Title of Invention

"NOVEL 1-(4-ARYL/HETEROARYLPIPERAZIN/PIPERAZIN/PIPERIDINE-1-YL)-N-(QUINOLOXY-6/7/8-YL/4-(UN)SUBSTITUTED -PYROLIDIN-2-OXO-1-YL)ALKANES/ALKANONES AND THEIR SALTS"

Abstract Novel 1 -(4-aryl/heteroarylpiperazin/piperazin/piperidin-1 -yl)-n-(quinoloxy-6/7/8-yl/4- (un)substituted-pyrrolidin-2-oxo-1 -yl)alkanes/alkanones Novel 1 -(4-aryl/heteroarylpiperazin/piperazin/piperidin-1 -yl)-n-(quinoloxy-6/7/8-yl/4- (un)substituted-pyrrolidin-2-oxo-l-yl)alkanes/alkanones and the process for the preparation of the same as potential antiischemic, anti-inflammatory and antihypertensive agents useful for the treatment of ischemia, inflammation, hypertension and other related CVS and CNS disorders.
Full Text The invention relates to novel l-(4-aryI/heteroarylpiperazin/piperidin-l-yl)-n-(quinoioxy-6/7/8-yI) 4-(un)substitiited-pyrrolidin-2-oxo-l-yl)alkanes/alkanones and their salts as therapeutic agents and a process for synthesis thereof.
alto
The invention Particularly relates to a process for the synthesis of novel l-(4-aryl/heteroaryl-
pipera2in/piperidin-l-yl)-n-(quinoloxy-6/7/8-yl/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 1 -(4-aryl/heteroarylpiperazin/piperidin- 1 -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 in 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/CR2 (R2=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-l-yl)-n- quinoloxy-6/7/8-yl/4-(un)substituted-pyiTolidin-2-oxo-l-yl)alkanes/alkanone3and
Q*JL, 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 III

(Formula III 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=0/H2, n=2-5.

Accordingly, the present invention provides novel l-(4-aryl/heteroarylpiperazin/piperazin/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-pyrrolidin-2-oxo-l-yI, R1 represents group like aryl and heteroaryl, Z=N/CR2 (R2=H, OH, COCH3), X=O/H, n=2-5 and the process for the preparation of the same which comprises condensing l-chloro-n-(quinoloxy-6/7/8-yl/4-(un) substituted pyrolidone-2-oxo-l-yl)alkanes/alkanones of the formula 1 with (4-aryl/heteroaryl)piperazine/piperdine of the formula II in the presence of base like potassium or sodium carbonate, potassium or sodium bicarbonate or powdered potassium hydroxide and solvent selected from acetone, tolune or dimethylformamide for a period varying between 6-36 hrs. to produce corresponding l-{4-aryl/heteroaryl/piperazine/piperidin-l-yl)-n-(quinoloxy 6/7/8-yl/4-un substituted pyrolidin-2-oxo-l-yl) alkanes/alkanones.
In an embodiment of the present invention Novel l-(4-aryl/heteroarylpiperazin/piperidin-l-yl)-n-(quinoloxy-6/7/8-yl/4-(un)subs-tituted-pyrrolidin-2-oxo-l-yl)alkanes/alkanones and their salts as claimed in the claim 1 wherein the said compounds have the structural formula as shown above 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, tri fluorom ethyl-phenyl, heteroaryl such as pyridyl Z=N/CR2 (R2=H, OH, COCH), X=H2, n=2-5.
In another embodiment of the present invention novel l-(4-aryl/heteroarylpiperazin/piperidin-l-yl)-n-(quinoloxy-6/7/8-yl/4-(un)substituted-pyrroli-din-2-oxo-l-yl)alkanones and their salts as claimed in claim 1 wherein the said compounds have the structural formula as shown above 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, trifluoromethyl-phenyl, heteroaryl such as pyridyl Z=N/CR2 (R2=H, OH, COCH3), X=O, n=2-5.
The method comprises condensing l-chloro-n-(quinoloxy-6/7/8-yl/4-(un)substituted pyrrolidin-2-oxo-l-yl)alkanes/alkanones of the formula 1 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 ISO'C for a period varying between 6-36 hours to reduce the corresponding-l-{4-aryl/heteroarylpiperazine/piperidine-l-yl)-n-(quinoloxy-
(Formula Removed)
1 [4-(4-FIuorophenyI)piperazin-l-ylJ-2-(pyrrolidin-2-oxo-l-yl)ethan-2-one of the formula III where n=2, X=O, Z=N, R= C4H«N-2-O, R'=C6H4-4-F
l-[4-(2-Metboxyphenyl)piperazin-l-ylj-3-{pyrrolidin-2-oxo-l-yl)propan-3-one of the formula HI where n=3, X=O, Z=N, R= C4H«N-2-O , Rl=CsH4-2-OCH3
l-|4-(TrifluoromethyIphenyl)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 ,RI=C6H4-4-CF3
l-[4-(3,4-DichIorophenyl)pipera2in-l-yIl-3-(pyrrolidin-2-oxo-l-yl)propan-3-one of the formula HI where n=3, X=O, Z=N, R= C4H6N-2-O , R1=C6H3.3,4-CI 2
l-[4-(2-Chlorophenyl)piperazin-l-yIl-3-(pyrrolidin-2-oxo-l-yl)propan-3-one of the formula III where n=3, X=O, Z=N, R= C4H6N-2-O , RJ=CsH4-2-Cl
!-[4-(2-Methoxyphenyl)piperazin-l-ylJ-2-(pyrrolidin-2-oxo-l- yl)ethan-2-one of the formula in where n=2, X=O, Z=N, R= C4H !-[4-(3,4-DichIorophenyi)piperazin-l-yl]-2-{pyrroIidin-2-oxo-l- yl)ethan-2-one of the formula ffl where n=2, X=O, Z=N, R= C4H6N-2-O R'=C6H4Cl 2
!-[4-{2-Chlorophenyl)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=C6H4-2-Cl
l-[4-(3-Trifluoromethylphenyl)piperazin-l-yIJ-2-(pyrrolidin-2-oxo-l-yl)ethan-2-one of the formula HI where n=2, X=O, Z=N, R= C4H6N-2-O,R1=C6H4-2-Cl
l-[4-(Phenyl)piperazin-l-ylJ-2-{pyrrolidin-2-oxo-l-yl)€than-2-one of the formula III where n=2, X=O, Z=N, R= C4
l-[4-(4-ChIorophenyIpiperazin-l-yl]-2-(pyrrolidin-2-oxo-l-yI)ethan-2-one of the formula III where n=4, X=O, Z=N, R= C4H6N-2-O,R1=C6H4-2-Cl
l-[4-(4-Chlorophenylpiperazin-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,R1=C6H4-2-Cl
!-[4-{3-trifluoromethylphenyl)piperazin-l-yl]-3-(quinoloxy-8-yI)propane of the formula III where n=3, X=H2, Z=N, R= C^NO, R'=C4H4-3-CF3
1-[4-(3-chlorophenyl)piperazin-l-yI]-3-(quinoloxy-8-yl) propane of the formula in where n=3 X=H2 , Z-N, R'=6H6NO,R=C6H4-4Cl
1-I4-(2-ChIorophenyi)piperazin-l-yI]-4-(quinoloxy-7-yI)butane of the formula III where n=4, X=H2, Z-N, R
l-[4-(4-hydroxy-4-phenyl)piperidin-l-yl)-4--(quinoloxy-7-vl)butane of the formula in where n=X=H2 , Z-N, R'=6H6NO,R=C6H4-4C
!-[4--(4-Hydroxy-4-phenyI)piperidin-l-yl-3-(quiDoioxy-8-yl)propaDe of the formula III where n=3, X=H2, Z=C, R= C9O, R'-C6H5, R2=OH
l-(4-(4-ethylphenyl)piperazin-l-yl]-3-(quinoloxy-8-yl)propane of the formula III where n=3, , R= C,HSNO, R^jH.
!-[4- Z=N, R=
l-[4^3-Metby!pheny!)piperazin-l-y!i-3-(quinoIoxy-8-y|)propflne of the formula ill where n=3, X=H2, Z=N, R= C,H6NO,, R'^CjH^CHj
!-[4-{3,4- l-[4-{4-Chloro-2-methylphenyl)piperazin-l-yl]-3-(quinoloxy-8-yl) propane of the formula III where n=3, X-H,, Z=N, R= C,H«NO, Rl=C4H,-2-CH3 -4-Cl
l-[4-(3-trifluoromethyl)phenylpiperazin-l-yl]-3-(quinoloxy-7-yl) propane of the formula III where n=3, X=H2, Z-N, R= QH^NO, Rl=CsH4-3-CF,
I-(4-(3-trinuoromethylphenyl)piperazin-l-yl]-3-(quinoioxy-6-yl) propane of the formula ffl where n=3, X=H2, Z-N, R= C
!-[4-{3-methoxyphenyl)piperazin-l-ylI-3-(quir,oloxy-8-yl) propane of the formula III where n=3, X»Hi, Z=N, R= C,HtNO, R1=C6H4-3-OCH3
l-[4-(2-methoxyphenyl)piperazin-l-yl]-3-(quinoloxy-8-yl) propane of the formula HI where n=3, X=»Hj, Z-N, R= C,H«NO, Rl=C4Hr2-OCH3
l-|4-(4-fluorophenyl)piperazin-l-yl]-3-(quinoloxy-7-yI) propane of the formula in where n=3, X~H2, Z=N, R=
!-{4-(2-methoxyphenyl)piperazin-l-yll-3-(quinoIoxy-7-yl) propane of the formula III where u=3, X=H2, Z=N, R= C,H6NO, R'=C«H l-(«K2-chlorophenyI)piperazin-l-yIj-3-{quinoloxy-7-yl) propane of the formula III where n=3, X~H2, Z=N, R= C,H«NO, R1=C6H4-2-Cl
!-[4- l-{4-(2-methoxyphenyl)piperazin-l-yl]-4-(quinoloxy-7-yl) butane of the formula HI where n=4, X=H2, Z=N, R= C,H l-[4- l-[4-(4-F!uorophenyl)piperazin-l-yl]-3-(quinoloxy-7-yl)propane of the formula UI where n=3, X=H2, Z=N, R= C,H6NO, R'^H
l-[4-(2-pyridyI)piperazin-l-yll-3-(quinoloxy-7-yl)propane of the formula III where n=3, X=H , Z=N, R= C,HSNO, R'
l-[4-(2-Methyl-4-chlorophenyl)piperazin-l-yl)-3-(quinoloxy-7-yl)propane of the formula III where n=3, X=H2, Z»N, R= C^NO, Rl=C6H3-2-CH3 -4-C1
l-[4-(3,4-dichlorophenyl)piperazin-l-yl]-3-{quinoloxy-7-yl)propane of the formula in where n=3, X=Hj, Z=N, R= C^NO, Rl=C6H4-3,4-Cl 2
l-[4^4-Methoxyphenyl)piperazin-l-yl)-3-(quinoloxy-7-yl)propane of the formula ffl where n=3, X=H2, Z=N, R= C
l-[4-(4-Chlorophenyl)piperazin-l-yl]-3-(quinoloxy-7-yl)propane of the formula HI where n=3, X-Hj, Z=N, R= C,H4NO, ^KTjH
l-[4-(4-Acetyl-4-phenyl)piperidin-l-yll-3-(quinoloxy-7-yl)propane of the formula HI where n=3, X=H2, Z-N, R= QH^NO, R^H, , RZ=COCH3
l-[4-(3-Chlorophenyl)piperazin-l-yl)-3--(quinoloxy-7-yl) propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO,R1=C6H4-3-CI
!-{4--(3-MethyIphenyl)piperazin-l-ylj-3-(quinoloxy-7-yl) propane of the formula III where n=3, X=H2, Z=N, R= C9H6NO,R1=C6H4-3-CH3
l-[4-{2-Chlorophenyl)piperazin-l-yll-3-(quinoloxy-6-yl) propane of the formula in where n-3, X=H2, Z=N, R= C9H6NO,R1=C6H4-2-CI
. !-[4-(4-ChIorophenyJ)piperazin-l-yl]-3-{quinoloxy-6-yI) propane of the formula III where n=3, X=H2,Z=N, R= C9H6NO,R1=C6H4-2-CI
l-[4-Hydroxy-4-phenylpiperidin-I-yl]-3-(quinoloxy-6-yl) propane of the formulaII where n=3,
X=HJ, z=c, R= C
l-[4-(3-Methylphenyl)piperazin-l-yl]-3-(quinoloxy-6-yI) propane of the formula in where n=3, X=H2, 2=Z=N, R= C9H6NO,R1=C6H4-2-CH3
1-[4-{2-PyridyJ)piperazia-i-yI]-3- (quinoIo3cy-6-yl)propane of the formula III where n=3, X=H, Z=N, R
l-l4-(2-Ethylphenyl)piperazin-l-yl]-3-(quinoloxy-6-yl) propane of the formula III where n=3, Z=N, R= C9H6NO,R1=C6H4-2-CI
l-[4-(4-Methoxyphenyl)piperazin-l-yll-3-(quinoloxy-6-yl) propane of the formula III where n=3, X=Z=N, R= C9H6NO,R1=C6H4-2-CI
l-[4-(2-Methoxyphenyl)piperazin-l-ylj-3-{quinoIoxy-6-yl) propane of the formula III where n-3, X=Z=N, R= C9H6NO,R1=C6H4-2-CI
Pharmacological Activities :
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 bod)' 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. Antiinflammatory Activity:
Some of these compounds were screened for Anti-inflammatory activity using Carrageenin induced paw oedema in rats in a dose of 100 nmol.p.o.and compared with Ibuprofen (100µmol.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 2 Removed)
(Table 3 Removed)
Tr = Transient, Pt ND= Not Done, - =
= Potentiation, i = Fall in blood pressure, I = Rise in blood pressure No Effect, R= Reversal, D= Decrease.
Table 3 : Antiinflammatory activity of the compounds.


(Table 3 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: I-[4-(4-F!uorophenyl)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-(4-fluorophenyl)-piperazine (0.54 g, 0.003 mol) and K2C03 (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 ml), the combined chloroform extracts were washed with water (3x20 ml), dried (Na^OJ, 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. 104*0. FTIR (KBr, cm'1): 3460, 2932,2824, 1738, 1694, 1512, 1242, 820;'H-NMR (CDC13): 6 (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(t, 2H, J=7.5 Hz, COCH2), 3.09-3.20(m, 6H,NCCH2)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
(Ml.
Example 2: l-[4-(4-F5aorophenyl)piperazin-l-yl]-3-[4-{4-ch!orophenyI)-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 120°C 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 (Na^SO^, concentrated and purified by column chromatography on silica gel column using MeOH (2%) in CHCl3as eluant. It was characterized as its dihydrochloride. Yield 0.22 g (53%), m.p. 186 C. FTIR (KBr, cm •*): 3466, 2943, 2822, 2785, 1682, 1501, 1234, 1163, 1092, 1015, 825, 754;'H-NMR (CDCI,): 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-CH2 (pyrrolidonc)), 6.85-7.00(m, 4H, ArH), 7.13-7.33(m, 4H, ArH); MS: m/z 415 (NT).
Example 3: l-[4-{4-Fluorophenyl)piperazin-l-yl]-3-[4-(3,4-dimethoxyphenyl)-pyrrolidin-2-oxo-l-yl]propane
A mixture of l-chloro-3-[4-(3,4-dimethoxyphenyl)-pyrrolidin-2-oxo-l-yl]propane (0.30 g, 0.001 mol), 1 -(4-fluorophenyl)piperazine (0.18 g, 0.001 mol) and K2C03 (0.14 g) in dry xylene (30 ml) was heated at \40°C 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 (Na^O^, 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. 141 Example 4:
l-[4-(4-FluorophenyI)piperazin-l-ylj-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), l-(4-fluorophenyl)-piperazine (0.54 g, 0.003 mol) and K2C03 (0.22 g) and N«! (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 (NajSO.J, concentrated and purified by column chromatography on silica gel column using ethylacetate as eluant. Yield 0.50 g (50%), m.p. 124'X:. FTIR(KBr, cm'1): 3454,3052,2966, 2906, 2826, 1734, 1694, 1512, 1242, 824; 'H-NMR (CDClj): 5 (ppm) 2.08(qn, 2H, J=7.26 Hz, 4-CH2 (pyrrolidone)), 2.6l(t, 2H, J=7.88 Hz, 3-CH2 (pyrrolidone)), 2.76-2.81(m, 4H, NfCH^), 3.16-3.20(m, 4H, N(CH2)2), 3.80-3.87(m, 4H, COCH2 & 5-CH2 (pyrrolidone)), 6.84-7.02(m, 4H, ArH); MS: m/z 305 (NT).
Example 5: !-[4-(2 A. mixture of l-chloro-3-(pyrrolidin-2-oxo-i-yi)propan-3-one (0.52 g, 0.003 mol), 1 -(2-methoxy-phenyl)piperazine (0.57 g, 0.003 mol) and K£03(0.42 g) and Nal (0.02 g) in dry DMF (10 ml) was heated at 180°C for 10 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. 150*C. FTIR (KBr, cnV '): 3390, 2954, 1740, 1678, 1594, 1500, 1246, 746;'H-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, CHj-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-(Trifluoromethylphenyl)piperazin-l-ylJ-3-(pyrroIidin-2-oxo-l-yl)propan-3-one
A mixture of l-chIoro-3-(pyrrolidin-2-oxo-l-yl)propan-3-one (0.52 g, 0.003 mol), l-(3-trifiuoro-methylphenyl)piperazine (0.73 g, 0.003 mol), Na2CO3 (0.31 g, 0.003 mol) and Nal (0.02 g) in dry
acsetone (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 Example 7: l-f4-(3,4-Dichlorophenyl)piperazin-l-yl]-3-(pyrrolidin-2-oxo-l-yI)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 K^Oj (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 (Na2SOj, concentrated and purified by column chromatography on silica gel column using MeOH (2%) in ethylacetate as eiuant. 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 (CDC13): 8 (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 (M-).
Example 8: l-[4-(2-Chlorophenyl)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-(2-chlorophenyi)-piperazine (0.39 g, 0.002 mol) and KpDj (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.
. FTIR (KBr,cnr'): 3462,2948,2822,1738,1690,1592, 1244, 760;'H-NMR(CDCli): 8 (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, NCCH^, 2.79-2.88(m, 2H, COCH^, 3.06-3.21(m, 6H, N(CH:)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 (Ml).
Example 9: !-[4- 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), K2CO3 (0.42 g) and Nal (0.06 g) in dry DMF (10 ml) was heated at 90°C 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): 6 (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), J.30-3.50(m, 4H, N(CH2)2), 3.72-3.81(m, 7H, OCHj, N-CH2,5-CH2 (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-{pyTrolidin-2-oxo-l-yl)ethan-2-one (0.54 g, 0.0034 mol), l-(3,4-dichloro-Dhenyl)piperazine dihydrochloride (0.98 g, 0.0037 mol), dry K£O3(0.53 g) and Nal (0.06 g) in dry 3MF (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 :rystalized with elher hexane. Yield 0.65 g (55%), m.p. 152.61(t, 2H, J=8.12 Hz, 3-CH2(pyrrolidone)), 2.75-2.80(m, 4H, NCCH^, 3.21-3.25(m, 4H, N(CH2)2), !.68-3.87(m, 4H, 5-CH2 (pyrrolidone) & N-CHj), 6.73(dd, 1H, J=2.68 & 8.76 Hz, ArH), 6.95(s, 1H, VrH), 7.24-7.28(m, 1H, ArH); MS: m/z 356 (M+).
Example 11: l-[4-(2-ChIorophenyI)piperazin-l-yl]-2-(pyrrolidin-2-oxo-l-yl)ethan-2-one
A mixture of l-chloro-2-(pyiTolidin-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 K€O3(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
(CDClj): 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-CH:), 6.96- 7.08(m, 2H, ArH), 7.18-7.37(m, 2H, ArH); MS: m/z 321 (M+).
Example 12: l-[4-(3-Trifluoromethylphenyi)piperazin-l-yl]-2-(pyrroiidin-2-oxo-l-yl)ethan-2-one
A mixture of l-chloro-2-(pyrroiiuin-2-oxo-l-yl)ethai]-2-one (0.48 g, 0.003 moi), i-(3-trifluoromethyi-phenyl)piperazine (0.76 g, 0.0033 mol), K2C03 (0.42 g) and Nal (0.06 g) in diy DMF (5 rnl) was heated at 90^ for 16 hours. It was diluted with water (20 ml). The resultant solid was recrystallized with ethylacetate. Yield 0.45 g (43%), m.p. 105 Example 13: l-[4-(PhenyI)piperazin-l-yll-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), Na2C03 (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. 103-105^. FTIR (KBr, cm'1): 3400, 2974,2828, 1736, 1698, 1598, 1500,
1240, 756;'H-NMR (CDC13): 8 (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-CH2 (pyrrolidone) & N-CH,), 6.85-6.95(m, 2H, ArH), 7.18-7.53(m, 3H, ArH); MS: m/z 287 (M4).
Example 14:
l-[4-(4-Ch!orophenyIpiperazin-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-(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 (CDC1,): 5 (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, NfCH^, 3.14-3.28(m, 4H, NCCHzU 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-Chiorophenylpiperazin-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), K£03(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 (CDCI3): d (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)a), 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-TrifluoromethyIphenyl)piperazin-l-yl]-3-(quinoloxy-8-yl)propane
A mixture of l-chloro-3-(quinoloxy-8-yl)propane (0.66 g, 0.003 mol), l-(3-trifluoromethyIphenyl)-piperazine (0.75 g, 0.0033 mol) and K2C03(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.crrT1): 3050, 2827, 1610, 1574, 1503, 1448, 1362, 1242, 1107, 1160, 1078, 993, 951, 822, 756, 731; 'H-NMR (CDCl,): 8 (ppm) 2.25(m, 2H, C-CH2-C), 2.68(m, 6H, NCH2), 3.25(1,4H, J=6.3 Hz, ArNCH2), 4.30(t, 2H, J=7.2 Hz, OCH2), 6.90-7.50(m, 8H, Ar), 8.05(dd, IH, J=9.0 & 1.8 Hz. Ar). S.85(m, 1H, Ar-H); MS: rn/z 415 (M+).
Example 17: l-[4-(3-chlorophenyI)piperazin-l-ylJ-3-(quinoIoxy-8-yI)propane
A mixture of l-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 (Na^O^), concentrated and purified by column chrornatography on silica gel using 1% MeOH in chloroform as eluant. It was crystallized with ether-hexane. Yield (0.60 g) (53%), m.p. 90 C. FTIR (KB^cnT1): 3030,2822, 1595, 1565, 1454, 1381, 1320, 1265, 1238, 1107, 788, 758; 'H-NMR (CDC13): 5 (ppm) 2.22(m, 2H, C-CH2-C), 2.65(m, 611, 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, IH, J=8.1 & 1.8 Hz, Ar), 8.85(m, IH, Ar); MS: m/z381 (M+).
Example 18: !-[4-(4-Fluorophenyl)piperazin-l-ylJ-4-(quinoloxy-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), K,CO3 (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 (Na^O^, concentrated and purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant. Yield (0.55 g) (52%), m.p. 53 Example 19: !-{4-(2-Chlorophenyl)piperazin-l-yl]-4-(quinoIoxy-7-yI)butane
A mixture of l-cWoro-4-(quinoloxy-7-yl)butane (0.470 g, 0.002 mol), l-(2-chlorophenyl)piperazine (0.392 g, 0.002 mol), K£03 (0.20 g) and Nal (0.01 g) in dry DMF (20 ml) was heated at 1 10«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 (Na^O^, concentrated and purified by column cnromatography on silica gel using 1% MeOH in chloroform as eluant. Yield (0.40 g) (51%), m.p. 125°C. FTIR (KBr,crrr '): 3870, 3734, 3324, 2942, 2822, 2332, 2212, 2116, 1916, 1618, 1474, 1238, 1148, 1030, 838, 754; 'H-NMR (CDC13): 6 (ppm) 1.90(m, 4H, C-OVQ, 2.53(t, 2H, j=7.6 Hz), 2.69(brs, 4H, N-CH2) 3. 10(brs, 4H, Ar-N-CH2), 4.17(t, 2H, J=6.0 Hz, O-CH,), 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
Example 20: l-[4-(4-hydroxy-4-pheny!)piperidin-l-yl}-4-(quino!oxy-7-yl)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 10°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 10"C. FTIR (KBr,cnV '): 3926, 3828, 3720, 3486, 2924, 2726, 2536, 2344, 2304, 2120, 1972, 1626, 1530, 1486, 1382, 1248, 1206, 1 124, 1050, 830, 640; H-NMR (CDClj): 5 (ppm) 1.85(m, 5H, C-CH:-C,OH), 2.67(m, 4H, CH2-C-OH), 2.99(m, 6H, NCH2), 4.16(m, 2H, OCH2), 7.12-7.85(m, 9H, Ar), p,08(d, iH, 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-phenyl)piperidin-l-yl]-3-(quinoloxy-8-yl)propane
A mixture of l-chloro-3-(quino!oxy-8-yl)propane (0.663 g, 0.003 mol), 4-(4-hydroxy-4-phenyl)-
piperidine (0.531 g, 0.003 mol), K2C03 (0.32 gm) and Nal (0.02 g) in dry DMF (20 ml) was heated at 1 W°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 NCH2), 4.32(t, 2H, J=7.2Hz,OCH2), 7.20-7.50(m, 8H, Ar), 8.10(m, 1H, Ar), 8.80(m, 1H, Ar) MS: m/z 362 (NT).
Example 22:
1 -[4-(4-ethy Ipheny I)piperazi n-1 -y I]-3-(q u inoloxy-8-y I)propa ne
A mixture of I-chloro-3-(quinoloxy-8-yl)propane (0.440 g, 0.002 mol), l-(4-ethylphenyl)piperazine (0.380 g, 0.002 mol), KjCO3 (0.20 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 (50 ml), extracted with chloroform (3x30 ml), the combined chloroform exuacis were washed with water (3x20 mi), dried (Na^SC) J, concentrated and purified by column chromatography on silica gel using 1% MeOH in chloroform as eiuant. Yield (0.35 g) (47%), m.p. 174°C. FTIR (KBr.cnV'): 3746, 3362, 3013, 2964, 2883, 2826, 1692, 1661, 1614, 1568, 1512, 1462, 1379, 1317, 1217,1186, 1146, 1107, 1030,928,824, 758,665; 'H-NMR (CDC13): 5 (ppm) 1.20(m, 3H, CH3), 2.55(qn, 2H, J=6.8 Hz, CH2CH,), 2.92(bs, 6H, NCH2), 3.30(hs, 4H, Ar-CHj), 4.38(t, 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 (Mf).
Example 23: l-[4-(2-Pyridyl)piperazin-l-yl]-3-(quinoloxy-8-yl)propane
A mixture of l-chloro-3-{quinoloxy-8-yl)propane(0..440g, 0.002 mol), l-(2-pyiidyl)piperazine (0.32 g, 0.002 mol), K2CO3 (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 (NajSOJ, concentrated and purified by column chromatography on silica gel using 1% MeOH in chloroform as eiuant. 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; "H-NMR (CDC1.0: 8 (ppm) 2.30(qn, 2H, J=5.6 Hz, C-CHrC), 2.65(m, 6H, NCHj). 3.07(t, 4H, J=5.6 Hz, ArNCH,), 4.36(t, 2H, J=6.0 Hz, OCH:), 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: m/z 348 (M4).
Example 24: l-[4-(3-Methylphenyl)piperazin-l-yl]-3-(quinoloxy-8-yl)propane
A mixture of l-ch!oro-3-(quinoIoxy-8-yl)propane (0.440 g, 0.002 mol), l-(3-methylphenyl)piperazine (0.352 g, 0.002 mol), K2C03 (0.40 g) and Nal (0.01 g) in dry DMF (20 ml) was heated at 1 lO'C 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 (Na^O^, 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 (CDClj): 5 (ppm) 2.15(m, 2H, C-CH2-C), 2.28(s, 3H, CHj), 2.60(m, 6H, NCH2), 3.15(t, 4H, J=4.5 Hz, ArNCH2), 4.30(t, 2H, J=7.2 Hz, OCH2), 6.60-6.7U(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/z 361 (M").
Example 25: 3-[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-dimethoxyphenyl)-piperazine (0.444 g, 0.003 mol), K.2CO3 (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 ml), the combined chloroform extracts were washed with water (3x20 ml), dried (Na2SO,,), 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.cm'1): 3682, 3398,3020, 2959, 2829, 2403, 2278,1583,1512,1462, 1379,1315, 1215, 1146, 1107, 1080, 1026, 974,760,669; 'H-NMR (CDClj): 6 (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=5.8Hz, Ar), 7.14(d, 1H, J=5.0 Hz, Ar), 7.40-7.5 l(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-methylphenyl)piperazin-l-yl]-3-(quinoloxy-8-yI) propane
A mixture of l-chloro-3-(quinoloxy-8-yl)propane (0.663 g, 0.003 mol), l-(4-chloro-2-methylphenyl)-piperazine (0.63 g, 0.003 mol), K2CO3 (0.40 g) and Nal (0.01 g) in dry DMF (20 m!) 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 duant Yield (0.50 g) (42%), m.p. 9TC. FTIR (KBr.cnT1): 3423, 2928, 2831, 1591, 1497, 1466, 1371, 1317,1265, 1225,1211,1188,1167,1111, 1038,824,804,793, 735; 'H-NMR (CDC13): 5 (ppm) 1.70(s, 3H, CH3), 2.25(m, 2H, CCH2-C), 2.54(m, 6H, NCH2), 3.12(m, 4H, ArNCH2), 4.36(t, 2H, J=4.6 Hz, OCHz), 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 (M+).
Example 27: l-[4-(3-trifluoromethyl)phenyIpiperazin-l-yI]-3-(quinoloxy-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 Na2C03 (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 (Na2S04) 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. 140°C. FTIR (KBr.cnT1): 3051,2972,2939, 2916, 2883, 1624, 1597, 1504, 1470, 1441, 1387, 1319, 1263, 1240, 1207, 1175, 1136, 1085, 1055,972,849, 831, 796,764; 'H-NMR (CDCL3). 5 (ppm) 2.40-2.70(m, 4H, NCH2, C-CH2-C), 3.21(bs, 4H, NCH2), 3.73(m, 4H, Ar-NCH,), 4.30(m, 2H, OCH2), 7.08-7.43(m, 7H, Ar), 7.77(m, 1H, Ar), 8.17(d, 1H, J=7.5 Hz, Ar), 8.85(bs, 1H, Ar); MS: m/z 415 (Mf).
Example 28:
!-[4-(3-trifluoromethylphenyl)piperazin-l-yIj-3-(quinoIoxy-6-yI)propane
A mixture of l-chloro-3-(quinoloxy-6-yl)propane (0.89 g, 0.004 mol), l-(3-trifluoromethylphenyl)-piperaz-'ne (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 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 1.00 g (62%), m.p. 240°C. FTIR (KBr.crn1): 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):5(ppm)2.10(qn, 2H, J=7.0 Hz, C- CH2-C), 2.68(m, 6H, NCH2), 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, 2H, Ar), 8.75(bs, 1H, Ar); MS: m/z415 (NT).
Example 29: l-[4-(3-methoxyphenyl)piperazin-l-yl]-3-(quinoloxy-8-yl)propane
A mixture of l-oh!oro-3-(quinoloxy-8-yl)propane (0.44 g, 0.002 mcl), l-(3-methoxypheny!)-piperazine (0.38 g, 0.002 mol), dry K2C03 (0.40 g) and Nal (0.01 g) in dry acetone (50 ml) was refluxed for 38 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 0.30 g (40%), m.p. 95°C. FTIR (KBr,cnV'): 3050, 3000, 2949, 2882, 2826, 1603, 1531, 1499, 1462, 1379, 1317, 1258, 1049, 756; 'H-NMR (CDC13): 6 (ppm) 2.45(bs, 2H, C-CH2- C), 3.00(m, 6H, NCH2), 3.42(bs, 4H, ArNCH2), 3.80(s, 3H, OCH3), 4.40(t, 2H, J=8 Hz, OCH2), 6.40-6.60(m, 2H, Ar), 7.10-7.50(m, 6H, Ar), 8.15(d, 1H, J=7.0 Hz, Ar), 8.95(m, 1H, Ar); MS: m/z 377 (M+).
Example 30: l-[4-(2-methoxyphenyl)piperazin-l-yl]-3-(quinoloxy-8-yl)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 (5 l%),m.p. 137 C. FTIR (KBr.cnV1): 3100,3000, 2950,2940,2830,2800, 1600,1560, 1550, 1490, 1450, 1370, 1230, 1170, 720 ; 'H-NMR (CDC!3): 6 (ppm) 2.25(m, 2H, C-CH2-C), 2.75(m, 6H, NCH,), 3.15(m, 4H, Ar-NCH,), 3.85(s, 3H, OCHJ, 4.35(t, 2H, J=8 Hz. OCHZX 6.85-?.45(m, 8H, Ar), 8.07(in, IH, Ar), 8.87(dd, IH, J=6.0 & 1.8 Hz, Ar); MS: m/z 377 (NT).
Example 31: !-[4-{4-fluorophenyI)piperazin-l-yl]-3-(quinoIoxy-8-yl)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), Na2CO., (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 dihydrochloridc. Yield 0.42 g (57%), m.p. 150°C. FTIR (KBr.cnT1): 3030, 2970,2940, 2840, 1590, 1510, 1465, 1380, 1320, 1220, 1110, 820, 'H-NMR (CDC13): 5 (ppm) 2.25(m, 2H, C-CH2-C), 2.70(m, 6H, NCH,), 3.15(m, 4H, Ar-NCHj), 4.40(t, 2H, J=8 Hz, OCH,), 6.90-7.50(m, 8H, Ar), 8.15(d, IH, J=6.3 Hz, Ar), 8.95(m, IH, Ar); MS: m/z 365 (M*).
Example 32: l-[4-{2-methoxyphenyI)piperazin-l-yI]-3-(quinoloxy-7-yl)propane
A mixture of l-chloro-3-(quino!oxy-7-yl)propane (0.88 g, 0.004 mol), l-(2-methoxyphenyl)-piperazine (0.76 g, 0.004 mol) and dry (Na2SO4) (0.40 g) in dry DMF (25 ml) was heated at 90"C for 10 hours. Reaction mixture was diluted with water, extracted with chloroform (3x30 ml), washed with water (3x20 ml), dried (Na2SO4) and purified by column 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-1): 3030,2946,2820, 1618, 1500, 1450, 1386, 1238, 1142, 744; 'H-NMR (CDClj): 6 (ppm) 2.1 l(qn, 2HT J=7.0 Hz, C-CH2-C), 2.68(m, 6H, NCH2), 3.09(bs, 4H, Ar-NCH2), 3.86(s, 3H, OCH3), 4.21(t, 2H, J=6.2 Hz, OCH2), 6.83-7.28(m, 6H, Ar), 7.42(d, IH, J=2.0 Hz, Ar), 7.69(d, IH, J=9.0 Hz, Ar), 8.06(d, IH, J=8.0 Hz, Ar), 8.82(m, IH, Ar); MS: m/z 377 (M+).
Example 33:
1-[4~(2-chlorophenyl)piperazin-l-yIJ-3-(quinoloxy-7-yl)propane
A mixture of l-chloro-3-(quinoloxy-7-yl)propane (0.44 g, 0.002 mol), I-(2-chlorophenyl)piperazine (0.40 g, 0.002 mol) and(Na2SO4) (0.40 g) in dry acetone (50 mi) 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 0.41 g (68%), m.p. 82°C. FTIR (KBr.crn1): 3054, 2948,2888, 2826, 1906, 1780, 1724, 1616, 1446, 1386, 1256, 1176, 1130, 1044, 838, 762; 'H-NMR (CDCI3): 5 (ppm) 2.14(qn, 2H, J=7.2 Hz, C-CH2-C), 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, AT), 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-yl)propane
A mixture of 1 chlorc-3-(quinc!oxy-7-yl)piOpane (0.22 g, 0.001 moi), 4-( 4-hydroxy-4-phenyl)-pipendine (0.18 g, 0.001 mol), K2CO3(0.20 g) and Nal (0.01 g) in dry aceione (50 mi) 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 C. FTIR (KBr,cm-'): 3124,2948,2822, 2348, 1618, 1498, 1448, 1390, 1320, 1262, 1174, 1126, 840, 768; 'H-NMR (CDC13): 5 (ppm) 1.78(m, 2H, C-CH2-C), 2.16(m, 4H, C-CH,-C), 2.47-2.69(m, 5H, NCH2 pipendine, 0-H), 2.87(m, 2H, NCH2, 4.19(t, 2H, J=6.2 Hz, OCH2), 7.17-7.71(m, 9H, Ar), 8.06(d, 1H, J=8.2 Hz, Ar), 8.78(m, 1H, Ar); MS: 362 m/z (M1).
Example 35: l-[4-(2-methoxyphenyl)piperazin-l-yl]-4-(quinoloxy-7-yI)butane
A mixture of l-chloro-4-(quinoloxy-7-yl)butane (0.47 g, 0.002 mol), l-(2-methoxyphenylpiperazine (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 dihydrochioride. Yield 0.60 g (77%), m.p. 160°C. FTIR (KBr.cm): 3050,
2944,2820, 1618, 1500, 1452, 1386, 1320, 1244, 1132, 1026, 840,754; 'H-NMR (CDC13): 8 (ppm) 1.78-2. 1 7(m, 4H, C-CH2-C), 2.55(t, 2H, J=7,2 Hz, NCH2-C-C), 2.73(bs, 4H, NCH2), 3.12(bs, 4H, Ar-NCH2), 3.86(s, 3H, OCH,), 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:
Example 36: l-[4-(2-chlorophenyl)pip€razin-l-yl]-5-(quinoIoxy-7-yI)pentane
A mixture of l-chloro-5-(quinoloxy-7-yl)pentane (0.24 g, 0.00 1 mol), 1 -(2-chlorophenyl)piperazine (0.19 g, 0.001 mol) and NaHC03 (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 (Na2SO4) and concentrated. It was purified by column chromatography on silica gel using 3% MeOH in chloroform as eluant. It was characterized as its dihydrochloride. Yield 0.18g(45%),m.p. 170 Example 37: !-[4-{4-FIuorophenyI)piperazin-l-yl]-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 KjCOj (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. 140°C.FnR(KBr,cm-'): 3747, 34 16, 2928, 2822, 2783, 2380, 1618, 1568, 1506, 1450, 1389, 1319, 1267, 1215, 1 173, 1 1 17, 1045, 1013, 968, 935, 912, 826, 766, 714, 617; 'H-NMR (CDC13): 8 (ppm) 2.10(qn, 2H, J=5.0 Hz, CH2), 2.64(m, 6H, NCH2), 3.14(m, 4H, Ar-NCH2), 4.21(t, 2K, J=5.0 Hz, OCH2), 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:
l-[4-(2-pyridyl)piperazin-l-yI]-3-(quinoloxy-7-yl)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 mo!) and K,CO, (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 (CDC13): 8 (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), 8.21(d, 1H, J=3.4Hz, Ar), 8.83(d, 1H, J=2.5Hz, Ar); MS: m/z 348 (M+).
Example 39: !-[4-{2-Methyl-4-chlorophenyI)piperazin-l-yl|-3-(quinoIoxy-7-yl)propane
A mixture of i-ch!cro-3-(quino!oAy-7-y!)prcpane (0.44 g. 0.002 mol), l-(2-methyl- 4-chlorophenyI)-piperazine (0.42 g, 0.002 mol) and K203(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. It was crystallized with ether-hexane. Yield 0.32 g (41%), m.p. 105C. FTIR (KBr.cnV1): 3801,3747, 3443, 2937,2820,2789,2378, 1618, 1497, 1446, 1385, 1315, 1265, 1215, 1171, 1142, 1111, 1047, 1005,972,939,903,839,812,768,739, 708,610; :H-NMR (CDC1.0: 5 (ppm) 1.25(m, 2H, CH^, 2.17(s, 3H, CH3), 2.75(bs, 6H, N(CH2)2), 3.20(bs, 4H, Ar-NCH2), 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 (Mv).
Example 40: l-[4-(3,4-dichlorophenyl)piperazin-l-yl]-3-(quinoloxy-7-yl)propane
A mixture of l-chloro-3-(quirioloxy-7-yl)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 (Na2SO4) concentrated and purified by column chromatography on silica gel using 1% MeOH in chloroform as eluant. Yield 0.65 g (52%), m.p. 120"€. FTIR (KBr, cm'1): 3870,3698, 3444, 2934, 2316, 1732, 1612, 1474, 1382, 1242, 1148,820; 'H-NMR (CDC1.,): 5 (ppm) 2.08(m, 2H, CH2), 2.63(m, 6H, NCH2), 3.19(m, 4H, Ar- NCH2), 4.2 l(t, 2H, J=6.4 Hz, 0-CH2), 6.74(dd, 1H, J=9.0 & 2.8 Hz, Ar), 6.95(d, IK, 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=9.0Hz, Ar), 8.05(m, IH.Ar), 8.82(d, 1H, J=5.2 Ar); MS: m/z416 (M*).
Example 41: l-[4-(4-MethoxyphenyI)piperazin-l-yl]-3-(quinoloxy-7-yl)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 chromatograpliy 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, 36»2, 3651, 3400, 2941,2880, 2814, 2754, 2702,2334, 1742, 1618, 1508, 1448, 1385, 1319, 1267, 1240, 1213, 1178,1122, 1042, 1014,970,935,835,802, 768, 716, 664, 617; 'H-NMR (CDC13): 5 (ppm) 2.10(qn, 2H, J=4.6 Hz, CH2), 2.65(m, 6H, NCH2), 3.12(m, 4H, Ar-NCH2), 3.77(s, 3H, 0-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: l-[4-(4-ChlorophenyI)piperazin-l-ylJ-3-(quinoloxy-7-yl)propane
A mixture of l-chloro-3-(quinoloxy-7-yl)propane (1.76 g, 0.008 mol), 4-chlorophenyipiperazine (2.15 g, 0.008 mol), K2C03 (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, cnT1): 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): 5 (ppm) 2.12(qn, 2H, J=4.6 Hz, CH2), 2.63(m, 6H, NCHJ, 3.13 (m, 4H, Ar-NCH,), 4.1 l(t, 2H, J=4.2 Hz, 0-CH2), 6.82-6.87(m, 2H, Ar), 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 (M1).
Example 43: l-[4-(4-Acetyl-4-phenyl)piperidin-l-yl]-3-(quinoIoxy-7-yl)propane
A mixture of l-chloro-3-(quinoloxy-7-yl)propane (0.663 g, 0.003 moI),4-( 4-acetyl-4-phenyl)-piperidine (0.609 g, 0.003 mol), K£03 (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. FTTR (KBr, cm-'): 3888,3782,3426,3164, 2826, 2328, 2252, 2026, 1916, 1816, 1622,1496, 3392, 1266, 1126, 1040, 978, 772, 704; H-NMR (CDCJj): 6 (ppm) 1.22(s, 3H, COCH,), 1.65(m, 2H, CH2), 2.13 (m, 4H, (CH2-C-CH2), 2.5 l(m, 4H, Ar-NCH,), 4.16(t, 2H, J=6.4 Hz, OCH,), 7.16- 7.40(m, SH, 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-Ch!orophenyl)piperazin-l-yl]-3-(quinoIoxy-7-yI)propane
A mixture of l-chloro-3-(quinoloxy-7-yl)propane (0.884 g, 0.004 mol), l-(3-chlorophenyl)piperazine (0.784 g, 0.004 mol), K2CO3., (0.60 g) and Nal (0.20 g) in dry DMF (30 ml) was heated at 130 C 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. 100°C. FTIR (KBr, cm'1): 3462,3252,2777, 2710,2604,2338, 1904, 1593, 1566, 3493, 1450, 1391, 1321, 1251, 1205, 1178,1146, 1107,1057, 1013,978,943,914,831,764,679, 650, 617; 'H-NMR (CDC13): 8 (ppm) 2.35(bs, 2H, GHz), 3.00(bs, 6H, NCH,), 3.47(bs, 4H, Ar-NCH2), 4.25(t, 2H, J=6.8 Hz, OCH2), 6.75-6.95(m, 3H, Ar) 7.10-7.30(m, 3H Ar), 7.45(d, 1H, J=6.8 Hz, Ar), 7.75d, 1H, J-9.0 Hz, Ar), 8.10(d, 1H, J=7.0Hz,Ar), 8.85(d, 1H, J=3.4, Ar); MS: m/z 381 (Ml
Example 45: l-[4-(3-MethylphenyI)piperazin-l-yl]-3-(quinoIoxy-7-yl)propane
A mixture of l-chloro-3-(quinoloxy-7-yl)propane (0.44 g, 0.002 mol), 1 -(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 1 l0 C for 12 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 0.40 g (56%), m.p. 75°C. FT1R (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): 8 (ppm) 2.1 l(m, 2H, CHj), 2.3l(s, 3H, CH3), 2.66 (m, 6H, NCH2, 3.20(bs, 4H, Ar-N-CH2), 4.2l(t, 2H, J=4.2 Hz, OCH2), 6.67-6.75(m, 3H, AT), 7.12-7.28(m, 4H, AT), 7.44(bs, 1H, Ar), 7.69(d, 1H, J=6.0 Hz, Ar), 8.06(d, 1H, J=5.4 Hz, Ar); MS: 361 (M*).'
Example 46: 1-[4~(2-ChIoropheny!)piperazin-!~yij-3-(quinoloxy-6-yl) propane
A mixture of l-chloro-3-(quinoloxy-6-yl)propane (0.37 g, 0.0016 mol), l-(2-chlorophenyl)piperazinc (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 (Na2SO4) 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.cnV1): 3740,3542,3018,2956,2814,2662,2412,2352, 1684, 1510, 1376, 1220, 1124, 1046, 928, 834, 758 ; 'H-NMR (CDC13) 5 (ppm): 2. l(qn, 2H, J=7.4Hz, O-C-CH2); 2.68(m, 6H, NCH,); 3.12(bs, 4H, Ar-NCH2); 4.18(t, 2H, J=6.4Hz, 0-CH2); 7.02(m, 1H, Ar); 7.1(d, 2H, J=2.8Hz, Ar); 7.19-7.4 l(m, 4H, Ar); 8.03(t, 2H, J=8.4 Hz, Ar); 8.76(d, 1H, J=2.8Hz, Ar); MS m/z 382(M+).
Example 47: l-[4-(4-Chlorophenyl)piperazin-l-yI)-3-(quinoloxy-6-yl) propane
A mixture of l-chloro-3-(quinoloxy-6-yl)propane (0.35 g, 0.0016 mol), 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 (Na^SO.,) and purified by column chromatography on silica gel using ethylacetate as eluant. Yield 0.50 g (83%), m.p. 120-123°C. FTIR (KBr,cn-1'): 3832, 3716, 3488, 3050, 2950, 2806, 2344, 1976, 1844, 16*2, 1612, 1504, 1366, 1232, 1142, 1032, 938, 826, cm'1; 'H- NMR(CDC13) 8 (ppm): 2.1(qn, 2H, J=6.8Hz, O-C-CHj); 2.67(m, 6H, NCH2); 3.21(t, 4H, J=4.8Hz, Ar-NCH2), 4.18(t, 2H, J=6.2Hz, 0-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-phenylpiperidin-l-yl]-3-(quinoloxy-6-yI) 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 120^ for 14 hours. It was diluted with water (50 ml), extracted with chloroform(3x30 rnl), washed \vilh water (3x20 mi), dried (Na2O4 and purified by column chromatography on silica gel using ethylacetate as eluant. Yield 0.40 g (70%), m.p. 135- 1381:. FTIR(KBr,cm-1): 3726, 3646, 3544,3402,3220,3022,2938,2804, 2604,2340,2114, 1936, 1706, 1628, 1530, 1394, 1234, 1146, 1054, 964,700 ; IH-NMR(CDC13): 8 (ppm) 1.8(m, 4H, Ar-C-CH2), 2.1-2.37(m, 3H, 0-C-CH2, OH), 2.51-2.94(m, 6H, NCHJ, 4.18(t, 2H, J=6Hz, OCH2), 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-l-ylj-3-(quinoloxy-6-yl) propane
\ mixture of l-chloro-3-(quinoloxy-6-yl)propane (0.33 g, 0.0015 mol), l-(3-methylphenyl)piperazine ;0.27 g, 0.0015 mol), baked dry K2C03 (0.30 g) and baked Nal (10 mg) in dry DMF (15 ml) was leated at \20 C for 10 hours. It was diluted with water (50 ml), extracted with chloroform(3x30 ml), vashed with water (3x20 ml), dried (Na,SO4) and purified by column chromatography on silica gel ising ethylacetate as eluant. Yield 0.30 g (56%), m.p. 80-83 C FTIR (KBr, cm1): 3702, 3340, 2948, !626, 2424, 2334, 1934, 1806, 1694, 1612, 1524, 1230, 1142, 1034, 758; 'H-NMR(CDCI3) 6 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(t, 2H, J=6Hz, 0-CH2), 6.68-6.76(m, 3H, Ar), 7.08-7. 4(m, 4H, Ar), 8.02(t, 2H, J=8Hz, Ar), 8.77(d,lH, J=4.0 Hz, Ar); MS m/z 361(M*).
Example 50: M4~(2-Pyridy!)piperazin-l-yI]-3-(quinoloxy-6-yl)propane
A mixture of l-ch!oro-3-(quinoloxy-6-yl)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 (15 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 (Na2S04) 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) 8 (ppm): 2.1(qn, 2H, J=6Hz, O-C-CH,), 2.63(m, 6H, NCH2), 3.57(t, 4H, J=5.5Hz, Ar-NCH2), 4. 1 7(t, 2H, J=6Hz, 0- CH2), 6.59-6.67(m, 2H, Ar), 7.08(d, IH, J=2.6Hz, Ar), 7.31- 7.47(m,3H,Ar), 8.02(t,2H,J=7Hz,Ar),8.19(d, IH, J=4Hz, Ar), 8.76(d, IH, J=3Hz, Ar); MS lll/z 348(^0.
Example 51: l-[4-(2-Ethylphenyl)piperazin-l-yl]-3-(quinoloxy-6-y!) propane
A mixture of l-chloro-3-(quinoloxy-6-yI)propane (0.40 g, 0.001 8 mol), l-(2-ethylphenyl)piperazine (0.38 g, 0.002 mol), baked K2C03 (0.30 g) and baked Nal ( 1 0 mg) in dry DMF ( 1 5 ml) was heated at 1 10°C for 12 hours. It was diluted with water (50 ml), extracted with chloroform (3x30 ml), washed with water (3x20 ml), dried (Na^OJ 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, 1 152, 1044, 938, 836, 756 Cm'1; H- NMR(CDC1,) : 5 (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-NCHi), 4. 1 8(t, 2H, J=6Hz, 0-CH2), 7.02- 7.4 1 (m, 7H, Ar), 8.02(t, 2H, J=8.5Hz, Ar), 8.77(m, IH, Ar); MS m/z 375(M*).
Example 52: l-[4-(4-MethoxyphenyI)piperazin-l-yI)-3-(quinoloxy-6-yl) propane
A mixture of l-chloro-3-(quinoloxy-6-yl)propane (0.44 g, 0.002 mol), l-(4-methoxyphenyl)-piperazine (0.53 g,0.002 mo!), 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 (Na2S04) 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,cnr'): 3826, 3732, 3424, 2944, 2818,2350, 1618, 1508, 1452, 1382, 1324, 1240, 1178, 1022, 972, 932, 830, 718 cm'1; 'H-NMR(CDC1,): 8 (ppm) 2.1(qn, 2H, J=7Hz, O-C-CHj), 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. IH, J=4Hz, Ar), 7.31-7.4l(m, 2H, Ar), 8.02(t, 2H, J=8Hz, Ar), 8.76(d, IH, J=2Hz, Ar); MS m/z 377 (M').
Example 53: l-[4-(2-MethoxyphenyI)piperazin-l-yl)-3-(quinoloxy-6-yI) propane
A mixture of l-chloro-3-(quinoloxy-6-yl)propane (0.50 g, 0.0022 mol), l-(2-methoxyphenyl)-piperazine (0.43 g, 0.0022 mol), baked K2C03 (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 ml), washed with water (3x30 ml), dried (Na2S04) 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; 1H-NMR(CDC1J) : 6 (ppm) 2.10(qn, 2H, J=6Hz, 0-C-CH2), 2.67(m, 6H, NCH2), 3.13(br s, 4H, Ar-NCH2), 3.87(s, 3H, OCH3), 4.18(t, 2H, J=6Hz, O-CH,), 6.88-6 97(m, 4H, Ar), 7.95(d, IH, J=2Hz, Ar), 7.31-7.4l(m, 2H, Ar), 8.02(t, 2H, J=8Hz, Ar), 8.76(m, IH, Ar); MS m/z 377 (M+).
Example 54: Antihypertensive/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 (MR). Right femoral vein and Trachea were cannulated for intravenous injections and artificial ventilation respectively. Control responses to intravenous injection of noradrenaline (2-4 jag); aceryl choline (1-2 jug); histamine (1-2 jag) and isoprenaline (1-2 jag) 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 ;.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, CaC!2 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 rsperfbsion. Prog. Cardiovas. Dis., 30,23-44, 1987). Ischemia was initiated by stopping the flow tor 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 µmol p.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 . Novel l-(4-aryl/heteroarylpiperazin/piperazin/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-pyrrolidin-2-
oxo-l-yl, R1 represents group like aryl and heteroaryl, Z=N/CR2 (R2=H, OH,
COCHs), X=O/H, n=2-5 and the process for the preparation of the same which
comprises condensing l-chloro-n-(quinoloxy-6/7/8-yl/4-(un) substituted pyrolidone-
2-oxo- 1 -lye)alkanes/alkanones of the formula 1 with (4-
aryl/heteroaryl)piperazine/piperdine of the formula II in the presence of base like
potassium or sodium carbonate, potassium or sodium bicarbonate or powdered
potassium hydroxide and solvent selected from acetone, tolune or
dimethylformamide for a period varying between 6-36 hrs. to produce corresponding
1 - { 4-aryl/heteroaryl/piperazine/piperidin- 1 -yl)-n-(quinoloxy 6/7/8-yl/4-un
substituted pyrolidin-2-oxo-l-yl) alkanes/alkanones.
2. Novel 1 -(4-aryl/heteroarylpiperazin/piperidin- 1 -yl)-n-(quinoloxy-6/7/8-yl/4-(un)substituted-pyrrolidin-2-oxo-l-yl)alkanes/alkanones and their salts as claimed in claim 1 substantially as herein described with reference to the examples.

Documents:

910-del-2003-abstract.pdf

910-del-2003-claims.pdf

910-del-2003-correspondence-others.pdf

910-del-2003-correspondence-po.pdf

910-del-2003-description (complete).pdf

910-del-2003-form-1.pdf

910-del-2003-form-19.pdf

910-del-2003-form-2.pdf

910-del-2003-form-3.pdf


Patent Number 242145
Indian Patent Application Number 910/DEL/2003
PG Journal Number 34/2010
Publication Date 20-Aug-2010
Grant Date 16-Aug-2010
Date of Filing 22-Jul-2003
Name of Patentee COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH
Applicant Address RAFI MARG, NEW DELHI-110001, INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 ALPANA SRIVASTAVA CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226001, U.P., INDIA.
2 KESHAV KISHOR AWASTHI CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226001, U.P., INDIA.
3 RAVISH CHANDRA TRIPATHI CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226001, U.P., INDIA.
4 SHEKAR SRIVASTAVA CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226001, U.P., INDIA.
5 JHAMA ARUN CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226001, U.P., INDIA.
6 RAM MOHAN SAXENA CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226001, U.P., INDIA.
7 MADHUR RAY CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226001, U.P., INDIA.
8 RAKESH SHUKLA CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226001, U.P., INDIA.
9 MANGAL PRASAD DUBEY CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226001, U.P., INDIA.
10 ANIL KUMAR SAXENA CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226001, U.P., INDIA.
11 SURESH KUMAR PANDEY CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226001, U.P., INDIA.
PCT International Classification Number A61K 31/452
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA