AU755526B2 - 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, a process for preparing such compounds and a method of treating above diseases using the compounds - Google Patents

Description

'/UU/U1 285/91 Regulation 3.2(2)

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT Application Number: Lodged: Invention Title: 1-[4-ARYLPIPERAZIN-1 -YL]-3 -[2-OXOPYRROLIDIN/PIP ERIDIN-1 -YL] PROPANES USED AS POTENTIAL THERAPEUTIC AGENTS FOR HYPERTENSION, ISCHEMIA, CARDIOVASCULAR AND OTHER ADRENERGIC RECEPTORS REALTED DISORDERS, A PROCESS FOR PREPARING SUCH COMPOUNDS AND A METHOD OF TREATING ABOVE DISEASES USING THE

COMPOUNDS

S.

o ee The following statement is a full description of this invention, including the best method of performing it known to us FIELD OF INVENTION The present invention relates to new 1- [4-Arylpiperazin-l-yl] [2oxopyrrolidin-l-yl]propanes and 1- [4-Arylpiperazin-l-yl]-3-[2-oxopiperidin-l-yl]propanes which can be used as therapeutic agents for hypertension, ischemia, cardiovascular and other adrenergic receptors related disorders, and a process for preparing said novel compounds. More, particularly the present invention relates to 1-[4- Arylpiperazin-l-yl]-3-[2-oxopyrrolidin-l-yl]propanes and 1-[4-Arylpiperazin-l-yl]-3-[2-oxopiperidin-1-yl]propanes, processes for preparing the said compounds and to their use in medicine.

Accordingly, the present invention-provides compounds of formula 1. f N

O

(CH

2 3 -N N-Ar ii Wherein Ar represents a phenyl ring substituted by the groups like halo, alkoxy, alkyl or heteroaryl and n 1 or n 2.

The compounds of the invention have shown to possess antihypertensive activity in different test models. The compounds also prevent post-ischemic reperfusion injury and may be useful in the treatment of hypertension, diseases arising out of I alterations/impairment in central peripheral circulationsi 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.

A method of preparation of the inventive compounds starts from the condensation of l-bromo-3-chloropropane with 2-pyrrolidone or 2-piperidone to give the key intermediate l-chloro-3-[2-oxopyrrolindin-l-yl]propanes of formula 3 or l-chloro-3-[2-oxopiperidin-l-y]propanes followed by its condensation with different 1-substituted piperazines of formula 4 to get the compounds of formula 1 (formulae 2 to 4 are shown in scheme 1 of the accompanying drawings).

Another method which is the subject matter of the copending US patent application number 08/954,516 is the process of which starts from the condensation of l-bromo-3chloropropane with different 1-substituted piperazines of 15 formula 4 to give the l-chloro-3-(4-substituted piperazin-loooo yl)propanes of formula 5 followed by their condensation with S.*i 2-pyrrolidone or 2-piperidone of formula 2 to get the compounds of formula 1.

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 useful in the method of the invention. The most preferred compound of the invention is 1-[4-(4-fluorophenyl)piperazin-l-yl]-3-[2-oxopyrrolidinl-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 such as alpha-adrenoceptor antagonists, ACE inhibitors, angiotensin I chymase inhibitors, renin inhibitors, angiotensin II antagonists, vasopressin V 1 antagonists, endothelin antagonists, endothelin-converting enzyme inhibitors, potassium channel activators, calcium channels antagonists, adenosine A 2 agonists, adenosine A 1 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 S. 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 alphal-adrenergic 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).

S 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 S 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 Saccompanying 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 1 (Luther, R.R. et al., Am. Heart 117, 842, 1989; Ames, R.P. Kiyasu, J.Y. J. Clin. Pharmacol., 29, 123, 1989), 2- [4-(4-fluorophenyl)piperazin- 1-yl]propanes]-1,4-benzothiazin- 3(4H)-one of formula V of the drawings 1 (Kajine, M. et al., Chem. Pharm. Bull., 39, 2885, 1991), uracil derivatives of formula VI VII of the accompanying drawings 1 (Klmm, Von K. et al., Arzneim. Forsch., 27, 1875, 1977), dihydropyridines of formula VIII of the accompanying drawings 1 (Suzuki, H. SSaruta, 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., Chem. 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. et al., Chem. Pharm. Bull., 37, 2225, 1989; Tricerri, S.Z. et al., US Pat. 4,894,460, 1990 Chem. Abst., 113, 132218b, 1990), zolertine of formula IX of the accompanying drawings 1 (Arya, V.P.

et al., Experientia, 23, 514, 1967; Hayao, S. et al., J. Med.

Chem., 10, 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 1 (Mayer, W.E. et al., J. Med. Chem., 32, 593, 1989), aryloxypro- Spanolamines of formula XII of the accompanying drawings 2 (Ing, H.R. Ormerod, J. Pharm. Pharmacol., 4, 21, 1952; Petrow, V. et al., J. Pharm. Pharmacol., 8, 666, 1956; Moran, N.C. and Perkins, Pharmacol. Exp. Ther., 124, 223, 1958), aryloxy/thioaryloxy arylpiperazinylpropanes of formula XIII of the accompanying drawings 2 (Agarwal, S.K. et al., Ind.

J. Chem., 21B, 435, 1982; Ind. J. Chem., 21B, 914, 1982; Ind. J. Chem., 30B, 413, 1991; Rao, J. et al., Ind. J.

Chem., 26B, 761, 1987; Saxena, A.K. et al., Ind. J. Chem., 32B, 1249, 1993), quinolylethanes of formula XIV of the accompanying drawings 2 (Murti, A. et al., Ind. J. Chem., 28B, 934, 1989), trimetazidine of formula XV of the accompanying drawings 2 (Fujita, Y, Jpn. J. Pharmacol., 17, 19, 1976), lidoflazine of formula XVI of the accompanying drawings 2 (Daenen, W. Flameng, W., 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. et al., Yaaxue Xuebao, 28, 548, 1993), pyrroloquinoline derivative of formula XIX of the accompanying drawings 2 (Jasserand, D. et al., Ger. Offen.

20 DE 4,128,015, 1993 Chem. Abst., 119, 139255f, 1993).

SUMMARY OF THE INVENTION The invention relates to, and it is an object to provide, 1-[4-arylpiperazin-l-yl]-3-[2-oxopyrrolidin/ 25 piperidin-1-yl]propanes as potential therapeutic agents for the treatment and alleviation of diseases such as hypertension, ischemia, cardiovascular and other adrenergic receptors related disorders; to a process for preparing said compounds and to a method of treating hypertension, 30 peripheral vascular diseases, reperfusion injury and ischemic diseases in mammals using said compounds.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel pharmacologically active substances, specifically new l-[4-arylpiperazin-lyl]-3-[2-oxopyrrolidin-l-yl]propanes and 1-[4-arylpiperazin- 1-yl]-3-[2-oxopiperidin-1-yl]propanes which are used as potential therapeutic agents for hypertension, ischemia, cardiovascular and other adrenergic receptors related disorders.

Accordingly, the invention provides novel compounds of formula 1.

N 0

(CH

2 3 -N N-N- Ar Wherein Ar represents pyridyl, or a phenyl ring substituted by the groups halo, alkoxy, alkyl or heteroaryl, n=1 or n=2 and the said compounds represented by following.

l-[4-(3-chlorophenyl)piperazin-1-yl]-3-[2- (b)oxopyrrolidin- 1-yl] propane; (b -[4-(4-chlorophenyl)piperazin-1-yl]-3-[ 2 oxopyrrolidin- l-yl] propane; l-[4-(3-fluorophenyl)piperazin-l-yl]-3-[ 2 oxopyrrolidin- 1-yl] propane; l-[4-(4-fluorophenyl)piperazin-l-yl1-3-[ 2 oxopyrrolidin- l-yl] propane; 1-[4-(4-ethylphenyl)piperazin-1-yl]-3-[2-oxopyrrolidin- 20 l-yllpropane; 1- (2-ethylphenyl)piperazin-l-yl] [2-oxopyrrolidin- 1-yl] propane; 1- (4-chlorophenyl)piperazin-1-yl]-3-[2-oxopiperidinl-yl] propane; 1- (3-chlorophenyl)piperazin-l-yl]-3- [2-oxopiperidinl-yl] propane; 1- (4-fluorophenyl)piperazin-1-yl]-3-[2-oxopiperidil l-yl] propane; 1- (2-ethylphenyl)piperazin-l-yl] [2-oxopiperidin- 1-yllpropane; 1-[4-(2-methoxyphenyl)piperazin-1-yl]->[2 oxopiperidin-l-yl] propane; l-[4-(2-pyridyl)piperazin-1-yl]-3-[12-oxopiperidin-lyllpropane; and 1-[4-(3-trifluoromethylphenyl)piperazin-l-yl]-3-[2oxopiperidin-l-yl]propane.

In the specification and claims, the compounds with n 1 designates 2-oxopyrrolidin-l-yl groups while with n 2 designates 2-oxopiperidin-l-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, CH,, CF,, alkoxy like methoxy, halo like chloro, fluoro etc. The compounds of this invention have useful biological activities and have in particular strong antihypertensive 15 and antiischemic activities.

Accordingly, this invention provides a process for the synthesis of compounds of formula I, which formula is shown above, wherein AR represents a heteroaryl ring or a phenyl ring substituted with a halogen, alkoxy, alkyl or heteroaryl, n 1 or n 2, said process comprising condensing 2-pyrrolidone of formula 2(n 1) or 2piperridone of formula 2(n 2) with 1-[4-substituted aryl piperazin-l-yl]-3-chloropropanes of formula 5 where Ar represents a phenyl ring substituted by a group like halo, 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 aryl piperazin-l-yl]-3-[2oxopyrrolidin/piperidin-1-yl] propanes of formula 1.

The invention also provides a pharmaceutical composition comprising a compound of formula 1 in admixture with a pharmaceutically acceptable conventional carriers and a process for the preparation of a pharmaceutical composition which comprises bringing a compound of the formula 1 into association with a pharmaceutically acceptable conventional carrier.

In addition, the invention provides a method of treatiln([ Iyrtension and peripheral viscular disp.ases in mNiluna1 Ilit r(mi prises administering to a subjec:. in neped thlere i: w f -r1 I amount of a compound of formula 1. Further, the present invmnLtion is for a method of antagonising peripheral alpha-a enric receptor in mammals,said method comprising administering to a patient subject in need thereof an effective amount.of a compound of formual 1.

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

It will be noted that according to the foregoing scheme,there are two methods leading to the synthesis of compounds of formula 1.shown earlier.

In the first method the 2-pyrrolidone n 1) or 2-piperidone S n is condensed with l-brorno-3-chloropropane 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-l1-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 conmpounds of formula 1. This reaction may be carried out in ,olvre1ts 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 compound of formula 1.

In the second method which is the subject matter of copending US patent application number 08/954,516, the substituted piperazine (formula 4 of scheme 1 of the accompanying drawings) was condensed with l-bromo-3chloropropane 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 l-chloro-3-(4-substituted piperazin-l- 15 yl)propane (formula 5 of scheme 1 of the accompanying drawings) 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 1500C for 1.15 to 14 hrs yield the required compounds of formula 1.

The 1-[4-arylpiperazin-l-yl]- 3 -[2-oxopyrroilidin-lyl]propanes (1 n=l) and l-[4arylpiperazin-lyl]-3-[ 2 oxopiperidin-lyl]propanes (1 n=2) in free form can, if 25 desired, be converted into 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 thsl.)re withl 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 S infarction angina pectoris, any cardiac surgical interventions, renal ischemia, circulatory insufficiency in extremities, stroke and trauma as shown for instance by the following data of the compound 1- 4 -fluorophenyl)piperazin-l-yl] [2-oxopyrrolidin-1-yl]propane.

oo Pharmacological activity 1. Acute toxicity (LiD) Mice 147.0 mg/kg i.p. 85.3-253) 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.

i treatm nt r ripor r inhibition o

CAT

Naturally occuring hypertensive cat.

16 110 195/195 49 n=4 20 22 >156.75 177/185 R 26 n=4 (ii) Normotensive cat SoVO 1 0 22 85 200/170 26 n=4 20 21 >102.5 185/165 34.75 n=4 12 0w Dose B.P. fall Dur. Heart rate Adrenaline No. of (uMol/kg (06) (mil.) Pre/post vasopressure exp.

treatment response inhibition

RAT

Hypertensive rat model preparzi t-i.nn 27 51 .34 6/32 0 .33 HnZ3 22 76 3 5 6/ 3 40 231,7 29 100 310/275 54 11=1 (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 11=2 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 (mill.) i) Spinal transected cat 2-10 14-18 15-30 (iiCv 0.34-1.36 8-10 10-15 (iii) Rat hind limb perfusion Total Percent change dose (ug) in flow no effect +-35 (Vasodilait..;11it On +50 (Vasodilatatj) 13 (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: 0* 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 antilistaminic activity ;i~i i 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 antihypertenjive effect.

(ii) Pretreatment with Ca++ channel blocker, verapamil significantly reduced antihypertensive effect 14 (iii) Pretreatment wth 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 15 Drug B.P. fall Dur. (Min.) Verapamil 55 22 (ii) Captopril 14 28 (iii) Compound 1 22 of formula 1, where, Ar=C 6

H

4 n=1 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 90 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.

Table 1: ug/mi on Compound administered at the time of reperfusion at the dose of 0.001 prolong period (90 min.) of ischemnic insult.

S. No. Compound Onset Percentage recovery (min.) 15 min. 30 min.

1. Controla 3 0.5 17.5 2. Compound 1 of formula 4 81.25 87.15 1, where Ar=C 6 1- 4 -4-F, n=1 3. Nifedipinea (10- 6 M) 12.5 10.66 0.0

S

OS@S

S

5555

S.

S S S S *5 S. S

S

5.55

S

555 5 0@5* 0S S 5* 55 0@OeSS

S

S

a Ischemnic insult (45 min.) Comparable results for hypotensive/anti hypertensive and antiischemnic activities were obtained with a number of other compounds of formula 1 (Table 2 3).

10 Table 2: Effect on blood pressure, heart rate and adrenaline vasopressure response at anaesthetized (pentobarbitone sodium 35 mg/kg (iv) cat Co mpou nd Dose B.P. Dur. (min.) Adrenalinea vasopressure of formula 1 (umol/kg fall response inhibition Ar n c 6 H 4 -4-F 1 2.0 25 71 9 10.0 31 >1 12 R

C

6

H-

4 -2-CAH 1 2.0 13 10 Pt 10.0 62 c 6 H 4 3-Cl 1 2.0 25 20 Pt 55 >57_

C

6 1-1 4 -4-C 2 1- 5 1 2.0 9 Tr I 110.0 20 14 Table 2 Contd...

Compd.

Dose (umol/kg n i.v.) B. P.

f all Dur. Adrenaliinea (min.) vasopressure response inhibition

C

6

H

4 -3-F.

C

6

H

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

C

6

H

4 -4-C1

C

6

H

4 -3-C1

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 10.0 1 2.0 10.0 1 2.0 .0 2 2.0 10.0 2 2.0 10.0 2 2.0 0 2 10.0 2 2.0 .0 2 2.0 10 .0 3 19 67 16 43 53 >71 9 62 Tr 63 >84 a R=Reversal; Pt~potentiation (was within 20w0) Table 3: Compound administered at the time of reperfusion at a dose of 0.001 ug/ml on brief period (1.6 min.) of ischemic insult.

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

Control 2.0 104.50 118.10 a

C

6

H

4 -4-F 1 1.5 81.25 78.12

C

6 H4-2-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 S C 6

H

4 -3-Cl 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-C1 1 1.0 87.50 120.80 S 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 pyrrolidone/piperidone and N-arylpiperazine which may be ethyl or butyl.

Example 1 Preparation of l-chloro-3-[ 2 -oxopyrrolidin-l-yl]propane 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 ml) was heated at 110 0 C with vigrous stirring, i-Bromin-3- 18 chioropropane (1.8 g, 12.0 mmcl) was added to thw n-ire reaction mixture after 3 hours and the heating at 1100(C was continued for 6 hours. The reaction mnixture was fil1t-l'i'd ;IIIrl xylene was removed under reduced pressure. The residue wais distilled under reduced pressure to give 3 B.P. 4' 0 mm., yield 1.52 g (80-1) IR (Neat) :2980, 2880, 1710, 146'0, 1420, 1280, 1050. 1 H NMR (CDCl 3 :1.92-2.18(m, 4H, 2- CH,) 2.40(t, 2H1, J=6.0 Hz, 3'-CH 2 3.42(t, 4H1, J=6.0 Hz, 5' 3 3.58(t, 211, J=6.0 Hz, l-CH 2 MS: m/z 161 Mol. formula C 7

H

12 N0C1 Found 51.96; H, 7.48; N, 8.61 Calcd.: C, 52.11; H, 7.45; N, 8.69%,.

(ii) A mixture of 2-pyrrolidone (10 g, 120.0 mmol) anid tinely pulverized sodium metal (2.76 g, 120.0 mmol) in dry xylene (600 ml) was heated at 150 0 C with vigrous stirring. 1-Bromo -3 *chloropropane (18.84 g, 120.0 mmol) was a--dded to the- :stirred reaction mixture after 30 minutes and the heating at 1500C was continued for 1 hour. The reaction mixture was filtered arnd xylene was removed under reduced pressure. Therein wa distilled under reduced pressure to give 3 B.P. 1-45 0 C/1 yield 16.09 g (iii) A mixture of 2-pyrrolidone (2 g, 23.0 mmcl) and timrcely pulverized sodium metal (0.529 g, 23.0 mmol) in dry tolviene (120 ml) was hleat-ed at..1.201)(' wit-lu vi:rms t-i rr-Ti 11( I Bruo 3 chl oropropane 3 .97 g 25 .0 m1 0) wo.s- ;,-dced 1-1c .5t i rrem reaction mixture after 6-7 hours and the heating at 120 0 C was,: continued for 7 hours. The reaction mixture was filter('d and toluene was remnoved under reduced pressure.Tile Yet-i rdm-~ was.,distilled under reduced pressure to give the compound 3 B.P. 1450C/1 mm., yield 2.86 g (iv) A mixture of 2-pyrrolidone (1 g, 12.0 mmol) and finely pulverized potassium metal (0.47 g, 12.0 mmol) in dry xyleine ml) was heated at 1500C with vigrous stirring. l-Bromo-3chloropropane (1.8 g, 12.0 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. The residue was distilled under reduced pressure to give 3 B.P. 1450C/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 1500C 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 1500C was continued for 3 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. 1450C/1 mm., yield 1.24 q Preparation of l-chloro-3- (2-oxopiperidin-1-yl)propane A mixture of 2-piperidone (1.19 g, 12.0 mmol) and finely pulverized sodium metal (0.28 g, 12.0 mmol) in dry xylene (70 ml) was heated at 1100C with vigrous stirring, l-bromo-3chloropropane (1.89 g, 12.0 mmol) was added to the stirred 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 chromatographed on silica gel using hexane and chloroform al eluant to get 3 B.P. 91 0 C/0.01 mm., yield 1.33 g (63.33%).

IR (Neat) 3862, 3298, 2950, 2474, 2324, 1640, 1478, 1432, 1 t6, 1184, 1096, 754. 1 H NMR (CDC13) 1.

7 9-2.36(m, 8H), 3.15- 1 .6 7 (m, 6H). MS: m/z 175 Mol. formula C 8

H

14 NOC1 Found C, 54.90; H, 8.28; N, 8.25 Calcd '4 69; 11, 8. 0 N, 7.977 Example 2 Preparation of 1-[ 4 -(3-chlorophenyl)piperazin-l-yl]-3-[2oxopyrrolidin-1-yl]propane of the formula 1, where Ar=C 6

H

4 3-C1, n=l 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. mminl) in dry DMF (5 ml) was stirred at 70 0 C for 14 hrs. The r,-:;icrion mixture was cooled, poured on water (20 ml) and the separated residue was extracted with CHC13 (2x25 ml). The extracts were dried over Na 2

SO

4 and concentrated under reduced pressure tr give 1- 3 -chlorophenyl)piperazin-l-yl] -3-[2-oxopyrrolidin-1yl]propane as an oil which was purified by flash column chromatography over silica gel using chloroform as eluent-, yield 1.50 g IR (Neat): 3020, 2820, 1660, 1590, 1450, 1210, 730.

H NMR (CDC1 3 1.30-2.60(m, 12H, 2, 1 2xN-CH 2 2.40- 3.50(m, 8H, 3 2xN-CH 2 6 4 0-7.20(m, 4H, ArIl) im/z ';21 (M 323 Mol. Formula C 1 7

H

24 C1N 3 0 Found C, 63.58; H, 7.82; N, 13.17 Calcd.: C, 63.44; 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 toluene (60 ml) was heated at 1200C with vigrous stirring for 6 hours, 1-[4-(3-chlorophenyl)piperazin-1-yl]-3chloropropane (3.26 g, 12.0 mmol) was added to this reaction mixture and the reaction mixture was heated under stirring at 1200C for 7 hour. The reaction mixture was filtered and toluene was removed under reduced pressure. The residue was chromatographed over flash silica gel using chloroform as eluent to give the title product, yield 2.65 g oil.

A mixture of 1-chloro-3-[2-oxopyrrolidin-1-yl]propane (1.0 g, 6.2 mmol), 1- 10 (3-chlorophenyl)piperazine (1.22 g, 6.2 mmol), anhydrous Na 2

CO

3 (0.33 gm 3.1 mmol) and Nal (0.093 g, 0.6 mmol) in dry toluene (10 ml) was stirred at 1100C for 12 hrs. The solvent was removed at reduced pressure and residue was i poured on water (20 ml). The separated residue was extracted with ethylacetate (3x20 ml), dried over Na 2

SO

4 and concentrated under reduced pressure to give 1-[4-(3-chlorophenyl)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 0.60 g A mixture of 1-chloro-3-[2-oxopyrrolidin-1-yl]propane (1 g, 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 xylene (15 ml) was stirred at 150°C for 14 hrs. The solvent was removed at reduced pressure and residue was poured on water (30 ml). The separated residue was extracted with 23 dichloromethane (2x25 ml), dried over Na 2 SOd and concentrated to give l-14-(3-chlorophenyl)piperazin-1--yl]-3-[2oxopyrrolidin-1-yll propane as an oil which was purified by flash column chromatography over silica gel using chloroform as eluent, yield 0.72 g Example 3 Preparation of 1- (4-chlorophenyl)piperazin-1-yl] -3- [2-oxopyrrolidin-1-yll propane of the formula 1, where A~=CH,-4-C1, n=1.

A mixture of l-chloro-3- [2-oxopyrrolidin-1-yl Ipropane (1 g, 6.2 rnmol), l-(4-chlorophenyl)piperazine (1.22 g, 6.2 inmol) anhydrous Na 2

CO

3 (0.33 g, 3.1 mmol) and Nal 09 g, 0.6 mmol) in dry DMF (5 ml) was stirred at 70 0 C for 12 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 N 2 S0 4 and concentrated under reduced pressure to give 1-[4-(4-chlorophenyl)piperazin-lyl] [2-oxopyrrolidin-l-yll propane which was purified by flash columnn chromatography over silica gel using chloroform as eluent, yield 1.48 g M. P. 78-800C. IR (KBr): 3440, 2820, 1660, 1490, 1230, 1130, 810. H NNR (CDCl 3 1.50-2.80(m, 12H, 4' 2, 1 2xN-CH 2 3.00-3.60(m, 8H, 3 2xN-CH 2 6.80(d, 2H, J=9.0 Hz, ArH, 0 to Cl) 7.20(d, 2H, J=9.0 Hz, ArH, m to Cl). MS: m/z 321 323 Mol. formula C, 7

H

2 4CN 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 vigorous stirring, 1-[4-(4-chlorophenyl)piperazin-1-yl)-3-chloropropane (3.26 g, 12.00 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. 78-800C.

A mixture of 2-pyrrolidone (1 g, 12 mmol) and finely pulverized potassium metal (0.47 g, 12.0 mmol) in dry xylene (60 ml) was heated at 1500C with vigorous stirring, 1-[4-(4-chlorophenyl)piperazin-1-yl)-3-chloropropane (3.26 g, :.12.0 mmol) was added to the stirred reaction mixture after 20 minutes and the 15 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 2.78 g M.P. 78-800C.

A mixture of 2-pyrrolidone (1 g, 12 mmol) and finely pulverized potassium 20 tert. butoxide (1.34 g, 12.0 mmol) in dry xylene (60 ml) was heated at 1500C with vigorous stirring, 1-[4-(4-chlorophenyl)piperazin-1-yl]-3-chloropropane (3.26 g, 12.0 mmol) was added to the stirred reaction mixture after 2 hours and the heating at 150 0 C was contiinued for 4 1cou r T hlle react i.olli mixture was filtered arid xylene wasr: remou.ved tiiidur 1reduced pressure to give 3 which w R S pi I I I f i ed hy F I a co hcc)I141 chromatography over silica gel using chloroform as Pluiuiilt-, yi-r23d 2.46 g M.P. 78-80C.

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

H

4 3-F, n=1 A mixture of 1-chloro-3-[ 2 -oxopyrrolidin-l-yl]propaile c, 6.2 mmol), l-( 3 -fluorophenyl)piperazine (1.12 g, 6.2 mmol), anhydrous K 2 C0 3 (0.434 g, 3.1 mmol) and KI (0.10 g, 0.6 rnmol) in dry DMF (5 ml) was stirred at 90 0 C for 12 hrs. The ieiction mixture was cooled, poured on water (25 ml) and the sf'plraited residue was extracted with CHC1 3 (2x25 ml The extrw'L:;' wf'Le dried over Na 2

SO

4 and concentrated under reduced pressure to give 1- 3 -fluorophenyl)piperazin-l-yl]-3- [2-oxopyrrolidin-lse*.yl]propane as an oil which was purified by flash :oitimn chromatography over silica gel using chloroform as elufli w, yif-'Ic] 1.32 g IR (Neat): 2920, 2800, 1650, 1440, 1240, 1150, o 1 740. H NMR (CDC13): 1.50-2.70(m, 12H, 2, 1 2xN CH.) 3.00-3.60(m, 8H, 3 2xN-CH 2 6.30-6.80(m, 4H, ArH). MS: m/z 305 307 (M+2) Mol. formula C 1 7

H

2 4

FN

3 0 Found C, 67.22; H, 7.72; N, 1..)7 Calcd. C, 66.88; H, 7. 92; N, 7 A mixture of 2 -pyrro].idone (1 g, 1.2 mmcl) aiud P i um,.1y pulverized sodium metal (0.28 g, 12.0 mmol) in dry xylene (60 ml) was heated at 150°C with vigorous stirring, 1-[4-(3-fluorophenyl)piperazin-1-yl]-3chloropropane (3.07 g, 12.0 mmol) was added to the stirred reaction mixture and the heating at 1500C was continued for 1 hour. The product was obtained by the similar method as in example 3, yield 2.94 g oil.

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

H

4 -4- F, n=1 A mixture of 1-chloro-3-[2-oxopyrrolidin-1-yl]propane (4 g, 25.0 mmol), 1- (4-fluorophenyl)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 120°C *o for 8 hrs. The reaction mixture was cooled, poured on water (30 ml) and the separated residue was extracted with CHC1 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 S: eluent, yield 5.72 g IR (Neat): 2920, 2820, 1660, 1500, 1250, 730. 1

H

NMR (CDC1 3 1.50-2.80 12H, 2, 1 2xN-CH2), 3.00-3.60 8H, 3 20 2xN-CH 2 6.70-7.10 4H, ArH). MS: m/z 305 Mol. formula C 7

H

2 4

FN

3 0 Found C, 66.55; H, 8.07; 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 metal (0.81 g, 35.0 mitiol) in dryl xyl iiu (180 ml) was heated at 150 0 C with vigrous stirring, I1- f Iiinrnpl-isiiy] )piperaziii I **Y1 1 -1 ('11c h nI y (q)I(U .96 5, '75. 0 I1H1I30 was added to the stirred reactiuii lixtuiro atter M( miltL-S ")iri the heating at 1501)C was continued for 1. hour. The. reacf~ion mixture was filtered and xyleiie was removed uiid(-i reilcFd pressure to give 3 which was purified by f lash cenlu~mn chromatography over silica gel using chloroform as elueit-, VjFeld.

9.15 g oil.

Example 6 Preparation of l-[ 4 -(4-ethylphenyl)piperazin1.yl] oxopyrrolidin-l..yl]propane of the formula 1, where Ar=C 6

H

4 4-C HS, n=1 A mixture of l-chloro-3- 2 -oxopyrrolidin-lyllpr-pii). (2 0.n g, 12.0 mmol), 1- 4 -ethylphenyl) piperazine (2.36 g, 12.( 0 111uol) anhydrous Na 2

CO

3 (0.658 g, 6.2 mmol) and Nal (0.18 g, J..Z iiil) in dry DMF (10 ml) was stirred at 800C for 12 hrs. The rec-.t.ion mixture was cooled, poured on water (30 ml) and the separated ***:residue was extracted with CHC1.

3 (2X:3ornl) The e~xt-ra(tS wure *.dried over Na 2 So 4 and concentrated under reduced pressure to give ylhey~ppeazn1-i]3[ 2 -oxopyrrolidin-lyljpropane as an oil which was purified by flash column chromatography over silica gel using chloroform as eluent, yield 2. 43 g (62.016) IR (Neat) :2940, 2800, 1660, 1440, 1000, (90.0, 800. 1H NMR (CDCl 3 1-20(t, 3H, J=6.0 Hz, CH 2

CH

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

CH

2

CH.

3 3.00 .60 (mn, 8H, 5' 3 &2N

CH

2 MS: m/z 315 Mol. formula C 19

H

2 9

N

3 0 Found C, 71.94; H, 9.16; N, 13 AL Calcd.: C, 72.34; H, 9.27; N, 13-12".

A mixture of 2-pyrrolidone (2 9, 24 mmuytoi) F.110 f ii11.ly pulverized sodium metal (0.56 g, 24.0 mmol) in dry xyleine (120 ml) was heated at 150 0 C with vigrous stirring, 1I- (4ethylplhenyl piperaziiii- 1 -cyi -3 chic) Ijc.)pI:p itir 38 j, 24 was added to the stirred reaction mixture after 30 minut-s and the heating at 150 0 C was continue d tor I hour TIwi pr IiiCt w;i obtained by the similar method as in exampif-^3, yi.e.d 6.4 i f oil.

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

H

4 2-C 2

H

5 n=1 A mixture of 1-clloro-3- [2-oxopyrr-o-l. i.ix'i-1-y i 3pr.Topaxei 0 12.0 mmol), l-(2-ethylphenyl)piperazine (2.36 g, 12.0 immiii) &:600: anhydrous Na 2

CO

3 (0.658 g, 6.2 mmol) and Nal (0.18 g, 1.2 mmol)

CO

in dry DMF (10 ml) was stirred at 80 0 C for 12 hrs. The r,-'Lurtinn mixture was cooled, poured on water (30 ml) and the 1JPl tF~d residue was extracted with CHC1 3 (2X20ml) The extract3 were dried over Na 2 So 4 and concentrated under reduced pressurfP 1-o iLve 1- (4-ethylphenyl)piperazin-1-yl] [2-oxopyrrolidini-- yl]propane as an oil which was purified by flash coiiili cIiromatography over silica gel us iiiq o:hii IA)( c )i eI y.i e I J 2. 1 7 g (60.01). IR (Neat): 2940, 2820, 1660, 1430, 1010, 900, ROO. IH NMR (CDC 3 1.24(t, 3H, J=6 Hz, CH 2

-CH

3 l.68-l.85(m, 2H, 4'-

CH

2 1.98-2.10 2H, 2-CH 2 2.34-2.50 4H, 3' 1-CH 2 2.62 (bs, 4H, 2xN-CH 2 2.68 2H, CH 3

-CH

2 2.94 4H, J=6.0 Hz, 2xN-CH 2 2.35 2H, Hz, 3-CH 2 3.42 2H, J=6.0 Hz, 5'-CH 2 7.00-7.28 4H, Ar-H) MS: m/z 315 Mol. formula C, 1

H

29 N30 Found C, 72.64; H, 9.11; N, 13.64 Calcd. C, 72.34; H, 9.27; N, 13.32%.

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 1500C with vigorous stirring, 1-[4-(3-ethylphenyl)piperazin-1-yl]-3-chloropropane (3.19 g, 10 12.0 mmol) was added to the stirred reaction mixture after 30 minutes and the heating at 1500C was continued for 1 hour. The product was obtained by the similar method as in example 3, yield 3.13 g oil.

.o Example 8 Preparation of 1-[4-(4-chlorophenyl)piperazin-1-yl]-3-[2-oxopiperidin-1-yl]propane of the formula 1, where Ar=C 6

H

4 -4-C1, 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) was heated at 1400C with vigorous stirring, 1-[4-(4-chlorophenyl)piperazin-1-yl]-3-chloropropane (2.72 g, 10 mmol) 20 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 eluant, yield 2.54 g m.p. 1060C. IR (Neat): 3761, 3408, 3017, 2957, 2882, 2826, 2785, 2502, 1659, 1599, 1499, 1456, 1385, 1346, 1219, 1148, 1105, 760, 667. PMR (CDC1 3 0.89-1.80 6H, 5' 2-CH 2 2.33-2.65 8H, 1 2xN-CH 2 3.15-3.62 8H, 3 2xN-CH 2 6.81-7.00 (2xdd, 4xArH) MS: m/z 337 Mol. formula C 1

H

2 6

N

3 0C1 Found C, 64.23; H, 7.87; N, 12.24 Calcd. C, 64.37; H, 7.80; N, 12.51%.

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°C with vigorous stirring, 1-[4-(4-chlorophenyl)piperazin-1-yl]-3chloropropane (2.72 g, 10 mmol) was added to the stirred reaction mixture after 2 hours and the heating at 1500C was continued for 4-hours. 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 10 chloroform as eluant, yield 2.17 g m.p. 1060C.

Example 9 Preparation of 1-[4-(3-chlorophenyl)piperazin-1-yl]-3-[2-oxopiperidin-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 1200C with vigorous stirring for 6 hours, 1-[4-(3-chlorophenyl)piperazin-1-yl]-3-chloropropane (2.72 g, 10 mmol) was added to this reaction mixture and the reaction mixture was heated under stirring at 1200C for 7 hours. The reaction mixture was filtered and toluene was removed under reduced pressure. The residue 20 was chromatographed over flash silica gel using chloroform as eluant to give 3, yield 2.59 g oil. IR (Neat): 3406, 2951, 2878, 1626, 1597, 1491, 1454, 1383, 1352, 1219, 1142, 1103. 1 H NMR (CDC1 3 1.17-1.84 6H, 2, 4'

CH

2 2.27-2.65 8H, 1, 3' 2xN-CH 2 3.15-3.37 8H, 3 2xN-CH 2 6.68-6.79 (dd, 2xArH), 7.05-7.11 1xArH), 7.19 1xArH). MS: m/z 335 (M Mol. formula C 18

H

2 6

N

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

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

H

4 -4- F, n=2 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 vigorous stirring, 1-[4-(4-fluorophenyl)piperazin-l-yl]-3-chloropropane (5.17 g, mmol) was added to the stirred reaction mixture after 30 minutes heating at 1500C was continued for 1 hour. The reaction mixture was filtered and xylene 10 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 oil. IR (Neat): 3408, 3014, 2931, 2880, 2825, 1626, 1508, 1458, 1219, 824, 760, 667. 1H NMR (CDC13) 1.72-1.86 6H, 5' 2-CH 2 2.37-2.69 8H, 1 2xN-CH2), 3.12-3.46 8H, 3 2xN-CH2), 6.83-7.00 (2xdd, 15 4xArH). MS: 319 Mol. formula C 19

H

2 6

N

3 0F Found C, 71.23; H, 8.26; N, 12.95 S Calcd. C, 71.47; H, 8.15; N, 13.17%.

A mixture of 1-chloro-3-[2-oxopiperidin-1-yl]propane (2.1g, 12 mmol), 1- (4-fluorophenyl)piperazine (2.16 g, 12 mmol), anhydrous Na 2

CO

3 (0.618 g, 6.2 mmol), and Nal (0.18 g, 1.2 mmol) in dry DMF (10 ml) was stirred at 80°C for 14 hrs. The reaction mixture was cooled, poured on water (30 ml) and the separated residue was extracted with CHCl 3 (2x35 ml). The extracts were dried over Na 2

SO

4 and concentrated under reduced pressure to give fluorophenyl)piperazin-1-yl]-3-[2-oxopiperidin-1-yl]propane as an oil which was purified by column chromatography over silica gel using chloroform as eluent, yield 2.40 g (63.0 Example 11 Preparation of 1-[4-(2-ethylphenyl)piperazin-1-yl]-3-[2-oxopiperidin- 1-yl]propane of the formula 1, where Ar=C 6

H

4 -2-C 2 H, 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 heated at 1500C with vigorous stirring, 1-[4-(2-ethylphenyl)piperazin-1-yl]-3-chloropropane (2.66 g, 10 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 10 column chromatography on silica gel using chloroform as eluant, yield 2.49 g o oil. IR (Neat): 3680, 3440, 3000, 2960, 2870, 2820, 1620, 1490, 1450, 1350, 1210, 1140, 1005, 920, 725. 'H NMR (CDC1 3 1.00 3H, CH 2

CH

3 1.20-1.90 6H, 5' 2-CH 2 2.20-3.50 18H, 3, 1 4xN-CH 2 C2CH2C), 7.00-7.20 4H, ArH). MS: m/z 329 Mol. formula C 20

H

31

N

3 0 Found C, 72.67; H, 9.60; N, 12.49 Calcd. C, 72.95; H, 9.42; N, 12.77%.

Example 12 Preparation of 1-[4-(2-methoxyphenyl)piperizin-1-yl]-3-[2oxopiperidin-1-yl]propane of the formula 1, where Ar=C6H5-2-

OCH

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 1500C with vigorous stirring, 1-[4-(2-methoxyphenyl)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 (CDCy) 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 Mol. formula C 19

H

2 9 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-1yl]propane of the formula 1, where Ar=2-pyridyl, n=2 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 vigorous stirring, 1-[4-(2-pyridyl)piperazine-1-yl]-3-chloropropane (4,78 g, mmol) was added to the reaction mixture after 30 minutes and the heating at 150°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 15 column chromatography over silica gel using chloroform as eluant, yield 4.39 g S. oil. IR (Neat): 3420, 2940, 2800, 1629, 1580, 1470, 1420, 1230, 1150, 1125, 960, 720. 1 H NMR (CDCl 3 1.50-2.20 6H, 5' 2-CH 2 2.25-2.80 8H, 1 2xN-CH 2 3.10-4.80 8H, 3 2xN-CH 2 6.48-6.75 2H, 3,5-pyridyl 7.40 1H, 4-pyridyl 8.15 1H, 6-pyridyl H) MS: m/z 302 Mol. formula C, 7

H

2 6

N

4 0 Found C, 67.32; H, 8.49; N, 18.38 Calcd. C, 67.52; H, 8.67; H, 18.53%.

Example 14 Preparation of 1-[4-(3-trifluoromethylphenyl)piperazin-1-yl]-3-[2oxopiperidin-1-yl]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 pulverized sodium metal (0.23 g, 10 mmol) in dry xylene (60 ml) was heated at 1500C with vigorous stirring, 1-[4-(3-CF 3 phenyl)piperazin-1-yl]-3-chloropropane (3.06 g, 10 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 furnished by flash column chromatography on silica gel using CHC1 3 as 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

(CDC]

3 1.75-1.93 6H, 5' 2-CH 2 2.35-2.75 8H, 1 2xN-CH2), 3.310-3.84 8H, 3 2xN-CH2), 7.04-7.10 (dd, 2H, 4, 6-ArH), 7.26 H, 2- ArH), 7.32-7.37 H, 5-ArH). MS: m/z 369 10 Mol. formula C 1 9

H

2 6

N

3 0F 3 Found C, 61.48; H, 7.23; N, 11.21 Calcd. C, 61.97; 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/kg 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 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); histamine (1-2 ug) and isoprenaline (1-2 ug) were taken before and after the administration of test doses of each compound. All the compounds were tested at fixed doses of and 10 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. 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 16 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) NaCI 137, KC1 5.4, CaCl 2 1.8 g, MgCI 2 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 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.

S(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.

For prolong period of ischemic insult (Becker, L.C. Ambrosio, G.

Myocardial consequences of reperfusion. Prog. Cardiovas. Dis., 30, 23-44, 1987). Ischemia was initiated by stopping the flow for 30 min. followed by min. reperfusion.

"Comprises/comprising" when used in this specification is taken to specify the presence of stated features, integers, steps or components but does not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof."

Claims (15)

1. 1-[4-Arylpiperazin-l-yl]-3-[2-oxopyrrolidin/ piperidin-l-yl]propanes used as potential therapeutic agents for hypertension, ischemia, cardiovascular and other adrenergic receptors related disorders, having general formula 1 N 0 (CH 2 3 -N N-Ar wherein Ar represents pyridyl, or a phenyl ring substituted with trifluoromethyl, halogen, alkoxy, alkyl or heteroaryl, and n=l or n=2.

2. The compound of claim 1, wherein the halogen is selected from the group consisting of chlorine, fluorine, bromine, and iodine, and mixtures thereof, the alkoxy is C-C 10 oxy, the alkyl is Ci-Ci 0 alkyl, and the heteroaryl is a pyridyl ring.

3. Compounds of formula 1 as claimed in claim 1 wherein the compound is selected from the group consisting of: l-[4-(3-chlorophenyl)piperazin-l-yl]-3-[2- oxopyrrolidin-l-yl]propane. 1-[4-(4-chlorophenyl)piperazin-l-yl]-3-(2- oxopyrrolidin-l-yl]propane. 1-[4-(3-fluorophenyl)piperazin-l-yl]-3-(2- oxopyrrolidin-1-yl]propane. 1-[4-(4-fluorophenyl)piperazin-l-yl]-3-[2- oxopyrrolidin-l-yl]propane. l-[4-(4-ethylphenyl)piperazin-l-yl]-3-(2- oxopyrrolidin-l-yl]propane. l-[4-(2-ethylphenyl)piperazin-1-yli-3-[2- oxopyrrolidin---yl IIpropane. l-[4-(4-chlorophenyl)piperazin-1-yl-3-12- oxopiperidin-l-yl ]propane. 1-[4-(3-chlorophenyl)piperazin-1-yl-3-[2- oxopiperidin- l-yl] propane. 1-[4-(4-fluorophenyl)piperazin-l-yl]-3-[2- oxopiperidin- l-yl Ipropane.. 1- (2-ethylphenyl)piperazin-1-yl] [2-oxopiperidin- l-yl Ipropane. 1- (2-methoxyphenyl)piperazin-l-yl] [2- oxopiperidin-l-yl] propane. l-[4-(2-pyridyl)piperazin-l-ylI-3-[2-oxopiperidin-l- yllpropane. (in) l-[4-(3-trifluorornethylphenyl)piperazin-1-yl]-3-[2- oxopiperidin- l-yl Ipropane.

4. A process for the synthesis of compounds of formula 1 as clainred in any one of claim 1 to 3, which ccuprises condensing an 0.:appropriately substituted phenylpiperazine of formula 4 xaIre Ar rprsets pyridyl, or a pl--il ring skstituitei with txiflixuar~etyl, h-Blc~e, alkoxy, alkyl or heteroaryl with l-chloro-3-[2- oxopyrrolidin-l-yll]propane of formula 3 or 1-chioro- [2 -oxopiperidin-l-yll propane of formula 3 in the presence of a base, A catalyst and an organic solvent at a temperature ranging from 70-120 0 C for a period varying between 8-14 hrs to produce the corresponding l-[4- substituted arylpiperazin-l-yl] [2-oxopyrrolidin-l- yllpropanes of formula 1 or 1- [4-substituted arylpiperazin-l-ylI [2-oxopiperidin-l-yllpropanes of formula 1 respectively. A process as claimed in claim 3 where the process for the synthesis of the intermediate 1-chloro-3-[2- oxopyrrolidin-l-yllpropane of formula 3 and l-chloro- 3- [2-oxopyperidin-l-yll propane of formula 3 comprises reacting 2-pyrrolidone of formula 2 or 2-piperidone of formula 2 with 1-bromo-3-c.hloropropane in the presence of at least one aromatic solvent selected from xylene, toluene and benzene; and a base comprising at least one of a pulverised sodium or potassium metal or potassium tert. butoxide at a temperature in the range of 110-1500C for a period ranging from 80 minutes to 14 hrs.

6. A process as claimed in claim 3 wherein the base used is selected from sodium carbonate or potassium carbonate.

7. A process as claimed in claim 3 wherein the catalyst used is selected from sodium iodide, potassium iodide.

8. A process as claimed in claim 3 wherein the molar ratio of the compounds of formula 3 and 4 is about 1:i. A process as claimed in claim 3 wherein the organic solvent used is present from about 0.8-2.4 ml per mmol of .oo: the reacting compounds 3 and 4 of formula 3.

10. A process as claimed in claim 3 wherein the molar ratio of the base to the compounds of formula 3 and 4 is about 1:2. e•

11. The process of claim 3, which further comprises converting the compound to a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound of formula 1 as defined in any one of claims 1 to 3 in admixture with a pharmaceutically acceptable carrier.

13. A process for the preparation of a pharmaceutical composition which comprises bringing a compound of the formula 1 as defined in claim 1 into association with a pharmaceutically acceptable additive.

14. A method of treating hypertension in mammals, that MR I omprises administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 3. A method of treating peripheral vascular diseases in mammals that comprises administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 3.

16. A method of antagonising peripheral alpha-adrenergic receptor in mammals that comprises administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 3. g. 17. A method of treating diseases arising out of alterations/impairment in central/peripheral circulations S* oar adrenergic receptr systems, selected frcm the grup cOnsisting of myocardial ischemia, myocardial infarction angina pectoris, any cardiac surgical interventions, renal ischemia, circulatory insufficiency in extremities, stroke and trauma that comprises administering to a subject in need thereof an effective amount of a compound according to any one of g claims 1 to 3.

18. A method of treating reperfusion injury in mammals that comprises administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 3, or a pharmaceutical preparation as claimed in claim 12.

19. A method of treating ischemic diseases in mammals that comprises administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 3, or a pharmaceutical preparation as claimed in claim 12. A method of treating ischemic diseases selected from the group comprising myocardial infarction angina toris, or cardiac surgical interventions in mammals that comprises administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 3, or a pharmaceutical preparation as claimed in claim 12. DATED this 3rd day of December 2001 COUNCIL OF SCIENTIFIC INDUSTRIAL RESEARCH WATERMARK PATENT TRADEMARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA .oo. 9 9 9 o* 9* 9 *o ego 9999*9 9 9 99 9 9 9.9. 9999 9999 IAS:KJS:BJD:SLB P7368AU00