Title of Invention	A NOVEL 1-ARYLALKYL-5-OXO-PROLINE CARBOXAMIDE USEFUL AS THROMBIN INHIBITORS AND A PROCESS FOR THE PREPARATION OF SAME
Abstract	A novel l-arylalkyl-5-oxo-prolinalmide useful as thrombin inhibitors and a process for the preparation of the same by reacting one mole equivalent of l-ω -arylalkyl-5-oxo-proline in an aprotic solvent in the presence of a carboxylic activating or coupling agent, and a tertiary nitrogen base in the temperature range of -20°C to 40oC for a period range of 2-8 hrs. to give corresponding carboxamides and isolating the compounds by conventional methods.

Title of Invention

A NOVEL 1-ARYLALKYL-5-OXO-PROLINE CARBOXAMIDE USEFUL AS THROMBIN INHIBITORS AND A PROCESS FOR THE PREPARATION OF SAME

Abstract

A novel l-arylalkyl-5-oxo-prolinalmide useful as thrombin inhibitors and a process for the preparation of the same by reacting one mole equivalent of l-ω -arylalkyl-5-oxo-proline in an aprotic solvent in the presence of a carboxylic activating or coupling agent, and a tertiary nitrogen base in the temperature range of -20°C to 40oC for a period range of 2-8 hrs. to give corresponding carboxamides and isolating the compounds by conventional methods.

Full Text	The present invention relates to a novel l-arylalkyl-5-oxo-prolinamides useful as inhibitors of thrombin an enzyme important in the blood coagulation cascade. These compounds are useful in the treatment of coagulation disorders. Thrombosis and its complication, embolism are a leading cause of morbidity and mortality in numerous cardio-vascular disorders including myocardial and cerebral infarction and thrombotic stroke. Thrombin (F Ha) is a trypsin like serine protease and a key enzyme in the blood coagulation cascade. Thrombin has a major role in the inhibition and propagation of fibrinogen, the natural substrate of thrombin dissolved in the blood plasma, to form fibrin, which can polymerize. Thrombin is also the main activator of platelet aggregation [ Ulrike obst etal, Helvetica Chimica Acta 83, 855 (2000); Anton E. P. Adang et al, Drugs of the Future 25(40, 369 (2000)]. The main objective of the present invention is to provide novel l-arylalkyl-5-oxo-prolinamides useful as inhibitors of the enzyme Thrombin. More particularly the present invention relates to the novel l-arylalkyl-5-oxo-prolinamides. These compounds are potentially useful in the treatment of blood coagulation disorders. Another objective of the present invention is to provide a process for the preparation of novel l-arylalkyl-5-oxo-prolinamides of the general formula 3 (Figure-1). Yet another objective of the present invention is to provide compounds useful in the treatment of cardiovascular disorders. Accordingly the present invention provides a novel l-arylalkyl-5-oxo-prolinalmide of general formula 3 wherein R is selected from the group consisting of phenyl, o-methoxyphenyl, o-chlorophenyl, m-bromophenyl, p-bromophenyl, p-cyanophenyl, p-methy phenyl, 2-phenyl-l-ethenyl, o,o'-dichlorophenyl and 2-phenylethyl; RI is H; R2 is selected from 4-pyridinyl methyl and N-(benzyloxycarbonyl)-4-piperidinyl methyl; RjR2 together is selected from -(CH2)n-CH(CH2NHCOOtBu)-(CH2)m- [where n=l, m=3 or n=2, m=2] and -(CH2)2-N(aryl)-(CH2)2- . The process used for this invention comprises of the reaction of one mole equivalent of 1-G)-arylalkyl-5-oxo-proline of the general formula 1, R = phenyl, o-methoxyphenyl, o-chlorophenyl, m-bromophenyl, p-bromophenyl, p-cyanophenyl, p-methylphenyl, 2-phenyl-1-ethenyl, o,o'-dichlorophenyl or 2-ethylphenyl with one mole equivalent of the amine of the general formula 2 where RI = H, R2 = 4-pyridinyl methyl or N-(benzyloxycarbonyl)-4-piperidinyl methyl or RiR2 = -(CH2)n-CH(CH2NHCOOtBu)-(CH2)m- [where n=l, m=3 or n=2, m=2] or -(CH2)2-N(aryl)-(CH2)2- in an aprotic solvent in the presence of a carboxylic activating or coupling agent, and a tertiary nitrogen base in the temperature range of -20°C to 40°C for a period range of 2-8 hrs. to give corresponding carboxamides of the formula 3 in the accompanying drawing and isolating the compounds by conventional methods. The compounds prepared by this invention were tested for their effect on human Thrombin (Table- 1), and they inhibited the enzyme activity by 31-90 percent at 12-56 nmol concentration. The compounds were also effective under in vivo condition and showed beneficiary effects in various anti-coagulatory screens. The representative compounds prepared by the process of the present invention are as follows 1. 5-{[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-1 -yljcarbonyl}-1 - phenylmethyl pyrrolidine-2-one (3a) 2. 5- {[4-(N-t-butoxycarbonyl-aminomethyl)piperidin-1 -yl]carbonyl}-1 - phenylmethyl pyrrolidine-2-one (3b) 3. 5-{[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-1 -yljcarbonyl}-1 -(2-chloro phenylmethyl)pyrrolidine-2-one(3c) 4. 5- {[4-(N-t-butoxycarbonyl-aminomethyl)piperidin-1 -yljcarbonyl}-1 -(2-methoxy phenylmethyl)pyrrolidine-2-one (3d) 5. 1 -(2-methoxyphenylmethyl)-5-oxo-N-(pyridin-4yl-methyl)pyrrolidine-2- carboxamide (3e) 6. 5- {[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-1 -yljcarbonyl} -1 -(3-bromo phenylmethyl)pyrrolidine-2-one (3^) 7. 5- {[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-1 -yljcarbonyl} -1 -(4-bromo phenylmethyl) pyrrolidine-2-one (3g) 8. 5- {[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-1 -yljcarbonyl}-1 -(4-methyl phenylmethyl)pyrrolidine-2-one (3h) 9. 5- {[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-1 -yljcarbonyl} -1 -(4-cyano phenylmethyl)pyrrolidine-2-one(3i) 10. 5- {[4-(N-t-butoxycarbonyl-aminomethyl)piperidin-1 -yljcarbonyl} -1 -(4-cyano phenylmethyl)pyrrolidine-2-one(3j) 11.5- {[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-1 -yljcarbonyl} -1 -[(E)-3- phenylprop-2-enylJpyrrolidine-2-one(3k) 12.5- {[4-(N-t-butoxycarbonyl-aminomethyl)piperidin-1 -yljcarbonyl} -1 -[(E)-3- phenylprop-2-enyl Jpyrrolidine-2-one (31) 13. 5- {[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-1 -yljcarbonyl}-1 -(3-phenyl propyl)pyrrolidine-2-one (3m) 14. 5-{[4-(N-t-butoxycarbonyl-aminomethyl)piperidin-1 -yljcarbonyl}-1 -(3-phenyl propyl)pyrrolidine-2-one (3n) 15.1 -phenylmethyl-5-oxo-N-(N-benzyloxycarbonylpiperidin-4yl-methyl)pyrrolidine-2-carboxamide (3o) 16.1 -(4-bromophenylmethyl)-5-oxo-N-(N-ben2yloxycarbonylpiperidin-4yl-methyl) pyrrolidine-2-carboxamide (3p) 17. 1 -[(E)-3phenylprop-2-enyl]-5-oxo-N-(N-benzyloxycarbonylpiperidin-4yl- methyl)pyrrolidene-2-carboxamide (3q) 18.1 -(3-phenylpropyl)-5-oxo-N-(piperidin-4yl-methyl)pyrrolidine-2-carboxamide (3r) 19. 5-{[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-1 -yl]carbonyl}-1 -(2,6 dichlorophenylmethyl)pyrrolidine~2-one(3s) 20. 1 -phenylmethyl-5- {[4-(2-fluorophenyl)piperazine-l -yl]carbonyl}pyrrolidine-2- one (3t) 21.1 -phenylmethyl-5- {[4-(3-chlorophenyl)piperazine-l -yl]carbonyl }pyrrolidine-2-one (3u) 22. l-phenylmethyl-5-{[4-(4-chloropkenyl)piperazine-l-yl]carbonyl}pyrrolidine-2- one (3v) 23. l-phenylmethyl-5-{[4-(4-methylphenyl)piperazine-l-yl]carbonyl}pyrrolidine-2- one (3w) 24. 1 -phenylmethyl-5-( {4-[4-(trifluoromethyl)phenyl]piperazine-l -yl} carbonyl) pyrrolidine-2-one (3x) (Table Remove) The following examples are given by the way of illustration and should not be construed to limit the scope of the present invention. Examplel 5-{[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-l-yl]carbonyl}-l-phenylmethyI pyrrolidine-2-one (3a) Acid la (2.2mmol, 0.50 gm.) and 1-hydroxybenzotriazole (3.3mmol, 0.44gm.) were dissolved in dry dichloromethane (80ml) in a three necked RBF fitted with a magnetic stirring bar, dry N2 inlet and rubber septa. The reaction mixture was cooled to 0° C (ice-salt bath), dicyclohexylcarbodiimide (2.6mmol, 0.54gm.) was added to it and the solution was magnetically stirred while being for 15 minutes. Amine 2c (2.2mmol, 0.48 gm.) dissolved in dry dichloromethane (20ml) was added drop wise to it and the stirring was continued for 2-3 hrs. at 0° C. The reaction mixture was then brought to the room temperature and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate, filtered and the filterate wa\| washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. Na2SC>4, and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D= +16.7 (c=0.43, CHC13); Mass m/z : 415 (M+) Example! 5-{[4-(N-t-butoxycarbonyI-ammomethyl) piperidin-1-yl] carbonyl}-l-phenylmethyl pyrrolidine-2-one (3b) Acid la (4.1mmol, 0.90 gm.) and 1-hydroxybenzotriazole (6.1mmol, 0.83gm.) were dissolved in dry dichloromethane (80ml) in a three necked RBF fitted with a magnetic stirring bar, dry N2 inlet and rubber septa. The reaction mixture was cooled to 0° C (ice-salt bath), dicyclohexylcarbodiimide (4.9mmol, l.Olgm.) was added to it and the solution was magnetically stirred while being for 15 minutes. Amine 2d (4.1mmol, 0.88 gm.) dissolved in dry dichloromethane (20ml) was added drop wise to it and the stirring was continued for 2-3 hrs. at 0° C. The reaction mixture was then brought to the room temperature and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate, filtered and the filterate was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. Na2SO4, and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D = -6.0 (c=0.13, MeOH); Mass m/z : 415 (M+) Examples 5-{[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-l-yl]carbonyI}-l-(2-chlorophenyl-methyl)pyrrolidine-2-one(3c) Acid Ic (1.9mmol, 0.50 gm.) and dry triethyl amine (5.7 mmol, 0.82 ml) were dissolved in dry dichloromethane (50ml) in an RBf fitted with a magnetic stirring bar. 2-chloro-l-methyl-pyridinium iodide (2.2mmol, 0.60 gm.) was added to it and the reaction mixture was set for refluxing for 2-3 hrs. during which a clear solution was obtained. The reaction mixture was cooled and Amine 2c (1.9mmol, 0.42 gm.) in dry dichloromethane (20ml) was added dropwise to it and again refluxed for 5-6 hrs. The reaction mixture was then brought to the room temperature and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. Na2SO4 and concentrated under reduced pressure.The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D = +2.5 (c=0.24, MeOH); Mass m/z : 448 [( M-l)+] Example4 5-{[4-(N-t-butoxycarbonyl-aminomethyl)piperldin-l-yl]carbonyl}-l-(2-methoxy phenylmethyl)pyrrolidine-2-one (3d) Acid Ib (2.0mmol, 0.50 gm.) and dry triethyl amine (4.0 mmol, 0.56 ml) were dissolved in dry THF (50ml) in a three necked RBF fitted with a magnetic stirring bar, dry N2 inlet and rubber septa. The reaction mixture was cooled to -20°C and magnetically stirred while being for 10 minutes. Isobutyl chloroformate (2.0mmol, 0.26 ml) was added dropwise to it at -20°C and the stirring was continued for 15 minutes. Now a solution of Amine 2d (2.0mmol, 0.43 gm.) in dry dichloromethane (20ml) was added dropwise to it in 10 minutes at -20°C. The reacton mixture was stirred for Ihr at 0°C to room temperature. The reaction mixture was quenched by adding saturated NFUCl solution and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 njl). The organic layer was separated, dried over anhyd.. NaaSC^ and concentrated under reduced pressure.The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D=+16.4 (c=0.18, MeOH); Mass m/z : 446 [(M+l)+] Examples l-(2-methoxyphenyImethyl)-5-oxo-N-(pyridiii-4yl-methyl)pyrrolidine-2-carboxamide (3e) Acid Ib (2.0mmol, 0.50 gm.) and dry triethyl amine (4.0 mmol, 0.56 ml) were dissolved in dry THF (50ml) in a three necked RBF fitted with a magnetic stirring bar, dry N2 inlet and rubber septa. The reaction mixture was cooled to -20°C and magnetically stirred while being for 10 minutes. Isobutyl chloroformate (2.0mmol, 0.26 ml) was added drop wise to it at -20°C and the stirring was continued for 15 minutes. Now a solution of Amine 2a (2.0mmol, 0.20ml) in dry dichloromethane (20ml) was added dropwise to it in 10 minutes at -20°C. The reacton mixture was stirred for Ihr at 0°C to room temperature. The reaction mixture was quenched by adding saturated NUjCl solution and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. Na2SO4 and concentrated under reduced pressure.The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D=-10.5 (c=0.31, MeOH); Mass m/z : 339 [ M+] Example6 5-{[3-(N-t-butoxycarbonyI-aminomethyl)piperidin-l-yl]carbonyl}-l-(3-bromo phenylmethyl)pyrrolidine-2-one (30 Acid Id (2.0mmol, 0.60 gm.), amine 2c (2.0mmol, 0.43 gm.) and diisopropylethyl amine (4.0 mmol, 0.70 ml) were dissolved in dry dichloromethane (80ml) in a three necked RBF fitted with a magnetic stirring bar, dry N2 inlet and rubber septa. The reaction mixture was cooled to 0° C (ice-salt bath) magnetically stirred while being for 10 minutes. A solution of Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (2.0 mmol, 1.04 gm.) in dry dichloromethane (20ml) was added drop wise to it and the stirring was continued for 2-3 hrs. at 0° C. The reaction mixture was then brought to the room temperature and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. Na2SO4) and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D = +2.5 (c=2.13, MeOH); Mass m/z : 494 (M+) Example? 5-{[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-l-yl]carbonyl}-l-(4-bromo phenylmethyl)pyrrolidine-2-one (3g) Acid le (2.0mmol, 0.60 gm.), amine 2c (2.0mmol, 0.43 gm.) and diisopropylethyl amine (4.0 mmol, 0.70 ml) were dissolved in dry dichloromethane (80ml) in a three necked RBF fitted with a magnetic stirring bar, dry N2 inlet and rubber septa. The reaction mixture was cooled to 0° C (ice-salt bath) magnetically stirred while being for 10 minutes. A solution of Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (2.0 mmol, 1.04 gm.) in dry dichloromethane (20ml) was added drop wise to it and the stirring was continued for 2-3 hrs. at 0° C. The reaction mixture was then brought to the room temperature and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. NaaSO^ and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D- +72.3 (c=0.33, CHC13); Mass m/z : 493 [(M-l)+] Example 8 5-{[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-l-yl]carbonyl}-l-(4-methyl phenylmethyl)pyrrolidine-2-one(3h) Acid Ig (2.1mmol, 0.50 gm.), amine 2c (2.1mmol, 0.46 gm.) and diisopropylethyl amine (4,2 mmol, 0.75 ml) were dissolved in dry dichloromethane (80ml) in a three necked RBF fitted with a magnetic stirring bar, dry N2 inlet and rubber septa. The reaction mixture was cooled to 0° C (ice-salt bath) magnetically stirred while being for 10 minutes. A solution of Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (2.1 mmol, 1.15 gm.) in dry dichloromethane (20ml) was added drop wise to it and the stirring was continued for 2-3 hrs. at 0° C. The reaction mixture was then brought to the room temperature and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. Na2S04, and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [ Example 9 5-{[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-l-yl]carbonyl}-l-(4-cyano phenylmethyl)pyrrolidine-2-one (3i) Acid If (2.0mmol, 0.50 gm.), amine 2c (2.0mmol, 0.44 gm.) and diisopropylethyl amine (4.0 mmol, 0.71 ml) were dissolved in dry dichloromethane (80ml) in a three necked RBF fitted with a magnetic stirring bar, dry NI inlet and rubber septa. The reaction mixture was cooled to 0° C (ice-salt hath) magnetically stirred while being for 10 minutes. A solution of Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (2.0 mmol, 1.06 gm.) in dry dichloromethane (20ml) was added drop wise to it and the stirring was continued for 2-3 hrs. at 0° C. The reaction mixture was then brought to the room temperature and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. Na2S04, and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [ct]D = -25.7 (c=0.07, MeOH); Mass m/z : 440 Example 10 5-{[4-(N-t-butoxycarbonyl-aminomethyl)piperidin-l-yl]carbonyl}-l-(4-cyano phenylmethyl)pyrrolidine-2-one(3j) Acid If (2.0mmol, 0.50 gm.), amine 2d (2.0mmol, 0.44 gm.) and diisopropylethyl amine (4.0 mmol, 0.71 ml) were dissolved in dry dichloromethane (80ml) in a three necked RBF fitted with a magnetic stirring bar, dry N2 inlet and rubber septa. The reaction mixture was cooled to 0° C (ice-salt bath) magnetically stirred while being for 10 minutes. A solution of Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (2.0 mmol, 1.06 gm.) in dry dichloromethane (20ml) was added drop wise to it and the stirring was continued for 2-3 hrs. at 0° C. The reaction mixture was then brought to the room temperature and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. NaaSO-i, and concentrated under reduced i pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D.-13.0 (c=0.20, MeOH);Oil; Mass nj/z : 440 (M+) Example!! 5-{[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-l-yl]carbonyl}-l-[(E)-3-phenyl prop-2-enyl]pyrrolidine-2-one (3k) Acid lh(2.0mmol, 0.50 gm.), amine 2c (2.0mmol, 0.44 grn.) and diisopropylethyl amine (4.0 mmol, 0.71 ml) were dissolved in dry dichloromethane (80ml) in a three necked RBF fitted with a magnetic stirring bar, dry N2 inlet and rubber septa. The reaction mixture was cooled to 0° C (ice-salt bath) magnetically stirred while being for 10 minutes. A solution of Benzotriazole-l-yl-oxy-tris-pyirolidino-phosphonium hexafluorophosphate (2.0 mmol, 1.06 grn.) in dry dichloromethane (20ml) was added drop wise to it and the stirring was continued for 2-3 hrs. at 0° C. The reaction mixture was then brought to the room temperature and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. Na2SO4, and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [ Examplel2 5-{[4-(N-t-butoxycarbonyI-aminomethyl)piperidin-l-yl]carbonyI}-l-[(E)-3-phenyl prop-2-enyl]pyrrolidine-2-one (31) Acid Ih (2.0mmol, 0.50 gm.), amine 2d (2.0mmol, 0.44 gm.) and diisopropylethyl amine (4.0 mmol, 0.71 ml) were dissolved in dry dichloromethane (80ml) in a three necked RBF fitted with a magnetic stirring bar, dry N2 inlet and rubber septa. The reaction mixture was cooled to 0° C (ice-salt bath) magnetically stirred while being for 10 minutes. A solution of Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (2.0 mmol, 1.06 gm.) in dry dichloromethane (20ml) was added drop wise to it and the stirring was continued for 2-3 hrs. at 0° C. The reaction mixture was then brought to the room temperature and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. NaiSO^ and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D- -7.9 (c=0.19, MeOH); Mass m/z : 441 (M+) Examplel3 5-{[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-l-yl]carbonyl}-l-(3-phenyl propyl)pyrrolidine-2-one (3m) Compound 3k (150 mg.) was dissolved in ethylacetate and taken in a Parr bottle. 5%Pd/C catalyst was added to it and set for hydrogenation at 60 psi for 2-3 hrs. After hydrogenation the reaction , the reaction mixture was filtered and the filterate was concentrated under reduced pressure.The compound thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [o]D- -6.0 (c=0.61, MeOH); Mass m/z : 443 (M+) Examplel4 5-{[4-(N-t-butoxycarbonyl-aminomethyl)piperidin-l-yl]carbonyl}-l-(3-phenyl propyl)pyrrolidlne-2-one (3n) , Compound 31 (150 mg.) was dissolved in ethylacetate and taken in a Parr bottle. 5%Pd/C catalyst was added to it and set for hydrogenation at 60 psi for 2-3 hrs. After hydrogenation the reaction , the reaction mixture was filtered and the filterate was concentrated under reduced pressure.The compound thus obtained was purified by column chromatography using ethyl acetate: hexane (4:1) as the eluant. [o]D. -9.4 (c=0.27, MeOH); Mass m/z : 443 (M+) ExamplelS l-phenylmethyl-5-oxo-N-(N-benzyloxyc«rbonylpiperidin-4yl-methyl)pyrrolidine-2-carboxamlde (3o) Acid la (2.2mmol, 0.50 gm.), amine 2b (2.2mmol, 0.56 gm.) and diisopropylethyl amine (4.4 mmol, 0.79 ml) were dissolved in dry dichloromethane (80ml) in a three necked RBF fitted with a magnetic stirring bar, dry NZ inlet and rubber septa. The reaction mixture was cooled to 0° C (ice-salt bath) magnetically stirred while being for 10 minutes. A solution of Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (2.2 mmol, 1.18 gm.) in dry dichloromethane (20ml) was added drop wise to it and the stirring was continued for 2-3 hrs. at 0° C. The reaction mixture was then brought to the room temperature and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. NaiSO^ and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant.. [ Examplel6 l-(4-bromophenylmethyl)-5-oxo-N-(N-benzyloxycarbonylpiperidin-4yl-methyl) pyrrolidine -2-carboxamide (3p) Acid le (l.Ommol, 0,30 gm.), amine 2b (jLOmmol, 0.25 gm.) and diisopropylethyl amine (2.0 mmol, 0.35 ml) were dissolved in dry dichloromethane (80ml) in a three necked RBF fitted with a magnetic stirring bar, dry NI inlet and rubber septa. The reaction mixture was cooled to 0° C (ice-salt bath) magnetically stirred while being for 10 minutes. A solution of Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (1.0 mmol, 0.52 gm.) in dry dichloromethane (20ml) was added drop wise to it and the stirring was continued for 2-3 hrs. at 0° C. The reaction mixture was then brought to the room temperature and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. NaaSO^ and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D= -2.5 (c=0.24, MeOH); Mass m/z : 529[( M+l)+] ExamplelT l-[(E)-3phenylprop-2-enyl]-5-oxo-N-(N-benzyloxycarbonylpiperidin-4yl-methyl) pyrrolidene-2-carboxamide (3q) Acid Ih (2.0mmol, 0.50 gm.), amine 2b (2.0mmol, 0.51 gm.) and diisopropylethyl amine (4.0 mmol, 0.71 ml) were dissolved in dry dichloromethane (80ml) in a three necked RBF fitted with a magnetic stirring bar, dry Na inlet and rubber septa. The reaction mixture was cooled to 0° C (ice-salt bath) magnetically stirred while being for 10 minutes. A solution of Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (2.0 mmol, 1.06 gm.) in dry dichloromethane (20ml) was added drop wise to it and the stirring was continued for 2-3 hrs. at 0° C. The reaction mixture was then brought to the room temperature and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. Na2SO4, and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [o]D- -3.6 (c=0.11, MeOH); Mass m/z : 475 (M+) ExamplelS l-(3-phenylpropyl)-5-oxo-N-(piperidin4yl-methyl)pyrrolidine-2-carboxamide(3r) Compound 3q (150mg.) was dissolved in ethylacetate and taken in a Parr bottle. 5%Pd/C catalyst was added to it and set for hydrogenation at 60 psi for 2-3 hrs. After hydrogenation the reaction, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The .compound thus obtained was purified by column chromatography using methanol:chloroform(l:24) as the eluant. [ct]D= +3.1 (c.=0.32, MeOH); Mass m/z : 343 Examplel9 5-{[3-{N-t-butoxycarbonyl-aminomethyl)piperidin-l-yI]carbonyl}-l-(2,6-dichloro phenylmethyl) pyrrolidine-2-one (3s) Acid li (Ummol, 0.50 gm.) and dry triethyl amine (5.1 mmol, 0.72 ml) were dissolved in dry dichloromethane (50ml) in an RBF fitted with a magnetic stirring bar. 2-chloro-l-methyl-pyridinium iodide (2.0mmol, 0.53 gm.) was added to it and the reaction mixture was set for refluxing for 2-3 hrs. during which a clear solution was obtained. The reaction mixture was cooled and Amine 2c (IJmmol, 0.37 gm.) in dry dichloromethane (20ml) was added dropwise to it and again refluxed for 5-6 hrs. The reaction mixture was then brought to the room temperature and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. NazSC^ and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D--26.5 (c=0.31, MeOH); Mass m/z : 484 (M4) Example20 l-phenylmethyl-5-{[4 (2 fluorophenyl)piperazine-l-yl]carbonyl}pyrrolidine-2-one (30 Acid la (4.5rnmol, 1.0 gm.) and dry triethyl amine (9.0 mmol, 1.27 ml) were dissolved in dry dioxane (50ml) in a three necked RBF fitted with a magnetic stirring bar, dry N2 inlet and rubber septa. The reaction mixture was cooled to -20°C and magnetically stirred while being for 10 minutes. Isobutyl chloroformate (4.5mmol, 0.60 ml) was added dropwise to it at -20°C and the stirring was continued for 15 minutes. Now a solution of l-(2-fluorophenyl)piperazine (4.5mmol, 0.72 ml) in dry dichloromethane (20ml) was added dropwise to it in 10 minutes at -2Q°C. The reacton mixture was stirred for Ihr at 0°C to room temperature. The reaction mixture was quenched by adding saturated NH4C1 solution and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. NajSC^ and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D = -22.6 (c=0.15, MeOH); Mass m/z : 382 [(M+l)+] Example! 1 l-phenylmethyl-5-{(4-(3-chlorophenyl)piperazine-l-yl]carbonyl}pyrrolidine-2-one (3u) Acid la (4.5mmol, 1.0 gm.) and dry triethyl amine (13.5 mmol, 1.91 ml) were dissolved in dry THF (50ml) in a three necked RBF fitted with a magnetic stirring bar, dry N2 inlet and rubber septa. The reaction mixture was cooled to -20°C and magnetically stirred while being for 10 minutes. Isobutyl chloroformate (4.5mmol, 0.60 ml) was added dropwise to it at -20°C and the stirring was continued for 15 minutes. Now a solution of l-(3-chlorophenyl)piperazine (4.5mmol, 1.06 gm.) in dry dichloromethane (20ml) was added dropwise to it in 10 minutes at -20°C. The reacton mixture was stirred for Ihr at 0°C to room temperature. The reaction mixture was quenched by adding saturated NHLtCl solution and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. Na2SO4 and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D - -21.4 (c=0.28, MeOH); Mass m/z : 398 (M) dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. Na2SO4 and concentrated under reduced pressure.The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D= -21.7 (c=0.23, MeOH); Mass m/z : 378 [(M+l)+] Example24 l-phenylmethyl-5-({4-[4-(trifluoromethyl)phenyl]piperazine-l-yl}carbonyl)pyrrolidine-2-one (3x) Acid la (4.5mmol, 1.0 gm.) and dry diethyl amine (13.5 mmol, 1.91 ml) were dissolved in dry dioxane (50ml) in a three necked RBF fitted with a magnetic stirring bar, dry N2 inlet and rubber septa. The reaction mixture was cooled to -20°C and magnetically stirred while being for 10 minutes. Isobutyl chloroformate (4.5mmol, 0.60 ml) was added dropwise to it at -20°C and the stirring was continued for 15 minutes. Now a solution of l-(4-trifluoromethylphenyl)piperazine (4.5mmol, 1.21gm.) in dry dichloromethane (20ml) was added dropwise to it in 10 minutes at -20°C. The reacton mixture was stirred for Ihr at 0°C to room temperature. The reaction mixture was quenched by adding saturated NUjCl solution and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. NaaSC^ and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D=-24.4 (c=0.32, MeOH); Mass m/z : 432 [( M+l)+] The advantages of the present invention is that it provides a new class of compounds which are thromibin inhibitors and are simpler than the existing standard drugs. The starting materials of the compounds of the present invention are cheap and easily available. The process described herein is simple, economically feasible and eco-fiiendly. Example22 l-phenylmethyl-S-{[4-(4-chIorophenyl)piperazine-l-yl]carbonyl}pyrrolidine-2-one (3v) Acid la (4.5mmol, 1.0 gm.) and dry triethyl amine (18.0 mmol, 2.55 ml) were dissolved in dry dioxane (50ml) in a three necked RBF fitted with a magnetic stirring bar, dry N2 inlet and rubber septa. The reaction mixture was cooled to -20°C and magnetically stirred while being for 10 minutes. Isobutyl chloroformate (4.5mmol, 0.60 ml) was added drop wise to it at -20°C and the stirring was continued for 15 minutes. Now a solution of l-(4-chlorophenyl)piperazine (4.5mmol, 1.23 gm.) in dry dichloromethane (20ml) was added dropwise to it in 10 minutes at -20°C. The reacton mixture was stirred for Ihr at 0°C to room temperature. The reaction mixture was quenched by adding saturated NRjCl solution and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. NajSC^ and;concentrated under reduced pressure.The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D = -29.5 (c=0.19, MeOH); Mass m/z : 398 (M+) Example23 l-phenylmethyl-5-{[4-(4-methylphenyl)piperazine-l-yl]carbonyl}pyrrolidine-2-one (3w) Acid la (4.5mmol, 1.0 gm.) and dry triethyl amine (18.0 mmol, 2.55 ml) were dissolved in dry dioxane (50ml) in a three necked RBF fitted with a magnetic stirring bar, dry NI inlet and rubber septa. The reaction mixture was cooled to -20°C and magnetically stirred while being for 10 minutes. Isobutyl chloroformate (4.5mmol, 0.60 ml) was added dropwise to it at -20°C and the stirring was continued for 15 minutes. Now a solution of l-(4-methylphenyl)piperazine (4.5mmol, 1.14 gm.) in dry dichloromethane (20ml) was added dropwise to it in 10 minutes at -20°C. The reacton mixture was stirred for Ihr at 0°C to room temperature. The reaction mixture was quenched by adding saturated NKUCl solution and concentrated under reduced pressure. The concentrate was We claim: 1. A novel l-arylalkyl-5-oxo-prolinalmide of general formula 3 useful as thrombin inhibitors and a process for the preparation of the same (Formula Removed) wherein R is selected from the group consisting of phenyl, o-methoxyphenyl, o-chlorophenyl, m-bromophenyl, p-bromophenyl, p-cyanophenyl, p-methy phenyl, 2-phenyl-1-ethenyl, o,o'-dichlorophenyl and 2-phenylethyl; R1 is H; R2 is selected from 4-pyridinyl methyl and N-(benzyloxycarbonyl)-4-piperidinyl methyl; R1R2 together is selected from -(CH2)„-CH(CH2NHCOOtBu)-(CH2)m-[where n=l, m=3 or n=2, m=2] and -(CH2)2-N(aryl)-CH2)2- and a process which comprises reacting one mole equivalent of l-ro-arylalkyl-5-oxo-proline of the general formula 1 of the drawing accompanying the specification R=phenyl, o-methoxyphenyl, o-chlorophenyl, m-bromophenyl, p-bromophenyl, p-cyanophenyl, p-methylphenyl, 2-phenyl-1-ethenyl, o,o'-dichlorophenyl or 2-ethylphenyl with one mole equivalent of the amine of the general formula 2 of the drawing accompanying the specification where R1=H, R2 = 4-pyridinyl methyl or N-(benzyloxycarbonyl)-4-piperidinyl methyl or R1R2 = -(CH2)n-CH(CH2NHCOOtBu)-(CH2)m-[where n=l, m=3 or n=2, m=2] or -(CH2)2-N(aryl)-CH2)2- in an aprotic solvent in the presence of a carboxylic activating or coupling agent, and a tertiary nitrogen base in the temperature range of -20°C to 40°C for a period range of 2-8 hrs. to give corresponding carboxamides of the formula 3 in the accompanying drawing and isolating the compounds by conventional methods. 2. A novel l-arylalkyl-5-oxo-prolinalmide useful as thrombin inhibitors and a process for the preparation of the same substantially as herein described with reference to examples and drawing accompanying this specification.

Full Text

The present invention relates to a novel l-arylalkyl-5-oxo-prolinamides useful as inhibitors of thrombin an enzyme important in the blood coagulation cascade. These compounds are useful in the treatment of coagulation disorders.
Thrombosis and its complication, embolism are a leading cause of morbidity and mortality in numerous cardio-vascular disorders including myocardial and cerebral infarction and thrombotic stroke. Thrombin (F Ha) is a trypsin like serine protease and a key enzyme in the blood coagulation cascade. Thrombin has a major role in the inhibition and propagation of fibrinogen, the natural substrate of thrombin dissolved in the blood plasma, to form fibrin, which can polymerize. Thrombin is also the main activator of platelet aggregation [ Ulrike obst etal, Helvetica Chimica Acta 83, 855 (2000); Anton E. P. Adang et al, Drugs of the Future 25(40, 369 (2000)].
The main objective of the present invention is to provide novel l-arylalkyl-5-oxo-prolinamides useful as inhibitors of the enzyme Thrombin. More particularly the present invention relates to the novel l-arylalkyl-5-oxo-prolinamides. These compounds are potentially useful in the treatment of blood coagulation disorders.
Another objective of the present invention is to provide a process for the preparation of novel l-arylalkyl-5-oxo-prolinamides of the general formula 3 (Figure-1).

Yet another objective of the present invention is to provide compounds useful in the treatment of cardiovascular disorders.
Accordingly the present invention provides a novel l-arylalkyl-5-oxo-prolinalmide of general formula 3 wherein R is selected from the group consisting of phenyl, o-methoxyphenyl, o-chlorophenyl, m-bromophenyl, p-bromophenyl, p-cyanophenyl, p-methy phenyl, 2-phenyl-l-ethenyl, o,o'-dichlorophenyl and 2-phenylethyl; RI is H; R2 is selected from 4-pyridinyl methyl and N-(benzyloxycarbonyl)-4-piperidinyl methyl; RjR2 together is selected from -(CH2)n-CH(CH2NHCOOtBu)-(CH2)m- [where n=l, m=3 or n=2, m=2] and -(CH2)2-N(aryl)-(CH2)2- .
The process used for this invention comprises of the reaction of one mole equivalent of 1-G)-arylalkyl-5-oxo-proline of the general formula 1, R = phenyl, o-methoxyphenyl, o-chlorophenyl, m-bromophenyl, p-bromophenyl, p-cyanophenyl, p-methylphenyl, 2-phenyl-1-ethenyl, o,o'-dichlorophenyl or 2-ethylphenyl with one mole equivalent of the amine of the general formula 2 where RI = H, R2 = 4-pyridinyl methyl or N-(benzyloxycarbonyl)-4-piperidinyl methyl or RiR2 = -(CH2)n-CH(CH2NHCOOtBu)-(CH2)m- [where n=l, m=3 or n=2, m=2] or -(CH2)2-N(aryl)-(CH2)2- in an aprotic solvent in the presence of a carboxylic activating or coupling agent, and a tertiary nitrogen base in the temperature range of -20°C to 40°C for a period range of 2-8 hrs. to give corresponding carboxamides of the formula 3 in the accompanying drawing and isolating the compounds by conventional methods.
The compounds prepared by this invention were tested for their effect on human Thrombin (Table- 1), and they inhibited the enzyme activity by 31-90 percent at 12-56 nmol concentration. The compounds were also effective under in vivo condition and showed beneficiary effects in various anti-coagulatory screens.

The representative compounds prepared by the process of the present invention are as follows
1. 5-{[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-1 -yljcarbonyl}-1 -
phenylmethyl pyrrolidine-2-one (3a)
2. 5- {[4-(N-t-butoxycarbonyl-aminomethyl)piperidin-1 -yl]carbonyl}-1 -
phenylmethyl pyrrolidine-2-one (3b)
3. 5-{[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-1 -yljcarbonyl}-1 -(2-chloro
phenylmethyl)pyrrolidine-2-one(3c)
4. 5- {[4-(N-t-butoxycarbonyl-aminomethyl)piperidin-1 -yljcarbonyl}-1 -(2-methoxy
phenylmethyl)pyrrolidine-2-one (3d)
5. 1 -(2-methoxyphenylmethyl)-5-oxo-N-(pyridin-4yl-methyl)pyrrolidine-2-
carboxamide (3e)
6. 5- {[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-1 -yljcarbonyl} -1 -(3-bromo
phenylmethyl)pyrrolidine-2-one (3^)
7. 5- {[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-1 -yljcarbonyl} -1 -(4-bromo
phenylmethyl) pyrrolidine-2-one (3g)
8. 5- {[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-1 -yljcarbonyl}-1 -(4-methyl
phenylmethyl)pyrrolidine-2-one (3h)
9. 5- {[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-1 -yljcarbonyl} -1 -(4-cyano
phenylmethyl)pyrrolidine-2-one(3i)
10. 5- {[4-(N-t-butoxycarbonyl-aminomethyl)piperidin-1 -yljcarbonyl} -1 -(4-cyano
phenylmethyl)pyrrolidine-2-one(3j)
11.5- {[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-1 -yljcarbonyl} -1 -[(E)-3-
phenylprop-2-enylJpyrrolidine-2-one(3k) 12.5- {[4-(N-t-butoxycarbonyl-aminomethyl)piperidin-1 -yljcarbonyl} -1 -[(E)-3-
phenylprop-2-enyl Jpyrrolidine-2-one (31)
13. 5- {[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-1 -yljcarbonyl}-1 -(3-phenyl
propyl)pyrrolidine-2-one (3m)
14. 5-{[4-(N-t-butoxycarbonyl-aminomethyl)piperidin-1 -yljcarbonyl}-1 -(3-phenyl
propyl)pyrrolidine-2-one (3n)

15.1 -phenylmethyl-5-oxo-N-(N-benzyloxycarbonylpiperidin-4yl-methyl)pyrrolidine-2-carboxamide (3o)
16.1 -(4-bromophenylmethyl)-5-oxo-N-(N-ben2yloxycarbonylpiperidin-4yl-methyl)
pyrrolidine-2-carboxamide (3p) 17. 1 -[(E)-3phenylprop-2-enyl]-5-oxo-N-(N-benzyloxycarbonylpiperidin-4yl-
methyl)pyrrolidene-2-carboxamide (3q) 18.1 -(3-phenylpropyl)-5-oxo-N-(piperidin-4yl-methyl)pyrrolidine-2-carboxamide
(3r)
19. 5-{[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-1 -yl]carbonyl}-1 -(2,6
dichlorophenylmethyl)pyrrolidine~2-one(3s)
20. 1 -phenylmethyl-5- {[4-(2-fluorophenyl)piperazine-l -yl]carbonyl}pyrrolidine-2-
one (3t)
21.1 -phenylmethyl-5- {[4-(3-chlorophenyl)piperazine-l -yl]carbonyl }pyrrolidine-2-one (3u)
22. l-phenylmethyl-5-{[4-(4-chloropkenyl)piperazine-l-yl]carbonyl}pyrrolidine-2-
one (3v)
23. l-phenylmethyl-5-{[4-(4-methylphenyl)piperazine-l-yl]carbonyl}pyrrolidine-2-
one (3w)
24. 1 -phenylmethyl-5-( {4-[4-(trifluoromethyl)phenyl]piperazine-l -yl} carbonyl)
pyrrolidine-2-one (3x)
(Table Remove)

The following examples are given by the way of illustration and should not be construed to limit the scope of the present invention.
Examplel
5-{[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-l-yl]carbonyl}-l-phenylmethyI pyrrolidine-2-one (3a)
Acid la (2.2mmol, 0.50 gm.) and 1-hydroxybenzotriazole (3.3mmol, 0.44gm.) were dissolved in dry dichloromethane (80ml) in a three necked RBF fitted with a magnetic stirring bar, dry N2 inlet and rubber septa. The reaction mixture was cooled to 0° C (ice-salt bath), dicyclohexylcarbodiimide (2.6mmol, 0.54gm.) was added to it and the solution was magnetically stirred while being for 15 minutes. Amine 2c (2.2mmol, 0.48 gm.) dissolved in dry dichloromethane (20ml) was added drop wise to it and the stirring was continued for 2-3 hrs. at 0° C. The reaction mixture was then brought to the room temperature and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate, filtered and the filterate wa| washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. Na2SC>4, and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D= +16.7 (c=0.43, CHC13); Mass m/z : 415 (M+)
Example!
5-{[4-(N-t-butoxycarbonyI-ammomethyl) piperidin-1-yl] carbonyl}-l-phenylmethyl pyrrolidine-2-one (3b)
Acid la (4.1mmol, 0.90 gm.) and 1-hydroxybenzotriazole (6.1mmol, 0.83gm.) were dissolved in dry dichloromethane (80ml) in a three necked RBF fitted with a magnetic stirring bar, dry N2 inlet and rubber septa. The reaction mixture was cooled to 0° C (ice-salt bath), dicyclohexylcarbodiimide (4.9mmol, l.Olgm.) was added to it and the solution was magnetically stirred while being for 15 minutes. Amine 2d (4.1mmol, 0.88 gm.) dissolved in dry dichloromethane (20ml) was added drop wise to it and the stirring was
continued for 2-3 hrs. at 0° C. The reaction mixture was then brought to the room temperature and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate, filtered and the filterate was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. Na2SO4, and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D = -6.0 (c=0.13, MeOH); Mass m/z : 415 (M+)
Examples
5-{[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-l-yl]carbonyI}-l-(2-chlorophenyl-methyl)pyrrolidine-2-one(3c)
Acid Ic (1.9mmol, 0.50 gm.) and dry triethyl amine (5.7 mmol, 0.82 ml) were dissolved in dry dichloromethane (50ml) in an RBf fitted with a magnetic stirring bar. 2-chloro-l-methyl-pyridinium iodide (2.2mmol, 0.60 gm.) was added to it and the reaction mixture was set for refluxing for 2-3 hrs. during which a clear solution was obtained. The reaction mixture was cooled and Amine 2c (1.9mmol, 0.42 gm.) in dry dichloromethane (20ml) was added dropwise to it and again refluxed for 5-6 hrs. The reaction mixture was then brought to the room temperature and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. Na2SO4 and concentrated under reduced pressure.The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D = +2.5 (c=0.24, MeOH); Mass m/z : 448 [( M-l)+]
Example4
5-{[4-(N-t-butoxycarbonyl-aminomethyl)piperldin-l-yl]carbonyl}-l-(2-methoxy phenylmethyl)pyrrolidine-2-one (3d)
Acid Ib (2.0mmol, 0.50 gm.) and dry triethyl amine (4.0 mmol, 0.56 ml) were dissolved in dry THF (50ml) in a three necked RBF fitted with a magnetic stirring bar, dry N2 inlet and rubber septa. The reaction mixture was cooled to -20°C and magnetically stirred while being for 10 minutes. Isobutyl chloroformate (2.0mmol, 0.26 ml) was added dropwise to it at -20°C and the stirring was continued for 15 minutes. Now a solution of Amine 2d (2.0mmol, 0.43 gm.) in dry dichloromethane (20ml) was added dropwise to it in 10 minutes at -20°C. The reacton mixture was stirred for Ihr at 0°C to room temperature. The reaction mixture was quenched by adding saturated NFUCl solution and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 njl). The organic layer was separated, dried over anhyd.. NaaSC^ and concentrated under reduced pressure.The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D=+16.4 (c=0.18, MeOH); Mass m/z : 446 [(M+l)+]
Examples
l-(2-methoxyphenyImethyl)-5-oxo-N-(pyridiii-4yl-methyl)pyrrolidine-2-carboxamide (3e)
Acid Ib (2.0mmol, 0.50 gm.) and dry triethyl amine (4.0 mmol, 0.56 ml) were dissolved in dry THF (50ml) in a three necked RBF fitted with a magnetic stirring bar, dry N2 inlet and rubber septa. The reaction mixture was cooled to -20°C and magnetically stirred while being for 10 minutes. Isobutyl chloroformate (2.0mmol, 0.26 ml) was added drop wise to it at -20°C and the stirring was continued for 15 minutes. Now a solution of Amine 2a (2.0mmol, 0.20ml) in dry dichloromethane (20ml) was added dropwise to it in
10 minutes at -20°C. The reacton mixture was stirred for Ihr at 0°C to room temperature. The reaction mixture was quenched by adding saturated NUjCl solution and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. Na2SO4 and concentrated under reduced pressure.The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D=-10.5 (c=0.31, MeOH); Mass m/z : 339 [ M+]
Example6
5-{[3-(N-t-butoxycarbonyI-aminomethyl)piperidin-l-yl]carbonyl}-l-(3-bromo phenylmethyl)pyrrolidine-2-one (30
Acid Id (2.0mmol, 0.60 gm.), amine 2c (2.0mmol, 0.43 gm.) and diisopropylethyl amine (4.0 mmol, 0.70 ml) were dissolved in dry dichloromethane (80ml) in a three necked RBF fitted with a magnetic stirring bar, dry N2 inlet and rubber septa. The reaction mixture was cooled to 0° C (ice-salt bath) magnetically stirred while being for 10 minutes. A solution of Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (2.0 mmol, 1.04 gm.) in dry dichloromethane (20ml) was added drop wise to it and the stirring was continued for 2-3 hrs. at 0° C. The reaction mixture was then brought to the room temperature and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. Na2SO4) and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D = +2.5 (c=2.13, MeOH); Mass m/z : 494 (M+)
Example?
5-{[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-l-yl]carbonyl}-l-(4-bromo phenylmethyl)pyrrolidine-2-one (3g)
Acid le (2.0mmol, 0.60 gm.), amine 2c (2.0mmol, 0.43 gm.) and diisopropylethyl amine (4.0 mmol, 0.70 ml) were dissolved in dry dichloromethane (80ml) in a three necked RBF fitted with a magnetic stirring bar, dry N2 inlet and rubber septa. The reaction mixture was cooled to 0° C (ice-salt bath) magnetically stirred while being for 10 minutes. A solution of Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (2.0 mmol, 1.04 gm.) in dry dichloromethane (20ml) was added drop wise to it and the stirring was continued for 2-3 hrs. at 0° C. The reaction mixture was then brought to the room temperature and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. NaaSO^ and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D- +72.3 (c=0.33, CHC13); Mass m/z : 493 [(M-l)+]
Example 8
5-{[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-l-yl]carbonyl}-l-(4-methyl phenylmethyl)pyrrolidine-2-one(3h)
Acid Ig (2.1mmol, 0.50 gm.), amine 2c (2.1mmol, 0.46 gm.) and diisopropylethyl amine (4,2 mmol, 0.75 ml) were dissolved in dry dichloromethane (80ml) in a three necked RBF fitted with a magnetic stirring bar, dry N2 inlet and rubber septa. The reaction mixture was cooled to 0° C (ice-salt bath) magnetically stirred while being for 10 minutes. A solution of Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (2.1 mmol, 1.15 gm.) in dry dichloromethane (20ml) was added drop wise to it and the stirring was continued for 2-3 hrs. at 0° C. The reaction mixture was then brought to the room temperature and concentrated under reduced pressure. The
concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. Na2S04, and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [ Example 9
5-{[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-l-yl]carbonyl}-l-(4-cyano phenylmethyl)pyrrolidine-2-one (3i)
Acid If (2.0mmol, 0.50 gm.), amine 2c (2.0mmol, 0.44 gm.) and diisopropylethyl amine (4.0 mmol, 0.71 ml) were dissolved in dry dichloromethane (80ml) in a three necked RBF fitted with a magnetic stirring bar, dry NI inlet and rubber septa. The reaction mixture was cooled to 0° C (ice-salt hath) magnetically stirred while being for 10 minutes. A solution of Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (2.0 mmol, 1.06 gm.) in dry dichloromethane (20ml) was added drop wise to it and the stirring was continued for 2-3 hrs. at 0° C. The reaction mixture was then brought to the room temperature and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. Na2S04, and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [ct]D = -25.7 (c=0.07, MeOH); Mass m/z : 440

Example 10
5-{[4-(N-t-butoxycarbonyl-aminomethyl)piperidin-l-yl]carbonyl}-l-(4-cyano phenylmethyl)pyrrolidine-2-one(3j)
Acid If (2.0mmol, 0.50 gm.), amine 2d (2.0mmol, 0.44 gm.) and diisopropylethyl amine (4.0 mmol, 0.71 ml) were dissolved in dry dichloromethane (80ml) in a three necked RBF fitted with a magnetic stirring bar, dry N2 inlet and rubber septa. The reaction mixture was cooled to 0° C (ice-salt bath) magnetically stirred while being for 10 minutes. A solution of Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (2.0 mmol, 1.06 gm.) in dry dichloromethane (20ml) was added drop wise to it and the stirring was continued for 2-3 hrs. at 0° C. The reaction mixture was then brought to the room temperature and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The
organic layer was separated, dried over anhyd.. NaaSO-i, and concentrated under reduced
i pressure. The crude material thus obtained was purified by column chromatography using
ethyl acetate : hexane (4:1) as the eluant.
[a]D.-13.0 (c=0.20, MeOH);Oil; Mass nj/z : 440 (M+)
Example!!
5-{[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-l-yl]carbonyl}-l-[(E)-3-phenyl prop-2-enyl]pyrrolidine-2-one (3k)
Acid lh(2.0mmol, 0.50 gm.), amine 2c (2.0mmol, 0.44 grn.) and diisopropylethyl amine (4.0 mmol, 0.71 ml) were dissolved in dry dichloromethane (80ml) in a three necked RBF fitted with a magnetic stirring bar, dry N2 inlet and rubber septa. The reaction mixture was cooled to 0° C (ice-salt bath) magnetically stirred while being for 10 minutes. A solution of Benzotriazole-l-yl-oxy-tris-pyirolidino-phosphonium hexafluorophosphate (2.0 mmol, 1.06 grn.) in dry dichloromethane (20ml) was added drop wise to it and the stirring was continued for 2-3 hrs. at 0° C. The reaction mixture was then brought to the room temperature and concentrated under reduced pressure. The

concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. Na2SO4, and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [ Examplel2
5-{[4-(N-t-butoxycarbonyI-aminomethyl)piperidin-l-yl]carbonyI}-l-[(E)-3-phenyl prop-2-enyl]pyrrolidine-2-one (31)
Acid Ih (2.0mmol, 0.50 gm.), amine 2d (2.0mmol, 0.44 gm.) and diisopropylethyl amine (4.0 mmol, 0.71 ml) were dissolved in dry dichloromethane (80ml) in a three necked RBF fitted with a magnetic stirring bar, dry N2 inlet and rubber septa. The reaction mixture was cooled to 0° C (ice-salt bath) magnetically stirred while being for 10 minutes. A solution of Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (2.0 mmol, 1.06 gm.) in dry dichloromethane (20ml) was added drop wise to it and the stirring was continued for 2-3 hrs. at 0° C. The reaction mixture was then brought to the room temperature and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. NaiSO^ and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D- -7.9 (c=0.19, MeOH); Mass m/z : 441 (M+)
Examplel3
5-{[3-(N-t-butoxycarbonyl-aminomethyl)piperidin-l-yl]carbonyl}-l-(3-phenyl propyl)pyrrolidine-2-one (3m)
Compound 3k (150 mg.) was dissolved in ethylacetate and taken in a Parr bottle. 5%Pd/C catalyst was added to it and set for hydrogenation at 60 psi for 2-3 hrs. After hydrogenation the reaction , the reaction mixture was filtered and the filterate was concentrated under reduced pressure.The compound thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [o]D- -6.0 (c=0.61, MeOH); Mass m/z : 443 (M+)
Examplel4
5-{[4-(N-t-butoxycarbonyl-aminomethyl)piperidin-l-yl]carbonyl}-l-(3-phenyl
propyl)pyrrolidlne-2-one (3n) ,
Compound 31 (150 mg.) was dissolved in ethylacetate and taken in a Parr bottle. 5%Pd/C catalyst was added to it and set for hydrogenation at 60 psi for 2-3 hrs. After hydrogenation the reaction , the reaction mixture was filtered and the filterate was concentrated under reduced pressure.The compound thus obtained was purified by column chromatography using ethyl acetate: hexane (4:1) as the eluant. [o]D. -9.4 (c=0.27, MeOH); Mass m/z : 443 (M+)
ExamplelS
l-phenylmethyl-5-oxo-N-(N-benzyloxyc«rbonylpiperidin-4yl-methyl)pyrrolidine-2-carboxamlde (3o)
Acid la (2.2mmol, 0.50 gm.), amine 2b (2.2mmol, 0.56 gm.) and diisopropylethyl amine (4.4 mmol, 0.79 ml) were dissolved in dry dichloromethane (80ml) in a three necked RBF fitted with a magnetic stirring bar, dry NZ inlet and rubber septa. The reaction mixture was cooled to 0° C (ice-salt bath) magnetically stirred while being for 10 minutes. A solution of Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium
hexafluorophosphate (2.2 mmol, 1.18 gm.) in dry dichloromethane (20ml) was added drop wise to it and the stirring was continued for 2-3 hrs. at 0° C. The reaction mixture was then brought to the room temperature and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. NaiSO^ and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant.. [ Examplel6
l-(4-bromophenylmethyl)-5-oxo-N-(N-benzyloxycarbonylpiperidin-4yl-methyl) pyrrolidine -2-carboxamide (3p)
Acid le (l.Ommol, 0,30 gm.), amine 2b (jLOmmol, 0.25 gm.) and diisopropylethyl amine (2.0 mmol, 0.35 ml) were dissolved in dry dichloromethane (80ml) in a three necked RBF fitted with a magnetic stirring bar, dry NI inlet and rubber septa. The reaction mixture was cooled to 0° C (ice-salt bath) magnetically stirred while being for 10 minutes. A solution of Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (1.0 mmol, 0.52 gm.) in dry dichloromethane (20ml) was added drop wise to it and the stirring was continued for 2-3 hrs. at 0° C. The reaction mixture was then brought to the room temperature and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. NaaSO^ and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D= -2.5 (c=0.24, MeOH); Mass m/z : 529[( M+l)+]
ExamplelT
l-[(E)-3phenylprop-2-enyl]-5-oxo-N-(N-benzyloxycarbonylpiperidin-4yl-methyl) pyrrolidene-2-carboxamide (3q)
Acid Ih (2.0mmol, 0.50 gm.), amine 2b (2.0mmol, 0.51 gm.) and diisopropylethyl amine (4.0 mmol, 0.71 ml) were dissolved in dry dichloromethane (80ml) in a three necked RBF fitted with a magnetic stirring bar, dry Na inlet and rubber septa. The reaction mixture was cooled to 0° C (ice-salt bath) magnetically stirred while being for 10 minutes. A solution of Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (2.0 mmol, 1.06 gm.) in dry dichloromethane (20ml) was added drop wise to it and the stirring was continued for 2-3 hrs. at 0° C. The reaction mixture was then brought to the room temperature and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. Na2SO4, and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [o]D- -3.6 (c=0.11, MeOH); Mass m/z : 475 (M+)
ExamplelS
l-(3-phenylpropyl)-5-oxo-N-(piperidin*4yl-methyl)pyrrolidine-2-carboxamide(3r)
Compound 3q (150mg.) was dissolved in ethylacetate and taken in a Parr bottle. 5%Pd/C catalyst was added to it and set for hydrogenation at 60 psi for 2-3 hrs. After hydrogenation the reaction, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The .compound thus obtained was purified by column chromatography using methanol:chloroform(l:24) as the eluant. [ct]D= +3.1 (c.=0.32, MeOH); Mass m/z : 343
Examplel9
5-{[3-{N-t-butoxycarbonyl-aminomethyl)piperidin-l-yI]carbonyl}-l-(2,6-dichloro phenylmethyl) pyrrolidine-2-one (3s)
Acid li (Ummol, 0.50 gm.) and dry triethyl amine (5.1 mmol, 0.72 ml) were dissolved in dry dichloromethane (50ml) in an RBF fitted with a magnetic stirring bar. 2-chloro-l-methyl-pyridinium iodide (2.0mmol, 0.53 gm.) was added to it and the reaction mixture was set for refluxing for 2-3 hrs. during which a clear solution was obtained. The reaction mixture was cooled and Amine 2c (IJmmol, 0.37 gm.) in dry dichloromethane (20ml) was added dropwise to it and again refluxed for 5-6 hrs. The reaction mixture was then brought to the room temperature and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. NazSC^ and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D--26.5 (c=0.31, MeOH); Mass m/z : 484 (M4)
Example20
l-phenylmethyl-5-{[4 (2 fluorophenyl)piperazine-l-yl]carbonyl}pyrrolidine-2-one
(30
Acid la (4.5rnmol, 1.0 gm.) and dry triethyl amine (9.0 mmol, 1.27 ml) were dissolved in dry dioxane (50ml) in a three necked RBF fitted with a magnetic stirring bar, dry N2 inlet and rubber septa. The reaction mixture was cooled to -20°C and magnetically stirred while being for 10 minutes. Isobutyl chloroformate (4.5mmol, 0.60 ml) was added dropwise to it at -20°C and the stirring was continued for 15 minutes. Now a solution of l-(2-fluorophenyl)piperazine (4.5mmol, 0.72 ml) in dry dichloromethane (20ml) was added dropwise to it in 10 minutes at -2Q°C. The reacton mixture was stirred for Ihr at 0°C to room temperature. The reaction mixture was quenched by adding saturated NH4C1 solution and concentrated under reduced pressure. The concentrate was dissolved in ethyl
acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. NajSC^ and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D = -22.6 (c=0.15, MeOH); Mass m/z : 382 [(M+l)+]
Example! 1
l-phenylmethyl-5-{(4-(3-chlorophenyl)piperazine-l-yl]carbonyl}pyrrolidine-2-one (3u)
Acid la (4.5mmol, 1.0 gm.) and dry triethyl amine (13.5 mmol, 1.91 ml) were dissolved in dry THF (50ml) in a three necked RBF fitted with a magnetic stirring bar, dry N2 inlet and rubber septa. The reaction mixture was cooled to -20°C and magnetically stirred while being for 10 minutes. Isobutyl chloroformate (4.5mmol, 0.60 ml) was added dropwise to it at -20°C and the stirring was continued for 15 minutes. Now a solution of l-(3-chlorophenyl)piperazine (4.5mmol, 1.06 gm.) in dry dichloromethane (20ml) was added dropwise to it in 10 minutes at -20°C. The reacton mixture was stirred for Ihr at 0°C to room temperature. The reaction mixture was quenched by adding saturated NHLtCl solution and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. Na2SO4 and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D - -21.4 (c=0.28, MeOH); Mass m/z : 398 (M*)
dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. Na2SO4 and concentrated under reduced pressure.The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D= -21.7 (c=0.23, MeOH); Mass m/z : 378 [(M+l)+]
Example24
l-phenylmethyl-5-({4-[4-(trifluoromethyl)phenyl]piperazine-l-yl}carbonyl)pyrrolidine-2-one (3x)
Acid la (4.5mmol, 1.0 gm.) and dry diethyl amine (13.5 mmol, 1.91 ml) were dissolved in dry dioxane (50ml) in a three necked RBF fitted with a magnetic stirring bar, dry N2 inlet and rubber septa. The reaction mixture was cooled to -20°C and magnetically stirred while being for 10 minutes. Isobutyl chloroformate (4.5mmol, 0.60 ml) was added dropwise to it at -20°C and the stirring was continued for 15 minutes. Now a solution of l-(4-trifluoromethylphenyl)piperazine (4.5mmol, 1.21gm.) in dry dichloromethane (20ml) was added dropwise to it in 10 minutes at -20°C. The reacton mixture was stirred for Ihr at 0°C to room temperature. The reaction mixture was quenched by adding saturated NUjCl solution and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. NaaSC^ and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D=-24.4 (c=0.32, MeOH); Mass m/z : 432 [( M+l)+]
The advantages of the present invention is that it provides a new class of compounds which are thromibin inhibitors and are simpler than the existing standard drugs. The starting materials of the compounds of the present invention are cheap and easily available. The process described herein is simple, economically feasible and eco-fiiendly.

Example22
l-phenylmethyl-S-{[4-(4-chIorophenyl)piperazine-l-yl]carbonyl}pyrrolidine-2-one (3v)
Acid la (4.5mmol, 1.0 gm.) and dry triethyl amine (18.0 mmol, 2.55 ml) were dissolved in dry dioxane (50ml) in a three necked RBF fitted with a magnetic stirring bar, dry N2 inlet and rubber septa. The reaction mixture was cooled to -20°C and magnetically stirred while being for 10 minutes. Isobutyl chloroformate (4.5mmol, 0.60 ml) was added drop wise to it at -20°C and the stirring was continued for 15 minutes. Now a solution of l-(4-chlorophenyl)piperazine (4.5mmol, 1.23 gm.) in dry dichloromethane (20ml) was added dropwise to it in 10 minutes at -20°C. The reacton mixture was stirred for Ihr at 0°C to room temperature. The reaction mixture was quenched by adding saturated NRjCl solution and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and was washed successively with dil. citric acid (3 x 50ml), dil sodium bicarbonate solution (3 x50 ml) and brine (1 x 50 ml). The organic layer was separated, dried over anhyd.. NajSC^ and;concentrated under reduced pressure.The crude material thus obtained was purified by column chromatography using ethyl acetate : hexane (4:1) as the eluant. [a]D = -29.5 (c=0.19, MeOH); Mass m/z : 398 (M+)
Example23 l-phenylmethyl-5-{[4-(4-methylphenyl)piperazine-l-yl]carbonyl}pyrrolidine-2-one
(3w)
Acid la (4.5mmol, 1.0 gm.) and dry triethyl amine (18.0 mmol, 2.55 ml) were dissolved in dry dioxane (50ml) in a three necked RBF fitted with a magnetic stirring bar, dry NI inlet and rubber septa. The reaction mixture was cooled to -20°C and magnetically stirred while being for 10 minutes. Isobutyl chloroformate (4.5mmol, 0.60 ml) was added dropwise to it at -20°C and the stirring was continued for 15 minutes. Now a solution of l-(4-methylphenyl)piperazine (4.5mmol, 1.14 gm.) in dry dichloromethane (20ml) was added dropwise to it in 10 minutes at -20°C. The reacton mixture was stirred for Ihr at 0°C to room temperature. The reaction mixture was quenched by adding saturated NKUCl solution and concentrated under reduced pressure. The concentrate was

We claim:
1. A novel l-arylalkyl-5-oxo-prolinalmide of general formula 3 useful as thrombin inhibitors and a process for the preparation of the same
(Formula Removed)
wherein R is selected from the group consisting of phenyl, o-methoxyphenyl, o-chlorophenyl, m-bromophenyl, p-bromophenyl, p-cyanophenyl, p-methy phenyl, 2-phenyl-1-ethenyl, o,o'-dichlorophenyl and 2-phenylethyl; R1 is H; R2 is selected from 4-pyridinyl methyl and N-(benzyloxycarbonyl)-4-piperidinyl methyl; R1R2 together is selected from -(CH2)„-CH(CH2NHCOOtBu)-(CH2)m-[where n=l, m=3 or n=2, m=2] and -(CH2)2-N(aryl)-CH2)2- and a process which comprises reacting one mole equivalent of l-ro-arylalkyl-5-oxo-proline of the general formula 1 of the drawing accompanying the specification R=phenyl, o-methoxyphenyl, o-chlorophenyl, m-bromophenyl, p-bromophenyl, p-cyanophenyl, p-methylphenyl, 2-phenyl-1-ethenyl, o,o'-dichlorophenyl or 2-ethylphenyl with one mole equivalent of the amine of the general formula 2 of the drawing accompanying the specification where R1=H, R2 = 4-pyridinyl methyl or N-(benzyloxycarbonyl)-4-piperidinyl methyl or R1R2 = -(CH2)n-CH(CH2NHCOOtBu)-(CH2)m-[where n=l, m=3 or n=2, m=2] or -(CH2)2-N(aryl)-CH2)2- in an aprotic solvent in the presence of a carboxylic activating or coupling agent, and a tertiary nitrogen base in the temperature range of -20°C to 40°C for a period range of 2-8 hrs. to give corresponding carboxamides of the formula 3 in the accompanying drawing and isolating the compounds by conventional methods.

2. A novel l-arylalkyl-5-oxo-prolinalmide useful as thrombin inhibitors and a process for the preparation of the same substantially as herein described with reference to examples and drawing accompanying this specification.

Documents:

1196-DEL-2001-Abstract-(12-01-2007).pdf

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1196-DEL-2001-Claims-(12-01-2007).pdf

1196-del-2001-claims.pdf

1196-DEL-2001-Correspondence-Others-(12-01-2007).pdf

1196-del-2001-correspondence-others.pdf

1196-del-2001-correspondence-po.pdf

1196-del-2001-description (complete).pdf

1196-DEL-2001-Drawings-(12-01-2007).pdf

1196-del-2001-drawings.pdf

1196-del-2001-form-1.pdf

1196-del-2001-form-18.pdf

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Patent Number

235205

Indian Patent Application Number

1196/DEL/2001

PG Journal Number

31/2009

Publication Date

31-Jul-2009

Grant Date

29-Jun-2009

Date of Filing

29-Nov-2001

Name of Patentee

COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH

Applicant Address

RAFI MARG, NEW DELHI-110 001,INDIA

Inventors:

#	Inventor's Name	Inventor's Address
1	DINESH KUMAR DIKSHIT	CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226 001 (U.P)
2	MADHU DIKSHIT	CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226 001 (U.P)
3	STUTI SRIVASTAVA	CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226 001 (U.P)
4	PRASHANT SHARMA	CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226 001 (U.P)

PCT International Classification Number

A61K 31/401

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA