours. It was diluted with water (20 ml) and resultant solid was recrystallized with ethylacetate. Yield 0.30 g (35%), m.p. 103-lOS'C. FTIR (KBr, cm'1): 3400, 2974,2828, 1736, 1698, 1598, 1500, 1240, 756;'H-NMR (CDC1,): δ (ppm) 2.04-2.ll(m, 2H, 4-CH2 (pyrrolidone)), 2.57-2.65(m, 2H, 3-CH2 (pyrrolidone)), 2.77-2.82(m, 4H, N(CH2)2), 3.19-3.29(m, 4H, N(CH2)2), 3.69-3.87(m, 4H, 5-CH, (pyrrolidone) & N-CH2), 6.85-6.95(m, 2H, ArH), 7.18-7.53(m, 3H, ArH); MS: m/z 287 (M+). Example 14: l-[4-(4-Chloropheny!piperazin-l-yl]-2-(pyrrolidin-2-oxo-l-yl)ethan-2-one A mixture of l-chloro-2-(pyrrolidin-2-oxo-l-yl)ethan-2-one (0.48 g, 0.003 mol), 1-(4-chlorophenyl)-piperazine dihydrochloride (0.90 g, 0.0033 mol), K2CO3(0.63 g) and Nal (0.06 g) in dry DMF (5 ml) was heated at 90^ for 16 hours. It was diluted with water (20 ml) to yield solid material which was recrystallized with ethylacetate. Yield 0.60 g(63%), m.p. 135-38"C. FTIR (KBr, cm): 3462,2902, 2826, 1740, 1664, 1594, 1498, 1226, 818; 'H-NMR (CDC13): δ (ppm) 2.07-2.19(m, 2H, 4-CH2 (pyrrolidone)), 2.56-2.60(m, 2H, 3-CH,(pyrrolidone)), 2.65-2.80(m, 4H, N(CH2)2), 3.14-3.28(m, 4H, N(CH2)2), 3.78-3.82(m, 4H, 5-CH2 (pyrrolidone) & N-CH2), 6.83(dd, 2H, J=2.28 & 9.02 Hz, ArH), 7.25(dd, 2H, J=3.38 & 6.68 Hz, ArH); MS: m/z 321 (M-). Example 15: l-[4-(4-Chlorophenylpiperazin-l-yIj-4-(pyrrolidin-2-oxo-l-yl)butan-4-one A mixture of l-chloro-4-(pyrrolidin-2-oxo-l-yl)butan-4-one (0.47 g, 0.0025 mol), l-(4-chlorophenyl)-piperazine dihydrochloride (0.67 g, 0.0025 mol), K2CO3(0.52 g) and Nal (0.08 g) in dry toluene (15 ml) was refluxed for 20 hours. The mixture was filtered, concentrated to yield an oil which was purified by column chromatography on silica gel using ethylacetate as eluant. It was characterized as its dihydrochloride. Yield 0.15 g (17%), m.p. 259-62°C. FTIR (Neat, cm'1): 3362, 2922, 2334, 1730, 1598, 1480, 1240, 1024, 808; 'H-NMR (CDC!3): δ (ppm) 0.76-0.83(m, 2H, CH2), 0.98-1.03(m, 2H, 4-CH2 (pyrrolidone)), 1.23-1.27(m, 2H, 3-CH2 (pyrrolidone)), 1.63-1.78(m, 4H, N(CH2)2), 2.02-2.04(m, 2H, COCH2), 3.14(bs, 4H, N(CH2)2), 3.69(bs, 4H, 5-CH2 (pyrrolidone) & CH2-N), 6.84(d, 2H, J=8.82 Hz, ArH), 7.23(d, 2H, J=9.2 Hz, ArH); MS: m/z 349 (M+). Example 16: l-\|4-(3-TrifluoromethyIphenyI)piperazin-l-ylJ-3-(quino!oxy-8-yl)propane A mixture of l-chloro-3-(quinoloxy-8-yl)propane (0.66 g, 0.003 mol), l-(3-trifluoromethylphenyl)-piperazine (0.75 g, 0.0033 mol) and K2CO3(0.4 g) in dry acetone (70 ml) was refluxed for 40 hours. Reaction mixture was filtered, concentrated and purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant. It was characterized as its dihydrochloride. Yield 0.56 g (45%),m.p. 135°C. FTIR(KBr,cm-1): 3050,2827, 1610, 1574, 1503, 1448, 1362, 1242, 1107, 1160, 1078, 993, 951, 822, 756, 731; 'H-NMR (CDC1.,): δ (ppm) 2.25(m, 2H, C-CH2-C), 2.68(m, 6H, NCH2), 3.25(t, 4H, J=6.3 Hz, ArNCH2), 4.30(t, 2H, J=7.2 Hz, OCH2), 6.90-7.50(m, 8H, Ar), 8.05(dd, 1H, J=9.0 & 1.8 Hz, Ar), 8.85(m, 1H, Ar-H); MS: m/z 415 (Mf). Example 17: l-[4-(3-ch!orophenyl)piperazin-l-yl]-3-(quinoIoxy-8-yI)propane A mixture of 1 -chloro-3-(quinoloxy-8-yI)propane (0.70 g, 0.0033 mol), l-(3-chlorophenyl)piperazine (0.58 g, 0.003 mol) and K2CO3 (0.4 g) in dry DMF (20 ml) was heated at 110°C for 15 hours. Reaction mixture was diluted with water (50 ml), extracted with chloroform (30x3 ml), the combined chloroform extracts were washed with water (20x3 ml), dried (Na2SO4, concentrated and purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant. It was crystallized with ether-hexane. Yield (0.60 g) (53%), m.p. 900C. FTIR (KBr,cm1): 3030, 2822, 1595, 1566, 1454, 1381, 1320, 1265, 1238, 1107, 788, 758; 'H-NMR (CDC13): δ (ppm) 2.22(m, 2H, C-CH2-C), 2.65(m, 6H, NCH2), 3.17(t, 4H, J-6.3 Hz, ArNCH2), 4.30(t, 2H, J-7.2 Hz, OCH2), 6.60-7.40(m, 8H, Ar), 8.05(dd, 1H, J=8.1 & 1.8 Hz, Ar), 8.85(m, 1H, Ar); MS: m/z 381 (Mf). Example 18: l-[4-(4-Fluoropheny!)piperazin-l-yl]-4-(quinoIoxy-7-yI) butane A mixture of l-chloro-4-(quinoloxy-7-yl) butane (0.705 g, 0.003 mol), l-(4-fluorophenyl)piperazine (0.54 g, 0.003 mol), K2CO3 (0.32 g) and Nal (0.02 g) in dry DMF (20 ml) was heated at 110°C for 12 hours. Reaction mixture was diluted with water (50 ml), extracted with chloroform (3x30 ml), the combined chloroform extracts were washed with water (3x20 ml), dried (NajSO4), concentrated and purified by column chromatography on silica gel using 1% MeOH in chioroform as eluant. Yield (0.55 g) (52%), m.p. 530C. FTIR (KBr,cm-1 ): 3844,3584,3416,3022, 2944, 2826,2404, 2348, 1708, 1632, 1564, 1510, 1442, 1384, 1218, 760, 662; 'H-NMR (CDC13): 5 (ppm) 1.86(m, 4H, C-CH2-C), 2.56(m, 6H, NCH2), 3.12(m, 4H, ArNCH2), 4.15(m, 2H, OCH2), 6.83-6.95(m, 4H, Ar), 7.17-7.29(m, 3H, Ar), 7.69(m, 1H, Ar), 8.06(d, 1H, J=8.2 Hz, Ar), 8.82(m, 1H, Ar); MS: 379 (M). Example 19: 1-{4-(2-Chlorophenyl)piperazin-l-ylj-4-(quinoloxy-7-yl)butane A mixture of l-chloro-4-(quinoloxy-7-yl)butane (0.470 g, 0.002 mol), l-(2-chlorophenyl)piperazine (0.392 g, 0.002 mol), K2CO3 (0.20 g) and Nal (0.01 g) in dry DMF (20 ml) was heated at 110°C for 16 hours. Reaction mixture was diluted with water (50 ml), extracted with chloroform (3x30 ml), the combined chloroform extracts were washed with water (3x20 ml), dried (Na2 -SO4), concentrated and purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant. Yield (0.40 g) (51%), m.p. 125°C. FTIR (KBr,cm-1): 3870, 3734, 3324, 2942, 2822, 2332, 2212, 2116, 1916, 1618, 1474, 1238, 1148, 1030, 838, 754; 'H-NMR (CDC13): δ (ppm) 1.90(m, 4H, C-CH2-C), 2.53(t, 2H, j=7.6 Hz), 2.69(brs, 4H, N-CH,) 3.lO(brs, 4H, Ar-N-CH2), 4.17(t, 2H, J=6.0 Hz, O-CH2), 6.96- 7.41(m, 7H, Ar), 7.69(d, 1H, j=9.0Hz,Ar), 8.07(d, 1H, J=8.4 Hz, Ar), 8.82(m, 1H, Ar); MS: 395 (M+). Example 20: l-[4-(4-hydroxy-4-phenyI)piperidin-l-yl]-4-(quinoloxy-7-yI)butane A mixture of l-chloro-4-(quinoloxy-7-yl)butane (0.705 g, 0.003 mol), 4-(4-hydroxy-4-phenyl}-piperidine (0.53 g, 0.003 mol), K2CO3 (0.32 g) and Nal (0.02 g) in dry DMF (20 ml) was heated at 1 lO^C for 14 hours. Reaction mixture was diluted with water (50 ml), extracted with chloroform (3x30 ml), the combined chloroform extracts were washed with water (3x20 ml), dried (Na2S04), concentrated and purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant. Yield (0.51 g) (45%), m.p. 1 lO0C. FTIR (KBr,cnT '): 3926, 3828, 3720, 3486, 2924, 2726, 2536,2344,2304,2120, 1972,1626, 1530, 1486, 1382, 1248, 1206, 1124, 1050, 830,640; 'H-NMR (CDCl3): δ (ppm) 1.85(m, 5H, C-CH2-C,OH), 2.67(m, 4H, CH2-C-OH), 2.99(m, 611, NCH2), 4.16(m, 21!, OCH2), 7.12-7.85(m, 9H, Ar), 8.08(c', 1H, J=8.0 Hz, Ar), 8,82(d, 1H, J=2.8 Hz, Ar), MS: m/z 376 (M+). Example 21: l-[4-(4-Hydroxy-4-pheny!)piperidin-l-yl]-3-(quinoloxy-8-yl)propane A mixture of l-chloro-3-(quinoloxy-8-yl)propane (0.663 g, 0.003 mol), 4-(4-hydroxy-4-phenyl)- piperidine (0.531 g, 0.003 mol), K2CO3 (0.32 gm) and Nal (0.02 g) in dry DMF (20 ml) was heated at 1 10°C for 12 hours. Reaction mixture was diluted with water (50 ml), extracted with chloroform (3x30 ml), the combined chloroform extracts were washed with water (3x20 ml), dried (Na2SO4), concentrated and purified by column chromatography on silica gel using 1% MeOH in chloroform aseluant Yield (0.50 g) (46%), m.p. 142°C FTIR (KBr,cm-'): 3300, 1370, 1310, 1250, 1180, 1100, 960, 810, 780, 740, 720, 690 'H-NMR (CDC1,): δ (ppm) 2.30(m, 2H, C- CH2-C), 3.00(m, 5H, CH2-C-OH,OH), 3.35(brs,6H, NCH2), 4.32(1, 2H, J=7.2Hz,OCH2), 7.20-7.50(m, 8H, Ar), 8.10(m, 1H, AT), 8.80(m, 1H, Ar) MS: m/z 362 (M+). Example 22: l-[4-(4-ethyIphenyI)piperazin-l-ylj-3-(quinoloxy-8-yl)propane A mixture of l-chloro-3-(quinoloxy-8-yl)propane (0.440 g, 0.002 mol), l-(4-ethylphenyl)piperazine (0.380 g, 0.002 mol), K2CO3 (0.20 g) and Nal (0.01 g) in dry DMF (20 ml) was heated at 1100C: for 14 hours. Reaction mixture was diluted with water (50 ml), extracted with chloroform (3x30 ml), the combined chloroform extracts were washed with water (3x20 ml), dried (Na2SO4, concentrated and purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant. Yield (0.35 g) (47%), m.p. 174°C. FTIR (KBr.cm): 3746, 3362, 3013, 2964, 2883, 2826, 1692, 3661, 1614, 1568, 1512, 1462, 1379, 1317, 1217, 1186, 1146, 1107, 1030,928,824, 758,665; 1H-NMR (CDC13): δ (ppm) 1.20(m, 3H, CH3), 2.55(qn, 2H, J=6.8 Hz, CH2CH,), 2.92(bs, 6H, NCH2), 3.30(bs, 4H, Ar-CHj, 4.38(1, 2H, J==6.8 Hz, OCH,), 6.90(d, 2H, J=8.2 Hz, Ar), 7.15(d, 2H, J=8.5 Hz, Ar), 7.40-7.50(m, 4H, Ar), 8.15(d, 1H, J=9.0 Hz, Ar), 8.92(m, 1H, Ar); MS: m/z(M'). Example 23: l-[4-(2-Pyridyl)piperazin-l-yl]-3-(quinoloxy-8-yl)propane A mixture of l-chloro-3-(quinoioxy-8-yijpropane(0..440g, 0.002 mol), l-(2-pyridyl)piperazine (0.32 g, 0.002 mol), K2CO, (0.32 g) and Nal (0.01 g) in dry DMF (20 ml) was heated at 110°C for 12 hours. Reaction mixture was diluted with water (50 ml), extracted with chloroform (3x30 ml), the combined chloroform extracts were washed with water (3x20 ml), dried (Na2SO4, concentrated and purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant. Yield (0.32 g) (49%), m.p. 166°C. FTIR (KBr,cm'): 2950, 2820, 1590, 1470, 1430, 1370, 1310, 1240, 1100,970, 810,760,720; 1H-NMR (CDCl3): δ (ppm) 2.30(qn, 2H, J=5.6 Hz, C-CHrC), 2.65(m, 6H, NCH2), 3.07(t, 4H, J-5.6 Hz, ArNCH2), 4.36(t, 2H, J=6.0 Hz, OCH2), 6.60-6.70(m, 2H, Ar), 7.12(d, 1H, J=8.4 Hz, Ar), 7.40-7.52(m, 5H, Ar), 8.10-8.20(m, 2H, Ar); MS: rn/z 348 (M1). Example 24: l-[4-(3-MethylphenyI)piperazin-l-yl]-3-(quinoIoxy-8-yl)propane A mixture of l-chloro-3-(quinoIoxy-8-yl)propane (0.440 g, 0.002 mol), l-(3-methylphenyl)piperazine (0.352 g, 0.002 mol), K2CO3 (0.40 g) and Nal (0.01 g) in dry DMF (20 ml) was heated at 1100C for 13 hours. Reaction mixture was diluted with water (50 ml), extracted with chloroform (3x30 ml), the combined chloroform extracts were washed with water (3x20 ml), dried (Na2SO4, concentrated and purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant. Yield (0.38 g) (54%), m.p. 210°C. FTIR (KBr,cm°): 2960, 2880, 2820, 1590, 1490, 1450, 1370, 1300, 1240, 1200, 1170,1130,1090,980, 720; 'H-NMR (CDCI3): δ (ppm) 2.15(m, 2H, C-CH2-C), 2.28(s, 3H, CH3), 2.60(m, 6H, NCH2), 3.15(t, 4H, J=4.5 Hz, ArNCH2), 4.30(t, 2H, J=7.2 Hz, OCH2), 6.60-6.70(m, 3H, Ar), 6.95-7.25(m, 3H, Ar), 7.30-7.40(m, 2H, Ar), 8.05(d, 1H, J=7.2 Hz, Ar), 8.85(dd, 1H, J=6.3 & 1.8 Hz, Ar); MS: m/z361 (M+). Example 25: l-[4-(3,4-dimethoxyphenyl)piperazin-l-ylj-3-(quinoloxy-8-yl) propane A mixture of l-chloro-3-(quinoloxy-8-yl)propane (0.442 g, 0.002 mol), l-(3,4-dimethoxypheny!)-piperazine (0.444 g, 0.003 mol), K2CO3 (0.40 g) and Nal (0.01 g) in dry DMF (20 ml) was heated at 110°C for 12 hours. Reaction mixture was diluted with water (50 ml), extracted with chloroform (3x30 mi), the combined chloroform extracts were washed with water (3x20 ml), dried (Na2SO4), concentrated and purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant. Yield (0.35 g) (44%), m.p. hygroscopic. FTIR (KBr cm1): 3682, 3398,3020, 2959, 2829, 2403, 2278,1583,1512,1462,1379,1315, 1215,1146,1107,1080,1026, 974,760,669; 'H-NMR (CDCl3): δ (ppm) 2.30(qn, 2H, CH2), 2.73(m, 6H,NCH2), 3.16(m, 4H, ArNCH2), 3.86(s, 3H, OCH3), 3.89(s, 3H, OCH3), 4.38(t, 2H, J=4.6 Hz, OCH ), 6.49(m, 1H, Ar), 6.62(d, 1H, J=1.80 Hz, Ar), 6.82(d, 1H, J=5.8 Hz, Ar), 7.14(d, 1H, J=5.0 Hz, Ar), 7.40-7.51(m, 3H, Ar), 8.15(dd, 1H, J=5.6 & 1.2 Hz, Ar), 8.97(m, 1H. Ar); MS: m/z 407(M+). Example 26: l-[4-(4-Chloro-2-niethylphenyl)piperazin-l-yIl-3-(quinoloxy-8-yl) propane A mixture of l-chloro-3-(quinoloxy-8-yl)propane (0.663 g, 0.003 mol),l-(4-chloro-2-methyIphenyl)-piperazine (0.63 g, 0.003 mol), K2CO3 (0.40 g) and Nal (0.01 g) in dry DMF (20 ml) was heated at 110°C for 16 hours. Reaction mixture was diluted with water (50 ml), extracted with chloroform (3x30 ml), the combined chloroform extracts were washed with water (3x20 ml), dried (Na2S04), concentrated and purified by column chromatography on silica gel using 1% MeOH in chloroform as eiuant. Yield (0.50 g) (42%), m.p. 97°C. FTIR (KBr.cm1): 3423, 2928, 2831, 1591, 1497, 1466, 1371, 1317, 1265, 1225, 1211, 1188, 1167, 1111, 1038,824,804,793, 735; 1H-NMR(CDC13): δ (ppm) 1.70(s, 3H, CH3), 2.25(m, 2H, CCH2-C), 2.54(m, 6H, NCH2), 3.12(m, 4H, ArNCH2), 4.36(1, 2H, J-4.6 Hz, OCH2), 6.82(d, 2H, J=6.0 Hz, Ar), 7.10-7.48(m, 5H, Ar), 8.12(d, 1H, J=5.6 Hz, Ar), 8.95(d, 1H, J=2.8 Hz, Ar); MS: m/z 395 (NT). Example 27: l-[4-(3-trifluoromethy!)phenylpiperazin-l-yl]-3-(qainoioxy-7-yl)propane A mixture of l-chloro-3-(quinoloxy-7-yl)propane (0.44 g, 0.002 mol), l-(3-trifluoromethylphenyl)-piperazine (0.46 g, 0.002 mol) and Na2CO3 (0.40 g) in dry DMF (20 ml) was heated at 110°C for 8 hours. Reaction mixture was diluted with water, extracted with chloroform (3x30 ml), the combined CHC13 extracts were washed with water (3x20 ml), dried (Na2SO.) and purified by column chromatography using 2% MeOH in CHC13 on silica gel column. It was characterized as its dihydrochloride. Yield 0.30 g(36%), m.p. 1400C. FTIR (KBr.cm'1): 305], 2972,2939,2916, 2883, 1624, 1597, 1504, 1470, 1441, 1387, 1319, 1263, 1240, 1207, 1175, 1136, 1085, 1055, 972, 849, 831,796,764; 'H-NMR (CDCL3): δ (ppm) 2.40~2.7Q(m, 4H, NCH2, C-CH2-C), 3..21(bs, 4H, NCH2), 3.73(m, 4H, Ar-NCH2), 4.30(m, 2H, OCH2), 7.08-7.43(m, 7H, Ar), 7.77(rn, 1H, Ar), 8.17(d, 1H, J=7.5 Hz, Ar), 8.85(bs, 1H, Ar); MS: m/z 415 (M4). Example 28: 1-[4-{3-trifluoromethylphenyl)piperazle-l-yl]-3-(quinoloxy-6-yI)propane A mixture of l-chloro-3-(quinoloxy-6-y!)propane (0.89 g, 0.004 mol), l-(3-trifluorornethylphenyl)-piperazine (0.92 g, 0.004 mol) and dry K2CO3 (0.54 g) in dry DMF (30 ml) was heated at 120°C for 10 hours. It was diluted with water (50 ml), extracted with chlorofoim(3x30 ml), washed with water (3x20 ml), dried (Na2SO4) and purified by column chromatography on silica gel using ethylacetate as eiuant. It was characterized as its dihydrochloride. Yield 1.00 g (62%), m.p. 240°C. FTIR (KBr.cm'1): 3050,2951,2883,2883,2826,2702,2189,2089, 1921, 1695, 1616, 1500, 1452, 1354, 1317, 1230, 1163, 1122, 1076, 1045, 995, 949, 839, 756; 'H-NMR (CDCl3): δ (ppm) 2.10(qn,2H, J-7.0 Hz, C- CH2-C), 2.68(m, 6H, NCH:), 3.40(m, 4H, Ar-NCH2), 4.18(t, 2H, J=8 Hz, OCH2), 7.10-7.55(m, 7H, Ar), 7.90-8. 10(m, 2H5 Ar), 8.75(bs, 1H, Ar); MS: m/z 415 (Mf). Example 29: 1-[4-{3-meihoxyphenyl)piperazin-l-yl]-3-(quinoloxy-8-yl)propane A mixture of I-ch:orc~3-(quinoloxy-8-yl)propane (0.44 g, 0.002 mol), l-(3-methoxyphenyl)-piperazine (0.38 g, 0.002 mol), dry K2CO3 (0.40 g) and Nal (0.01 g) in dry acetone (50 mi) was refluxed for 38 hours. Reaction mixture was filtered, concentrated and purified by column chromatography on silica gel using 2% MeOH in chloroform as eiuant. It was characterized as its dihydrochloride. Yield 0.30 g (40%), m.p. 95°C. FTIR (KBr.cm1): 3050, 3000, 2949, 2882, 2826, 1603, 1531, 1499, 1462, 1379, 1317, 1258, 1049, 756; 'H-NMR (CDC13): δ (ppm) 2.45(bs, 2H, C-CKr C), 3.00(m, 6H, NCH2), 3.42(bs, 4H, ArNCH2), 3.80(s, 3H, OCH3), 4.40(t, 2H, J=8 Hz, OCH:), 6.40-6.60(m, 2H, Ar), 7. 1 0-7.50(m, 6H, Ar), 8. 1 5(d, 1 H, J=7.0 Hz, Ar), 8.95(m, 1 H, Ar); MS: m/z 377 (M). l-[4-(2-metfaoxyphenyI)piperazin-l-yl]-3-(quinoloxy-8-yI)propane A mixture of l-chloro-3-(quinoloxy-8-yl)propane (0.44 g, 0.002 mol), l-(2-methoxyphenyl)-piperazine (0.38 g, 0.002 mol), dry K2CO3 (0.40 g) and tetra butylammonium iodide (0.01 g) in dry toluene (50 ml) was refluxed for 36 hours. Reaction mixture was filtered, concentrated and purified by column chromatography on silica gel using 2% MeOH in chloroform as eluant. It was characterized as its dihydrochloride. Yield 0.38 g(51%), m.p. 137oC. FUR (KBr,cm1): 3100,3000, 2950,2940,2830,2800, 1600, 1560, 1550, 1490, 1450, 1370, 1230, 1170, 720 ; 'H-NMR(CDCI,): 5 (ppm) 2.25(m, 2H, C-CH2-C), 2.75(m, 6H, NCH, 3.15(m, 4H, Ar-NCHj), 3.85(s, 3H, OCH3), 4.35(t, 2H, J=8 Hz, OCH2), 6.85-7.45(m, 8H, Ar), 8.07(m, !H, Ar), 8.87(dd, 1H, J=6.0 & 1.8 Hz, Ar); MS: m/z 377 (NT). Example 31: l-[4-(4-fluorophenyl)piperazin-l-yl]-3-(quinoIoxy-8-y!)propane A mixture of l-chloro-3-(quinoloxy-8-yl)propane (0.44 g, 0.002 mol), l-(4-fluorophenyl)piperazine (0,36 g, 0.002 mol), Na2CO3 (0.35 g) and Nal (0.01 g) in dry DMF (10 ml) was heated at 90°C for 12 hours. It was diluted with water and extracted with chloroform (3x30 ml), washed with water (3x20 ml), dried (Na2SO4) and concentrated to give an oil. This oil was- purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant and was characterized as its dihydrochloride. Yield 0.42 g (57%), m.p. 150°C. FTIR (KBr,cm1): 3030, 2970, 2940, 2840, 1590, 1510, 1465, 1380, 1320, 1220, 1110, 820; 'H-NMR (CDC13): δ (ppm) 2.25(m, 2H, C-CH2-C), 2.70(m, 6H, NCH2), 3.15(m, 4H, Ar-NCH2), 4.40(t, 2H, J=8 Hz, OCH2), 6.90-7.50(m, 8H, Ar), 8.15(d, 1H, J=6.3 Hz, Ar), 8.95(m, 1H, Ar); MS: m/z 365 (M). Example 32: l-[4-(2-methoxyphenyl)piperazin-l-yl]-3-(quinoloxy-7-yl)propane A mixture of l-chloro-3-(quinoloxy-7-yl)propane (0.88 g, 0.004 mol), l-(2-methoxyphenyl)-piperazine (0.76 g, 0.004 mol) and dry NaHCO., (0.40 g) in dry DMF (25 ml) was heated at 900C for 10 hours. Reaction mixture was diluted with water, extracted with chloroform (3x30 ml), washed vvith water (3x20 mi), dried (Na2SO4) and purified by comma chromatography on silica gel using 3% MeOH in chloroform as eluant. It was characterized as its dihydrochloride. Yield 0.77 g (52%), m.p. 87°C. FTIR (KBr,cm-'): 3030,2946,2820,2618,1500, 1450,1386, 1238, 1142,744; 'H-NMR (CDC13): 6 (ppm) 2.1 l(qn, 2H, J=7.0 Hz, C-CH2-C), 2.68(m, 6H, NCH2), 3.09(bs, 4H, Ar-NCH2), 3.86(s, 3H, OCH3), 4.2l(t, 2H, J=6.2 Hz, OCH2), 6.83-7.28(m, 6H, Ar), 7.42(d, 1H, J=2.0 Hz, Ar), 7.69(d, 1H, J=9.0 Hz, Ar), 8.06(d, 1H, J=8.0 Hz, Ar), 8.82(m, 1H, Ar); MS: m/z 377 (M). Example 33: l-[4-(2-ch!orophenyl)piperazin-l-yl]-3-{quinoloxy-7-yl)propane A mixture of l-chloro-3-(quinoloxy-7-yI)propane (0.44 g, 0.002 mol), l-(2-chlorophenyl)piperazine (0.40 g, 0.002 mol) and K2CO3 (0.40 g) in dry acetone (50 ml) was refluxed for 35 hours. Reaction mixture was filtered, concentrated and purified by column chromatograpby on silica gel using 4% MeOH in chloroform as eluant. It was crystallized with ether-hexane. Yield 0.41 g (68%), m.p. 82°C. FTIR (KBr.cm1): 3054,2948, 2888, 2826, 1906, 1780, 1724, 1616,1446,1386, 1256,1176, 1130, 1044, 838, 762; 'H-NMR (CDC13): 5 (ppm) 2.14(qn, 2H, J=7.2 Hz, C-CHrC), 2.60(m, 6H, NCH2), 3.10(m, 4H, Ar-NCH2), 4.21(t, 2H, J=6.2 Hz, OCH2), 6.96-7.44(m, 7H, Ar), 7.70(d, 1H, J=8.8 Hz, Ar), 8.07(d, 1H, J=2.0 Hz, Ar-H), 8.81-8.92(m, 1H, Ar); MS: m/z 381 '(M+). Example 34: l-{4-(4-hydroxy-4-phenyl)piperidine-l-yl]-3-(quinoloxy-7-yI)propane A mixture of l-chloro-3-(quinoloxy-7-yl)propane (0.22 g, 0.001 mol), 4-( 4-hydroxy-4-phenyl)-piperidine (0.18 g, 0.001 mol), K2CO3 (0.20 g) and Nal (0.01 g) in dry acetone (50 ml) was refluxed for 35 hours. Reaction mixture was filtered, concentrated and purified by column chromatography on silica gel using 4% MeOH in chloroform as eluant. It was crystallized with ether-hexane. Yield 0.21 g(58%),m.p. 141. FTIR (KBR,cm-1): 3124,2948,2822, 2348,1618,1498, 1448,1390,1320, 1262, 1174, 1126, 840, 768; 'H-NMR (CDC13): δ (ppm) 1.78(m, 2H, C-CHrC), 2.16(m, 4H, C-CHrC), 2.47-2,69(rn, 5H, NCH2 piperidine, O-H), 2.87(m, 2H, NCH2) 4.19(1, 2H, J=6,2 Hz, OCH2), 7.17-7.7 l(m, 9H, Ar), 8.06(d, 1H, J-8.2 Hz, Ar), 8.78(m, IH, Ar); MS: 362 m/z(M'). Example 35: l-[4-(2-methoxyphenyI)piperazin-l-y]j-4-(quino!oxy-7-yI)butane A mixture of l-chloro-4--(quinoloxy-7-yl)butane (0.47 g, 0.002 mol), l-(2-methoxyphenyIpiperazine (0.38 g, 0.002 mol), dry K2CO3 (0.40 g) and Nal 20 ml) was heated at 140°C for 8 hours. Reaction mixture was diluted with water, extracted with chloroform (3x30 ml), dried (Na2SO4), concentrated and purified by column chromatography on silica gel using 4% MeOH in chloroform as eluant. It was characterized as its dihydrochloride. Yield 0.60 g (77%), m.p. 160°C. FTIR (KBr.cm1): 3050, 2944,2820,1618, 1500, 1452,1386, 1320, 1244, 1132, 1026, 840, 754; 'H-NMR (CDCl3): 8δ (ppm) 1.78-2.17(m, 4H, C-CCH2-c), 2.55(t, 2H, J=7.2 Hz, NCH-.-C-C), 2.73(bs, 4H, NCH2), 3.12(bs, 4H, Ar-NCH2), 3.86(s, 3H, OCH3), 4.16(t, 2H, J-6.0 Hz, OCH2), 6.83-6.96(m, 4H, Ar), 7,17- 7.29(m, 2H, Ar), 7.41(bs, IH, Ar), 7.70(d, IH, J=8.8 Hz, Ar), 8.07(d, IH, J=7.6 Hz, Ar), 8.83(m, IH, Ar); MS: m/z391 (M+). Example 36: l-[4-(2-chIorophenyl)piperazin-l-yI]-S-(quino!oxy-7-yl)pentane A mixture of l-chloro-5-(quinoIoxy-7-y])pentane (0.24 g, 0.001 mol), l-(2-chlorophenyl)piperazine (0.19 g, 0.001 mol) and NaHCO, (0.24 g) in dry DMF (10ml) was heated at 130°C for 8 hours. Reaction mixture was diluted with water and extracted with chloroform (3x30 ml), washed with water (3x20 ml), dried (Na2S04) and concentrated. It was purified by column chromatography on silica gel using 3% MeOH in chloroform as eluant. It was characterized as its dihydrochioride. Yield 0.18 g(45%), m.p. 170^. FTIR(KBr,cm1): 3050, 2938, 2818, 1620, 1448, 1384, 1322, 1264, 1132, 840, 758; 'H-NMR (CDC13): δ (ppm) 1.62-1.98(m, 6H, C-CHrC), 2.48(t, 2H, J=6.8 Hz, NCH2-C-C), 2.56(bs, 4H, NCH2), 3.10(bs, 4H, Ar-NCH2), 4.14(t, 2H, J=6.4 Hz, OCH,), 6.96-7.07(m, 4H, Ar), 7.29-7.40(m, 3H, Ar), 7.70(d, IH, J=9.0 Hz, Ar), 8.07(d, IH, J=8.2 Hz, Ar), 8.82(m, IH, Ar); MS: m/z 409 (M). Example 37: 1-[4-(4-Fluorophenyl)piperazin-l-ylj-3-(quinoloxy-7-yI)propane A mixture of l-chloro-3-(quinoloxy-7-yl)propane (0.44 g, 0.002 mol), l-(4-fluorophenyl)piperazine (0.36 g, 0.002 mol) and K2C03 (0.40 g) in dry acetone (50 ml) was refluxed for 35 hours. Reaction mixture was filtered, concentrated and purified by column chromatography on silica gel using 3% MeOH in chloroform as eluant. It was crystallized with ether-hexane. Yield 0.40 g (57%), m.p. 1400C.FTIR (KBr,cm-'): 3747,3416, 2928,2822, 2783, 2380, 1618, 1568, 1506, 1450, 1389, 1319, 1267,1215,1173,1117, 1045,1013,968,935, 912, 826, 766, 714, 617; 'H-NMR (CDC13): δ (ppm) 2.10(qn, 2H, J=5.0 Hz, CH2), 2.64(m, 6H, NCH2), 3.14(m, 4H, Ar-NCH2), 4.21(t, 2H, J=5.0 Hz, OCH,), 6.86-6.99(m, 3H, Ar), 7.10-7.29(m, 3H, Ar), 7.42(d, IH, J=1.6, Ar), 7.70(d, IH, J=6Hz, Ar)8.07(d, IH, J=5.8Hz, Ar), 8.3(d, IH, J=3.0Hz, Ar); MS: m/z 365 (M+). Example 38: 1-[4-(2-pyridyi)piperazin-l-yl]-3-(quinoloxy-7-yI)propane A mixture of l-chloro-3-(7-quinolyloxy)propane (0.663 g, 0.003 mol), l-(2-pyridyl)piperazine (0.48 g, 0.003 mol) and KaCO3 (0.40 g) in dry acetone (50 ml) was refluxed for 35 hours. Reaction mixture was filtered, concentrated and purified by column chromatography on silica gel using 4% MeOH in chloroform as eluant. It was crystallized with ether-hexane. Yield 0.50 g (48%), m.p. 60°C. FTIR (KBr,cm-!): 3393, 3020, 2924, 2854, 2322, 1599, 1392, 1215, 1092, 1026, 932, 758; 'H-NMR (CDC1.,): δ (ppm) 2.16(qn, 2H, J=6.8, CH2), 2.69(m, 6H, NCH2), 3.64(m, 4H, Ar-NCH2), 4.24(t,2H, J=7.0Hz, OCH2)6.60-6.68(m, 2H, Ar), 7.18- 7.26(m, 2H, Ar), 7.40-7.52(m, 2H, Ar), 7.72(dlH, J=8.8Hz, Ar), 8.08(d, 1H, J=8.0Hz, Ar), 8.2I(d, 1H, J=3.4Hz, Ar), 8.83(d, 1H, J=2.5Hz, Ar);MS:m/z 348 (M+). Example 39: l-[4-(2-MethyI-4-chlorophenyl)piperazin-l-yl]-3-(quinoloxy-7-yl)propane A mixture of l-chloro-3-(quinoloxy-7-yl)propane (0.44 g, 0.002 mol), l-(2-methyl- 4-chlorophenyl)-pip-erazine (0.42 g, 0.002 mol) and K2CO3(0.40g) in dry acetone (50 ml) was refluxed for 30 hours. Reaction mixture was filtered, concentrated and purified by column chromatography on silica gel using 3% MeOH in chloroform as eluant. ft was crystallized with ether-hexane. Yield 0.32 g (41 %), m.p. 1051C. FTIR (KBr.cnT1): 3801, 3747, 3443, 2937, 2820, 2789, 2378, 1618, 1497, 1446, 1385, 1315, 1265, 1215, 1171, 1342, 1111, 1047, 1005,972,939,903,839,812,768,739, 708,610; 'H-NMR (CDC1,): δ (ppm) 1.25(m, 2H, CH,), 2.17(s, 3H, CH,), 2.75(bs, 6H, N(CH2)2), 3.20(bs, 4H, Ar-NCH,), 3.60(m, 2H, OCH2), 7.26-7.44(m, 4H, Ar), 7.47(m, 1H, Ar), 7.80- 7.86(m, 2H, Ar), 8.35(d, 1H, J=5.0 Hz, Ar), 8.85(s, 1H, Ar); MS: m/z 395 (M+). Example 40: l-[4-(3,4-dichlorophenyI)piperazin-l-yIJ-3-(quinoIoxy-7-yl)propane A mixture of l-chloro-3-(quinoloxy-7-yI)propane (0.663 g, 0.003 mol), 3,4-dichlorophenylpiperazine (0.69 g, 0.003 mol), K2CO3 (0.50 g) and Nal (0.02 g) in dry DMF (20 ml) was heated at 120°C for 15 hours. Reaction mixture was diluted with water, extracted with chloroform (3x30 ml), washed with water (3x20 ml), dried (Na2S04), concentrated and purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant. Yield 0.65 g (52%), m.p. 1200C. FTIR (KBr, cm'1): 3870, 3698, 3444, 2934, 2316, 1732, 1612, 1474, 1382, 1242, 1148,820; 'H-NMR (CDCI,): 5 (ppm) 2.08(m, 2H, CH2), 2.63(m, 6H, NCH2), 3.19(m, 4H, Ar- NCH2), 4.21(t, 2H, J=6.4 Hz, 0-CH2), 6.74(dd, 1H, J=9.0 & 2.8 Hz, Ar), 6.95(d, 1H, J=2.8 Hz, Ar), 7.17-7.30(m, 3H, Ar), 7.42(d, 1H, J=2.6 Hz, Ar), 7.70(d, 1H, J=9.0 Hz, Ar), 8.05(m, 1H, Ar), 8.82(d, 1H, J=5.2 Ar); MS: m/z 416 (M). Example 41: ]-[4-(4-i\!ethoxyphenyl)piperazin-l-yJj-3-(quino!oxy-7-yI)propane A mixture of l-chloro-3-(quinoloxy-7-yl)propane (0.44 g, 0.002 mol), 4-methoxyphenylpiperazine (0.38 g, 0.002 mol), K2CO3 (0.40 g) and Nal (0.01 g) in dry DMF (20 ml) was heated at 110°C for 15 hours. Reaction mixture was diluted with water, extracted with chloroform (3x30 ml), washed with water (3x20 ml), dried (Na2SO4, concentrated under vaccum and purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant. Yield 0.39 g (40%), m.p. 124-126°C. FTIR (KBr, cm'1): 3813, 3746, 3682, 3651, 3400, 2941, 2880, 2814, 2754, 2702, 2334, 1742, 1618, 1508, 1448, 1385, 3319, 1267, 1240, 1213, 1178, 1122, 1042, 1014, 970, 935, 835, 802, 768,716, 664, 617; 'H-NMR (CDC13): 5 (ppm) 2.10(qn, 2H, 3=4.6 Hz, CH2), 2.65(m, 6H, NCH2), 3.12(m, 4H, Ar-NCH2), 3.77(s, 3H, O-CH3), 4.21(t, 2H, J=4.2 Hz, OCH2), 6.82-6.93(m, 3H, Ar), 7.19-7.43(m, 4H, Ar), 7.70(d, 1H, J=6.0 Hz, Ar), 8.08(d, 1H, J=6.0 Hz, Ar), 8.83(m, 1H, Ar); MS: m/z 378 (M~). Example 42: 1-[4-(4-Chlorophenyl)piperazin-l-yI]-3-(quinoloxy-7-yI)propane A mixture of I-chloro-3-(quinoloxy-7-yl)propane (1.76 g, 0.008 mol), 4-chlorophenylpiperazine (2.15 g, 0.008 mol), K2CO3 (1.10 g) and Nal (0.60 g) in dry DMF (50 ml) was heated at 110°C for 12 hours. Reaction mixture was diluted with water, extracted with chloroform (3x50 ml), washed with water (3x20 ml), dried (Na2SO4), concentrated under vaccum and purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant. Yield 1.70 g (56%), m.p. 100°C. FTIR (KBr, cm-'): 3427, 2929,2825,2362,2333, 1618, 1497, 1448, 1387, 1323, 1265, 1232, 1213, 1175, 1142, 1042, 1009, 968, 935, 910, 822, 764, 669, 617; 'H-NMR (CDC13): δ (ppm) 2.12(qn, 2H, JN4.6 Hz, CH2), 2.63(m, 6H, NCR,), 3.13 (m, 4H, Ar-NCH^ 4.1 l(t, 2H, J=4.2 Hz, O-CH2), 6.82-6.87(m, 2H, AT), 7.18-7.29(m, 4H, Ar), 7.42(d, 1H, J=4.0 Hz, Ar), 7.70(d, 1H, J-6.0 Hz, Ar), 8.07(dd, 1H, J=5.4 & 1.0 Hz, Ar), 8.83(dd, 1H, J-3.0 & 1.8 Hz, Ar); MS: m/z 381 (NT). Example 43: l-[4-(4-Acetyl-4-phenyI)piperidin-l-yl]-3-(quinoloxy-7-yl)propane A mixture of l-chloro-3-(quinoloxy-7-yl)propane (0.663 g, 0.003 mol),4-( 4-acetyl-4-phenyl)-piperidine (0.609 g, 0.003 mol), K2O3 (0.40 g) and Nal (0.01 g) in dry DMF (20 ml) was heated at 110°C for 14 hours. Reaction mixture was diluted with water, extracted with chloroform (3x30 ml), washed with water (3x20 ml), dried (Na2S04), concentrated under vaccum and purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant. Yield 0.52 g (45%), m.p. 110°C. FTIR (KBr, cm'1): 3888,3782,3426,3164,2826, 2328,2252,2026,1916,1816,1622,1496, 1392,1266,1126,1040,978,772,704; 'H-NMR (CDCl3): δ (ppm) 1.22(s, 3H, COCH;), 1.65(m, 2H, CH2), 2.13 (m, 4H, (CH2-C-CH2), 2.5 l(m, 4H, Ar-NCH2), 4.16(t, 2H, J=6.4 Hz, OCH2), 7.16- 7,40(m, 8H, Ar), 7.69(d, 1H, J=8.8 Hz, Ar), 8.06(d, 1H, J-8,2 Hz, Ar), 8.8l(m, 1H, Ar); MS: m/z 388 (M+). Example 44: l-[4-(3-Chlorophenyl)piperazin-l-yl]-3-(quinoLoxy-7-yI)propane A mixture of l-chloro-3-(quinoloxy-7-yl)propane (0.884 g, 0.004 mol), l-(3-chIorophenyl)piperazine (0.784 g, 0.004 mol), K2CO., (0.60 g) and Nal (0.20 g) in dry DMF (30 ml) was heated at 1300C for 14 hours. Reaction mixture was diluted with water, extracted with chloroform (3x30 ml), washed with water (3x25 ml), dried (Na2SO4), concentrated under vaccum and purified by column chromatography on silica gel using chloroform as eluant. Yield 0.80 g (68%), m.p. l00'0C FTIR (KBr, cm'1): 3462,3252,2777, 2710,2604,2338,1904,1593, 1566, 1493, 1450, 1391, 1321,1251, 1205,1178,1146,1107,1057,1013,978,943,914,831,764,679, 650,617;'H-NMR (CDC13): δ (ppm) 2.35(bs, 2H, CH2), 3.00(bs, 6H, NCH,), 3.47(bs, 4H, Ar-NCH,), 4.25(1,2H, J=6.8 Hz, OCH,), 6.75-6.95(m, 3H, Ar) 7.10-7.30(m, 3H Ar), 7.45(d, 1H, J=6.8 Hz, Ar), 7.75(d, 1H, J=9.0 Hz, Ar), 8.10(d, 1H, J=7.0 Hz, Ar), 8.85(d, 1H, J=3.4, Ar); MS: m/z 381 (M+). Example 45: l-[4-(3-MethylphenyI)piperazin-l-yI]-3-(quinoloxy-7-yl)propane A mixture ofl-chloro-3-(quino]oxy-7-yl)propane (0.44 g, 0.002 mol),l-(3-methylphenyI)piperazine (0.352 g, 0.002 mol), K2CO3 (0.40 g) and Nal (0.01 g) in dry DMF (20 ml) was heated at 1 10°C for 12 hours. Reaction mixture was diluted with water, extracted with chloroform (3x30 ml), washed with water (3x20 ml), dried (Na,SO4), concentrated under vaccum and purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant. Yield 0.40 g (56%), m.p. 75°C. FTIR (KBr, cm'1): 3400, 3040,2930,2878, 2822,2374, 1908, 1664, 1616,1499, 1448,1387, 1323,1246,1178,1144,1043,1003,964,912, 839,770,692,658, 617; 'H-NMR (CDCl3): δ (ppm) 2.11(m, 2H, CH2), 2.3l(s, 3H, CH3), 2.66 (m, 6H, NCH2), 3.20(bs, 4H, Ar-N-CH2), 4.21(t, 2H, J=4.2 Hz, OCH2), 6.67-6.75(m, 3H, Ar), 7.12-7.28(m, 4H, Ar), 7.44(bs, IH, Ar), 7.69(d, IH, J=6.0 Hz, Ar), 8.06(d, IH, J=5.4 Hz, Ar); MS: 361 (M+). Example 46: l-{4-(2-ChIorophenyl)piperazsn-l-yl]-3-(quinoloxy-6-yI) propane A mixture of l-chloro-3-(quinoloxy-6-yl)propane (0.37 g, 0.0016 mol), l-(2-chlorophenyl)piperazine (0.48 g, 0.0019 mol), baked K2CO3 (0.41 g) and baked Nal (10 mg)in dry DMF (10 ml) was heated at 120°C for 10 hours. It was diluted with water (50 ml), extracted with chloroform(3x30 ml), washed with water (3x20 ml), dried (NajSO4) and purified by column chromatography on silica gel using ethylacetate as eluant. It was characterized as its dihydrochloride. Yield 0.40 g (53%), m.p. 160°C. FTIR (KBr,cm): 3740,3542,3018,2956,2814,2662,2412,2352, 1684, 1510, 1376, 1220, 1124,1046, 928, 834, 758 ; 'H-NMR (CDC13) 6 (ppm): 2.l(qn, 2H, J=7.4Hz, O-C-CH2); 2.68(m, 6H, NCH2); 3.12(bs, 4H, Ar-NCH2); 4.18(t, 2H, J=6.4Hz, O-CH2); 7.02(m, IH, Ar); 7J(d, 2H, J=2.8Hzs Ar); 7.19-7.41(m, 4H, Ar); 8.03(t, 2H, .1=8.4 Hz, Ar); 8.76(d, IH, J=2.8Hz, Ar); MS rn/z 382(M+). Example 47: l-[4-(4-Chlorophenyl)piperazin-l-yl\|-3-(quinoloxy-6-yl) propane A mixture of l-chloro-3-(quinoloxy-6-yl)propane (0.35 g, 0.0016 mot), l-(4-chlorophenyl)piperazine (0.45 g, 0.0017 mol), baked K2CO3 (0.50 g) and baked Nal (10mg) in dry DMF (10 ml) was heated at 120°C for 12 hours. It was diluted with water (50 ml), extracted with chloroform(3x30 ml), washed with water (3x20 ml), dried (Na2SO4,) and purified by column chromatography on silica gel using ethylacetate as eluant. Yield 0.50 g (83%), m.p. 120-123°C. FTIR (KBr,cm1): 3832, 3716, 3488, 3050, 2950, 2806, 2344, 1976, 1844, 1682, 1612, 1504, 1366, 1232, 1142, 1032, 938, 826, cm-1; 'H- NMR(CDC13) δ (ppm): 2.1(qn, 2H, J=-6.8Hz, O-C-CH2); 2.67(m, 6H, NCH2); 3.21(t, 4H, J=4.8Hz, Ar-NCH2), 4.18(t, 2H, J=6.2Hz, O-CH2), 6.84(d, 2H, J=8.8Hz, Ar), 7.09(d, IH, J=2.4Hz, Ar) 7.18-7.4(m, 4H, Ar), 7.98(t, 2H, J=8.6Hz, Ar), 8.76(d, IH, J=3.4Hz, Ar); MS m/z382(M+). Example 48: l-[4-Hydroxy-4-phenylpiperidm-l-yl]-3-(quinoloxy-6-yl) propane A mixture of l-chloro-3-(quinoloxy-6-yl)propane (0.35 g, 0.0016 mol),4-(4-hydroxy-4-phenyl)-piperidine (0.30 g, 0.0017 mol), baked K2CO3 (0.40 g) and baked Nal (10 mg)in dry DMF (15 ml) was heated at 120X? for 14 hours. It was diluted with water (50 ml), extracted with chloroform(3x30 ml), washed with water (3x20 ml), dried (Na2SO4) and purified by column chromatography on silica gel using ethylacetate as eluant. Yield 0.40 g (70%), m.p. 135- 138 C. FTIR(KBr,cm1): 3726,3646, 3544,3402,3220,3022,2938,2804, 2604,2340,2114, 1936, 1706, 1628, 1530, 1394, 1234, 1146, 1054, 964,700 ; 1H-NMR(CDC1.,): δ (ppm) 1.8(m, 4H, Ar-C-CH2), 2.1-2.37(m, 3H, O-C-CH2, OH), 2.51-2.94(m, 6H, NCH2), 4.18(t, 2H, J=6Hz, OCH,), 7.09(d, IH, J=2.2Hz, Ar), 7.30-7.55(m, 7H, Ar), 8.02(t, 2H, J=8Hz, Ar); MS m/z 362 (M+). Example 49: l-[4-(3-MethylphenyI)piperazin-I-yl]-3-(quinoloxy-6-yl) propane A mixture of l-chloro-3-(quino!oxy-6-yl)propane (0.33 g, 0.0015 mol), l-(3-methylphenyl)piperazine (0.27 g, 0.0015 mol), baked dry K2CO3 (0.30 g) and baked Nal (10 mg) in dry DMF (15 ml) was heated at 120^ for 10 hours. It was diluted with water (50 ml), extracted with chloroform(3x30 ml), washed with water (3x20 ml), dried (Na2O4) and purified by column chromatography on silica gel using ethylacetate as eluant. Yield 0.30 g (56%), m.p. 80-830C. FTIR (KBr, cm1): 3702, 3340,2948, 2626, 2424, 2334, 1934, 1806, 1694, 1612, 1524, 1230, 1142, 1034, 758; 'H-NMR(CDCI3) δ (ppm):2.16(qn, 2H, J=6Hz, O-C-CH2), 2.32(s, 3H, CH3), 2.72(br s, 6H, NCH2), 3.28(br s, 4H, Ar-NCH2), 4.19(1,2H, J=6Hz, O-CH2), 6.68-6.76(m, 3H, Ar), 7.08-7.4(m, 4H, Ar), 8.02(t, 2H, J=8; Iz, Ar), 8.77(d,3H, J=4.0 Hz, Ar); MS m/z 36 l(M'). Example 50: l-[4-(2-PyridyI)piperazin-l-yl]-3-(quinoloxy-6-yI)propane A mixture of l-chloro-3-(quinoloxy-6-y!)propane (0.19 g, 0.0009 mol), l-(2-pyridyl)piperazine (0.16 g, 0.001 mol), baked K2CO3 (0.14 g) and baked Nal (10 mg)in dry DMF (35 ml) was heated at 100°C for 10 hours. It was diluted with water (50 ml), extracted with chloroform (3x30 ml), washed with water (3x20 ml), dried (Na2SO4) and purified by column chromatography on silica gel using ethylacetate as eluant. Yield 0.150 g (50%), m.p. 122-125°C. FTIR (KBr, cm'1): 3734,3604,3404, 2942,2832,2486,2356,2108, 1684, 1600, 1548, 1488, 1444, 1382, 1312, 1232, 1164, 1028,836, 776; 'H-NMR(CDC13) δ (ppm): 2.1(qn, 2H, J=6Hz, O-C-CH2), 2.63(m, 6H, NCH2), 3.57(t, 4H, J=5.5Hz, Ar-NCH2), 4.17(t, 2H, J=6Hz, O- CH2), 6.59-6.67(m, 2H, Ar), 7.08(d, 1H, J=2.6Hz, Ar), 7.31- 7.47(m, 3H, Ar), 8.02(t, 2H, J=7Hz, Ar), 8.19(d, 1H, J=4Hz, Ar), 8.76(d, 1H, J=3Hz, Ar); MS m/z 348(M+). Example 51: l-[4-(2-Ethylphenyl)piperazin-l-yI]-3-(quinoloxy-6-yI) propane A mixture of l-chloro-3-(quino!oxy-6-yl)propane (0.40 g, 0.0018 mol), l-(2-ethylphenyl)piperazine (0.38 g, 0.002 mol), baked K2CO3 (0.30 g) and baked Nal (10 mg) in dry DMF (15 ml) was heated at 110°C for 12 hours. It was diluted with water (50 ml), extracted with chloroform (3x30 ml), washed with water (3x20 ml), dried (Na,S04) and purified by column chromatography on silica gel using ethylacetate as eluant. It was characterized as its dihydrochloride. Yield 0.44 g (54%), m.p. 226-30°C. FTIR(KBr,cm-'): 3374, 2956, 2818, 2668, 2484, 2352, 2102, 1916, 1676, 1622, 1542, 1500, 1452, 1380, 1322, 1226, 1152, 1044, 938, 836, 756 Cm-1; 'H- NMR(CDCl3): δ (ppm) 1.25(t, 3H, J=6Hz, CH3), 1.81(br s, 2H, CH2-Ar), 2.1 l(qn, 2H, J=6Hz, O-C-CH2), 2.7(m, 6H, NCH2), 2.96(t, 4H, J=4Hz, Ar-NCHz), 4.18(1,2H, J=6Hz, 0-CH2), 7.02- 7.4l(m, 7H, Ar), 8.02(t, 2H, J=8.5Hz, Ar), 8.77(m, lH,Ar);MS m/z 375(M+). Example 52: l-[4-(4-MethoxypSienyl)piperazin-l-yl]-3-(quinoloxy-6-yl) propane A mixture of l-chloro-3-(quino!oxy-6-yl)propane (0.44 g, 0.002 mol), l-(4-methoxyphenyl)-piperazine (0.53 g, 0.002 mol), baked K2CO, (0.50 g) and baked Nal (15 mg) in dry DMF (20 ml) was heated at 120°C for 10 hours. It was diluted with water (50 ml), extracted with chloroform (3x30 ml), washed with water (3x20 ml), dried (Na2SO4) and purified by column chromatography on silica gel using ethylacetate as eluant. It was characterized as its dihydrochloride. Yield 0.47 g (53%), m.p. 125-129°C. FTIR(KBr,cM'): 3826, 3732, 3424, 2944, 2838, 2350, 1618, 1508, 1452, 1382, 1324, 1240, 1178, 1022, 972, 932, 830, 718 cm1; 'H-NMR(CDC1,): δ (pprn) 2.1(qn, 2H, J-THz, O-C-CH2), 2.65(m, 6H, NCH,), 3.13(t, 4H, J=4Hz, Ar-NCH2), 3.77(s, 3H, OCH3), 4.18(t, 2H, J=8Hz, 0-CH2), 6,82-6.94(m, 4H, Ar), 7.09(d, 1H, J=4Hz, Ar), 7.31-7.4l(m, 2H, Ar), 8.02(1, 2H, J=8Hz, Ar), 8.76(d, 1H, J=2Hz, Ar); MS m/z 377 (MJ). Example 53: l-[4-(2-Methoxyphenyl)piperazin-l-yl]-3-(quinoloxy-6-yI) propane A mixture of l-chloro-3-(quinoloxy-6-yl)propane (0.50 g, 0.0022 mol), ]-(2-methoxyphenyl)-piperazine (0.43 g, 0.0022 mol), baked K2CO3 (0.31 g, 0.0022 mol) and baked Nal (10 mg) in dry DMF (20 ml) was heated at 90°C for 10 hours. It was diluted with water (50 ml), extracted with chloroform(3x30 rnl), washed with water (3x30 ml), dried (Na2SO4) and purified by column chromatography on silica gel using ethylacetate as eluant. It was characterized as its dihydrochloride. Yield 0.50 g (50%), m.p. 195-200°C. FTIR(KBr,cm-'): 3456, 3286, 3068, 2946, 2724, 1608, 1554, 1498, 1450, 1398, 1244, 1120, 1032, 970, 914, 872, 834, 794, 754, 612; 'H-NMR(CDC13) : δ (ppm) 2.10(qn, 2H, J=6Hz, O-C-CH2), 2.67(m, 6H, NCH2), 3.13(br s, 4H, Ar-NCH,), 3.87(s, 3H, OCH3), 4.18(r, 2H, J=6Hz, O-CH,), 6.88-6,97(n, 4K Ar), 7,95(d, 1H, J=2Hz, Ar), 7.3 l-7.41(m, 2H, Ar), 8.02(t, 2H, J=8Hz, Ar), 8.76(m, 1H, Ar); MS m/z 377 (M+). Example 54: Antihyperteusive/hypotensive activity (a) Cats (2.6-4.0 kg) of either sex anaesthetized with pentobarbitone sodium (40 mg/kg i.v.) and showing basal mean arterial blood pressure below 150 mm (Hg) were categorised as normotensive and above 150 mm Hg as hypertensive. Arterial blood pressure (BP) was recorded from one of the carotid artery through a stathum P23 DC pressure transducer and 7P1 low level DC preamplifier on a Grass Model P7 Polygraph, Signals from 7P1 preamplifier were used to trigger 7P4 Tachograph preamplifier for recording the heart rate (HR). Right femoral vein and Trachea were cannulated for intravenous injections and artificial ventilation respectively. Control responses to intravenous injection of noradrenaline (2-4 ug); acetyl choline (1-2 jug); histamine (1-2 µg) and isoprenaline (1-2 ug) were taken before and after the administration of test doses of each compounds. The compounds were tested at fixed doses of 2.0 and 10 µM/kg i.v. Significant results are given in Table 1. (b) Antihypertensive activity was observed in naturally hypertensive cats, rat abdominal aorta coarctation model of hypertension (Liu, J;. Bishop, S.P. & Overbeck, H. W. Morphometric evidence for non pressure related arterial wall thickening in hypertension Circ. Res. 62, 1001-1010,1988) and L-NAME (No synthase inhibitor) induced hypertensive cats. Example 55 : Cardioprotective/antiischemic activity The rats were killed by decaptitation, heart were rapidly excised and placed in ice-cold HEPES tyrode buffer. Then isolated hearts were perfused retrogradely through coronary arteries using the Langendorff technique. The perfusion buffer consisted (in mM) NaCl 137, KC1 5.4, CaCl2 1.8, MgCl21.0, glucose 11.2 and HEPES 3.0. The buffer (pH 7.4) was continuously gassed with oxygen and maintained at 37°C. Coronary flow rate was maintained at 10 ml/min. The heart contracted spontaneously. The perfused heart was allowed to equillibrate for 30 min. before initiation of any insult protocol. The test compounds were given at the time of reperfusion. Some of the compounds were dissolved in ethanol. Final concentration of ethanol in the perfusion buffer was 0.0001% and had no effect of its own on the parameter used. (a) For brief period of ischemic insult (Hideo et al. Pathophysiology and pathogenesis of stunned myocardium. J. Clin. Invest., 79,950-961,1987). Ischemia was initiated by stopping the flow for 16 min. followed by 30 min. reperfusion period. The durations were decided on the initial pilot experiments leading to 50% recovery of function. (b) For prolong period of ischemic insult (Becker, L.C. & Ambrosio, G. Myocardial consenquences of reperfusion. Prog. Cardiovas. Dis., 30, 23-44, 1987). Ischemia was initiated by stopping the flow for 30 min. followed by 30 min. reperfusion. Example 56: Antiinflammatory Activity: The oedema in one of the hind paw of rats is induced by injection of 0.1 ml of 1% carrageenin solution into the planter aponeurosis. Volume of the paw is measured plethysmographically immediately after and three hours after the injection of the irritant. The difference in the volume gives the amount of oedema developed. Mean percent inhibition of the oedema between control group and compound treated group is calculated and compared with the group receiving standard drug Ibuprofen (100 µmolp.o.). Each group consist of five adult rats of either sex weighing 125-150 g. Results are summarised in Table No. 3. We Claim: 1. A process for the preparation of 1-(4-aryl/heteroarylpiperazin/piperidin-1- yl) - n - ( quinoloxy-6/7/8-yl/4- (un)substituted pyrrolidin - 2 - oxo - 1- yl)alkanes/alkanones and their salts useful as therapeutic agent and having the formula III as shown in the drawing accompanying this specification, wherein R represents groups such as quinoloxy-6/7/8-yl,4- (un)substituted -pyrrolidin-2-one-1-yl; R1 represents group such as phenyl, halophenyl, alkylphenyl, alkoxyphenyl, pyridyl, trifluorophenyl; n=2-5; X=0/H2 and Z=N/CR2 (R2 = H, OH, COCH3) which comprises condensing of a compound of the formula 1 comprising a group selected from 1-chloro-n-(quinoloxy-6/7/8-yl/4-(un)substituted-pyrrolidin-2-oxo-1-yl)- alkanes/alkan-2-ones with 4-(aryl/heteroaryl)piperazin/piperidin-1-yl of formula II, wherein the meaning of R,R1, n, X,Z is as above, in the presence of a base and an organic solvent as defined herein, in presence of a catalyst as described herein at temperature ranging 80°C-130°C, to produce the corresponding 1-(4-aryl/heteroarylpiperazin/piperidin-1-yl)-n- (quinoloxy - 6/7/ 8 - yl / 4 - (un) substituted - pyrrolidin - 2 - oxo - 1 - yl)alkanes/alkanones of formula III, purifying the products by conventional methods such as herein described, converting free base compounds of formula III into their corresponding salts by known methods. 2. A process as claimed in claim 1 wherein the bases used are selected from sodium/potassium carbonate, sodium/potassium bicarbonate potassium hydroxide. 3. A process as claimed in claims 1-2, wherein the organic solvents used are selected from acetone, toluene, dimethylformamide. 4. A process as claimed in claims 1 - 3, wherein the catalyst is selected from potassium/sodium iodide, tetrabutylammonium iodide. 5. A process as claimed in claims 1-4, wherein the salt of formula III is hydrochloride. 6. A process for the preparation of 1-(4-aryl/heteroarylpiperazin/piperidin-1- yl)-n-(quinoloxy-6/7/8-yl/4-(un)substituted-pyrrolidin-2-oxo-1-yl) alkanes/ alkanones and their salts useful as therapeutic agent substantially as herein described with reference to the examples.

Full Text

The invention particularly relates to a process tor the synthesis of novel l-(4-aryl/heteroaryl- piperazin/piperidin-1-yl)-n-(quinoloxy-6/7/8-y!/4-(un)substituted-pyrrolidin-2-oxo-l- yl)alkanes/alkanones and their salts as potential antiischemic, antiinflammatory and antihypertensive
agents useful for the treatment of ischemia, inflammation, hypertension and other related CVS and
CNS disorders.
The novel l-(4-aryl/heteroarylpiperazin/piperidin-l-yl)-n-(quinoloxy-6/7/8-yl/4-(un)substituted pyrrolidin-2-oxo-l-yl)alkanes/alkanones prepared by the process of the present invention having formula III as shown in the drawing accompanying this specification, where R represents groups like quinoloxy-6/7/8-yl, 4-(un)substituted-pyrrolidin-2-oxo-l-yl, R1 represents group like aryl and heteroaryl, Z=N/CR: (R^H, OH, COCH3), X=O/H2, n=2-5. These compounds have antiischemic, antiinflammatory, anxiolytic and/or antihypertensive activities and would be useful for the treatment of ischemia, inflammation, hypertension and other related CVS and CNS disorders.
The main objective of the present invention is to provide novel l-(4-aryl/heteroarylpiperazin/ piperidin- 1 -yl)n-(quinoloxy-6/7/8-yl/ 4-(un)substituted-pyrrolidin-2-oxo- 1 -yi)alkanes/alkanones and

their salts/a process for the synthesis of the compounds of the formula III as defined above which would be useful for disease conditions amenable to treatment with agents acting against ischemia,inflammation, hypertension and other related CVS and CNS disorders.
The compounds of the present invention may be prepared by the methods well known with art and familiar to a well versed synthetic organic chemist. The process used for the preparation of the compounds of the formula III according to the present inventions are illustrated in the reaction scheme as shown in the accompanying drawing. Accordingly the present invention provides novel l-(4-aryl/heteroarylpiperazin/piperidin-l-yl)-n-(quinoloxy-6/7/8-yl/4-(un)substituted-pyrrolidin-2-oxo-l-yl)alkanes/ alkanones and their salts of the formula given below.
(Formula Removed)
wherein R represents groups like quinoloxy-6/7/8-yl, 4-(un)substituted-pyrro!idin-2-oxo-l-yl, R' represents group like phenyl, halophenyl, alkylphenyl, alkoxyphenyl, trifluoromethylphenyl, heteroaryl such as pyridyl etc., Z=N/CR2 (R2=H, OH, COCH3), X=0/H2, n=2-5
Accordingly the present invention provides a process for the preparation of 1-(4-aryl/heteroarylpiperazin/piperidin-1-yl) - n - ( quinoloxy-6/7/8-yl/4- (un)substituted pyrrolidin - 2 - oxo - 1-yl)alkanes/alkanones and their salts useful as therapeutic agent and having the formula III as shown in the drawing accompanying this specification, wherein R represents groups such as quinoloxy-6/7/8-yi,4-(un)substituted -pyrrolidin-2-one-1-yl; R1 represents group such as phenyl, halophenyl, alkylphenyl, alkoxyphenyl, pyridyl, trifluorophenyl; n=2-5; X=O/H2 and Z=N/CR2 (R2 = H, OH, COCH3) which comprises condensing of a compound of the formula 1 comprising a group selected from 1-chloro-n-(quinoloxy-6/7/8-yl/4-(un)substituted-pyrroltdin-2-oxo-1-yl)-alkanes/alkan-2-ones with 4-(aryl/heteroaryl)piperazin/piperidin-1-yl of formula II, wherein the meaning of R,R1, n, X,Z is as above, in the presence of a base and an organic solvent as defined herein, in presence of a catalyst as described herein at temperature ranging 80°C-130°C, to produce the corresponding 1-(4-aryl/heteroarylpiperazin/piperidin-1-yl)-n-(quinoloxy - 6/7/ 8 - yl / 4 - (un) substituted - pyrrolidin - 2 - oxo - 1 -yl)alkanes/alkanones of formula III, purifying the products by conventional methods such as herein described, converting free base compounds of formula III into their corresponding salts by known methods.
In an embodiment of the present invention the bases used may be such as potassium or sodium carbonate, potassium or sodium bicarbonate , potassium hydroxide.
In another embodiment of the present invention the solvents used may be such as acetone, toluene, dimethyl formamide.
In yet another embodiment of the present invention the reaction may be catalyzed by the addition of the catalyst such as potassium or sodium iodide, tetrabutylammonium iodide.
In a feature of the invention the free bas ecompounds of formula 111 may be converted to the salts such as hydrochloride.
The method comprises condensing 1-chloro-n-(quinoloxy-6/7/8-yl/4-(un)substituted pyrrolidin-2-oxo-1-yljalkanes/alkanones of the formula I with (4-aryl/heteroaryl)piperazine/piperidine of the formula II in the presence of bases like potassium or sodium carbonate, potassium or sodium bicarbonate or powdered potassium hydroxide and suitable solvent such as acetone , toluene or dimethylformide at temperatures ranging upto 130°C for a period varying between 6-36 hours to produce the corresponding 1-( 4- aryl/ heteroarylpiperazin/piperidin -1- )- n -( quinoloxy-

6/7/8-yl/4-(un)substituted pyrrolidin-2-oxo-l-yl)alkanes/alkanones of the formula III where R represents groups like quinoloxy-6/7/8-yl, 4-(un)substituted pyrrolidin-2-oxo-l-yl; R1 represents group like phenyl, halophenyl, alkylphenyl, alkoxyphenyl, trifluoromethylphenyl, heteroaryl such as pyridyl etc.; Z=N/CR2 (R2=H, OH, COCH3); XO/H2 n=2-5. The reaction may be facilitated and reaction time can be decreased by adding catalyst like sodium/potassium iodide or tetrabutyl ammonium iodide.
In the above synthesis, where specific bases, solvents etc. are mentioned, it is to be understood that the other bases, solvents may be used. Similarly, the reaction temperature and duration of the reaction may be adjusted according to the desired results.
Preferred compounds according to the invention and capable of being produced by the reaction sequences described above are given below.

(Formula Removed)
wherein R represents groups like quinoloxy-6/7/8-yl, 4-(un)substituted-pyrrolidin-2-oxo-l-yl, R1 represents group like phenyl, halophenyl, alkylphenyl, alkoxyphenyl, trifluoromethylphenyl, heteroaryl such as pyridyl etc., Z=N/CR2 (R2=H, OH, COCH3), X=O/H2, n=2-5.
The preferred compounds of formula in prepared by the process of present invention are as follows.
1-[4-(4-Fluorophenyi)piperazin-l-yl]-3-(pyrrolidin-2-oxo-l-yI)propan-3-one of the formula III where n=3, X=O, Z=N, R= CAN-2-O, R'=C6H4-4-F
1-[4-(4-FluorophenyI)piperazin-l-yl]-3-[4-(4-chlorophenyI)pyrrolidin-2-oxo-l-ylJpropane of the formula III where n-3, X=H2, Z=N, R= C4H5N-2-O-4-C6H4-4-Cl, R'=C6H4-4-F
l-[4-(4-FIuorophenyI)piperazin-l-yI]-3-[4-{3,4-dimethoxyphenyI)pyrrolidin-2-oxo-l-yl]propane of the formula III where n=3, X=H2, Z=N, R=C4HsN-2-O-4-C6H3-3,4-(OCH3)2, R1=C6H4-4-F
l-[4-(4-FIuorophenyI)piperazin-l-yIJ-2-(pyrrolidin-2-oxo-l-yl)ethan-2-one of the formula III where n=2, X=O, Z=N, R= C4H6N-2-O, R1=C6H4-4-F
l-[4-(2-m ethoxyphenyI)piperazin-l-yl]-3-(pyrrolidin-2-oxo-l-yl)propan-3-one of the formula m where n=3, X=O, Z=N, R= C4H6N-2-O , R'=C6H4-2-OCH3
l-[4-(Trifluoromethylphenyl)piperazin-l-yl]-3-{pyrrolidin-2-oxo-l-yI)propan-3-one of the formula III where n=3, X=O, Z=N, R= C4H6N-2-O ,R1=C6H4-4-CF3
l-[4-(3,4 -Dichlorophenyl)piperazin-l-yl]-3-(pyrrolidin-2-oxo-l-yl)propan-3-one of the formula m where n=3, X=O, Z=N, R= C4H6N-2-O , R1=C6H33,4-C1 2
l-[4-(2-Chlorophenyl)piperazin-l-yl]-3-(pyrroIidin-2-oxo-l-yl)propan-3-one of the formula III where n=3, X=O, Z=N, R= C4H6N-2-O , R'=C6H4-2-CI
1-[4-(2-Methoxyphenyl)piperazin-l-yI]-2-{pyrroIidin-2-oxo-l- yI)ethan-2-one of the formula III where n=2, X=O, Z=N, R= C4H6N-2-O, R1=C6H4-2-OCH3
l-[4-(3,4-DichlorophenyI)piperazin-l-yl]-2-(pyrrolidin-2-oxo-l- yl)ethan-2-one of the formula III where n=2, X=O, Z=N, R= C4H6N-2-O R1=C6H4-3,4-Cl 2
l-[4-(2-ChlorophenyI)piperazin-l-yI]-2-(pyrroLidin-2-oxo-l-yl)ethan-2-one of the formula III where n=2, X=O, Z=N, R= C4H6N-2-O, R1=H2-Z-CI
l-[4-(3-TrifluoromethylphenyI)piperazin-l-yl]-2-(pyrrolidin-2-oxo-l-yl)ethan-2-one of the formula III where n=2, X=O, Z=N, R= C4H6N-2-O, R'=C6H4-3-CF3
l-[4-(Phenyl)piperazin-l-yI]-2-(pyrrolidin-2-oxo-l-yl)ethan-2-one of the formula III where n=2, X=O, Z=N, R= C4H4N-2-O, R1=C6H5
l-[4-(4-Chlorophenylpipernzin-l-yl]-2-(pyrro!idin-2-oxo-l-yl)ethan-2-one of the formula III where n=2, X=O, Z=N, R= C6H6N-N-2-O , R1=C6H4-4-Cl
l-[4-(4-ChlorophenyIpiperazin-l-yl]-4-(pyrrolidin-2-oxo-l-yl)butan-4-one of the formula III where n=4, X=O, Z=N, R= C4H6N-2-O R'=C6H4--4-Cl
l-[4-(3-trifluoromethylphenyl)piperazin-l-yl]-3-(quinoloxy-8-yl)propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO, R1=CsH4-3-CF3
l-[4-(3-chIorophenyl)piperazin-l-yl]-3-(quinoloxy-8-yI) propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO,Rl=C6H4-4-Cl
1-[4-{2-ChlorophenyI)piperazin-l-yl]-4-{quinoIoxy-7-yI)butaneof the formula III where n=4, X=H2, Z=N, R= C9H6NO,R1=C6H4-2-Cl
I-[4-(4-hydroxy-4-phenyI)piperidin-l-yl)-4-(quinoIoxy-7-yl)butane of the formula III where n=4, X=H2, Z=C, R= C9H4NO, Rl=C6Hs, R2=OH
1-[4-(4-Hydroxy-4-phenyl)piperidin-l-yI-3-{quinoIoxy-8-yl)propane of the formula III where n=3, X=H2, Z=C, R= C9H6NO, R1C6H, , R2=OH
l-[4-(4-ethylphenyl)piperazin-l-yl]-3-(quinoloxy-8-yI)propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO, R1=C6H4-4-C2H5
1-[4-{2-PyridyI)piperazin-l-y3]-3-(quinoIoxy-8-yl)propaneof the formula III where n=4, X=H2,
Z=N, R=
!-[4-(3-MethyIphenyI)piperazin-l-yI]-3-{quinoIoxy-8-yl)propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO,, R'=C6H4-3-CH3
!-{4-(3,4-diraethoxyphenyl)piperazin-l-yl]-3-{quinoloxy-&-yJ) propane of the formula III where n=3, X=H2, Z=N, R= CsH^NO, R}=C6Hr3t4-(OCH3)2
l-[4-(4-Chloro-2-methylphenyl)piperazin-l-yl]-3-(quinoloxy-8-yI) propane of the formula III where n=3, X=H2, Z^=N, R= C9H6NO, R1=C4H3-2-CH3 -4-Cl
l-[4-(3-trifluoromethyl)phenylpiperazin-l-ylJ-3-(quinoloxy-7-yl) propane of the formula III where n=3, X=H2, Z=N, R= C,H4NO, R1=C6H4-3-CF3
I-[4-(3-trifluoromethyIphenyl)piperazin-l-yl]-3-(quinoloxy-6-yl) propane of the formula HI where n=3, X=H2, Z=N, R= C,H6NO, R1=C6H4-3-CF3
l-[4-(3-methoxyphenyl)piperazin-l-yl]-3-(quinoloxy-8-yl) propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO, R1=C6H4-3-OCH3
1-[4-{2-methoxyphenyl)piperazin-l-yI]-3-(quinoIoxy-8-yl) propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO, Rl=C6H42-OCH3
1-[4-{4-fluorophenyI)piperazin-l-yl]-3-(qumoloxy-7-yl) propane of the formula III where n=3, X=H2, Z=N, R= C,H6NO, R1=C6H4-4-F
l-[4-(2-methoxyphenyI)piperazin-l-yl]-3-(quinoIoxy-7-y|) propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO, R'=C6H4-2-OCH3
1-[4-{2-chIorophenyl)piperazin-l-yI]-3-(quinoIoxy-7-yI) propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO, R1=C6H4-2-CI
l-[4-(4-hydroxy-4-phenyl)piperidine-l- yl]-3-(quinoloxy-7-yl) propane of the formula III where n=3, X=H2, Z=C, R= C9H6NO, Rl=C6H5, R2= OH
1-[4-(2-methoxyphenyI)piperazin-l-yl]-4-{quinoloxy-7-yl) butane of the formula III where n=4, X=H2, Z=N, R= C9H6NO, R1=C6H4-2-OCH3
1-[4-(2-chlorophenyI)piperazin-l-yI]-5-(quinoloxy-7-yl) pentane of the formula III where n=5, X=H2, Z=N, R= C9H6NO, RJ=C6H4-2-CI
l-[4-(4-FluorophenyI)piperazin-l-yl]-3-(quinoloxy-7-yl)propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO, R'=C6H4-4-F
l-[4-(2-pyridyl)piperazin-l-yl]-3-{quinoloxy-7-yl)propane of the formula III where n=3, X=H2, Z=N, R= C,H6NO, R1=C5H5N
l-[4-(2-Methyl-4-chIorophenyl)piperazin-l-yl]-3-(quinoloxy-7-yl)propane of the formula III where n=3, X=H2, Z=N, R= C,H6NO, RI=C6H3-2-CH3 -4-C1
l-[4-(3,4-dichlorophenyl)piperazin-l-yl]-3-(quinoloxy-7-yl)propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO, R1=-
l-[4-(4-Methoxyphenyl)piperazin-1-yL)-3-(quInoloxy-7-yS)propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO, R'=C6H4-4-OCH3
1-[4-(4-Chlorophenyl)piperazin-l-yl]-3-(qu!noIoxy-7-yI)propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO, R'=C6H4-4-Cl
l-[4-(4-AcetyI-4-phenyl)piperidin-l-yl]-3-(quinoloxy-7-yl)propane of the formula III where n=3, X=H2, Z=N, R= C,H6NO, Rl=C6H5 , R2=COCH3
1-[4-{3-ChIorophenyl)piperazin-l-yl]-3-(quuioIoxy-7-yl) propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO, R'=C6H4-3-Cl
1-[4-{3-MethylphenyI)piperazin-l-yI]-3-(quinoIoxy-7-yl) propane of the formula III where n=3, X=H2, Z=N, R= C,H6NO, Rl=C6H4-3-CH3
l-[4-(2-Chlorophenyl)piperazin-l-yl]-3-(quinoloxy-6-yl) propane of the formula III where n=3, X=H2, Z=N, R= C,H6NO, Rl=C6R4-2-Cl
l-[4-(4-ChIorophenyl)piperazin-l-yl]-3-{quinoloxy-6-yl) propane of the formula III where n=3, X=H2, Z=N, R= , Rl=C6H4-4-Cl
l-(4-Hydroxy-4-phenylpiperidin-l-yIJ-3-{quinoIoxy-6-yl) propane of the formula HI where n=3, X=H2, Z=C, R= CsH^NO, R1-C6H5, R2=OH
1-[4-{3-Methylphenyl)piperazin-l-yI]-3-(quinoloxy-6-yI) propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO, R1=C6H4-3-CH3
1-[4-(2-Pyridyl)piperazin-l-yI]-3-(quinoloxy-6-yI)propane of the formula III where n=3, X=H , Z=N, R= C9H6NO, R1=C5H5N
1-{4-{2-Ethylphenyl)piperazin-l-yl]-3-(quinoloxy-6-yl) propane of the formula III where n=3, X=H2, Z=N, R= C,H6NO, R1=HC6H4-2-C2H5.
1-[4-(4-Methoxyphenyl)piperazin-l-ylJ-3-(quinoloxy-6-yI) propane of the formula III where n=3, X=H2, Z=N, R= C9H6O, R1=C6H4-4-OCH3
l-l4-(2-Methoxyphenyl)piperazin-l-yl]-3-(quinoIoxy-6-yl) propane of the formula HI where n=3, X=H2, Z=N, R- C9H6NO, R1=C6H4-2-OCH3.
PharmacologicaS Acdvitics :
The compounds of invention show marked anti-ischemic/cardioprotective activity with few of them showing mild hypotensive activity and can be used as therapeutic agents in disease arising out of ischemia such as myocardial ischemia. Angina Pectoris myocardial infarction, any cardiac surgical intervention renal ischemia, stroke and trauma. Some of the compounds have also shown antiinflammatory activity and can be used as therapeutic agents in diseases arising out of inflammatory disorders like rheumatism, arthretis etc.
Cardioprotective Activities:
The most important and intersting observations is cardioprotective/anti-ischemic activity against myocardial stunning at a much smaller dose. Isolated perfused rat heart preparation (Langendorff) were allowed to equilibriate for 30 min. before subjecting to 45 min. of global ischemia followed by 30 min. reperfusion period. Compounds under test were administered during reperfusion period at a concentration of 10 nM.
The recovery of mechanical function (start of heart beat) with treated group was much earlier than control group. The incidence of reperfusion induced arrhythmia was either reduced or absent with test compounds when compared with control. Results are given in Table No. 1.
2. Effect on blood pressure, heart rate, respiration and on standard vasopressor and
vasopressor responses.
Pentobarbitone sodium (40 mg/kg i.p.) Anaesthetized cats of either sex weight 2.5-4.0 kg body weight were used for this study. Majority of them were normotensive but three of them were naturally hypertensive (basal mean arterial blood pressure > 160 mm Hg). Results are summarised in Table No. 2.
3. Antiinfiammatory Activity:
Some of these compounds were screened for Anti-inflammatory activity using Carrageenin induced paw oedema in rats in a dose of 100 µmol.p.o.and compared with Ibuprofen (l00µmoI.p.o.). p.o.). Results are summarised in Table No. 3.
Table 1: Isolated perfused rat heart preparation No flow - 45'(Global ischemia) Dose -10 nM (Given at the time of reperfusion)

(Table Removed)
** = Mild Hypotensive, * = Weak Hypotensive.
Table 2: CVS data of the compounds

(Table Removed)
Tr = Transient, Pt ND= Not Done, - =
= Potentiation, J = Fall in blood pressure, f = Rise in blood pressure ; No Effect, R= Reversal, D= Decrease.
Table 3 : Antiinflammatory activity of the compounds.

(Table Removed)
The following examples are given below to illustrate the details of the invention and should not be construed to limit the scope of the present invention.
Example 1: l-[4-(4-Fluorophenyl)piperazin-l-yI]-3-(pyrrolidin-2-oxo-l-yl)propan-3-one
A mixture of l-chloro-3-(pyrrolidin-2-oxo-l-yl)propan-3-one (0.52 g, 0.003 mol), l-(4-fluorophenyl)-piperazine (0.54 g, 0.003 mol) and K2CO3 (0.42 g) in dry DMF (20 ml) was heated at 90°C for 10 hours. It was diluted with water (50 ml), extracted with chloroform (3x30 mi), the combined chloroform extracts were washed with water (3x20 ml), dried (Na2SO4), concentrated and purified by column chromatography on silica gel column using ethyl acetate as eluant. It was and crystalized with hexane-ether. Yield 0.50 g(53%), m.p. 104C FTIR (KBr, cm'1): 3460, 2932,2824,1738, 1694, 1512, 1242, 820;'H-NMR (CDC13): 5 (ppm) 2.04(qn, 2H, J=7.72 Hz, 4-CH2 (pyrrolidone)), 2.56-2.69(m, 6H, 3-CH2 (pyrrolidone), N(CH2)2), 2.80(1, 2H, J=7.5 Hz, COCH2), 3.09-3.20(m, 6H,
N(CH2)2, N-CH2), 3.82(t, 2H, J=7.3 Hz, 5-CH2 (pyrrolidone)), 6.82-7.00(m, 4H, ArH); MS: m/z 319
(M+)
Example 2: l-[4-(4-FIuorophenyl)piperazin-l-yI}-3-[4-(4-chlorophenyI)-pyrrolidin-2-oxo-l-yl]propane
A mixture of l-chloro-3-[4-(4-chlorophenyl)-pyrrolidin-2-oxo-l-yl)propane (0.27 g, 0.001 mol), l-(4-fluorophenyl)piperazine (0.18 g, 0.001 mol) and K2CO3 (0.14 g) in dry DMF (20 ml) was heated at 1200C for 12 hours. It was diluted with water (50 ml), extracted with chloroform (3x30 ml), the combined chloroform extracts were washed with water (3x20 ml), dried (NaSO4), concentrated and purified by column chromatography on silica gel column using MeOH (2%) in CHC13as eluant. It was characterized as its dihydrochloride. Yield 0.22 g (53%), m.p. 1860C. FT1R (KBr, cm-1): 3466, 2943, 2822, 2785, 1682, 1501, 3234, 1163, 1092, 1015, 825, 754;'H-NMR (CDC1,): 8 (ppm) 1.78(qn, 2H, J=7.32 Hz, CH2), 2.38-2.46(m, 3H, 4-CH & 3-CH2 (pyrrolidone)), 2.53-2.62(m, 4H, N(CH2)2), 3.09-3.14(m, 4H, N(CH2)2), 3.36-3.43(m, 4H, N-CH2), 3.73-3.78(m, 2H, 5-CH, (pyrrolidone)), 6.85-7.00(m, 4H, ArH), 7.13-7.33(m, 4H, ArH); MS: m/z 415 (NT).
Example 3: 1-[4-{4-FIuorophenyl)piperazin-l-yl]-3-[4-(3,4-dimethoxyphenyl)-pyrrolidin-2-oxo-l-yllpropane
A mixture of l-chloro-3-[4-(3,4-dimethoxyphenyl)-pyrrolidin-2-oxo-l-yl]propane (0.30 g, 0.001 mol), l-(4-fluorophenyl)piperazine (0.18 g, 0.001 mol) and K2CO3 (0.14 g) in dry xylene (30 ml) was heated at 1400C for 15 hours. It was diluted with water (60 ml), extracted with chloroform (3x30 ml), the combined chloroform extracts were washed with water (3x30 ml), dried (Na2O4), concentrated and purified by column chromatography on silica gel column using MeOH (2.5%) in CHC13 as eluant. It was characterized as its dihydrochloride. Yield 0.25 g (57%), m.p. 1410C FT1R (KBr, cm'1): 3381,3022,2920,1576,1215,759;'H-NMR (CDC13): o (ppm) 1.75-1.82(m, 4H, CH2,3~CH2 (pyrrolidone)), 2.39-2.47(m, 2H, CH2-N), 2.57-2.62(m, 4H, N(CH2)2), 2.75-2.79(m, 1H, 4-CH (pyrrolidone)), 3.09-3.14(m, 4H, N(CH2)2), 3.36-3.43(m, 4H, N- CH^ 5-CH2(pyrrolidone)), 3.87(s, 6H, 2(OCH3)), 6.72-7.00(m, 7H, ArH); MS: m/z 438 (M4-3).
Example 4: l-[4-(4-Fluorophenyl)piperazin-l-yIj-2-(pyrroIidin-2-oxo-l-yl)ethan-2-one
A mixture of l-chloro-2-{pyrrolidin-2-oxo-l-yl)ethan-2-one (0.54 g, 0.0034 mol), l-(4-fluorophenyi)-piperazine (0.54 g, 0.003 mol) and K2CO3 (0.22 g) and Nal (0.05 g) in dry DMF (7 ml) was heated at 80°C for 18 hours. It was diluted with water (20 ml), extracted with ethylacetate (3x50 ml), the combined ethylacetate extract was washed with water (3x30 ml), dried (Na2SO4, concentrated and purified by column chromatography on silica gel column using ethylacetate as eluant. Yield 0.50 g (50%), m.p. 1240C. FTIR (KBr, cm'1): 3454,3052, 2966, 2906, 2826, 1734, 1694, 1512, 1242, 824; 'H-NMR (CDC13): 5 (ppm) 2.08(qn, 2H, J=7.26 Hz, 4-CH2 (pyrrolidone)), 2.61(t, 2H, J-7.88 Hz, 3-CH2 (pyrrolidone)), 2.76-2.81(m, 4H, N(CH2)2), 3.16-3.20(m, 4H, NfCH^), 3.80-3.87(m, 4H, COCH2 & 5-CH2 (pyrrolidone)), 6.84-7,02(m, 4H, ArH); MS; m/z 305 (M4).
Example 5: 1-{4-(2-Methoxyphenyl)piperazin-l-yl]-3-(pyrrolidin-2-oxo-l-yl)propan-3-one
A mixture of 3-chloro-3-(pyrrolidin-2-oxo-l-yl)propan-3-one (0.52 g, 0.003 mol), l-(2-methoxy-phenyl)piperazine (0.57 g, 0.003 mol) and K2O3(0.42 g) and Nal (0.02 g) in dry DMF (10 ml) was heated at 180°C for 30 hours. It was diluted with water (40 ml), extracted with chloroform (3x30 ml), the combined chloroform extract was washed with water (3x20 ml), dried (Na2S04), concentrated and purified by column chromatography on silica gel column using ethylacetate as eluant. It was characterized as its dihydrochloride. Yield 0.54 g (54%), m.p. 1500C. FTIR (KBr, cm-1 '): 3390, 2954, 1740, 1678, 1594, 1500, 1246, 746;1H-NMR (CDC13): 5 (ppm) 2.02-2.08(m, 2H, 4-CH2 (pyrrolidone)), 2.56-2.61(m, 2H, 3-CH2 (pyrrolidone)), 2.83-2.88(m, 2H, CH2), 2.94-2.97(m, 2H, CH2-N), 3.12-3.23(m, 8H, 2 x N-(CH2)2), 3.78-3.88(m, 5H, OCH3 & 5-CH2(pyrrolidone)), 6.84-7.03(m, 4H, ArH), MS: m/z 331 (M+).
Example 6: l-[4-(TrifluoromethyJphenyl)piperazin-l-ylJ-3-(pyrrolidin-2-oxo-l-yI)propan-3-one
A mixture of l-chloro-3-(pyrrolidin-2-oxo-l-yl)propan-3-one (0.52 g, 0.003 mol), l-(3-trifluoro-methylphenyl)piperazine (0.73 g, 0.003 mol), Na2CO3 (0.31 g, 0.003 mol) and Nal (0.02 g) in dry
acetone (50 ml) was refluxed on water bath for 40 hours. Reaction mixture was filtered, concentrated and purified by column chromatography on silica gel column using ethylacetate as eluant. It was characterized as its dihydrochloride. Yield 0.58 g (53%), m.p. 155 0C. FTIR (KBr, cm -1): 3370,2922, 1674,1338, 1138;'H-NMR (CDC13): 6 (ppm) 2.04-2.08(m, 2H, 4-CH2 (pyrrolidone)), 2.39(bs, 4H, COCH2, 3-CH2 (pyrrolidone)), 2.57-2.95(m, 6H, N(CH2)2 & CH2-N), 3.14-3.27(m, 4H, N(CH2)2), 3.82(t, 2H, J=7.14 Hz, 5-CH2(pyrrolidone)), 6.97-7.16(m, 2H, ArH), 7.30-7.51(m, 2H, ArH); MS: m/z 369 (M+).
Example 7: 1-[4-(3,4-Dichlorophenyl)piperazin-l-yI]-3-(pyrroIidin-2-oxo-l-yl)propan-3-one
A mixture of l-chloro-3-(pyrrolidin-2-oxo-l-yl)propan-3-one (0.35 g, 0.002 mol), l-(3,4-dichloro-phenyl)piperazine (0.46 g, 0.002 mol) and K2O3(0.26 g) and Nal (0.02 g) in dry DMF (25 ml) was heated at 100°C for 8 hours. The reaction mixture was diluted with water (50 ml), extracted with ethylacetate (3x30 ml), the combined ethylacetate extract was washed with water (3x30 ml), dried (Na2S04), concentrated and purified by column chromatography on silica gel column using MeOH (2%) in ethylacetate as eluant. It was characterized as its dihydrochloride. Yield 0.25 g (34%), m.p. 156°C. FTIR (KBr, cm'1): 3418, 3022, 1714, 1592, 1224, 758;'H-NMR (CDCI3): 5 (ppm) 2.00-2.ll(m, 2H, 4-CH2 (pyrrolidone)), 2.57-2.67(m, 6H, 3-CH2(pyrrolidone) & N(CH2)2), 2.76-2.88(m, 2H, COCH2), 3.12- 3.19(m, 6H, CH2-N & N(CH2)2), 3.82(t, 2H, J=7.12 Hz, 5-CH2 (pyrrolidone)), 6.69-6.76(m, 1H, ArH), 6.93-6.98(m, 1H, ArH), 7.23-7.33(m, 1H, ArH); MS: m/z 370 (MO.
Example 8: l-|4-(2-ChIorophenyl)piperazin-l-yl]-3-(pyrro!idin-2-oxo-l-yl)propan-3-one
A mixture of l-chloro-3-(pyrrolidin-2-oxo-l-yl)propan-3-one (0.35 g, 0.002 mol), l-(2-chlorophenyl)-piperazine (0.39 g, 0.002 mol) and K2CO3 (0.26 g) and Nal (0.02 g) in dry DMF (25 ml) was heated at 90°C for 10 hours. The reaction mixture was diluted with water (40 ml), extracted with ethylacetate (3x30 ml), the combined ethylacetate extract was washed with water (3x30 ml), dried (Na2SO4), concentrated and purified by column chromatography on silica gel column using 1% MeOH in ethylacetate as eluant. It was characterized as its dihydrochloride. Yield 0.30 g (45%), m.p.
160°C. FTIR (KBr, cm'1): 3462,2948,2822,1738,1690,1592, 1244,760;'H-NMR (CDC1,): δ (ppm) 2.04(qn, 2H, J=7.24 Hz, 4-CH2 (pyrrolidone)), 2.61(t, 2H, J=8.04 Hz, 3-CH, (pyrrolidone)), 2.71-2.73(m, 4H, l N(CH)2, 2.79-2.88(m, 2H, COCH2), 3.06-3.21(m, 6H, N(CH2)2 & CH2-N), 3.82(t, 2H, J=7.06 Hz, 5-CH2 (pyrrolidone)), 7.01(dd, 2H, J=1.54 & 8.08 Hz, ArH), 7.20(d, 1H, J=7.22 Hz, ArH), 7.34(dd, 1H, J=1.46 & 7.78 Hz, ArH); MS: m/z 335 (Mf).
Example 9: l-[4-(2-MethoxyphenyI)piperazin-l-yI]-2-(pyrrolidin-2-oxo-l-yI)ethan-2-one
A mixture of l-chloro-2-(pyrrolidin-2-oxo-l-yl)ethan-2-one (0.54 g, 0.0034 mol), l-(2-methoxy-phenyl)piperazine (0.71 g, 0.0037 mol), K2CO, (0.42 g) and Nal (0.06 g) in dry DMF (10 ml) was heated at 90T: for 15 hours. It was diluted with water (20 ml), extracted with ethylacetate (3x30 ml). The combined ethylacetate extract was washed with water (3x20 ml), dried (Na2SO4) and concentrated to give an oil which was purified by column chromatography on silica gel using ethylacetate as eluant. Yield 0.25 g (25%), oil. FTIR (Neat, cm'1): 3372, 2948, 2830, 1676, 1598, 1302, 1240, 754;'H-NMR (CDC13): δ (ppm) 1.99-2.02(m, 2H, 4-CH2 (pyrrolidone)), 2.80-2.84(m, 2H, 3-CH2 (pyrrolidone)), 2.98-3.13(m, 4H, N(CH2)2), 3.30-3.50(m, 4H, N(CH2)2), 3.72-3.81(m, 7H, OCH3, N-CH2, 5-CH, (pyrrolidone)), 6.77-7.02(m, 4H, ArH); MS: m/z 317 (M').
Example 10: l-[4-(3,4-DichIorophenyl)piperazin-l-yl]-2-(pyrrolidin-2-oxo-l-yl)ethan-2-one
A mixture of l-chloro-2(pyrrolidin-2-oxo-l-yl)ethan-2-one (0.54 g, 0.0034 mol), 1 -(3,4-dichloro-phenyl)piperazine dihydrochlonde (0.98 g, 0.0037 mol), dry k2co3(0.53 g) and Nal (0.06 g) in dry DMF (5 ml) was heated at 100°C for 12 hours. It was diluted with water (40 ml) and crude solid obtained was purified by column chromatography on silica gel using ethylacetate as eluant. It was crystalized with ether hcxane. Yield 0.65 g (55%), m.p. 1520C. FTIR (KBr, cm'1): 3448,2840, 1698, 1594, 1480, 1240, 808;'H-NMR (CDC13): 8 (ppm) 2.08(qn, 2H, J=7.28 Hz, 4-CH2 (pyrrolidone)), 2.61(1,2H, J=8.12 Hz, 3-CH2(pyrrolidone)), 2.75-2.80(m,4H, N(CH2)2, 3.21-3.25(m, 4H, N(CH2)2), 3.68-3.87(m, 4H, 5-CH2 (pyrrolidone) & N-CH,), 6.73(dd, 1H, J=2.68 & 8.76 Hz, ArH), 6.95(s, 1H, ArH), 7.24-7.28(m, 1H, ArH); MS: m/z 356 (M+).
Example 11: l-[4-(2-ChLorophenyl)piperazin-l-ylj-2-(pyrroIidin-2-oxo-l-yl)ethan-2-one
A mixture of l-chLoro-2-(pyrrolidin-2-oxo-l-yl)ethan-2-one (0.54 g, 0.0034 mol), l-(2-chlorophenyl)-piperazine monohydrochloride (0.86 g, 0.0037 mol), dry K2CO3 ,(0.53 g) and Nal (0.02 g) in acetone (50 ml) was refluxed at 80°C for 36 hours. Reaction mixture was filtered, concentrated to give an
011 which was purified by column chromatography on silica gel using ethylacetate as eluant. Yield
0.20 g (19%), oil. FTIR (Neat, cm' '): 3352, 3014, 2828, 1740, 1700, 1594, 1226, 758; H-NMR
(CDC13): 8 (ppm) 2.05(m, 2H, 4-CH2 (pyrrolidone)), 2.54(t, 2H, J=8.0 Hz, 3-CH2 (pyrrolidone)),
2.80-2.85(m, 4H, N(CH2)2), 3.09-3.17(m, 4H, N(CH2)2), 3.80-3.87(m, 4H, 5-CH2 (pyrrolidone)) &
N-CH2), 6.96- 7.08(m, 2H, ArH), 7.18-7.37(m, 2H, ArH); MS: m/z321 (M+).
Example 12: l-[4-(3-Trifluoromethylphenyl)piperazin-l-yl]-2-(pyrroIidin-2-oxo-l-yI)ethan-2-one
A mixture of l-chloro-2-(pyrrolidin-2-oxo-l-yl)ethan-2-one (0.48 g, 0.003 mol), l-(3-trifluoromethyl-phenyl)piperazine (0.76 g, 0.0033 mol), K2CO3 (0.42 g) and Nal (0.06 g) in dry DMF (5 ml) was heated at 90°C for 16 hours. It was diluted with water (20 ml). The resultant solid was recrystallized with ethylacetate. Yield 0.45 g (43%), m.p. 1050C. FTIR (KBr, cm'1): 3436,2830, 1722,1608,1328, 1162, 956;'H-NMR (CDC13): 5 (ppm) 2.09(qn, 2H, J=7.66 Hz, 4-CH2 (pyrrolidone)), 2.61(t, 2H, J=8.12 Hz, 3-CH2 (pyrrolidone)), 2.82-2.86(m, 4H, N(CH )2)i2 3.30-3.34(m, 4H, N(CH ) ),2 2 3.80-3.87(m, 4H, 5-CH2 (pyrrolidone) & NCH2), 7.05-7.38(m, 4H, ArH); MS: m/z 355 (M4).
Example 13: l-[4-(PhenyI)piperazin-l-yI]-2-(pyrrolidin-2-oxo-l-yl)ethan-2-one
A mixture of l-chloro-2-(pyrrolidin-2-oxo-l-yl)ethan-2-one (0.48 g, 0.003 mol), phenylpiperazine (0.54 g, 0.0033 mol), Na2CO3 (0.32 g) and Nal (0.04 g) in dry DMF (5 ml) was heated at 90°C for
12 hours. It was diluted with water (20 ml) and resultant solid was recrystallized with ethylacetate.
Yield 0.30 g (35%), m.p. 103-lOS'C. FTIR (KBr, cm'1): 3400, 2974,2828, 1736, 1698, 1598, 1500,
1240, 756;'H-NMR (CDC1,): δ (ppm) 2.04-2.ll(m, 2H, 4-CH2 (pyrrolidone)), 2.57-2.65(m, 2H,
3-CH2 (pyrrolidone)), 2.77-2.82(m, 4H, N(CH2)2), 3.19-3.29(m, 4H, N(CH2)2), 3.69-3.87(m, 4H,
5-CH, (pyrrolidone) & N-CH2), 6.85-6.95(m, 2H, ArH), 7.18-7.53(m, 3H, ArH); MS: m/z 287 (M+).
Example 14:
l-[4-(4-Chloropheny!piperazin-l-yl]-2-(pyrrolidin-2-oxo-l-yl)ethan-2-one
A mixture of l-chloro-2-(pyrrolidin-2-oxo-l-yl)ethan-2-one (0.48 g, 0.003 mol), 1-(4-chlorophenyl)-piperazine dihydrochloride (0.90 g, 0.0033 mol), K2CO3(0.63 g) and Nal (0.06 g) in dry DMF (5 ml) was heated at 90^ for 16 hours. It was diluted with water (20 ml) to yield solid material which was recrystallized with ethylacetate. Yield 0.60 g(63%), m.p. 135-38"C. FTIR (KBr, cm): 3462,2902, 2826, 1740, 1664, 1594, 1498, 1226, 818; 'H-NMR (CDC13): δ (ppm) 2.07-2.19(m, 2H, 4-CH2 (pyrrolidone)), 2.56-2.60(m, 2H, 3-CH,(pyrrolidone)), 2.65-2.80(m, 4H, N(CH2)2), 3.14-3.28(m, 4H, N(CH2)2), 3.78-3.82(m, 4H, 5-CH2 (pyrrolidone) & N-CH2), 6.83(dd, 2H, J=2.28 & 9.02 Hz, ArH), 7.25(dd, 2H, J=3.38 & 6.68 Hz, ArH); MS: m/z 321 (M-).
Example 15: l-[4-(4-Chlorophenylpiperazin-l-yIj-4-(pyrrolidin-2-oxo-l-yl)butan-4-one
A mixture of l-chloro-4-(pyrrolidin-2-oxo-l-yl)butan-4-one (0.47 g, 0.0025 mol), l-(4-chlorophenyl)-piperazine dihydrochloride (0.67 g, 0.0025 mol), K2CO3(0.52 g) and Nal (0.08 g) in dry toluene (15 ml) was refluxed for 20 hours. The mixture was filtered, concentrated to yield an oil which was purified by column chromatography on silica gel using ethylacetate as eluant. It was characterized as its dihydrochloride. Yield 0.15 g (17%), m.p. 259-62°C. FTIR (Neat, cm'1): 3362, 2922, 2334, 1730, 1598, 1480, 1240, 1024, 808; 'H-NMR (CDC!3): δ (ppm) 0.76-0.83(m, 2H, CH2), 0.98-1.03(m, 2H, 4-CH2 (pyrrolidone)), 1.23-1.27(m, 2H, 3-CH2 (pyrrolidone)), 1.63-1.78(m, 4H, N(CH2)2), 2.02-2.04(m, 2H, COCH2), 3.14(bs, 4H, N(CH2)2), 3.69(bs, 4H, 5-CH2 (pyrrolidone) & CH2-N), 6.84(d, 2H, J=8.82 Hz, ArH), 7.23(d, 2H, J=9.2 Hz, ArH); MS: m/z 349 (M+).
Example 16: l-|4-(3-TrifluoromethyIphenyI)piperazin-l-ylJ-3-(quino!oxy-8-yl)propane
A mixture of l-chloro-3-(quinoloxy-8-yl)propane (0.66 g, 0.003 mol), l-(3-trifluoromethylphenyl)-piperazine (0.75 g, 0.0033 mol) and K2CO3(0.4 g) in dry acetone (70 ml) was refluxed for 40 hours. Reaction mixture was filtered, concentrated and purified by column chromatography on silica gel
using 1% MeOH in chloroform as eluant. It was characterized as its dihydrochloride. Yield 0.56 g (45%),m.p. 135°C. FTIR(KBr,cm-1): 3050,2827, 1610, 1574, 1503, 1448, 1362, 1242, 1107, 1160, 1078, 993, 951, 822, 756, 731; 'H-NMR (CDC1.,): δ (ppm) 2.25(m, 2H, C-CH2-C), 2.68(m, 6H, NCH2), 3.25(t, 4H, J=6.3 Hz, ArNCH2), 4.30(t, 2H, J=7.2 Hz, OCH2), 6.90-7.50(m, 8H, Ar), 8.05(dd, 1H, J=9.0 & 1.8 Hz, Ar), 8.85(m, 1H, Ar-H); MS: m/z 415 (Mf).
Example 17: l-[4-(3-ch!orophenyl)piperazin-l-yl]-3-(quinoIoxy-8-yI)propane
A mixture of 1 -chloro-3-(quinoloxy-8-yI)propane (0.70 g, 0.0033 mol), l-(3-chlorophenyl)piperazine (0.58 g, 0.003 mol) and K2CO3 (0.4 g) in dry DMF (20 ml) was heated at 110°C for 15 hours. Reaction mixture was diluted with water (50 ml), extracted with chloroform (30x3 ml), the combined chloroform extracts were washed with water (20x3 ml), dried (Na2SO4, concentrated and purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant. It was crystallized with ether-hexane. Yield (0.60 g) (53%), m.p. 900C. FTIR (KBr,cm1): 3030, 2822, 1595, 1566, 1454, 1381, 1320, 1265, 1238, 1107, 788, 758; 'H-NMR (CDC13): δ (ppm) 2.22(m, 2H, C-CH2-C), 2.65(m, 6H, NCH2), 3.17(t, 4H, J-6.3 Hz, ArNCH2), 4.30(t, 2H, J-7.2 Hz, OCH2), 6.60-7.40(m, 8H, Ar), 8.05(dd, 1H, J=8.1 & 1.8 Hz, Ar), 8.85(m, 1H, Ar); MS: m/z 381 (Mf).
Example 18: l-[4-(4-Fluoropheny!)piperazin-l-yl]-4-(quinoIoxy-7-yI) butane
A mixture of l-chloro-4-(quinoloxy-7-yl) butane (0.705 g, 0.003 mol), l-(4-fluorophenyl)piperazine (0.54 g, 0.003 mol), K2CO3 (0.32 g) and Nal (0.02 g) in dry DMF (20 ml) was heated at 110°C for 12 hours. Reaction mixture was diluted with water (50 ml), extracted with chloroform (3x30 ml), the combined chloroform extracts were washed with water (3x20 ml), dried (NajSO4), concentrated and purified by column chromatography on silica gel using 1% MeOH in chioroform as eluant. Yield (0.55 g) (52%), m.p. 530C. FTIR (KBr,cm-1 ): 3844,3584,3416,3022, 2944, 2826,2404, 2348, 1708, 1632, 1564, 1510, 1442, 1384, 1218, 760, 662; 'H-NMR (CDC13): 5 (ppm) 1.86(m, 4H, C-CH2-C), 2.56(m, 6H, NCH2), 3.12(m, 4H, ArNCH2), 4.15(m, 2H, OCH2), 6.83-6.95(m, 4H, Ar), 7.17-7.29(m, 3H, Ar), 7.69(m, 1H, Ar), 8.06(d, 1H, J=8.2 Hz, Ar), 8.82(m, 1H, Ar); MS: 379 (M).
Example 19: 1-{4-(2-Chlorophenyl)piperazin-l-ylj-4-(quinoloxy-7-yl)butane
A mixture of l-chloro-4-(quinoloxy-7-yl)butane (0.470 g, 0.002 mol), l-(2-chlorophenyl)piperazine (0.392 g, 0.002 mol), K2CO3 (0.20 g) and Nal (0.01 g) in dry DMF (20 ml) was heated at 110°C for 16 hours. Reaction mixture was diluted with water (50 ml), extracted with chloroform (3x30 ml), the combined chloroform extracts were washed with water (3x20 ml), dried (Na2 -SO4), concentrated and purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant. Yield (0.40 g) (51%), m.p. 125°C. FTIR (KBr,cm-1): 3870, 3734, 3324, 2942, 2822, 2332, 2212, 2116, 1916, 1618, 1474, 1238, 1148, 1030, 838, 754; 'H-NMR (CDC13): δ (ppm) 1.90(m, 4H, C-CH2-C), 2.53(t, 2H, j=7.6 Hz), 2.69(brs, 4H, N-CH,) 3.lO(brs, 4H, Ar-N-CH2), 4.17(t, 2H, J=6.0 Hz, O-CH2), 6.96- 7.41(m, 7H, Ar), 7.69(d, 1H, j=9.0Hz,Ar), 8.07(d, 1H, J=8.4 Hz, Ar), 8.82(m, 1H, Ar); MS: 395 (M+).
Example 20: l-[4-(4-hydroxy-4-phenyI)piperidin-l-yl]-4-(quinoloxy-7-yI)butane
A mixture of l-chloro-4-(quinoloxy-7-yl)butane (0.705 g, 0.003 mol), 4-(4-hydroxy-4-phenyl}-piperidine (0.53 g, 0.003 mol), K2CO3 (0.32 g) and Nal (0.02 g) in dry DMF (20 ml) was heated at 1 lO^C for 14 hours. Reaction mixture was diluted with water (50 ml), extracted with chloroform (3x30 ml), the combined chloroform extracts were washed with water (3x20 ml), dried (Na2S04), concentrated and purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant. Yield (0.51 g) (45%), m.p. 1 lO0C. FTIR (KBr,cnT '): 3926, 3828, 3720, 3486, 2924, 2726, 2536,2344,2304,2120, 1972,1626, 1530, 1486, 1382, 1248, 1206, 1124, 1050, 830,640; 'H-NMR (CDCl3): δ (ppm) 1.85(m, 5H, C-CH2-C,OH), 2.67(m, 4H, CH2-C-OH), 2.99(m, 611, NCH2), 4.16(m, 21!, OCH2), 7.12-7.85(m, 9H, Ar), 8.08(c', 1H, J=8.0 Hz, Ar), 8,82(d, 1H, J=2.8 Hz, Ar), MS: m/z 376 (M+).
Example 21: l-[4-(4-Hydroxy-4-pheny!)piperidin-l-yl]-3-(quinoloxy-8-yl)propane
A mixture of l-chloro-3-(quinoloxy-8-yl)propane (0.663 g, 0.003 mol), 4-(4-hydroxy-4-phenyl)-
piperidine (0.531 g, 0.003 mol), K2CO3 (0.32 gm) and Nal (0.02 g) in dry DMF (20 ml) was heated at 1 10°C for 12 hours. Reaction mixture was diluted with water (50 ml), extracted with chloroform (3x30 ml), the combined chloroform extracts were washed with water (3x20 ml), dried (Na2SO4), concentrated and purified by column chromatography on silica gel using 1% MeOH in chloroform aseluant Yield (0.50 g) (46%), m.p. 142°C FTIR (KBr,cm-'): 3300, 1370, 1310, 1250, 1180, 1100, 960, 810, 780, 740, 720, 690 'H-NMR (CDC1,): δ (ppm) 2.30(m, 2H, C- CH2-C), 3.00(m, 5H, CH2-C-OH,OH), 3.35(brs,6H, NCH2), 4.32(1, 2H, J=7.2Hz,OCH2), 7.20-7.50(m, 8H, Ar), 8.10(m, 1H, AT), 8.80(m, 1H, Ar) MS: m/z 362 (M+).
Example 22: l-[4-(4-ethyIphenyI)piperazin-l-ylj-3-(quinoloxy-8-yl)propane
A mixture of l-chloro-3-(quinoloxy-8-yl)propane (0.440 g, 0.002 mol), l-(4-ethylphenyl)piperazine (0.380 g, 0.002 mol), K2CO3 (0.20 g) and Nal (0.01 g) in dry DMF (20 ml) was heated at 1100C: for 14 hours. Reaction mixture was diluted with water (50 ml), extracted with chloroform (3x30 ml), the combined chloroform extracts were washed with water (3x20 ml), dried (Na2SO4, concentrated and purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant. Yield (0.35 g) (47%), m.p. 174°C. FTIR (KBr.cm): 3746, 3362, 3013, 2964, 2883, 2826, 1692, 3661, 1614, 1568, 1512, 1462, 1379, 1317, 1217, 1186, 1146, 1107, 1030,928,824, 758,665; 1H-NMR (CDC13): δ (ppm) 1.20(m, 3H, CH3), 2.55(qn, 2H, J=6.8 Hz, CH2CH,), 2.92(bs, 6H, NCH2), 3.30(bs, 4H, Ar-CHj, 4.38(1, 2H, J==6.8 Hz, OCH,), 6.90(d, 2H, J=8.2 Hz, Ar), 7.15(d, 2H, J=8.5 Hz, Ar), 7.40-7.50(m, 4H, Ar), 8.15(d, 1H, J=9.0 Hz, Ar), 8.92(m, 1H, Ar); MS: m/z(M').
Example 23: l-[4-(2-Pyridyl)piperazin-l-yl]-3-(quinoloxy-8-yl)propane
A mixture of l-chloro-3-(quinoioxy-8-yijpropane(0..440g, 0.002 mol), l-(2-pyridyl)piperazine (0.32 g, 0.002 mol), K2CO, (0.32 g) and Nal (0.01 g) in dry DMF (20 ml) was heated at 110°C for 12 hours. Reaction mixture was diluted with water (50 ml), extracted with chloroform (3x30 ml), the combined chloroform extracts were washed with water (3x20 ml), dried (Na2SO4, concentrated and purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant. Yield (0.32 g) (49%), m.p. 166°C. FTIR (KBr,cm'): 2950, 2820, 1590, 1470, 1430, 1370, 1310, 1240,

1100,970, 810,760,720; 1H-NMR (CDCl3): δ (ppm) 2.30(qn, 2H, J=5.6 Hz, C-CHrC), 2.65(m, 6H, NCH2), 3.07(t, 4H, J-5.6 Hz, ArNCH2), 4.36(t, 2H, J=6.0 Hz, OCH2), 6.60-6.70(m, 2H, Ar), 7.12(d, 1H, J=8.4 Hz, Ar), 7.40-7.52(m, 5H, Ar), 8.10-8.20(m, 2H, Ar); MS: rn/z 348 (M1).
Example 24:
l-[4-(3-MethylphenyI)piperazin-l-yl]-3-(quinoIoxy-8-yl)propane
A mixture of l-chloro-3-(quinoIoxy-8-yl)propane (0.440 g, 0.002 mol), l-(3-methylphenyl)piperazine (0.352 g, 0.002 mol), K2CO3 (0.40 g) and Nal (0.01 g) in dry DMF (20 ml) was heated at 1100C for 13 hours. Reaction mixture was diluted with water (50 ml), extracted with chloroform (3x30 ml), the combined chloroform extracts were washed with water (3x20 ml), dried (Na2SO4, concentrated and purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant. Yield (0.38 g) (54%), m.p. 210°C. FTIR (KBr,cm°): 2960, 2880, 2820, 1590, 1490, 1450, 1370, 1300, 1240, 1200, 1170,1130,1090,980, 720; 'H-NMR (CDCI3): δ (ppm) 2.15(m, 2H, C-CH2-C), 2.28(s, 3H, CH3), 2.60(m, 6H, NCH2), 3.15(t, 4H, J=4.5 Hz, ArNCH2), 4.30(t, 2H, J=7.2 Hz, OCH2), 6.60-6.70(m, 3H, Ar), 6.95-7.25(m, 3H, Ar), 7.30-7.40(m, 2H, Ar), 8.05(d, 1H, J=7.2 Hz, Ar), 8.85(dd, 1H, J=6.3 & 1.8 Hz, Ar); MS: m/z361 (M+).
Example 25: l-[4-(3,4-dimethoxyphenyl)piperazin-l-ylj-3-(quinoloxy-8-yl) propane
A mixture of l-chloro-3-(quinoloxy-8-yl)propane (0.442 g, 0.002 mol), l-(3,4-dimethoxypheny!)-piperazine (0.444 g, 0.003 mol), K2CO3 (0.40 g) and Nal (0.01 g) in dry DMF (20 ml) was heated at 110°C for 12 hours. Reaction mixture was diluted with water (50 ml), extracted with chloroform (3x30 mi), the combined chloroform extracts were washed with water (3x20 ml), dried (Na2SO4), concentrated and purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant. Yield (0.35 g) (44%), m.p. hygroscopic. FTIR (KBr cm1): 3682, 3398,3020, 2959, 2829, 2403, 2278,1583,1512,1462,1379,1315, 1215,1146,1107,1080,1026, 974,760,669; 'H-NMR (CDCl3): δ (ppm) 2.30(qn, 2H, CH2), 2.73(m, 6H,NCH2), 3.16(m, 4H, ArNCH2), 3.86(s, 3H, OCH3), 3.89(s, 3H, OCH3), 4.38(t, 2H, J=4.6 Hz, OCH ), 6.49(m, 1H, Ar), 6.62(d, 1H, J=1.80 Hz, Ar), 6.82(d, 1H, J=5.8 Hz, Ar), 7.14(d, 1H, J=5.0 Hz, Ar), 7.40-7.51(m, 3H, Ar), 8.15(dd, 1H, J=5.6 & 1.2 Hz, Ar), 8.97(m, 1H. Ar); MS: m/z 407(M+).
Example 26: l-[4-(4-Chloro-2-niethylphenyl)piperazin-l-yIl-3-(quinoloxy-8-yl) propane
A mixture of l-chloro-3-(quinoloxy-8-yl)propane (0.663 g, 0.003 mol),l-(4-chloro-2-methyIphenyl)-piperazine (0.63 g, 0.003 mol), K2CO3 (0.40 g) and Nal (0.01 g) in dry DMF (20 ml) was heated at 110°C for 16 hours. Reaction mixture was diluted with water (50 ml), extracted with chloroform (3x30 ml), the combined chloroform extracts were washed with water (3x20 ml), dried (Na2S04), concentrated and purified by column chromatography on silica gel using 1% MeOH in chloroform as eiuant. Yield (0.50 g) (42%), m.p. 97°C. FTIR (KBr.cm1): 3423, 2928, 2831, 1591, 1497, 1466, 1371, 1317, 1265, 1225, 1211, 1188, 1167, 1111, 1038,824,804,793, 735; 1H-NMR(CDC13): δ (ppm) 1.70(s, 3H, CH3), 2.25(m, 2H, CCH2-C), 2.54(m, 6H, NCH2), 3.12(m, 4H, ArNCH2), 4.36(1, 2H, J-4.6 Hz, OCH2), 6.82(d, 2H, J=6.0 Hz, Ar), 7.10-7.48(m, 5H, Ar), 8.12(d, 1H, J=5.6 Hz, Ar), 8.95(d, 1H, J=2.8 Hz, Ar); MS: m/z 395 (NT).
Example 27: l-[4-(3-trifluoromethy!)phenylpiperazin-l-yl]-3-(qainoioxy-7-yl)propane
A mixture of l-chloro-3-(quinoloxy-7-yl)propane (0.44 g, 0.002 mol), l-(3-trifluoromethylphenyl)-piperazine (0.46 g, 0.002 mol) and Na2CO3 (0.40 g) in dry DMF (20 ml) was heated at 110°C for 8 hours. Reaction mixture was diluted with water, extracted with chloroform (3x30 ml), the combined CHC13 extracts were washed with water (3x20 ml), dried (Na2SO.) and purified by column chromatography using 2% MeOH in CHC13 on silica gel column. It was characterized as its dihydrochloride. Yield 0.30 g(36%), m.p. 1400C. FTIR (KBr.cm'1): 305], 2972,2939,2916, 2883, 1624, 1597, 1504, 1470, 1441, 1387, 1319, 1263, 1240, 1207, 1175, 1136, 1085, 1055, 972, 849, 831,796,764; 'H-NMR (CDCL3): δ (ppm) 2.40~2.7Q(m, 4H, NCH2, C-CH2-C), 3..21(bs, 4H, NCH2), 3.73(m, 4H, Ar-NCH2), 4.30(m, 2H, OCH2), 7.08-7.43(m, 7H, Ar), 7.77(rn, 1H, Ar), 8.17(d, 1H, J=7.5 Hz, Ar), 8.85(bs, 1H, Ar); MS: m/z 415 (M4).

Example 28: 1-[4-{3-trifluoromethylphenyl)piperazle-l-yl]-3-(quinoloxy-6-yI)propane
A mixture of l-chloro-3-(quinoloxy-6-y!)propane (0.89 g, 0.004 mol), l-(3-trifluorornethylphenyl)-piperazine (0.92 g, 0.004 mol) and dry K2CO3 (0.54 g) in dry DMF (30 ml) was heated at 120°C for 10 hours. It was diluted with water (50 ml), extracted with chlorofoim(3x30 ml), washed with water (3x20 ml), dried (Na2SO4) and purified by column chromatography on silica gel using ethylacetate as eiuant. It was characterized as its dihydrochloride. Yield 1.00 g (62%), m.p. 240°C. FTIR (KBr.cm'1): 3050,2951,2883,2883,2826,2702,2189,2089, 1921, 1695, 1616, 1500, 1452, 1354, 1317, 1230, 1163, 1122, 1076, 1045, 995, 949, 839, 756; 'H-NMR (CDCl3): δ (ppm) 2.10(qn,2H, J-7.0 Hz, C- CH2-C), 2.68(m, 6H, NCH:), 3.40(m, 4H, Ar-NCH2), 4.18(t, 2H, J=8 Hz, OCH2), 7.10-7.55(m, 7H, Ar), 7.90-8. 10(m, 2H5 Ar), 8.75(bs, 1H, Ar); MS: m/z 415 (Mf).
Example 29: 1-[4-{3-meihoxyphenyl)piperazin-l-yl]-3-(quinoloxy-8-yl)propane
A mixture of I-ch:orc~3-(quinoloxy-8-yl)propane (0.44 g, 0.002 mol), l-(3-methoxyphenyl)-piperazine (0.38 g, 0.002 mol), dry K2CO3 (0.40 g) and Nal (0.01 g) in dry acetone (50 mi) was refluxed for 38 hours. Reaction mixture was filtered, concentrated and purified by column chromatography on silica gel using 2% MeOH in chloroform as eiuant. It was characterized as its dihydrochloride. Yield 0.30 g (40%), m.p. 95°C. FTIR (KBr.cm1): 3050, 3000, 2949, 2882, 2826, 1603, 1531, 1499, 1462, 1379, 1317, 1258, 1049, 756; 'H-NMR (CDC13): δ (ppm) 2.45(bs, 2H, C-CKr C), 3.00(m, 6H, NCH2), 3.42(bs, 4H, ArNCH2), 3.80(s, 3H, OCH3), 4.40(t, 2H, J=8 Hz, OCH:), 6.40-6.60(m, 2H, Ar), 7. 1 0-7.50(m, 6H, Ar), 8. 1 5(d, 1 H, J=7.0 Hz, Ar), 8.95(m, 1 H, Ar); MS: m/z 377 (M*).
l-[4-(2-metfaoxyphenyI)piperazin-l-yl]-3-(quinoloxy-8-yI)propane
A mixture of l-chloro-3-(quinoloxy-8-yl)propane (0.44 g, 0.002 mol), l-(2-methoxyphenyl)-piperazine (0.38 g, 0.002 mol), dry K2CO3 (0.40 g) and tetra butylammonium iodide (0.01 g) in dry toluene (50 ml) was refluxed for 36 hours. Reaction mixture was filtered, concentrated and purified
by column chromatography on silica gel using 2% MeOH in chloroform as eluant. It was characterized as its dihydrochloride. Yield 0.38 g(51%), m.p. 137oC. FUR (KBr,cm1): 3100,3000, 2950,2940,2830,2800, 1600, 1560, 1550, 1490, 1450, 1370, 1230, 1170, 720 ; 'H-NMR(CDCI,): 5 (ppm) 2.25(m, 2H, C-CH2-C), 2.75(m, 6H, NCH, 3.15(m, 4H, Ar-NCHj), 3.85(s, 3H, OCH3), 4.35(t, 2H, J=8 Hz, OCH2), 6.85-7.45(m, 8H, Ar), 8.07(m, !H, Ar), 8.87(dd, 1H, J=6.0 & 1.8 Hz, Ar); MS: m/z 377 (NT).
Example 31: l-[4-(4-fluorophenyl)piperazin-l-yl]-3-(quinoIoxy-8-y!)propane
A mixture of l-chloro-3-(quinoloxy-8-yl)propane (0.44 g, 0.002 mol), l-(4-fluorophenyl)piperazine (0,36 g, 0.002 mol), Na2CO3 (0.35 g) and Nal (0.01 g) in dry DMF (10 ml) was heated at 90°C for 12 hours. It was diluted with water and extracted with chloroform (3x30 ml), washed with water (3x20 ml), dried (Na2SO4) and concentrated to give an oil. This oil was- purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant and was characterized as its dihydrochloride. Yield 0.42 g (57%), m.p. 150°C. FTIR (KBr,cm1): 3030, 2970, 2940, 2840, 1590, 1510, 1465, 1380, 1320, 1220, 1110, 820; 'H-NMR (CDC13): δ (ppm) 2.25(m, 2H, C-CH2-C), 2.70(m, 6H, NCH2), 3.15(m, 4H, Ar-NCH2), 4.40(t, 2H, J=8 Hz, OCH2), 6.90-7.50(m, 8H, Ar), 8.15(d, 1H, J=6.3 Hz, Ar), 8.95(m, 1H, Ar); MS: m/z 365 (M*).
Example 32: l-[4-(2-methoxyphenyl)piperazin-l-yl]-3-(quinoloxy-7-yl)propane
A mixture of l-chloro-3-(quinoloxy-7-yl)propane (0.88 g, 0.004 mol), l-(2-methoxyphenyl)-piperazine (0.76 g, 0.004 mol) and dry NaHCO., (0.40 g) in dry DMF (25 ml) was heated at 900C for 10 hours. Reaction mixture was diluted with water, extracted with chloroform (3x30 ml), washed vvith water (3x20 mi), dried (Na2SO4) and purified by comma chromatography on silica gel using 3% MeOH in chloroform as eluant. It was characterized as its dihydrochloride. Yield 0.77 g (52%), m.p. 87°C. FTIR (KBr,cm-'): 3030,2946,2820,2618,1500, 1450,1386, 1238, 1142,744; 'H-NMR (CDC13): 6 (ppm) 2.1 l(qn, 2H, J=7.0 Hz, C-CH2-C), 2.68(m, 6H, NCH2), 3.09(bs, 4H, Ar-NCH2), 3.86(s, 3H, OCH3), 4.2l(t, 2H, J=6.2 Hz, OCH2), 6.83-7.28(m, 6H, Ar), 7.42(d, 1H, J=2.0 Hz, Ar), 7.69(d, 1H, J=9.0 Hz, Ar), 8.06(d, 1H, J=8.0 Hz, Ar), 8.82(m, 1H, Ar); MS: m/z 377 (M).
Example 33:
l-[4-(2-ch!orophenyl)piperazin-l-yl]-3-{quinoloxy-7-yl)propane
A mixture of l-chloro-3-(quinoloxy-7-yI)propane (0.44 g, 0.002 mol), l-(2-chlorophenyl)piperazine (0.40 g, 0.002 mol) and K2CO3 (0.40 g) in dry acetone (50 ml) was refluxed for 35 hours. Reaction mixture was filtered, concentrated and purified by column chromatograpby on silica gel using 4% MeOH in chloroform as eluant. It was crystallized with ether-hexane. Yield 0.41 g (68%), m.p. 82°C. FTIR (KBr.cm1): 3054,2948, 2888, 2826, 1906, 1780, 1724, 1616,1446,1386, 1256,1176, 1130, 1044, 838, 762; 'H-NMR (CDC13): 5 (ppm) 2.14(qn, 2H, J=7.2 Hz, C-CHrC), 2.60(m, 6H, NCH2), 3.10(m, 4H, Ar-NCH2), 4.21(t, 2H, J=6.2 Hz, OCH2), 6.96-7.44(m, 7H, Ar), 7.70(d, 1H, J=8.8 Hz, Ar), 8.07(d, 1H, J=2.0 Hz, Ar-H), 8.81-8.92(m, 1H, Ar); MS: m/z 381 '(M+).
Example 34: l-{4-(4-hydroxy-4-phenyl)piperidine-l-yl]-3-(quinoloxy-7-yI)propane
A mixture of l-chloro-3-(quinoloxy-7-yl)propane (0.22 g, 0.001 mol), 4-( 4-hydroxy-4-phenyl)-piperidine (0.18 g, 0.001 mol), K2CO3 (0.20 g) and Nal (0.01 g) in dry acetone (50 ml) was refluxed for 35 hours. Reaction mixture was filtered, concentrated and purified by column chromatography on silica gel using 4% MeOH in chloroform as eluant. It was crystallized with ether-hexane. Yield 0.21 g(58%),m.p. 141. FTIR (KBR,cm-1): 3124,2948,2822, 2348,1618,1498, 1448,1390,1320, 1262, 1174, 1126, 840, 768; 'H-NMR (CDC13): δ (ppm) 1.78(m, 2H, C-CHrC), 2.16(m, 4H, C-CHrC), 2.47-2,69(rn, 5H, NCH2 piperidine, O-H), 2.87(m, 2H, NCH2) 4.19(1, 2H, J=6,2 Hz, OCH2), 7.17-7.7 l(m, 9H, Ar), 8.06(d, 1H, J-8.2 Hz, Ar), 8.78(m, IH, Ar); MS: 362 m/z(M').
Example 35: l-[4-(2-methoxyphenyI)piperazin-l-y]j-4-(quino!oxy-7-yI)butane
A mixture of l-chloro-4--(quinoloxy-7-yl)butane (0.47 g, 0.002 mol), l-(2-methoxyphenyIpiperazine (0.38 g, 0.002 mol), dry K2CO3 (0.40 g) and Nal 20 ml) was heated at 140°C for 8 hours. Reaction mixture was diluted with water, extracted with chloroform (3x30 ml), dried (Na2SO4), concentrated and purified by column chromatography on silica gel using 4% MeOH in chloroform as eluant. It was characterized as its dihydrochloride. Yield 0.60 g (77%), m.p. 160°C. FTIR (KBr.cm1): 3050,
2944,2820,1618, 1500, 1452,1386, 1320, 1244, 1132, 1026, 840, 754; 'H-NMR (CDCl3): 8δ (ppm) 1.78-2.17(m, 4H, C-CCH2-c), 2.55(t, 2H, J=7.2 Hz, NCH-.-C-C), 2.73(bs, 4H, NCH2), 3.12(bs, 4H, Ar-NCH2), 3.86(s, 3H, OCH3), 4.16(t, 2H, J-6.0 Hz, OCH2), 6.83-6.96(m, 4H, Ar), 7,17- 7.29(m, 2H, Ar), 7.41(bs, IH, Ar), 7.70(d, IH, J=8.8 Hz, Ar), 8.07(d, IH, J=7.6 Hz, Ar), 8.83(m, IH, Ar); MS: m/z391 (M+).
Example 36: l-[4-(2-chIorophenyl)piperazin-l-yI]-S-(quino!oxy-7-yl)pentane
A mixture of l-chloro-5-(quinoIoxy-7-y])pentane (0.24 g, 0.001 mol), l-(2-chlorophenyl)piperazine (0.19 g, 0.001 mol) and NaHCO, (0.24 g) in dry DMF (10ml) was heated at 130°C for 8 hours. Reaction mixture was diluted with water and extracted with chloroform (3x30 ml), washed with water (3x20 ml), dried (Na2S04) and concentrated. It was purified by column chromatography on silica gel using 3% MeOH in chloroform as eluant. It was characterized as its dihydrochioride. Yield 0.18 g(45%), m.p. 170^. FTIR(KBr,cm1): 3050, 2938, 2818, 1620, 1448, 1384, 1322, 1264, 1132, 840, 758; 'H-NMR (CDC13): δ (ppm) 1.62-1.98(m, 6H, C-CHrC), 2.48(t, 2H, J=6.8 Hz, NCH2-C-C), 2.56(bs, 4H, NCH2), 3.10(bs, 4H, Ar-NCH2), 4.14(t, 2H, J=6.4 Hz, OCH,), 6.96-7.07(m, 4H, Ar), 7.29-7.40(m, 3H, Ar), 7.70(d, IH, J=9.0 Hz, Ar), 8.07(d, IH, J=8.2 Hz, Ar), 8.82(m, IH, Ar); MS: m/z 409 (M).
Example 37: 1-[4-(4-Fluorophenyl)piperazin-l-ylj-3-(quinoloxy-7-yI)propane
A mixture of l-chloro-3-(quinoloxy-7-yl)propane (0.44 g, 0.002 mol), l-(4-fluorophenyl)piperazine (0.36 g, 0.002 mol) and K2C03 (0.40 g) in dry acetone (50 ml) was refluxed for 35 hours. Reaction mixture was filtered, concentrated and purified by column chromatography on silica gel using 3% MeOH in chloroform as eluant. It was crystallized with ether-hexane. Yield 0.40 g (57%), m.p. 1400C.FTIR (KBr,cm-'): 3747,3416, 2928,2822, 2783, 2380, 1618, 1568, 1506, 1450, 1389, 1319, 1267,1215,1173,1117, 1045,1013,968,935, 912, 826, 766, 714, 617; 'H-NMR (CDC13): δ (ppm) 2.10(qn, 2H, J=5.0 Hz, CH2), 2.64(m, 6H, NCH2), 3.14(m, 4H, Ar-NCH2), 4.21(t, 2H, J=5.0 Hz, OCH,), 6.86-6.99(m, 3H, Ar), 7.10-7.29(m, 3H, Ar), 7.42(d, IH, J=1.6, Ar), 7.70(d, IH, J=6Hz, Ar)8.07(d, IH, J=5.8Hz, Ar), 8.3(d, IH, J=3.0Hz, Ar); MS: m/z 365 (M+).
Example 38:
1-[4-(2-pyridyi)piperazin-l-yl]-3-(quinoloxy-7-yI)propane
A mixture of l-chloro-3-(7-quinolyloxy)propane (0.663 g, 0.003 mol), l-(2-pyridyl)piperazine (0.48 g, 0.003 mol) and KaCO3 (0.40 g) in dry acetone (50 ml) was refluxed for 35 hours. Reaction mixture was filtered, concentrated and purified by column chromatography on silica gel using 4% MeOH in chloroform as eluant. It was crystallized with ether-hexane. Yield 0.50 g (48%), m.p. 60°C. FTIR (KBr,cm-!): 3393, 3020, 2924, 2854, 2322, 1599, 1392, 1215, 1092, 1026, 932, 758; 'H-NMR (CDC1.,): δ (ppm) 2.16(qn, 2H, J=6.8, CH2), 2.69(m, 6H, NCH2), 3.64(m, 4H, Ar-NCH2), 4.24(t,2H, J=7.0Hz, OCH2)6.60-6.68(m, 2H, Ar), 7.18- 7.26(m, 2H, Ar), 7.40-7.52(m, 2H, Ar), 7.72(dlH, J=8.8Hz, Ar), 8.08(d, 1H, J=8.0Hz, Ar), 8.2I(d, 1H, J=3.4Hz, Ar), 8.83(d, 1H, J=2.5Hz, Ar);MS:m/z 348 (M+).
Example 39: l-[4-(2-MethyI-4-chlorophenyl)piperazin-l-yl]-3-(quinoloxy-7-yl)propane
A mixture of l-chloro-3-(quinoloxy-7-yl)propane (0.44 g, 0.002 mol), l-(2-methyl- 4-chlorophenyl)-pip-erazine (0.42 g, 0.002 mol) and K2CO3(0.40g) in dry acetone (50 ml) was refluxed for 30 hours. Reaction mixture was filtered, concentrated and purified by column chromatography on silica gel using 3% MeOH in chloroform as eluant. ft was crystallized with ether-hexane. Yield 0.32 g (41 %), m.p. 1051C. FTIR (KBr.cnT1): 3801, 3747, 3443, 2937, 2820, 2789, 2378, 1618, 1497, 1446, 1385, 1315, 1265, 1215, 1171, 1342, 1111, 1047, 1005,972,939,903,839,812,768,739, 708,610; 'H-NMR (CDC1,): δ (ppm) 1.25(m, 2H, CH,), 2.17(s, 3H, CH,), 2.75(bs, 6H, N(CH2)2), 3.20(bs, 4H, Ar-NCH,), 3.60(m, 2H, OCH2), 7.26-7.44(m, 4H, Ar), 7.47(m, 1H, Ar), 7.80- 7.86(m, 2H, Ar), 8.35(d, 1H, J=5.0 Hz, Ar), 8.85(s, 1H, Ar); MS: m/z 395 (M+).
Example 40: l-[4-(3,4-dichlorophenyI)piperazin-l-yIJ-3-(quinoIoxy-7-yl)propane
A mixture of l-chloro-3-(quinoloxy-7-yI)propane (0.663 g, 0.003 mol), 3,4-dichlorophenylpiperazine (0.69 g, 0.003 mol), K2CO3 (0.50 g) and Nal (0.02 g) in dry DMF (20 ml) was heated at 120°C for 15 hours. Reaction mixture was diluted with water, extracted with chloroform (3x30 ml), washed
with water (3x20 ml), dried (Na2S04), concentrated and purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant. Yield 0.65 g (52%), m.p. 1200C. FTIR (KBr, cm'1): 3870, 3698, 3444, 2934, 2316, 1732, 1612, 1474, 1382, 1242, 1148,820; 'H-NMR (CDCI,): 5 (ppm) 2.08(m, 2H, CH2), 2.63(m, 6H, NCH2), 3.19(m, 4H, Ar- NCH2), 4.21(t, 2H, J=6.4 Hz, 0-CH2), 6.74(dd, 1H, J=9.0 & 2.8 Hz, Ar), 6.95(d, 1H, J=2.8 Hz, Ar), 7.17-7.30(m, 3H, Ar), 7.42(d, 1H, J=2.6 Hz, Ar), 7.70(d, 1H, J=9.0 Hz, Ar), 8.05(m, 1H, Ar), 8.82(d, 1H, J=5.2 Ar); MS: m/z 416 (M).
Example 41: ]-[4-(4-i\!ethoxyphenyl)piperazin-l-yJj-3-(quino!oxy-7-yI)propane
A mixture of l-chloro-3-(quinoloxy-7-yl)propane (0.44 g, 0.002 mol), 4-methoxyphenylpiperazine (0.38 g, 0.002 mol), K2CO3 (0.40 g) and Nal (0.01 g) in dry DMF (20 ml) was heated at 110°C for 15 hours. Reaction mixture was diluted with water, extracted with chloroform (3x30 ml), washed with water (3x20 ml), dried (Na2SO4, concentrated under vaccum and purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant. Yield 0.39 g (40%), m.p. 124-126°C. FTIR (KBr, cm'1): 3813, 3746, 3682, 3651, 3400, 2941, 2880, 2814, 2754, 2702, 2334, 1742, 1618, 1508, 1448, 1385, 3319, 1267, 1240, 1213, 1178, 1122, 1042, 1014, 970, 935, 835, 802, 768,716, 664, 617; 'H-NMR (CDC13): 5 (ppm) 2.10(qn, 2H, 3=4.6 Hz, CH2), 2.65(m, 6H, NCH2), 3.12(m, 4H, Ar-NCH2), 3.77(s, 3H, O-CH3), 4.21(t, 2H, J=4.2 Hz, OCH2), 6.82-6.93(m, 3H, Ar), 7.19-7.43(m, 4H, Ar), 7.70(d, 1H, J=6.0 Hz, Ar), 8.08(d, 1H, J=6.0 Hz, Ar), 8.83(m, 1H, Ar); MS: m/z 378 (M~).
Example 42: 1-[4-(4-Chlorophenyl)piperazin-l-yI]-3-(quinoloxy-7-yI)propane
A mixture of I-chloro-3-(quinoloxy-7-yl)propane (1.76 g, 0.008 mol), 4-chlorophenylpiperazine (2.15 g, 0.008 mol), K2CO3 (1.10 g) and Nal (0.60 g) in dry DMF (50 ml) was heated at 110°C for 12 hours. Reaction mixture was diluted with water, extracted with chloroform (3x50 ml), washed with water (3x20 ml), dried (Na2SO4), concentrated under vaccum and purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant. Yield 1.70 g (56%), m.p. 100°C. FTIR (KBr, cm-'): 3427, 2929,2825,2362,2333, 1618, 1497, 1448, 1387, 1323, 1265, 1232,
1213, 1175, 1142, 1042, 1009, 968, 935, 910, 822, 764, 669, 617; 'H-NMR (CDC13): δ (ppm) 2.12(qn, 2H, JN4.6 Hz, CH2), 2.63(m, 6H, NCR,), 3.13 (m, 4H, Ar-NCH^ 4.1 l(t, 2H, J=4.2 Hz, O-CH2), 6.82-6.87(m, 2H, AT), 7.18-7.29(m, 4H, Ar), 7.42(d, 1H, J=4.0 Hz, Ar), 7.70(d, 1H, J-6.0 Hz, Ar), 8.07(dd, 1H, J=5.4 & 1.0 Hz, Ar), 8.83(dd, 1H, J-3.0 & 1.8 Hz, Ar); MS: m/z 381 (NT).
Example 43: l-[4-(4-Acetyl-4-phenyI)piperidin-l-yl]-3-(quinoloxy-7-yl)propane
A mixture of l-chloro-3-(quinoloxy-7-yl)propane (0.663 g, 0.003 mol),4-( 4-acetyl-4-phenyl)-piperidine (0.609 g, 0.003 mol), K2O3 (0.40 g) and Nal (0.01 g) in dry DMF (20 ml) was heated at 110°C for 14 hours. Reaction mixture was diluted with water, extracted with chloroform (3x30 ml), washed with water (3x20 ml), dried (Na2S04), concentrated under vaccum and purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant. Yield 0.52 g (45%), m.p. 110°C. FTIR (KBr, cm'1): 3888,3782,3426,3164,2826, 2328,2252,2026,1916,1816,1622,1496, 1392,1266,1126,1040,978,772,704; 'H-NMR (CDCl3): δ (ppm) 1.22(s, 3H, COCH;), 1.65(m, 2H, CH2), 2.13 (m, 4H, (CH2-C-CH2), 2.5 l(m, 4H, Ar-NCH2), 4.16(t, 2H, J=6.4 Hz, OCH2), 7.16- 7,40(m, 8H, Ar), 7.69(d, 1H, J=8.8 Hz, Ar), 8.06(d, 1H, J-8,2 Hz, Ar), 8.8l(m, 1H, Ar); MS: m/z 388 (M+).
Example 44: l-[4-(3-Chlorophenyl)piperazin-l-yl]-3-(quinoLoxy-7-yI)propane
A mixture of l-chloro-3-(quinoloxy-7-yl)propane (0.884 g, 0.004 mol), l-(3-chIorophenyl)piperazine (0.784 g, 0.004 mol), K2CO., (0.60 g) and Nal (0.20 g) in dry DMF (30 ml) was heated at 1300C for 14 hours. Reaction mixture was diluted with water, extracted with chloroform (3x30 ml), washed with water (3x25 ml), dried (Na2SO4), concentrated under vaccum and purified by column chromatography on silica gel using chloroform as eluant. Yield 0.80 g (68%), m.p. l00'0C FTIR (KBr, cm'1): 3462,3252,2777, 2710,2604,2338,1904,1593, 1566, 1493, 1450, 1391, 1321,1251, 1205,1178,1146,1107,1057,1013,978,943,914,831,764,679, 650,617;'H-NMR (CDC13): δ (ppm) 2.35(bs, 2H, CH2), 3.00(bs, 6H, NCH,), 3.47(bs, 4H, Ar-NCH,), 4.25(1,2H, J=6.8 Hz, OCH,), 6.75-6.95(m, 3H, Ar) 7.10-7.30(m, 3H Ar), 7.45(d, 1H, J=6.8 Hz, Ar), 7.75(d, 1H, J=9.0 Hz, Ar), 8.10(d, 1H, J=7.0 Hz, Ar), 8.85(d, 1H, J=3.4, Ar); MS: m/z 381 (M+).
Example 45: l-[4-(3-MethylphenyI)piperazin-l-yI]-3-(quinoloxy-7-yl)propane
A mixture ofl-chloro-3-(quino]oxy-7-yl)propane (0.44 g, 0.002 mol),l-(3-methylphenyI)piperazine (0.352 g, 0.002 mol), K2CO3 (0.40 g) and Nal (0.01 g) in dry DMF (20 ml) was heated at 1 10°C for 12 hours. Reaction mixture was diluted with water, extracted with chloroform (3x30 ml), washed with water (3x20 ml), dried (Na,SO4), concentrated under vaccum and purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant. Yield 0.40 g (56%), m.p. 75°C. FTIR (KBr, cm'1): 3400, 3040,2930,2878, 2822,2374, 1908, 1664, 1616,1499, 1448,1387, 1323,1246,1178,1144,1043,1003,964,912, 839,770,692,658, 617; 'H-NMR (CDCl3): δ (ppm) 2.11(m, 2H, CH2), 2.3l(s, 3H, CH3), 2.66 (m, 6H, NCH2), 3.20(bs, 4H, Ar-N-CH2), 4.21(t, 2H, J=4.2 Hz, OCH2), 6.67-6.75(m, 3H, Ar), 7.12-7.28(m, 4H, Ar), 7.44(bs, IH, Ar), 7.69(d, IH, J=6.0 Hz, Ar), 8.06(d, IH, J=5.4 Hz, Ar); MS: 361 (M+).
Example 46: l-{4-(2-ChIorophenyl)piperazsn-l-yl]-3-(quinoloxy-6-yI) propane
A mixture of l-chloro-3-(quinoloxy-6-yl)propane (0.37 g, 0.0016 mol), l-(2-chlorophenyl)piperazine (0.48 g, 0.0019 mol), baked K2CO3 (0.41 g) and baked Nal (10 mg)in dry DMF (10 ml) was heated at 120°C for 10 hours. It was diluted with water (50 ml), extracted with chloroform(3x30 ml), washed with water (3x20 ml), dried (NajSO4) and purified by column chromatography on silica gel using ethylacetate as eluant. It was characterized as its dihydrochloride. Yield 0.40 g (53%), m.p. 160°C. FTIR (KBr,cm): 3740,3542,3018,2956,2814,2662,2412,2352, 1684, 1510, 1376, 1220, 1124,1046, 928, 834, 758 ; 'H-NMR (CDC13) 6 (ppm): 2.l(qn, 2H, J=7.4Hz, O-C-CH2); 2.68(m, 6H, NCH2); 3.12(bs, 4H, Ar-NCH2); 4.18(t, 2H, J=6.4Hz, O-CH2); 7.02(m, IH, Ar); 7J(d, 2H, J=2.8Hzs Ar); 7.19-7.41(m, 4H, Ar); 8.03(t, 2H, .1=8.4 Hz, Ar); 8.76(d, IH, J=2.8Hz, Ar); MS rn/z 382(M+).
Example 47: l-[4-(4-Chlorophenyl)piperazin-l-yl|-3-(quinoloxy-6-yl) propane
A mixture of l-chloro-3-(quinoloxy-6-yl)propane (0.35 g, 0.0016 mot), l-(4-chlorophenyl)piperazine
(0.45 g, 0.0017 mol), baked K2CO3 (0.50 g) and baked Nal (10mg) in dry DMF (10 ml) was heated at 120°C for 12 hours. It was diluted with water (50 ml), extracted with chloroform(3x30 ml), washed with water (3x20 ml), dried (Na2SO4,) and purified by column chromatography on silica gel using ethylacetate as eluant. Yield 0.50 g (83%), m.p. 120-123°C. FTIR (KBr,cm1): 3832, 3716, 3488, 3050, 2950, 2806, 2344, 1976, 1844, 1682, 1612, 1504, 1366, 1232, 1142, 1032, 938, 826, cm-1; 'H- NMR(CDC13) δ (ppm): 2.1(qn, 2H, J=-6.8Hz, O-C-CH2); 2.67(m, 6H, NCH2); 3.21(t, 4H, J=4.8Hz, Ar-NCH2), 4.18(t, 2H, J=6.2Hz, O-CH2), 6.84(d, 2H, J=8.8Hz, Ar), 7.09(d, IH, J=2.4Hz, Ar) 7.18-7.4(m, 4H, Ar), 7.98(t, 2H, J=8.6Hz, Ar), 8.76(d, IH, J=3.4Hz, Ar); MS m/z382(M+).
Example 48: l-[4-Hydroxy-4-phenylpiperidm-l-yl]-3-(quinoloxy-6-yl) propane
A mixture of l-chloro-3-(quinoloxy-6-yl)propane (0.35 g, 0.0016 mol),4-(4-hydroxy-4-phenyl)-piperidine (0.30 g, 0.0017 mol), baked K2CO3 (0.40 g) and baked Nal (10 mg)in dry DMF (15 ml) was heated at 120X? for 14 hours. It was diluted with water (50 ml), extracted with chloroform(3x30 ml), washed with water (3x20 ml), dried (Na2SO4) and purified by column chromatography on silica gel using ethylacetate as eluant. Yield 0.40 g (70%), m.p. 135- 138 C. FTIR(KBr,cm1): 3726,3646, 3544,3402,3220,3022,2938,2804, 2604,2340,2114, 1936, 1706, 1628, 1530, 1394, 1234, 1146, 1054, 964,700 ; 1H-NMR(CDC1.,): δ (ppm) 1.8(m, 4H, Ar-C-CH2), 2.1-2.37(m, 3H, O-C-CH2, OH), 2.51-2.94(m, 6H, NCH2), 4.18(t, 2H, J=6Hz, OCH,), 7.09(d, IH, J=2.2Hz, Ar), 7.30-7.55(m, 7H, Ar), 8.02(t, 2H, J=8Hz, Ar); MS m/z 362 (M+).
Example 49: l-[4-(3-MethylphenyI)piperazin-I-yl]-3-(quinoloxy-6-yl) propane
A mixture of l-chloro-3-(quino!oxy-6-yl)propane (0.33 g, 0.0015 mol), l-(3-methylphenyl)piperazine (0.27 g, 0.0015 mol), baked dry K2CO3 (0.30 g) and baked Nal (10 mg) in dry DMF (15 ml) was heated at 120^ for 10 hours. It was diluted with water (50 ml), extracted with chloroform(3x30 ml), washed with water (3x20 ml), dried (Na2O4) and purified by column chromatography on silica gel using ethylacetate as eluant. Yield 0.30 g (56%), m.p. 80-830C. FTIR (KBr, cm1): 3702, 3340,2948, 2626, 2424, 2334, 1934, 1806, 1694, 1612, 1524, 1230, 1142, 1034, 758; 'H-NMR(CDCI3) δ (ppm):2.16(qn, 2H, J=6Hz, O-C-CH2), 2.32(s, 3H, CH3), 2.72(br s, 6H, NCH2), 3.28(br s, 4H,
Ar-NCH2), 4.19(1,2H, J=6Hz, O-CH2), 6.68-6.76(m, 3H, Ar), 7.08-7.4(m, 4H, Ar), 8.02(t, 2H, J=8; Iz, Ar), 8.77(d,3H, J=4.0 Hz, Ar); MS m/z 36 l(M').
Example 50: l-[4-(2-PyridyI)piperazin-l-yl]-3-(quinoloxy-6-yI)propane
A mixture of l-chloro-3-(quinoloxy-6-y!)propane (0.19 g, 0.0009 mol), l-(2-pyridyl)piperazine (0.16 g, 0.001 mol), baked K2CO3 (0.14 g) and baked Nal (10 mg)in dry DMF (35 ml) was heated at 100°C for 10 hours. It was diluted with water (50 ml), extracted with chloroform (3x30 ml), washed with water (3x20 ml), dried (Na2SO4) and purified by column chromatography on silica gel using ethylacetate as eluant. Yield 0.150 g (50%), m.p. 122-125°C. FTIR (KBr, cm'1): 3734,3604,3404, 2942,2832,2486,2356,2108, 1684, 1600, 1548, 1488, 1444, 1382, 1312, 1232, 1164, 1028,836, 776; 'H-NMR(CDC13) δ (ppm): 2.1(qn, 2H, J=6Hz, O-C-CH2), 2.63(m, 6H, NCH2), 3.57(t, 4H, J=5.5Hz, Ar-NCH2), 4.17(t, 2H, J=6Hz, O- CH2), 6.59-6.67(m, 2H, Ar), 7.08(d, 1H, J=2.6Hz, Ar), 7.31- 7.47(m, 3H, Ar), 8.02(t, 2H, J=7Hz, Ar), 8.19(d, 1H, J=4Hz, Ar), 8.76(d, 1H, J=3Hz, Ar); MS m/z 348(M+).
Example 51: l-[4-(2-Ethylphenyl)piperazin-l-yI]-3-(quinoloxy-6-yI) propane
A mixture of l-chloro-3-(quino!oxy-6-yl)propane (0.40 g, 0.0018 mol), l-(2-ethylphenyl)piperazine (0.38 g, 0.002 mol), baked K2CO3 (0.30 g) and baked Nal (10 mg) in dry DMF (15 ml) was heated at 110°C for 12 hours. It was diluted with water (50 ml), extracted with chloroform (3x30 ml), washed with water (3x20 ml), dried (Na,S04) and purified by column chromatography on silica gel using ethylacetate as eluant. It was characterized as its dihydrochloride. Yield 0.44 g (54%), m.p. 226-30°C. FTIR(KBr,cm-'): 3374, 2956, 2818, 2668, 2484, 2352, 2102, 1916, 1676, 1622, 1542, 1500, 1452, 1380, 1322, 1226, 1152, 1044, 938, 836, 756 Cm-1; 'H- NMR(CDCl3): δ (ppm) 1.25(t, 3H, J=6Hz, CH3), 1.81(br s, 2H, CH2-Ar), 2.1 l(qn, 2H, J=6Hz, O-C-CH2), 2.7(m, 6H, NCH2), 2.96(t, 4H, J=4Hz, Ar-NCHz), 4.18(1,2H, J=6Hz, 0-CH2), 7.02- 7.4l(m, 7H, Ar), 8.02(t, 2H, J=8.5Hz, Ar), 8.77(m, lH,Ar);MS m/z 375(M+).
Example 52: l-[4-(4-MethoxypSienyl)piperazin-l-yl]-3-(quinoloxy-6-yl) propane
A mixture of l-chloro-3-(quino!oxy-6-yl)propane (0.44 g, 0.002 mol), l-(4-methoxyphenyl)-piperazine (0.53 g, 0.002 mol), baked K2CO, (0.50 g) and baked Nal (15 mg) in dry DMF (20 ml) was heated at 120°C for 10 hours. It was diluted with water (50 ml), extracted with chloroform (3x30 ml), washed with water (3x20 ml), dried (Na2SO4) and purified by column chromatography on silica gel using ethylacetate as eluant. It was characterized as its dihydrochloride. Yield 0.47 g (53%), m.p. 125-129°C. FTIR(KBr,cM'): 3826, 3732, 3424, 2944, 2838, 2350, 1618, 1508, 1452, 1382, 1324, 1240, 1178, 1022, 972, 932, 830, 718 cm1; 'H-NMR(CDC1,): δ (pprn) 2.1(qn, 2H, J-THz, O-C-CH2), 2.65(m, 6H, NCH,), 3.13(t, 4H, J=4Hz, Ar-NCH2), 3.77(s, 3H, OCH3), 4.18(t, 2H, J=8Hz, 0-CH2), 6,82-6.94(m, 4H, Ar), 7.09(d, 1H, J=4Hz, Ar), 7.31-7.4l(m, 2H, Ar), 8.02(1, 2H, J=8Hz, Ar), 8.76(d, 1H, J=2Hz, Ar); MS m/z 377 (MJ).
Example 53: l-[4-(2-Methoxyphenyl)piperazin-l-yl]-3-(quinoloxy-6-yI) propane
A mixture of l-chloro-3-(quinoloxy-6-yl)propane (0.50 g, 0.0022 mol), ]-(2-methoxyphenyl)-piperazine (0.43 g, 0.0022 mol), baked K2CO3 (0.31 g, 0.0022 mol) and baked Nal (10 mg) in dry DMF (20 ml) was heated at 90°C for 10 hours. It was diluted with water (50 ml), extracted with chloroform(3x30 rnl), washed with water (3x30 ml), dried (Na2SO4) and purified by column chromatography on silica gel using ethylacetate as eluant. It was characterized as its dihydrochloride. Yield 0.50 g (50%), m.p. 195-200°C. FTIR(KBr,cm-'): 3456, 3286, 3068, 2946, 2724, 1608, 1554, 1498, 1450, 1398, 1244, 1120, 1032, 970, 914, 872, 834, 794, 754, 612; 'H-NMR(CDC13) : δ (ppm) 2.10(qn, 2H, J=6Hz, O-C-CH2), 2.67(m, 6H, NCH2), 3.13(br s, 4H, Ar-NCH,), 3.87(s, 3H, OCH3), 4.18(r, 2H, J=6Hz, O-CH,), 6.88-6,97(n, 4K Ar), 7,95(d, 1H, J=2Hz, Ar), 7.3 l-7.41(m, 2H, Ar), 8.02(t, 2H, J=8Hz, Ar), 8.76(m, 1H, Ar); MS m/z 377 (M+).
Example 54: Antihyperteusive/hypotensive activity
(a) Cats (2.6-4.0 kg) of either sex anaesthetized with pentobarbitone sodium (40 mg/kg i.v.) and
showing basal mean arterial blood pressure below 150 mm (Hg) were categorised as normotensive and above 150 mm Hg as hypertensive. Arterial blood pressure (BP) was recorded from one of the carotid artery through a stathum P23 DC pressure transducer and 7P1 low level DC preamplifier on a Grass Model P7 Polygraph, Signals from 7P1 preamplifier were used to trigger 7P4 Tachograph preamplifier for recording the heart rate (HR). Right femoral vein and Trachea were cannulated for intravenous injections and artificial ventilation respectively. Control responses to intravenous injection of noradrenaline (2-4 ug); acetyl choline (1-2 jug); histamine (1-2 µg) and isoprenaline (1-2 ug) were taken before and after the administration of test doses of each compounds. The compounds were tested at fixed doses of 2.0 and 10 µM/kg i.v. Significant results are given in Table 1.
(b) Antihypertensive activity was observed in naturally hypertensive cats, rat abdominal aorta coarctation model of hypertension (Liu, J;. Bishop, S.P. & Overbeck, H. W. Morphometric evidence for non pressure related arterial wall thickening in hypertension Circ. Res. 62, 1001-1010,1988) and L-NAME (No synthase inhibitor) induced hypertensive cats.
Example 55 : Cardioprotective/antiischemic activity
The rats were killed by decaptitation, heart were rapidly excised and placed in ice-cold HEPES tyrode buffer. Then isolated hearts were perfused retrogradely through coronary arteries using the Langendorff technique. The perfusion buffer consisted (in mM) NaCl 137, KC1 5.4, CaCl2 1.8, MgCl21.0, glucose 11.2 and HEPES 3.0. The buffer (pH 7.4) was continuously gassed with oxygen and maintained at 37°C. Coronary flow rate was maintained at 10 ml/min. The heart contracted spontaneously.
The perfused heart was allowed to equillibrate for 30 min. before initiation of any insult protocol. The test compounds were given at the time of reperfusion. Some of the compounds were dissolved in ethanol. Final concentration of ethanol in the perfusion buffer was 0.0001% and had no effect of its own on the parameter used.
(a) For brief period of ischemic insult (Hideo et al. Pathophysiology and pathogenesis of stunned myocardium. J. Clin. Invest., 79,950-961,1987). Ischemia was initiated by stopping the flow for
16 min. followed by 30 min. reperfusion period. The durations were decided on the initial pilot experiments leading to 50% recovery of function.
(b) For prolong period of ischemic insult (Becker, L.C. & Ambrosio, G. Myocardial consenquences of reperfusion. Prog. Cardiovas. Dis., 30, 23-44, 1987). Ischemia was initiated by stopping the flow for 30 min. followed by 30 min. reperfusion.
Example 56: Antiinflammatory Activity:
The oedema in one of the hind paw of rats is induced by injection of 0.1 ml of 1% carrageenin solution into the planter aponeurosis. Volume of the paw is measured plethysmographically immediately after and three hours after the injection of the irritant. The difference in the volume gives the amount of oedema developed. Mean percent inhibition of the oedema between control group and compound treated group is calculated and compared with the group receiving standard drug Ibuprofen (100 µmolp.o.). Each group consist of five adult rats of either sex weighing 125-150 g. Results are summarised in Table No. 3.

We Claim:
1. A process for the preparation of 1-(4-aryl/heteroarylpiperazin/piperidin-1-
yl) - n - ( quinoloxy-6/7/8-yl/4- (un)substituted pyrrolidin - 2 - oxo - 1-
yl)alkanes/alkanones and their salts useful as therapeutic agent and
having the formula III as shown in the drawing accompanying this
specification, wherein R represents groups such as quinoloxy-6/7/8-yl,4-
(un)substituted -pyrrolidin-2-one-1-yl; R1 represents group such as
phenyl, halophenyl, alkylphenyl, alkoxyphenyl, pyridyl, trifluorophenyl;
n=2-5; X=0/H2 and Z=N/CR2 (R2 = H, OH, COCH3) which comprises
condensing of a compound of the formula 1 comprising a group selected
from 1-chloro-n-(quinoloxy-6/7/8-yl/4-(un)substituted-pyrrolidin-2-oxo-1-yl)-
alkanes/alkan-2-ones with 4-(aryl/heteroaryl)piperazin/piperidin-1-yl of
formula II, wherein the meaning of R,R1, n, X,Z is as above, in the
presence of a base and an organic solvent as defined herein, in presence
of a catalyst as described herein at temperature ranging 80°C-130°C, to
produce the corresponding 1-(4-aryl/heteroarylpiperazin/piperidin-1-yl)-n-
(quinoloxy - 6/7/ 8 - yl / 4 - (un) substituted - pyrrolidin - 2 - oxo - 1 -
yl)alkanes/alkanones of formula III, purifying the products by conventional
methods such as herein described, converting free base compounds of
formula III into their corresponding salts by known methods.
2. A process as claimed in claim 1 wherein the bases used are selected from
sodium/potassium carbonate, sodium/potassium bicarbonate potassium
hydroxide.

3. A process as claimed in claims 1-2, wherein the organic solvents used
are selected from acetone, toluene, dimethylformamide.
4. A process as claimed in claims 1 - 3, wherein the catalyst is selected from
potassium/sodium iodide, tetrabutylammonium iodide.
5. A process as claimed in claims 1-4, wherein the salt of formula III is
hydrochloride.
6. A process for the preparation of 1-(4-aryl/heteroarylpiperazin/piperidin-1-
yl)-n-(quinoloxy-6/7/8-yl/4-(un)substituted-pyrrolidin-2-oxo-1-yl) alkanes/
alkanones and their salts useful as therapeutic agent substantially as
herein described with reference to the examples.

Documents:

1451-del-1999-abstract.pdf

1451-del-1999-claims.pdf

1451-del-1999-correspondence-po.pdf

1451-del-1999-description (complete).pdf

1451-del-1999-form-1.pdf

1451-del-1999-form-19.pdf

1451-del-1999-form-2.pdf

1451-del-1999-form-3.pdf

correspondence-others.tif

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Patent Number

219883

Indian Patent Application Number

1451/DEL/1999

PG Journal Number

28/2008

Publication Date

11-Jul-2008

Grant Date

14-May-2008

Date of Filing

05-Nov-1999

Name of Patentee

COUNCIL SCIENTIFIC AND INDUSTRIAL RESEARCH

Applicant Address

Inventors:

#	Inventor's Name	Inventor's Address
1	SHEKAR SRIVASTAVA
2	JHARNA ARUN
3	RAVISH CHANDRA TRIPATHI
4	SURESH KUMAR PANDEY
5	ALPANA SRIVASTAVA
6	MANGAL PRASAD DUBEY
7	RAM MOHAN SAXENA
8	RAKESH SHUKLA
9	KESHAV KISHOR AWASTHI
10	ANIL KUMAR SAXENA

PCT International Classification Number

A61K 31/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA