AU762684B2 - A process for the synthesis of 1-(4-arylpiperazin-1-YL)-3-(2-oxopyrrolidin/piperidin-1-YL) propanes used as potential therapeutic agents for hypertension, ischemia, cardiovascular and other adrenergic receptors related disorders - Google Patents

Description

'/UU/U11 28/5/01 Regulation 3.2(2)

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT te Application Number: Lodged: Invention Title: A PROCESS FOR THE SYNTHESIS OF 1- [4-ARYLPIPERAZIN-1-YL]-3- [2-OXOPYRROLIDIN/PIPERIDIN-1-YL] PROPANES USED AS POTENTIAL THERAPEUTIC AGENTS FOR HYPERTENSION, ISCHEMIA, CARDIOVASCULAR AND OTHER ADRENERGIC RECEPTORS RELATED DISORDERS The following statement is a full description of this invention, including the best method of performing it known to FIELJ~ OF'THE INVENTION The p~resen~t invention relates, to a 1:roces,.r; tor the sy11I:jl.eID:1; ot, novel 1- [4-Arylpiperaz in 1-yl]1 [2-oxopyrrolidin- l-I. ]1i~~ and 1- [4-Arylpiperazin-l-yl] [2-oxopiperidin-l-vL nopne which can be used as therapeutic agents for hyperte:nsio.n, ische mia, cardiovascular and other adrenergic receptors related cdisorders. M1ore, particularly the present invention relates, to a process f or the systhesis of 1- [4 -Arylpiperazin-1I-yi.] 1.'2-x.

pyi-rolidin-1-yl] propanes and 1- [4 -Arylpiperazin-1-yl] oxopi pe)i~lin 1-yl] ropne ,and to theiri. us-.e in mied iciiie.

This invention provides the compounds of the formula 1.

Wherein Ar represents a phenyl ring substituted by halogen, alkoxy, alkyl or heteroaryl and n =1or n 2.

The. compounds of the invention have Shown toposr nthve tensa.;ve activity inl different. Les-t 1inodeisr') 'I'lie c j) 1 i prf-vent post i~schemic repertusioni -injury anid may heii.-.cii In I-it t t:rea tmenIlt of hyp.)e rtens on, d i s ea e r a ri.r i. iiq 1l o* a].t.era-tiaonis!imirmz~ii-ient in centr~i]. peripheral 1c c].ti.csand adrenerq::ic receptors systems,suha mocrilihei ,iyczardial infarction (MI) angina pectoris, any cardiac sin-cical mtii e-rvent ions rena]. ischernia cirri.iiatory iisuff :iciell~w il ti~ni.J.Sstroke and trw..ma.

A *l]W:i].method. of .rp rat n. h ~netix' emoiA 11 from the condensation of l-bromo-3-chloropropane with 2pyrrolidone or 2-piperidone to give the key intermed L;l e 1chloro-3-[2-oxopyrrolindin-l-yl]propanes of formula 3 or 1chloro-3-[2-oxopiperidin-l-yl]propanes followed by its condensation with different 1-substituted piperazines of formula 4 to get the compounds of formula 1 and the said method is the subject matter of the co-pending US application number According to the method, the process of which starts from the condensation of l-bromo-3-chloropropane with different 1substituted piperazines of formula 4 to give the l-chloro-3-(4substituted piperazin-1-yl)propanes of formula 5 followed by their condensation with 2-pyrrolidone or 2-piperidone of formula 2 to get the compounds of formula 1 (formulae 2 to 5 are shown in scheme 1 of the accompanying drawings).

The compounds of the present invention can be used as pharmaceutical compositions comprising compounds of the present invention with a suitable pharmaceutical carrier. Preferably, these compositions are used to produce antihypertensive and antiischemic activities and contain an effective amount of the compounds S ill tile method of the invention .''The Tmo;t:It rc: ferred (c(m)old(111(1 of the invention is 1-[4-(4-fluorophenyl)piperazin-l-yl]-3-[2oxopyrrolidin-1-yl]propane BACKGROUND OF THE INVENTION Hypertension is the most common of all cardiovascular diseases afflicting about 10-20% adult population. Several classes of drugs may be used in the treatment and management of hypertension suh as alpha-adrenoepor anagoniss, ACE in* such as alpha-adrenoceptor antagonists, ACE inhibitors, o• n1(iotensin I chymase inhibitors, renin inhibitors, aniJ. euii:;:n II antagonists, vasopressin V] antagonists, endl- helin antagonists, endothelin-converting enzyme inhibitors, potassium channel activators, calcium channels antagonists, adenosine A 2 agonists, adenosine Al antagonists, neutral endopeptidase inhibitiors, dual-action ACE and neutral endopeptidase inhibitors.

These drugs belong to structurally diverse class of heterocyclics including substituted arylpiperazines. In this context, the 1-[4- Arylpiperazin-l-yl]-3-[2-oxopyrrolidin-l-yl]propanes and 1-[4- Arylpiperazin-l-yl]-3-[2-oxopiperidin-l-yl]propanes of the formula 1 are structurally novel compounds and show significant antihypertensive and antiischemic activities. Thus, these compounds would be useful in the treatment of hypertension and in preventing post-ischemic reperfusion injury (ischemia).

The most commonly used antihypertensive drugs are ACE's inhibitors (captopril and related drugs), Ca++ channel blocker (nifedipine, verapamil, diltiazen) and peripheral alphaadrenergic antagonist such as prazosin. As these drugs have one or the other side effects, there has been a continuous search for new and safe antihypertensive agents acting by these mechanism and by other novel mechanism which include mainly endothelin antagonists [Gulati, A. and Srimal, R.C. Drug Dev. Res., 26, 361, 1992; Antihypertensive Drugs. The Year's Drug News, 145-167, ;1994].

There are no drugs available to prevent post-ischemic reperfusion injury. However, the existing drugs or chemical agents like Ca++ channel blockers [Hensch, G. Cardiovascular Res., 26, 14, 1992; Karin Pazyklenk, Robert A. Kloner. Cardiovascular Research, 26, 82, 1992], KATP openers [Allen W. Gomoll et al., J. Pharmacol.

Exp. Ther., 281, 24, 1997; Arthur A.M. Wilde, Cardiovascular Research, 35, 181, 1997] Na+/H exchange inhibitors [Worfgang Scholz et al., Cardiovas. Res., 29, 260, 1995], have been shown to promote myocardial salvage and enhance function recovery in vivo, only when given before or during ischemic episode. However, administration of these agents only during reperfusion does not result in cardioprotective activity (Grover, G.J. et al., Cardiovasc. Drugs Ther., 4, 465, 1990 Eur. J. Pharmacol., 191, 11, 1990; Mizumura, T. et al., Circulation, 92, 1236, 1995). Besides the use of antiischemic agents in prevention of ischemic/reperfusion injury, there is an unmet medical need for agents to treat post-ischemic reperfusion injury which may simulate the real clinical situation of myocardial infarction.

PRIOR ART Among a large number of the molecules incorporating arylpiperazines and showing antihypertensive activity, some relevent ones are thienopyrimidine-2,4-diones of formula I of the acccompanying drawings 1 (US Patent No. 4,670560, 1989), pyrazoles of formula II of the accompanying drawings- 1 (Arya, V.P.

et al., Experentia, 23, 514, 1967), tetrazoles of formula III of the accompanying drawings- 1 (Hayae, S. et al. J. Med. Chem., 400, 1967), prazocin analogs of formula IV of the accompanying drawings-l (Luther, R.R. et al., Am. Heart 117, 842, 1989; A~me's,'R.P. Kiyasu, J.Y. J. Clin. Pharmacol., 29, 123, 1989);~ 2- 13- (4-fluorophenyl)piperazin- 1-yllpropanesl -1,4-benzotlhiazini- 3(4H) -one of formula V of the accompanying drawings 1 (Kajine, M. et al., C'hem. Pharm. Bull., 39, 2885, 1991), uiracil (ifl.Lv;v tives of formula VI VII of the accompanying drawings I (Klmm, Von K. et al., Arznein. Forsch., 27, 1875, 1977), clhydropyridines of formula VIII of the acompanying drawings 1 (Suzuki, H. Saruta, T. Cardiovasc. Drug Rev., 7, 25, 1989; Kubo, K. and Karasawa, A. 10th Int. Cong. Pharmacol., 734, 1987; Drugs of the Future, 14, 291, 1989; Meguro, K. et al., Chemi. Pharm. Bull., 33, 3787, 1985; Nakaya, H. et al., Eur. J. Pharmacol., 146, 35, 1988; Kakihand, M. et al., Jpn. J. Pharmacol., 48, 223, 1988; Takenaka, T. et al., Arzneim. Forsch., 26, 2127, 1976; Kajimo, M. er al., Chein. Pharm. Bull., 37, 2225, 1989; Tricerri, S.Z. et al., UTS Pat.. 4,894,460, 1990 :C'hein. Abst., 113, 132218b, 1990), zolertine of formula IX of the accompaning drawings- 1 (Arya, V.P. et al., Experientia, 23, 514, 1967; Hayao, S. et al., J. Med. Chew., 400, 1967) thiepin derivatives of formula X of the accompanying drawings- 2 (Uno, H. et al., US Pat. 4, 749, 703, 1988), triazolylamine of formula XI of the accompanying drawings-i (Mayer, W.E. et al., J. Med. Chewn., 32, 593, 1989), aryloxypropanolamines of formula XTI of the accompanying drawings- 2 (Ing, H.R. Ormerod, J. Pharmn. Pharmacol., 4, 21, 1952; Petrow, V. et al., J. Pharm. Pharmacol., 8, 666, 1956; Moran, N.C. and Perkins, Pharinacol. Exp. Ther., 124, 223, 1958), *aryloxy/thioaryloxy arylpiperazinylpropanes of formula XIII of the accompanying drawings- 2 (Agarwal, S.K. et al., Indi. JT.

Chm., 21B, 435, 1982; I. J. Chewi., 21B, 914, 1982; luid. Ji.

Chem., 30B, 413, 1991; Rao, J. etal., Ind. J. Chem., 26B, 761, 1987; Saxena, A.K. etal., Ind. J. Chem., 32B, 1249, 1993), quinolyethanes of formula XIV of the accompanying drawings- 2 (Murti, A. et al., Ind. J. Chem., 28B, 934, 1989), trimetazidine of formula XV of the drawing 2 (Fujita, Y, Jpn. J. Pharmacol., 1 7 19, 1976), lidoflazine of formula XVI of the drawing 2 (Daenen, W. Flameng, Angiology, 32, 543, 1981), isoquinolylmethyl derivatives of formula XVII of the accompanying drawings-2 (Nakajiza, T. et al., Arzneim-Forsch., 37, 674, 1987), dihydropyridazinone derivative of formula XVIII of the accompanying drawings- 2 (Yao, F.M. etal., Yaaxue Xuebao, 28, 548, 1993), pyrroloquinoline 10 derivative of formula XIX of the accompanying drawings- 2 (Jasserand, D. et al., Ger. Offen. DE 4,128,015, 1993 Chem. Abst., 119, 139255f, 1993).

DETAILED DESCRIPTION OF THE INVENTION The invention is mainly centered around the following objects The first object of the invention is to provide a Process for preparing novel 15 molecules incorporating piperazine flanked on one side by aromatic system and on the other side by 2-(oxo-pyrrolidin-1-yl)propanes or 2-(oxopiperidin-1-yl) propanes that exhibit better therapeutic efficacy to treat hypertension over the existing antihypertensive agents.

(ii) The second object of the invention is to provide a process for preparing S 20 novel 1-(4-arylpiperazin-1-yl)-3-(2-oxopyrrolidin-1-yl)propanes and 1-(4-arylpiperazin-1-yl)-3-(2-oxopiperidin-1-yl)propanes exhibiting activity against ischemic reperfusion inljury for which there is no agent available till date I tle best of our knowledge.

(iii) The third object of the invention is to provide 1-(4arylpiperazin-l-yl)-3- (2-oxopyrrolidin-l-yl)propanes anld 1 (4arylpiperazin-l-yl)-3-(2-oxopiperidin-l-yl)propanes as therapeutic agents for the diseases arising out of alterations/impairment in central peripheral circulations and adrenergic receptors systems, such as myocardial ischemia, myocardial infarction (MI), angina pectoris, any cardiac surgical interventions renal ischemia, circulatory insufficiency in extremities, stroke and trauma.

This invention is concerned with novel pharmacologically active substances and relates to new 1-(4-arylpiperazin-l-yl)-3- (2oxopyrrolidin-1-yl)propanes and 1-(4-arylpiperazin-l-yl)-3-(2oxopiperidin-l-yl) propanes as potential therapeutic aget- for hypertension, ischemia, cardiovascular and other adrenergic receptors related disorders.

Accordingly, this invention provides a process for preparing compounds of the formula 1 which are used as potential theraputic agents for hypertension, ischemia, cardiovascular and other adrenergic receptors, related disorders, Wherein Ar represents a phenyl ring substituted by th (CH N-Ar Wherein Ar represents a phenyl ring substituted by the rrnips 8 like halo, alkoxy, alkyl or heteroaryl, n=l or n=2.

Therefore, the present invention provides a process for the syntheses of compounds of formula 1 which formula is shown above, wherein Ar represents a phenyl ring substituted with a halogen, alkoxy, alkyl or heteroaryl, n 1 or n 2, said process comprising condensing 2-pyrrolidone for formula 2 or 2piperidone of formula 2 with 1-[4-substituted arylpiperazin-l-yl]-3-chloropropanes of formula 5 where Ar represents a heteroaryl ring or a phenyl ring substituted by halogen, alkoxy, alkyl or heteroaryl in the presence of a base and organic solvent at a temperature ranging from 120-150 0 C for a period varying between 90 min. to 14 hrs. to produce the corresponding 1-[4-substituted arylpiperazin-l-yl]-3-[2- 15 oxopyrrolidin/piperidine-l-yl]propanes of formula 1 (formulae 1 to 5 are shown in scheme 1 of the accompanying drawings).

The preferred compound of formula 1 are shown herebelow: 1-[4-(3-chlorophenyl)piperazin-l-yl]-3-[2-oxopyrrolidin-lyl]propane.

20 1-[4-(4-chlorophenyl)piperazin-l-yl]-3-[2-oxopyrrolidin-lyl]propane.

S* 1-[4-(3-fluorophenyl)piperazin-l-yl]-3-[2-oxopyrrolidin-lyl]propane.

1-[4-(4-fluorophenyl)piperazin-l-yl]-3-[2-oxopyrrolidin-lyl]propane.

1-[4-(4-ethylphenyl)piperazin-l-yl]-3-[2-oxopyrrolidin-lyl]propane.

1-[4-(2-ethylphenyl)piperazin-l-yl]-3-[2-oxopyrrolidin-lyllpropane.

1- (4-chlorophenyl)piperazin-1-yl] [2-oxopiperidini-1yl] propane.

l-[4-(3-chlorophenyl)piperazin-1-yl] [2-oxopiperidin-iyl] propane.

1- (4-fluorophenyl)piperazin-1-yl] [2-oxopiperidini-lyl] propane.

l1 (2-ethylphenyll)piperazin-1-yl] 12-oxopiperidin-iyl] propane.

1- (2-methoxyphenyl)piperazin-1-yl] [2-oxopiperidin-lyl] propane.

l-[4-(2-pyridyl)piperazin-1-yi]-3-[2-oxopiperidin-lyl] propane.

(in) 1- (3-trifluoromethylphenyl)piperazin-1-yl] [2oxopiperidin-l-yl] propane.

In the specification and claims, the compounds with ni 1 designates 2-oxopyrrolidin-l-yl while with n 2, 2-oxopiperidinl-yl groups. Aryl designates a pyridyl or phenyl, or a phenyl group substituted by one or more alkyl, alkoxy or halogen groups.

A preferred group of compound comprises those in which n 1 or n 2, aryl group is 2 or 4-pyridyl, phenyl, or phenyl group substituted by alkyl groups like H, C 2

H

5

CF

3 alkoxy like methoxy, halo like chloro, fluoro etc. The compounds of this invention have useful biological activities and have inl particular strong antihypertensive and antiischemic activities.

DESCRIPTION OF PREFERRED EMBODIMENTS *.The general reaction sequence leading to 1-t[4-arylpiperazii-l- [2-oxopyrrolidin-l-yllpropanes or 1-[4-arylpiperazin-1-yl] 3-[2-oxopiperidin-l-yl]propanes is shown in scheme 1 of the accompanying drawings.

It will be noted that according to the foregoing schemes there are two general methods leading to the synthesis of 1. In the first general method the 2-pyrrolidone n 1) or 2piperidone n is condensed with l-bromo-3-chloroprop;ine in presence of bases selected from potassium tert. butoxide, pulvarised alkali metals selected from sodium or potassium in nonpolar solvents selected from benzene, xylene, toluene at a temperature ranging from 110 to 150 0 C for 1.15 to 14 hrs to give l-chloro-3- [2-oxo-pyrrolidin-1-yl]propane n 1) or l-chloro-3-[2-oxopiperidin-l-yl]propane n 2) which on condensation with appropriately substituted piperazines, gave the required compounds of formula 1. This reaction may be carried out in solvents selected from acetone, methylethyl ketone, tetrahydrofuran or dimethylformamide using bases selected from triethylamine, pyridine, sodium or potassium carbonate and catalysts selected from sodium/potassium iodide to improve the yield of the compounds of formula 1 and the said method is the subject matter of the copending US application number According to the method, the substituted piperazine was condensed with l-bromo-3-chloropropane in presence of bases selected from sodium or potassium carbonate and catalytic amounts of sodium or potassium iodide in solvents selected from DMF, toluene, xylene etc. at a temperature ranging from 70 to 1500C for 8 to 14 hrs to give 1-chlro-3-(4-substituted piperazin-ll)'propane which on condensation with 2-oxo-pyrrolidine or 2oxopiperidine in presence of bases selected from potassium tert.

butoxide or pulverised sodium or potassium in nonpolar :solvents selected from xylene, toluene at a temperature ranging from 110 to 150 0 C for 1.15 to 14 hrs yield the required compounds of formula 1.

The 1-[4-arylpiperazin-l-yl]-3-[2-oxopyrrolidin-l-yl]propanes (1 n=l) and 1-[4-arylpiperazin-l-yl]-3-[2-oxopiperidin-l-yl]propanes (1 n=2) in free form can, if desired be converted in to their non-toxic pharmaceutically acceptable acid addition and quaternary ammonium salts. Salts which may be formed comprise, for example, salts with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulphate and phosphate. They may also comprise salts with organic acids including mono basic acids such as acetate or propionate and especially those with hydroxy organic acids and dibasic acids such as the citrate, tartarate, malate and maleate. Among useful quaternary ammonium salts are those formed by such alkyl halides as methyl iodine and n-hexyl bromide.

The compounds of the invention show marked antihypertensive alpha-adrenergic blocking and antiischemic activities and can be used as therapeutic agents in diseases arising out of alterations/impairment in central peripheral circulations and adrenergic receptors systems, such as myocardial ischemia, myocardial infarction angina pectoris, any cardiac surgical interventions, renal ischemia, circulatory insufficiency in extremities, stroke and trauma as shown for instance by the a..

'-f6llowing data of the compound 1-[4-(4-fluorophenyl)piperazini-lyl] f2-oxopyrrolidin-l-yllpropane.

Pharmacological activity 1. Acute toxicity.

(LD

50 Mice 147.0 mg/kg i.p. 8S.3-253) 562.0 mg/kg p.o. 383-825) 2. Effect on blood pressure, heart rate and adrenaline vasopressor response of anaesthetized (pentobarbitone sodium 60 mg/kg i.p. in cat and rat respectively) normotensive &hypertensive rat cat model preparations.

Dose B.P. fall Dur. Heart rate Adrenaline No. of (uMol/kg (min.) Pre/post vasopressure exp.

treatment response inhibition

CAT

Naturally occuring hypertensive cat 16 110 195/195 49 n=4 22 >156.75 177/185 R 26 n=4 P ose B.P. fall Dur. Heart rate Adrenaline No. ot (uMol/k"g (min.) Pre/post vasopressure exp.

i~.)treatment respoiise (ii) Normotensive cat 22 85 200/170 26 n=4 21 >102.5 185/165 34.75 n=4 Dose B.P. fall Dur. Heart rate Adrenaline No. of (uP'o1/kg (min.) Pre/post vasopreSSure exp.

treatment response inhibition

RAT

Hypertensive rat model preparation 27 51 346/320 33 n=3 22 76 356/340 23 11=5 29 100 310/275 54 11=l (ii) Normotensive rat model preparation 2 i.v. 25 11 350/370 +7 R 22 n=2 i.v. 10 3 315/360 +14 R 28 n= i.v. 21 27.5 315/285 -9.5 R 42 n=2 i.d. Intraduodenal route; R=Reversal 3. Possible site and mechanism of action

SITE

Dose B.P. fall Dur.

(umol/kg 006) (mim.) Spinal transected cat 2-10 14-18 15-30 (ii) ICV 0.34-1.36 8-10 10-15 (iii) Rat hind limb perfusion **Total Percent change dose (ug) in flow no effect +35 (Vasodilatationi) +50 (Vasodilatatiol) (II) MECHANISM OF ACTION In vitro Isolated aortic strip: Endothelin induced contraction was inhibited significantly.

Even after washing the preparation endothelin caused relaxation rather than contraction.

(ii) Isolated Guinea pig ileum preparation endothelin relaxation rather than contraction.

Compound showed significant antihistaminic activity (0.5-5.0 ug/ml).

(iii) Langendorffs perfused rat heart preparation: Lower dose of this compound (1 ug) showed some negative chronotropic effect (30% for 10 min.) but higher doses ug) showed less negative chronotropic effect (26 5% for 14 5 min. respectively).

(iv) Konzett and Rossler preparation: Compound showed some antihistaminic activity against histamine induced bronchoconstriction.

Rat aortic ring preparation: NE induced contraction was inhibited by the compound.

In vivo Drug antagonism studies at 2 uMol dose i.v. in cat: Pretreatment with alphal-adrenergic receptor blocker, prazosin significantly reduced antihypertensive effect.

(ii) Pretreatment with Ca channel blocker, verapamil significantly reduced antihypertensive effect e o 6 (iii), Pretreatment with captopril (an ACE inhibitor) or Dup-753 (an angiotension II-receptor antagonist) also reduced the antihypertensive effect (iv) ATP sensitive potassium channel (KATP) blocker glibenclamide pretreatment only partially reduced the fall in blood pressure.

Pretreatment with, atropine sulphate, mepyramine maleate, propranolol, or yohimbine failed to alter the antihypertensive effect of this compound.

Comparative antihypertensive effect with clinically used antihypertensive drugs at 2 uMol/kg i.v. dose in cat Drug B.P. fall Dur.(Min.) Verapamil 55 22 (ii) Captopril 14 28 (iii) Compound 1 of 22 formmula 1, where Ar=C 6

H

4 n=l Cardioprotective activity The most interesting observation is its cardioprotective effect against myocardial stunning at a much smaller dose than antihypertensive dose. Further, in Langendorff perfused rat heart preparation subjected to even upto min. global ischemia, the compound at 0.001 ug/ml conc.

given at the time of reperfusion revived normal rhythmic contraction started within 2 min. (Table 1) and incidence of reperfusion induced arrhythmia were abolished.

Ta 16-1: Compound administered at the time of reperfusion at the dose of 0.001 ug/mi on prolong period (90 min.) of ischemic insult.

S.No. Compound Onset Percentage recovery (min.) 15 min. 3 0 mim.

1. Controla 3 0.5 1.

2. Compound 1 of 4 81.25 87.15 formmula 1, where Ar=C 6

H

4 n=1 3. Nifegipinea 2.5 0.66 0.0

M)

a Ischemic insult (45 min.) Comparable results for hypotensive/antihypertensive and antiischemic activities were obtained with a number of other compounds of formula 1 (Table 2 3).

Table 2: Effect on blood pressure, heart rate and adrenaline vasopressure response at anaesthetized (pentobar-bitone sodium 35 mg/kg cat.

Compound of Dose B.P. Dur. Adrenalinea formula 1 (umol/kg fall (min.) vasopressure Ar n oresponse inhibition

C

6

H

4 -4-F 1 2.0 25 71 9 10.0 31 >112 R

C

6

H

4 -2-C 2

H

5 1 2.0 13 10 Pt.

10.0 62

C

6 11 4 -3-Cl 1 2.0 25 20 Pt 10.0 55 >57-

C

6

H

4 -4-C 2

H

5 1 2.0 9 Tr- 10.0 20 14- Table 2 Contd a.

*aa.

a a. a. a a a a.

a. a a a a.

Compd.

Dose (unol /kq U i. B. P.

fall Dur.

(mil.) Adrenal Thea vasopressuxrinhibit ion

C

6

H

4 -3-F

C

6

H

4 -2 -OCH 3 2 -Pyridyl 2- Pyridyl

C

6

H

4 -4-Cl

C

6

H

4 -3-Cl

C

6

H

4 -3-CF 3

C

6

H

4 -2 -C 2 H 5

C

6

H

4 -4-F 1 2.0 .0 1 2.0 .0 1 2.0 10.0 2 2.0 10.0 2 2.0 .0 2 2.0 .0 2 .0 2 2.0 .0 2 2.0 10.0 3 19 67 16 43 53 >71 9 62 Tr 63 >84 0b 00 0 0 00 0000 *0 0 0* 00 0000 0000 0000 00 0000 0000 00 0 *0 0 00 0* 00 0 0 00 00 a R=Reversal; Pt=potentiation (was within I

I

Table 3: Compound administered at the time of reperfusioi at a dose of 0 .001 tiy/iuI on1 briel: period (1J6 in.) )I ischemic insult.

Compound of formula 1 Onset Percentage recovery Ar n (min.) 15 mim. 30 mini.

Control 2.0 104.50 118.10C1

C

6

H

4 -4-F 1 1.5 81.25 78.12

C

6

H

4 -2-C 2

H

5 1 3.0 106.06 136.36

C

6

H

4 -3-Cl 1 1.0 50.00 88.80

C

6

H

4 -4-C 2

H

5 1 2.0 103.03 60.60

C

6

H

4 -3-F 1 2.0 120.00 180.00

C

6

H

4 -3-C1 2 3.0 31.50 39.40

C

6

H

4 -2-OCH 3 1 2.0 45.40 59.09)

C

6

H

4 -4-Cl 1 1.0 87.50 120.80 2-Pyridyl 2 2.0 47.60 71.40 a Arrhythmia present The following examples are provided by the way of illustration of the present invention and should in noway be construed as a limitation thereof including the linker (propyl) between pyrro-'lidone/piperidone and N-arylpiperazine which may be ethyl or butyl.

Example 1 Preparation of 1-chloro-3- L 2 -oxopyrrolidin-1-yllpropane Wi A mixture of 2-pyrrolidone (1 g, 12.0 mmol) and finely pulverized sodium metal (0.28 g, 12.0 mmol) in dry xylene (60 mil) was heated at 1l0 0 C with vigrous stirring, 1 1.*ruo-3 cli ro.opn q, 12) n0 n i1) wan i llf-i t- I-h ii -ii d reaction mixture after 3 hours and the heating at 1100C was continued for 6 hours. The reaction mixture was filtered and xylene was removed under reduced pressure. The residue was distilled under reduced pressure to give 3 B.P. 145 0 C/1 mm., yield 1.52 g IR (Neat) 2980, 2880, 1710, 1460, 1420, 1280, 1050. 'H NMR (CDC3) 1.92-2.18 4H, 4' 2-CH 2 2.40 2H, J=6.0 Hz, 3'-CH 2 3.42 4H, J=6.0 Hz, 5' 3-CH 2 3.58 2H, J=6.0 Hz, 1-CH 2 MS: m/z 161 Mol. formula C7H 12 NOCI :Found C, 51.96; H, 7.48; N, 8.61 10 A xCalcd. C, 52.11; H, 7.45; N, 8.69%.

10 (ii) A mixture of 2-pyrrolidone (10 g, 120.0 mmol) and finely pulverized o sodium metal (2.76 g, 120.0 mmol) in dry xylene (600 ml) was heated at 1500C with vigrous stirring. 1-Bromo-3-chloropropane (18.84 g, 120.0 mmol) was added to the stirred reaction mixture after 30 minutes and the heating at 1500C was continued for 1 hour. The reaction mixture was filtered and xylene was 15 removed under reduced pressure. The residue was distilled under reduced pressure to give 3 B.P. 1450C/1 mm., yield 16.09 g (iii) A mixture of 2-pyrrolidone (2 g, 23.0 mmol) and finely pulverized sodium metal (0.529 g, 23.0 mmol) in dry toluene (120 ml) was heated at 1200C with .vigrous stirring. 1-Bromo-3-chloropropane (3.97 g, 25.0 mmol) was added to the stirred reaction mixture after 6-7 hours and the heating at 1200C was continued for 7 hours. The reaction mixture was filtered and toluene was removed under reduced pressure. The residue was distilled under reduced pressure to give the compound 3 B.P. 145°C/1 mm., yield 2.86 g S(iv) A mixture of 2-pyrrolidone (1 g, 12.0 mmol) and finely pulverized potassium metal (0.47 g, 12.0 mmol) in dry xylene ml) was heated at 150 0 C with vigrous stirring. 1-P.ronin-3chloropropane (1.8 g, 12 0 nunol) was added to thl ired reaction mixture after 20 minutes and the heating at 150 0 C was continued for 1 hour. The reaction mixture was filterr( and xylene was removed under reduced pressure. The residue was distilled under reduced pressure to give 3 B.P. 145 0 C/1 mm., yield 1.43 g A mixture of 2-pyrrolidone (1 g, 12.0 mmol) and potassium tert. butoxide (1.34 g, 12.0 mmol) in dry xylene (60 ml) was heated at 150 0 C with vigrous stirring. l-Bromo-3-chloropropane (1.8 g, 12.0 mmol) was added to the stirred reaction mixture after 2 hours and the heating at 150 0 C was continued for 3 hours.

The reaction mixture was filtered and xylene was removed under reduced pressure. The residue was distilled under r -ducl:ed pressure to give 3 B.P. 145 0 C/1 mm., yield 1.24 g Preparation of l-chloro-3-( 2 -oxopiperidin-l-yl)propane A mixture of 2-piperidone (1.19 g, 12.0 mmol) and finely pulverized sodium metal (0.28 g, 12.0 immol) in dry xylene (70 ml) was heated at 110 0 C with vigrous stirring, l-bromo-3-chloropropane (1.89 g, 12.0 mmol) was added to the stirred reaction mixture after 3 hours and the heating at 110 0 C was continued for 6 hours.

O The reaction mixture was filtered and xylene was removed under reduced pressure. The residue was chromatographed on silica gel using hexane and chloroform as eluant to get 3

B.P.

91 0 C/0.01 mm., yield 1.33 g IR (Neat) 3862, 3298, f*o 2 950, 2474, 2324, 1640, 1478, 1432, 1336, 1184, 1096, 754. -1HNMR (CDC1 3 1.79-2.36(m, 8H), 3.15-3'67(m, 6H) MS: m/z 175 Mol. formula C 8

H

14 N0C1 Found 54.90; H, 8.28; N, 82 Calcd.: C, 54.69; H, 8.03; N, Example 2 Preparation of 1- (3-chlorophenyl)piperazin-i-y11 (2oxopyrrolidin-1-yll propane of the formula 1, where Ar=C 6

H

4 -3-C1, n=1 A mixture of l-chloro-3-(2-oxopyrrolidini-l-yllpropan'e (1 c1, 6.2 mmol),, 1- 3 -chlorophenyl)piperazine (1.22 g, 6.2 mmol) anhydrous Na 2

CO

3 (0.33 g, 3.1 mmol) and Nal (0.093 g, 0.6 mmol) in dry DMF ml) was stirred at 70 0 C for 14 hrs. The reaction mixture-( was cooled, poured on water (20 ml) and the separated residue was extracted with CHC1 3 (2x25 ml) The extracts were dried over Na 2

SO

4 and concentrated under reduced pressure to give 1- (3cl1orophenyl)piperazin-l-yll [2-oxopyrrolidin-l--yl] rpai a~s an oil which was purified by flash column chromnatographiy over silica gel using chloroform as eluent, yield 1.50 g (757.) IR (Neat): 3020, 2820, 1660, 1590, 1450, 1210, 730. 1 H NMR (CDCl 3 fees l.30-2.60(m, 12H, 1 2xN-CH 2 2.40-3.50(m, 8H1, 3 .0 so 2xN-CH 2 6.40-7.20(m, 4H, ArH) MS: m/z 321 323 Mol. Formula C 17

H

24 C1N 3 0 :Found 63.58; H, 7.82; N, 11.17 C, 63.44; H, 7.52; N, 13.0)6%.

(b A mixtiire of 2 -py.-rol'I~doi e (I :12 iiiii.) Illd 1i rlo1y 00*0 0 pulverized sodium metal (0.28 g, 12.0 mnmol) in dry tolii'u- 5555a ml) was heated at 120*C with vigrous stirring for 6 houir-,, 1- [4- 3 -chlorophenyl)piperazin-l-y1] -3-chioropropane (3.26 C1, 12.0 "'mmol) was added to this reaction mixture and the reaction mixture was heated under stirring at 1200C for 7 hour. The rfeaction mixture was fi.ltered and toluene was removed under reduced pressure. The residue was chroinatographed over f lash !si i ,ei using chloroform as eluent to give the title product, yipeld 2.65 g oil.

A mixture of 1-chloro-3- [2-oxopyrrolidini-1-yllprpiiw g, 6.2 mmol), l-(3-chlorophen-yl)piperaziine (1.22 g, 6.2 mnmol), anhydrous Na 2

CO

3 (0.33 g, 3.1 mmol) and Nal (0.093 g, 0.6 minol) in dry toluene (10 ml) was stirred at 1100C2 for 12 hirs. The solvent was removed at reduced pressure and residue was poured onl water (20 ml) The separated residue was extracte(l with ethylacetate (3x20 ml), dried over Na 2

SO

4 and concentrated under reduced pressure to give 1-14- (3-chlorophenyl)piperazini-l-yl] -3- 2 -oxopyrrolidin-1-yll propane as an oil which was purified by flash column chromatography over silica gel usingchnrin a eluent, yield 0.60 g A mixture of l-chloro-3- [2-oxopyrrolidinl1yllpropliiip (1 q, 6 mmo1),1l3-cli rpi y )p ieraziie 1 .22 g Iu 1ol aifhydrnus Na 9

C(O

3 (0 .33 q, 31. 1 mimni azid Na)T (0 .003l 0 6 miw in dry xylene (15 mul) was stirred at 1500C2 tor 14 solvent was removed at reduced pressure and residue was potured onl water (30 ml) The separated residue was extracted with dichloromethane (2x25 ml) dried over Na 2

SO

4 and concentrated to give 1- (3-chlorophenyl)piperazin-l-yl] [2-oxopyrrolidini-lyllpropane as an oil which was purified by flash column chromatography over silica gel using chloroform as eluent, yield 0.72 g (361).

Example 3 Preparation of 1-[4-(4-chlorophenyl)piperazin-1-yl]-3-[ 2 oxopyrrolidin-1-yl]propane of the formula 1, where Ar=C 6

H

4 -4-CI, n=1 A mixture of 1-chloro-3-[2-oxopyrrolidin-1-yl]propane(1 g, 6.2 mmol), 1-(4chlorophenyl)piperazine(1.22 g, 6.2 mmol) anhydrous Na 2

CO

3 (0.33 g, 3.1 mmol) and Nal (0.09 g, 0.6 mmol) in dry DMF (5 ml) was stirred at 700C for 12 hrs. The reaction mixture was cooled, poured on water (20 ml) and the separated residue was extracted with CHCI 3 (2x25 ml). The extracts were dried 10 over Na 2

SO

4 and concentrated under reduced pressure to give i chlorophenyl)piperazin-1-yl)-3-[2-oxopyrrolidin-1-yl]propane which was purified by flash column chromatography over silica gel using chloroform as eluent, yield 1.48 g M.P. 78-80 0 C. IR (KBr) 3440, 2820, 1660, 1490, 1230, 1130, 810. 'H NMR (CDCI 3 1.50-2.80 12H, 2, 1 2xN-CH 2 3.00-3.60 (m, 15 8H, 3 2xN-CH 2 6.80 2H, J=9.0 Hz, ArH, o to CI), 7.20 2H, J=9.0 Hz, S ArH, m to Cl). MS: m/z 321 (M 323 Mol. formula C 17

H

24

CIN

3 0 Found C, 63.84; H, 7.32; N, 13.12 Calcd. C, 63.44; H, 7.52; N, 13.06%.

A mixture of 2-pyrrolidone (1 g, 12 mmol) and finely pulverized sodium metal (0.28 g, 12.0 mmol) in dry xylene (60 ml) was heated at 1400C with vigrous stirring, 1-[4-(4-chlorophenyl)piperazin-1-yl)-3-chloropropane (3.26 g, 12.0 mmol) was added to the stirred reaction mixture after 30 minutes and the heating at 1400C was continued for 1 hour. The reaction mixture was filtered and xylene was removed under reduced 'pressure to give 3 which was purified by flash column chromatography over silica gel using chloroform as eluent, yield 2.83 g M.P. 78-80 0

C.

A mixture of 2-pyrrolidone (1 g, 12 mmol) and f inply pulverized potassium metal (0.47 g, 12.0 mmol) in dry xylene ml) was heated at 150 0 C with vigrous stirring, chlorophenyl)piperazin-l-yl]-3-chloropropane (3.26 g, 12. mminol.) was added to the stirred reaction mixture after 20 minutes and the heating at 150 0 C was continued for 1 hour. The reaction mixture was filtered and xylene was removed under reduced pressure to give 3 which was purified by flash column chromatography over silica gel usiigi chloroform as eluielit y-i~-lId 2.78 g M.P. 78-80 0

C.

A mixture of 2-pyrrolidone (1 g, 12 mmol) and finely pulverized potassium tert. butoxide (1.34 g, 12.0 mmol) in dry xylene (60 ml) was heated at 150 0 C with vigrous stirring, 1-[4- 4 -chlorophenyl)piperazin-l-yl] -3-chloropropane (3.26 g, 12.0 e mmol) was added to the stirred reaction mixture after 2 hours and the heating at 150 0 C was continued for 4 hour. The reaction mixture was filtered and xylene was removed under reduced pressure to give 3 which was purified by flash collumn chromatography over silica gel using chloroform as eluent, yield 2.46 g M.P. 78-80 0

C.

Example 4 Preparation of 1-[ 4 3 -fluorophenyl)piperazin-l-yl]-3- [2oxopyrrolidin-1-yl]propane of the formula 1, where Ar=C 6

H

4 n=1 3-F, n=l 11 A mixture of l-chloro-3-[2-oxopyrrolidin-l-yllpropanie (1 9, 6.2 mmol) 1-(3-fluorophenyl)piperazine 12 g, 6.2 iimcn) anhydrous K 2 C0 3 (0.434 g, 3.1 mmol) and KI (0.10 g, 0.6 mmol) in dry DMF (5 ml) was stirred at 901C for 12 hrs. The ]:e;ict-.ion mixture was cooled, poured on water (25 ml) and the separa.:ted residue was extracted with CHC1 3 (2x25 ml) The extracts were dried over Na 2

SO

4 and concentrated under reduced pressure to give 1-14- (3-fluorophenyl)piperazi---yl] -3-[12-oxopyrrolidin--lyllpropane as an oil which was purified by flash column chromatography over silica gel using chloroform as eluent, yield 1.32 g (69.60-) IR (Neat): 2920, 2800, 1650, 1440, 1240, 1150, 740. 1 H NMR (CDCl 3 1.50-.2.70(m, 12H, 2, 1 2xN-CH 2 3.00-3.60(m, 8H, 3 &2xN-CH 2 6.30-6.80(m, 4H, ArH) MS: m/z 305 307 Mol. formula C 17

H

24

FN

3 0 Found 67.22; H, 7.72; N, 13.97 Calcd.: C, 66.88; H, 7.92; N, 1-1.7E A mixture of 2-pyrrolidone (1 g, 12 mmol) and finely pulverized sodium metal (0.28 g, 12.0 mmol) in dry xylene m1l) was heated at 150 0 C with vigrous stirring, 1[-3 fluorophenyl)piperazin-l-yl] -3-chloropropane (3.07 g, 12.0( mmol) was added to the stirred reaction mixture and the heating at 150 0 C was continued for 1 hour. Ther producrt was obtainei=d by the similar method as in example 3, yield 2.94 g (8216), oil.

Example Preparation of l-[ 4 -(4-fluorophenyl)piperazin-1-yl] oxopyrrolidin-1-yllpropane of the formula 1, where Ar=C 6

H

4 4-F, n=l a a

S*

A mixture of 1-chloro-3-[2-oxopyrrolidin-1-yl]propane (4 g, 25.0 mmol), 1-(4fluorophenyl)piperazine (4.47 g, 25.0 mmol), anhydrous Na 2

CO

3 (1.325 g, 12.5 mmol) and Nal (0.38 g, 2.5 mmol) in dry DMF (20 ml), was stirred at 1200C for 8 hrs. The reaction mixture was cooled, poured on water (30 ml) and the separated residue was extracted with CHCI 3 (2x30 ml). The extracts were dried over Na 2

SO

4 and concentrated under reduced pressure to give fluorophenyl)piperazin-1-yl]-3-[2-oxopyrrolidin-1-yl]propane as an oil which was purified by flash column chromatography over silica gel using chloroform as eluent, yield 5.72 g IR (Neat) 2920, 2820, 1660, 1500, 1250, 730. 1

H

10 NMR (CDC13) 1.50-2.80 12H, 2, 1 2xN-CH 2 3.00-3.60 8H, 3 2xN-CH 2 6.70-7.10 4H, ArH). MS m/z 305 Mol. formula C1 7

H

24

FN

3 0 Found C, 66.55; H, 8.07; N, 13.69 Calcd. C, 66.86; H, 7.92; N, 13.76%.

A mixture of 2-pyrrolidone (3 g, 35 mmol) and finely pulverized sodium 15 metal (0.81 g, 35.0 mmol) in dry xylene (180 ml) was heated at 1500C with vigrous stirring, 1-[4-(4-fluorophenyl)piperazin-1-yl]-3-chloropropane (8.96 g, 35.0 mmol) was added to the stirred reaction mixture after 30 minutes and the heating at 1500C was continued for 1 hour. The reaction mixture was filtered and xylene was removed under reduced pressure to give 3 which was purified by flash column chromatography over silica gel using chloroform as eluent, yield 9.15 g oil.

Example 6 Preparation of 1- (4-ethylphenyl)piperazin-l-y1] [2oxopyrrolidin-l-yll propane of the formula 1, where Ar=C 6

H

4 4-C 2

H

5 n=1 A mixture of l-chloro-3- [2-oxopyrrolidiin-l-yljpropanie (2.0 g, 12.0 mmol), l-(4-ethylphenyl)piperazine (2.36 g, 12.0 mmol), anhydrous Na 2

CO

3 (0.658 g, 6.2 mmol) and NaT (0.18 g, 1.2 mmol) in dry DMF (10 ml) was stirred at 80 0 C for 12 hrs. The reaction mixture was cooled, poured on water (30 ml) and the separated residue was extracted with CHC1 3 (2X30m1) The extracts were dried over Na 2 So 4 and concentrated under reduced pressure to give 1- (4-ethylphenyl)piperazin-l-yl] -3-[12-oxopyrrolidin-l-yl] propane as an oil which was purified by flash column chromnatography over silica gel using chloroform as eluent, yield 2.43 g IrR (Neat) :2940, 2800, 1660, 1440, 1000, 900, 800. 1H NMR (CDC1 3 1.20(t, 3H, J=6.0 Hz, CH 2

CH

3 1.60-2.80(m, 14H, 3',41,2,1 2xN-CH 2

CH

2

CH

3 3 .00-3.60 8H, 5' 3 2xN-CH 2 V. MS: m/z 315

(M)

Niol. formula C 19

H

2 9

N

3 0 :Found 71.94; H, 9.16; N, 13.1.5 .:Calcd.: C, 72.34; H, 9.27; N, 13.32%.

A mixture of 2-pyrrolidone (2 g, 24 mmol) and finely V pulverized sodium metal (0.56 g, 24.0 tumol) in dry xyriif' (1-20 ml) was heated at 150 0 C with vigrous stirring, ethylphenyl)piperazin-1-yl] -3-chloropropane (6.38 g, 24.0 inmol) was added to the stirred reaction mixture after 30 minutes and the heating at 150 0 C was continued for 1 hour. The prondi'I- was obtained by the similar method as in example-3, yield G.42 g oil.

Example 7 Preparation of 1- (2-ethylphenyl)piperazin-1-ylJ [2oxopyrrolidin-l-yll propane of the formula 1, where Ar=C 6

H

4 2-C 2

H

5 n=1 A mixture of 1-chloro-3- [2-oxopyrrolidin-l-yll propane (2.0 g, 12.0 mmol) l-(2-ethylphenyl)piperazine (2.36 g, 12. 0 mmol), anhydrous Na 2

CO

3 (0.658 g, 6.2 mmol) and Nal (0.18 g, 1.2 mmol) in dry DMF (10 ml) was stirred at 80 0 C for 12 hrs. The re'action mixture was cooled, poured on water (30 ml) and the separated residue was extracted with CHC1 3 (2X20ml) The extracts were dried over Na 2 So 4 and concentrated under reduced pressure give 1-[4-(4-ethylphenyl)piperazin-1-yl]-3-[2-oxopyrrolidin-1-yl] propane as-an oil which was purified by flash column chromatography over silica gel using chloroform as eluent, yield '2.17 g (60.00-) IR (Neat): 2940, 2820, 1660, 1430, 1010, 900, 800. 1H NMR (CDCl 3 1.24(t, 3H, J=6 Hz, CH 2

-CH

3 1.68-1.85(111, 2H, 4'- CH 2 1. 9 8 -2.10(m, 2 H, 2 CH 2 2 .3 4 -2 50(m, 4 H, 3'1 I CH 2 2. 62 4H, 2xN-CH 2 2. 68 q, 2H, Lii 3 2 2. 94 4H, J=6. 0 Hz, 2xN-CH 2 2.35(t, 2H, J=6.0 Hz, 3-CH 2 3.42(t, 2H, J=6.0 Hz,

-CH

2 7.00-7.28(m, 4H, Ar-H). MS: m/z 315 V Mol. formula C 19

H

29 N30 :Found 72.64; H, 9.11; N, 13.64 Calcd.: C, 72.34; H, 9.27; N, 13.329- A mixture of 2-pyrrolidone (1 g, 12 mmcl) and finely pulverized sodium metal (0.28 g, 12.0 mmol) in dry xylene (60 ml) was heated at 150 0 C with vigrous stirring, 'ethylphenyl)piperazin-1-yl]-3-chloropropane (3.19 g, 12.0 nmiol) was added to the stirred reaction mixture after 30 minutes and the heating at 150 0 C was continued for 1 hour. The product was obtained by the similar method as in example-3, yield 3.13 g oil.

Example 8 Preparation of 1-[4-(4-chlorophenyl)piperazin-l-yl]-3- [2oxopiperidin-1-yl]propane of the formula 1, where Ar=C 6 11 4 -4- Cl, n=2 A mixture of 2-piperidone (1 g, 10 mmol) and finely pulverized sodium metal (0.23 g, 10 mmol) in dry xylene (60 ml) wa-, heated at 140 0 C with vigrous stirring, 1-[4-(4-chlorophenyl)piperazin-lyl]-3-chloropropane (2.72 g, 10 mmol) was added to the stirred reaction mixture after 30 minutes and the heating at 140 0 C was continued for 1 hour. The reaction mixture was filtered and xylene was removed under reduced pressure to give 3 which was purified by flash column. chromatography over silica gel using chloroform as eluant, yield 2.54 g m.p. 106 0 C. IR (Neat): 3761, 3408, 3017, 2957, 2882, 2826, 2785, 2502, 1659, 1599, 1499, 1456, 1385, 1346, 1219, 1148, 1105, 760, 667. PMR (CDC 3 0.89- 1.80(m, 6H, 2-CH 2 2.33-2.65(m, 8H, 3',1 2xN-:H.) 3.15-3.62(m, 8H, 6',3 2xN-CH 2 6.81-7.00(2xdd, 4xArH). MS: m/z 337 (M+2) Mol. formula C 18

H

26

N

3 0CI Found C, 64.23; H, 7.87; N, 12.24 Calcd.: C, 64.37; H, 7.80; N, 1 2.51%.

A mixture of 2-piperidone (1.0 g, 10 mmol) and finely pulverized potassium tert. butoxide (1.12 g, 10 mmol) in dry xylene (60 ml) was heated at 150 0 C with vigrous stirring, 1-[4- (4-chlorophenyl)piperazin-1-yl]-3-chloropropane (2.72 g, 10 mmol) was added to the stirred reaction mixture after 2 hours and the heating at 150 0 C was continued for 4-hour. The reaction mixture was filtered and xylene was removed under reduced presiure to give 3 which was purified by flash column chromatography ove'r sili'ca gel using chloroform as eluant, yield 2.17 g m.p.

106 0

C.

Example 9 Preparation of 1-[4-(3-chlorophenyl)piperazin-1-yl]-3-[2oxopiperidin-1-yl]propane of the formula 1, where Ar=C 6

H

4 -3-Cl, n=2 A mixture of 2-piperidone (1.0 g, 10 mmol) and finely pulverized sodium metal (0.23 g, 10 mmol) in dry toluene (60 ml) was heated at 120 0 C with vigrous stirring for 6 hours, chlorophenyl)piperazin-1-yl]-3-chloropropane (2.72 g, 10 mmol) was added to this reaction mixture and the reaction mixture was 4 heated under stirring at 120 0 C for 7 hour. The reaction mixture was filtered and toluene was removed under reduced pressure. The 'residue was chromatographed over flash silica gel usinq r)clornform as eluant to give 3, yield 2.59 g oil. IR (Neat): 3406, 2951, 2878, 1626, 1597, 1491, 1454, 1383, 1352, 1219, 1142, S1103. 1 H NMR (CDC 3 1.17-1.84(m, 6H, 2, 4' 5'-CH2) 2.27- S2.65(m, 8H, 1, 3' 2xN-CH 2 3.15-3.37(m, 8H, 3 2xN-CH 2 6.68-6.79(dd, 2xArH), 7.05-7.11(t, IxArH), 7.19(s, IxArH) MS: m/z 335 Mol. formula C 18

H

2 6

N

3 0C1 Found C, 64.17; H, 7.92; N, 12.21 Calcd.: C, 64.37; H, 7.80; N, 12.51%.

Example Preparation of l-[ 4 -(4-fluorophenyl)piperazin-1-yi] [2oxopiperidin-1-yll propane of the formula 1, where Ar=C 6

H

4

F,

n=2 A mixttiure of 2-iprdw (2 20) miwi.) riiid fiinrKI.y il i sodium metal (0.46 g, 20 mmol) in dry xylene (120 ml) was heated at l50 0 C with vigrous stirring, 1-14- (4-fluorophenlyl)piperazi:ii-1yll-3-chloropropane (5.17 g, 20 mmol) was added to the stirred reaction mixture after 30 minutes out the heating at 15011C was continued for 1 hour. The reaction mixture was filterp-d and xylene was removed under reduced pressure to give 3 which was purified by flash column chromatography over silica gel using chloroform as eluant, yield 4.64 g (721) oil. IR (Neat) :3408, 3014, 2931, 2880, 2825, 1626, 1508, 1458, 1219, 824, 760, 667. 'H NMR (CDCl 3 l .72-1.86(m, 6H, 5' 2-CH 2 2.37-2.69(m, 8H, 1 2xN-CH 2 3.12-3.46(m1, 8H, 3 &2xN-CH 2 6.83- 7.00(2xdd, 4xArH) MS: 319 Mol. formula C 1 9

H

2 6

N

3 0F Found 71.23; H, 8.26; N, 12.95 V Calcd.: C, 71.47; H, 8.15; N, 13.170%,.

A mixture of l-chloro-3- 2 -oxopiperidin-l-yllpropaile (2.1 g, 12 mmol), l-(4-fluorophenyl)piperazine (2.16 g, 12 mmol), anhydrous Na 2

CO

3 (0.618 g, 6.2 mmol) and Na (0.18 g, 1.2 mmol) in dry DMF (10 ml) was stirred at 80 0 C for 14 hrs. The reaction mixture was cooled, poured on water (30 ml) and the separated residue was extracted with CHC1 3 (2x35 ml) The extracts were dried over Na 2 O and concentrated under reduced pressure to give 4 -fluorophenyl)piperazin-iliyl]-3-[2-oxopiperidini-lyl]propane as an oil which was purified by column chromatography over silica gel using chloroform as eluent, yield 2.40 g Example 11 Preparation of 1- (2-ethylphenyll)piperazin-i-yiJ [2oxopiperidin-1-yllpropane of the formula 1, where Ar=C 6

H

4 -2-C 2

H

5 n=2 A mixture of 2-piperidone 1.0 g, 10 mmol) and finely pulverized sodium metal (0.23 g, 10 mmol) in dry xylene (60 ml) was hieated at 150 0 C with vigrous stirring, 1- [14- (2-ethylphenyl)piperazin-lyl clloropropaxie (2 .66 yj, 10 minol) was added to tLicr 1:i,:c reaction mixture after 30 minutes and the heating at 150 0 C was continued for 1 hour. The reaction mixture was filtered and xylene was removed under reduced pressure to give 3 which was purified by flash column chromatography on silica gel using chloroform as eluant, yield 2.49 g oil. IR (Neat) :3680, 3440, 3000, 2960, 2870, 2820, 1620, 1490, 1450, 1350, 121-0, 1140, 1005, 920, 725. HNMR (CDCl) 1.00(t, 3H, CH 2 CH) 1 .20-1.90(m, 6H, 5' 2-CH 2 2.20-3.50(m, 18H, 3, 1 4xN-CH 2 CHCH.) 7.00-7.20(m, 4H, ArH) MS: m/z 329 Mol. formula C 20

H

3 1

N

3 0 Found 72.67; H, 9.60; N, 12.49 Calcd.: C, 72.95; H, 9.42; N, -12-77'k.

Example 12 Preparation of 1- (2-methoxyphenyl)piperazin-1-yl] [2oxopiperidin-l-yllpropane of the formula 1, where Ar=C6H5-2-oc11 3 n=2 A mixture of 2-piperidone 1.0 g, 10 mmol) and finely pulverized :potassium metal (0.40 g, 10 mmol) in dry xylene (60 ml) was heated at 150 0 C with vigrous stirring, (2methoxyphenyl)piperazin-1-yl]-3-chloropropane (2.52 g, 10 mmol) was added to the stirred reaction mixture after 20 minutes and the heating at 1500C was continued for 1 hour. The reaction mixture was filtered and xylene was removed under reduced pressure to give 3 which was purified by flash column chromatography over silica gel using chloroform as eluant, yield 2.41 g oil. IR (Neat) 2945, 1626, 1500, 1460, 1242, 908, 735, 648. PMR (CDCI 3 1.69-1.84 6H, 5' 2-CH 2 2.26-2.70 8H, 1 2xN-CH 2 3.07-3.36 8H, 3 2xN-CH 2 3.75 3H, OCH 3 6.76-6.95 4H, ArH). MS m/z 331 10 Mol. formula C 1 9

H

29 N30 2 Found C, 68.61; H, 8.92; N, 12.56 Calcd. C, 68.85; H, 8.81; N, 12.68%.

Example 13 Preparation of 1-[4-(2-pyridyl)piperazin-1-yl]-3-[2-oxopiperidin-1-yl] propane of the formula 1, where Ar=2-pyridyl, n=2 15 A mixture of 2-piperidone (2 g, 20 mmol) and finely pulverized sodium metal (0.46 g, 20 mmol) in dry xylene (120 ml) was heated at 1500C with vigrous stirring, 1-[4-(2-pyridyl)piperazin-1-yl]-3-chloropropane (4.78 g, 20 mmol) was added to the reaction mixture after 30 minutes and the heating at 1500C was continued for 1 hour. The reaction mixture was filtered and xylene was removed 20 under reduced pressure to give 3 which was purified by flash column chromatography over silica gel using chloroform as eluant, yield 4.39 g oil. IR (Neat) 3420, 2940, 2800, 1629, 1580, 1470, 1420, 1230, 1150, 1125, 960, 720. 1 H NMR (CDCI 3 1.50-2.20 6H, 5' 2-CH 2 2.25-2.80 8H, 3',1 2xN-CH 2 3.10-4.80 8H, 3 2xN-CH 2 6.48-6.75 2H, pyridyl 7.40 1H, 4-pyridyl 8.15 1H, 6-pyridyl m/z 302 Mol. formula C 17

H

2 6

N

4 0 :Found 67.32; H, 8.49; N, 18.38 Calcd.: C, 67.52; H, 8.67; N, 18.51,%.

Example 14 Preparation of 1- (3-trifluoromethylphenyl)piperazin..ylj -3- (2 -oxopiperidin-1-yll propane of the formula 1, where Ar=C 6

H

4 -3-

CF

3 n=2 A mixture of 2-piperidone (1.0 g, 10 mmol) and finely fulverized sodium metal (0.23 g, 10 mmol) in dry xylene (60 ml) was hieated :at 50 C with vigorous stirring, l-[4-(3-CF 3 -phenyl)piperazin-iyl]-73-chloropropane (3.06 9, 10 mmol) was added to tlie stirred reaction mixture after 30 minutes and the heating at 15(C was continued for 1 hour. The reaction mixture was filtered and xylene was furnished by flush column chromatography on silica gel using CHC1 3 a s eluant, yield 2.80 g oil. IR (Neat): 3402, 3015, 2951, 2880, 2827, 2785, 1622, 1449, 1450, 1352, 1315, 1217, 1167, 1126, 1076, 997, 951. 1 H NMR (CDCl 3 1.75-1.93(m, 6H, 4', 2-CH 2 2.35-2.75(m, 8H, 31,1 2xN-CH 2 3.310-3.84(m, 8H, 2 2) 3 2xN-CH 2 7.04-7.10(dd, 2H, 4, 6-ArH), 7.26(s, H, 2-ArH), 7.32-7.37(t, H, 5-ArH) MS: mi/z 369 .:Mol. formula C 19

H

6

N

3

OF

3 Found 61.48; H, 7.23; N, 11.21 19 2 3 3 Calcd.: C, 61.79; H, 7.05; N, 11.38%-.

Example *Antihypertensive/hypotensive activity Cats (2.6-4.0 kg) of either sex anaesthetized with pentobarbitone sodium (40 mg/k<g and showing baf-ai mean *arterial blood pressure below 150 mm (Hg) were catejo-rised :as normotensive and above 150 mm Hg as hypertensive.

Arterial blood pressure (BP) was recorded from one W:t the carotid artery through a stathum P23 DC pressure transducer and 7P1 low level DC preamplifier on a Crass Mod:,1 ?7 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 ug) hi:stamine (1-2 ug) and isoprenaline (1-2 ug) were taken before and after the administration of test doses of each compoundl(s.

All the compounds were tested at fixed doses of 2.0 and uM/kg i.v. Significant results are given in Table 2.

Antihypertensive activity was observed in naturally hypertensive cats, rat abdominal aorta coarctation model of hypertension (Liu, J; Bishop, S.P. Overbeck, H.W.

M).1phlom etric evi dnc-n for 1111 prnsuire re latd nrt-nri ;I I w; ll thickening in hypertension Circ. Res. 62, 1001-1010, 1988) and L-NAME (No synthase inhibitor) induced hypertensive cats.

Example 16 Cardioprotective/antiischemic activity The rats were killed by decaptitation, heart were rapidly ec:<is.ed 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, CaCl 2 1.8, MgCl 2 1.0, glucose 11.2 and HEPES The buffer (pH 7.4) was continuously gassed with oxy and 3.0. The buffer (pH 7.4) was continuously gassed with oxyqen and "maiiltained at 37 0 C. Coronary- flow rate was maintained at mi/miiji. The heart contracted spontaneously.

The perfused heart was allowed to equilibrate for 30 mini. floforeinitiation of any insult protocol.. The test comj~ouidsw~ q.i vl at the time of reperfusion. Some of the compounds were dissolved in ethanol. Final concentration of ethanol in the perfusion buffer was 0.00011 and had no effect of its own on the parameter used.

For brief period of ischemic insult (Hideo P r al.

Pathophysiology and pathogenesis of stunned myocardiuim. Ji.

Clin. Invest., 79, 950-961, 1987). Ischemia was initiated by stopping the flow for 16 min. followed by 30 miii.

reperfusion period. The durations were decided on the initial pilot experiments leading to 50% recovery of function.

For prolong period of ischeinic insult (Becker, L.C. Ambrosia, G. Myocardial consenquences of reperfusion. Ping..

Cardiovas. Dis., 30, 23-44, 1987). Ischemia was initiated by sto:pping the flow for 30 mmn. followed by 30 mUin.reii If.

0* a.

a a a a a a. a a.

a.

a. a a.

a.

Claims (4)

1. A process for the synthesis of compounds of formula 1 N O (CH 2 3 -N N-Ar 1 wherein Ar represents a phenyl ring substituted by halogen, alkoxy, alkyl or heteroaryl, n 1 or n 2; said compounds are used as potential therapeutic agents for hypertension, ischemic, cardiovascular and other .adrenergic receptors related disorders, said process comprising condensing 2- I* pyrrolidone of formula 2 or 2-piperidone of formula 2 with 1-[4-substituted arylpiperazin-l-yl]-3- choloropropanes of formula 5 where Ar represents a phenyl ring substituted by halogen, alkoxy, alkyl or heteroaryl in S the presence of a base and organic solvent at a temperature ranging from 120-150 0 C for a period varying between 90 min. to 14 hrs. to produce the corresponding 1-[4-substituted arylpiperazin-l-yl]-3-[2-oxopyrrolidin/piperidine-l- yl]propanes of formula 1.

2. A process as claimed in claim 1 wherein the preferred compounds are defined here below 1-[4-(3-chlorophenyl)piperazin-l-yl]-3-[2- oxopyrrolidin-1-yl]propane. 1- (4-chlorophenyl)piperazin-1-yl3 [2- oxopyrrolidin-1-yl] propane. 1-[4-(3-fluorophenyl)piperazin-1-yl]-3-[2- oxopyrrolidin-1-yl] propane. 1- [4-(4-fluoropheny1)piperazin-21-y1]-3- [2- oxopyrrol idin- 1-yl Ipropane. 1- (4-ethylphenyl)piperazin-1-yl] [2-oxopyrrolidin- 1-yl] propane. 1- (2-ethylphenyl)piperazin-1-yl] [2-oxopyrrolidin- 1-yllpropane. 1- (4-chlorophenyl)piperazin-1-yl] [2-oxopiperidin- 1-yllpropane. 1- (3-chlorophenyl)piperazin-1-yl] [2-oxopiperidin -1-yl] propane. 1- (4-fluorophenyl)piperazin-1-yl] [2-oxopiperidin 1-ylpropane. 1- (2-methoylphenyl)piperazin-1-yl -3-[2-xpprdn 1-yl] di1ylpropane. 1- (2-pyridyl)piperazin-1-yl] [2-oxopiperidin-1- yl] propane. (in) 1- (3-trifluoromethylphenyl)piperazin-1-y11 [2- oxopiperidin-1-yll propane. 39

3. A process as claimed in claim 1 wherein the molar ratio of the compounds of formula 2 and 5 is 1:1.

4. A process as claimed in claim 1 wherein the solvent used is selected from toluene or xylene and the amount of the solvent used ranges from 5 to 6 ml per mmol of the reacting compounds of formula 2 and A process as claimed in claim 1 where atomic/molar ratio of the base sodium/potassium metal or potassium tert. butoxide to the compounds of formula 2 and 5 is 1:1. DATED this 17th day of March 2003 COUNCIL OF SCIENTIFIC INDUSTRIAL RESEARCH WATERMARK PATENT TRADE MARK ATTORNEYS 290 BURWOOD ROAD *HAWTHORN VICTORIA 3122 AUSTRALIA P13717AU00 KJS/BJD/SLB •co