Process for preparation of indolizine based derivatives as potential phosphodiestrase 3 (PDE3) inhibitors

Abstract

The present invention provides compounds of general formula 1 useful as potential phosphodiesterase3 (PDE3) inhibitory agents and a process for the preparation thereof. The derivatives of formula 1 can be employed as therapeutics in human and veterinary medicine, where they can be used, for example, for the treatment and prophylaxis of the following diseases: heart failure, dilated cardiomyopathy, platelet inhibitors, cancer and obstructive pulmonary diseases. ##STR00001##

Claims

1. A process for preparation of a compound of formula 1 ##STR00033## wherein Z is COOC.sub.2H.sub.5, and R is a substituted phenyl of formula: ##STR00034## wherein A=H, alkyl, alkoxy, halo B=H, alkyl, alkoxy, halo C=H, alkyl, alkoxy, halo said process comprising a. reacting a substituted aromatic aldehyde of formula 2 ##STR00035## wherein A, B, and C are as above, with an olefin of formula 3 ##STR00036## wherein Z is COOC.sub.2H.sub.5 in the presence of a catalyst with stirring, and isolating a compound of formula 4; ##STR00037## wherein A., B, C, and Z are as above, b, adding pyridine to said compound of formula 4 in the presence of an organic solvent, under an argon atmosphere, followed by adding an acetylchloride and isolating the acetylated compound of formula 5; which forms ##STR00038## wherein A, B. C, and Z are as above, and c. reacting said acetylated compound of formula 5 with a substituted 2-pyrolidine-2-ylidene acetate of formula 6 a wherein Z is COOC.sub.2H.sub.5 in presence of an organic solvent and a base, and isolating a compound of formula 1 ##STR00039##

2. The process as claimed in claim 1, wherein said catalyst is selected from the group consisting of quinuclidine 3-HQD (3-hydroxy quinuclidine), 3-quinuclidone, DBU, pyrrocoline, DMAP (dimethylaminopyride), TMPDA (N,N,N.sup.1,N.sup.1-tetramethyl-1,3-propanediamine), imidazole, TMG (tetramethyl guanidine), triethyl amine, dimethyl sulfide/TiCl.sub.4, TiCl.sub.4, trialkylphosphines and RhH(PPh.sub.3).sub.4.

3. The process as claimed in claim 1, comprising reacting the substituted aromatic aldehyde of formula 2 and said olefin at a temperature ranging from 25 C. to 35 C.

4. The process as claimed in claim 1, comprising reacting said acetylchloride and said compound of formula 4 in the presence of an organic solvent and a base at 0 C. for a time period of from 10 minutes to 20 minutes and reacting said solution and said compound of formula 4 at 25-35 C. for 1-2 hours.

5. The process as claimed in claim 1, comprising reacting said compound of formula 6 a and said compound of formula 5 at 0 C. for 3 hours.

6. The process of claim 1, wherein said compound of formula 1 is: ##STR00040## ##STR00041##

7. The process as claimed in claim 1, wherein said base is selected from the group consisting of NaH(100%), NaH(60%), NaOMe, NaOEt and t-BuOK.

8. The process as claimed in claim 1, wherein said organic solvents of steps b and c are selected from the group consisting of tetrahydrofhran, acetonitrile and dimethylformamide.

9. The process as claimed in claim 1, wherein said compound of formula 4 is selected from the group consisting of ethyl 2-(hydroxyl(phenyl)methyl)acrylate, ethyl 2-((fluorophenyl)(hydroxyl)methyl)acrylate, ethyl 2-((3-fluorophenyl)hydroxyl)methyl)acrylate, ethyl-2-((4-fluorophenyl)(hydroxul)methy)pacrylate, ethyl 2-((2-chlorophenyl)hydroxyl)methyl)acrylate, ethyl 2-((3-chlorophenyl)(hydroxyl)methyl)acrylate, ethyl 2-((4-chlorophenyl)(hydroxyl)methyl)acrylate, ethyl 2((2,4-dichlorophenyl)hydroxyl)methyl)acrylate, ethyl 2-((bromophenyl)(hydroxyl)methyl)acrylate, ethyl-2-(hydroxyl(2-(trifluoromethyl)phenyl)methyl)acrylate, ethyl-2(hydroxyl(4(trifluoromethyl)phenyl)methyl)acrylate and ethyl 2-(hydroxyl(p-tolyl)methyl)acrylate.

10. The process as claimed in claim 1, wherein said compound of formula 5 is selected from the group consisting of ethyl 2-(acetoxy(phenyl)methyl)acrylate, ethyl 2-(acetoxy (2-fluorophenyl)methyl)methyl)acrylate,ethyl 2-(acetoxy(3-fluorophenyl)methyl)acrylate and ethyl2-(acetoxy(2-fluorophenyl)methyl)acrylate.

11. The process of claim 4, wherein said base is pyridine.

Description

BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS

(1) FIG. 1: Scheme 1 illustrates the process for preparation of compound of formula 5.

(2) FIG. 2: Scheme 2 illustrates the process for preparation of compound of formula 1.

DETAILED DESCRIPTION OF THE INVENTION

(3) The precursor substituted aromatic aldehydes (2a-p), activated olefines (3a) and 1,4-diazabicyclo[2.2.2]octane (DABCO) are commercially available and indolizines (1a-p) of formula have been prepared as illustrated in the Schemes (1-2).

(4) i. The substituted aromatic aldehydes (2a-p) reacted with the activated olefins (3a) using DABCO at room temperature (25-35 C.) for 10-12 h to obtain desired Baylis-Hillman adducts (4a-p).

(5) ii. To a solution of Baylis-Hillman adducts (4a-p) in dichloromethane at 0 C., under argon atmosphere pyridine was added after 10 min acetyl chloride, was added and allow it to stir at room temperature (25-35 C.) for 2 h to obtain desired acetylated Baylis-Hillman adducts (5a-p).

(6) All the indolizine based derivatives have been synthesized and were purified by column chromatography using solvents like ethyl acetate, hexane, chloroform and methanol.

(7) Procedure of Indolizine formations: To a solution of NaH (60% in paraffin oil) and dry THF (Z)-ethyl 2-(pyrrolidin-2-ylidene)acetate (6a) was added at 0 C. under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adducts (5a-p) in dry THF was added slowly and allowed to stir at ambient temperature for 3 h. After completion of the reaction solvent was removed under reduced pressure and the residue was diluted with ice cold-water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, solvent evaporated under reduced pressure and purified by column chromatography by using silica gel with ethylacetate/hexane as eluent.

(8) These new analogues of indolizine based derivatives were screened for their phosphodiesterase3 (PDE3) inhibition activity and found as potential phosphodiesterase3 inhibitors. The synthesized molecules presented here are of immense biological significance.

(9) ##STR00015## ##STR00016##
General Procedure for the Preparation Baylis-Hillman Adducts (4a-p)

(10) Substituted aromatic aldehydes (2a-p) (10 mmol), activated olefin (3a) (20 mmol) and DABCO (30 mol % with respect to aldehyde) were mixed and allowed to stir at room temperature until completion of the reaction (TLC), 10-12 h. After completion, the reaction mixture was diluted with water (15 mL) and extracted with ether (325 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, solvent was removed under reduced pressure and purified by column chromatography using 10% EtOAc in hexane as eluent to afford pure Baylis-Hillman adducts (4a-p) in 80-90% yield.

(11) IUPAC Names of the Baylis-Hillman Adducts (4a-p)

(12) ethyl 2-(hydroxy(phenyl)methyl)acrylate (4a) ethyl 2-((2-fluorophenyl)(hydroxy)methyl)acrylate (4b) ethyl 2-((3-fluorophenyl)(hydroxy)methyl)acrylate (4c) ethyl 2-((4-fluorophenyl)(hydroxy)methyl)acrylate (4d) ethyl 2-((2-chlorophenyl)(hydroxy)methyl)acrylate (4e) ethyl 2-((3-chlorophenyl)(hydroxy)methyl)acrylate (4f) ethyl 2-((4-chlorophenyl)(hydroxy)methyl)acrylate (4g) ethyl 2-((2,4-dichlorophenyl)(hydroxy)methyl)acrylate (4h) ethyl 2-((2-bromophenyl)(hydroxy)methyl)acrylate (4i) ethyl 2-((3-bromophenyl)(hydroxy)methyl)acrylate (4j) ethyl 2-((4-bromophenyl)(hydroxy)methyl)acrylate (4k) ethyl 2(hydroxy(2-(trifluoromethyl)phenyl)methyl)acrylate (4l) ethyl 2-(hydroxy(4-(trifluoromethyl)phenyl)methyl)acrylate (4m) ethyl 2-(hydroxy(p-tolyl)methyl)acrylate (4n) ethyl 2-((4-ethylphenyl)(hydroxy)methyl)acrylate (4o) ethyl 2-(hydroxy(4-isopropylphenyl)methyl)acrylate (4p)
General Procedure for the Preparation of Acetylated Baylis-Hillman Adducts (5a-p)

(13) To a well stirred solution of Baylis-Hillman adduct (4a-p) (10 mmol) in dichloromethane (30 mL) at 0 C. under argon atmosphere pyridine (11 mmol) was added slowly and stirred for 10 min. Then acetyl chloride (11 mmol) was added and allowed to stir at room temperature until the reaction completed (TLC) 1-2 h. After completion of the reaction, diluted the reaction with water (15 mL) and extracted with dichloromethane (225 ml). The combined organic layers were washed with sat. CuSO.sub.4 solution until pyridine removed, then the layers were separated and dried over Na.sub.2SO.sub.4, solvent was removed under reduced pressure. The resulting residue was subjected to column chromatography using 5% EtOAc in hexane as eluent to afford pure compounds acetylated Baylis-Hillman adducts (5a-p) in 90-95% yield.

(14) IUPAC Names of the Acetylated Baylis-Hillman Adducts (5a-p)

(15) ethyl 2-(acetoxy(phenyl)methyl)acrylate (5a) ethyl 2-(acetoxy(2-fluorophenyl)methyl)acrylate (5b) ethyl 2-(acetoxy(3-fluorophenyl)methyl)acrylate (5c) ethyl 2-(acetoxy(4-fluorophenyl)methyl)acrylate (5d) ethyl 2-(acetoxy(2-chlorophenyl)methyl)acrylate (5e) ethyl 2-(acetoxy(3-chlorophenyl)methyl)acrylate (5f) ethyl 2-(acetoxy(4-chlorophenyl)methyl)acrylate (5g) ethyl 2-(acetoxy(2,4-dichlorophenyl)methyl)aerylate (5h) ethyl 2-(acetoxy(2-bromophenyl)methyl)aerylate (5i) ethyl 2-(acetoxy(3-bromophenyl)methyl)acrylate (5j) ethyl 2-(acetoxy(4-bromophenyl)methyl)acrylate (5k) ethyl 2-(acetoxy(2-(trifluoromethyl)phenyl)methyl)acrylate (5l) ethyl 2-(acetoxy(4-(trifluoromethyl)phenyl)methyl)acrylate (5m) ethyl 2-(acetoxy(p-tolyl)methyl)acrylate (5n) ethyl 2-(acetoxy(4-ethylphenyl)methyl)acrylate (5o) ethyl 2-(acetoxy(4-isopropylphenyl)methyl)acrylate (5p)

EXAMPLES

(16) The following examples are given by way of illustration.

Example 1

(17) ##STR00017##

Ethyl 6-benzyl-5-oxo-1,2,3,5-tetrahydro-8-indolizinecarboxylate (1a)

(18) To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) and dry THF (5 mL) (Z)-ethyl 2-(pyrrolidin-2-ylidene)acetate (6a) (155 mg, 1 mmol) was added slowly at 0 C. under argon atmosphere and stirred for 15 min. Then ethyl 2-(acetoxy(phenyl)methyl)acrylate (5a) (246 mg, 1 mmol) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (310 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 1a as white solid (212 mg, 72% yield).

(19) .sup.1H NMR (300 MHz, CDCl.sub.3): 7.62 (s, 1H), 7.25-7.14 (m, 4H), 4.25 (q, J=7.0 Hz, 2H), 4.14 (t, J=7.5 Hz, 2H), 3.80 (s, 2H), 3.49 (t, J=7.9 Hz, 2H), 2.26-2.16 (m, 2H), 1.33 (t, J=Hz, J=7.0 Hz, 3H); .sup.13C NMR (75 MHz, CDCl.sub.3): 165.0, 161.9, 155.0, 139.5, 137.4, 129.1, 129.0, 128.4, 126.2, 105.4, 60.6, 49.2, 36.0, 33.6, 20.8, 14.3; MS (ESI); m/z 298 [M+H].sup.+; HRMS (ESI): m/z [M+H].sup.+ calculated for C.sub.18H.sub.20NO.sub.3; 298.1443; found: 298.1456.

Example 2

(20) ##STR00018##

Ethyl 6-(2-fluorobenzyl)-5-oxo-1,2,3,5-tetrahydro-8-indolizinecarboxylate (1b)

(21) To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) and dry THF (5 mL) (Z)-ethyl 2-(pyrrolidin-2-ylidene)acetate (6a) (155 mg, 1 mmol) was added slowly at 0 C. under argon atmosphere and stirred for 15 min. Then ethyl 2-(acetoxy(2-fluorophenyl)methyl)acrylate (5b) (264 mg, 1 mmol) (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (310 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 1b as pale yellow solid (234 mg, 75% yield).

(22) .sup.1H NMR (75 MHz, CDCl.sub.3); 7.66 (s, 1H), 7.36-6.96 (m, 4H), 4.25 (q, J=7.0 Hz, 3H), 4.14 (t, J=7.5 Hz, 2H), 3.84 (s, 2H), 3.49 (t, J=7.9 Hz, 2H), 2.26-2.19 (m, 3H), 1.33 (t, J=7.0 Hz, 3H); .sup.13C NMR (75 MHz, CDCl.sub.3): 161.8, 155.3, 137.7, 129.6, 128.2, 124.6, 124.6, 115.8, 115.5, 113.2, 112.9, 105.4, 60.6, 49.2, 35.7, 33.6, 20.7, 14.3; MS (ESI): m/z 316 [M+H].sup.+; HRMS (ESI): m/z [M+H].sup.+ calculated for C.sub.18H.sub.19NO.sub.3F: 316.1348; found: 316.1353.

Example 3

(23) ##STR00019##

Ethyl 6-(3-fluorobenzyl)-5-oxo-1,2,3,5-tetrahydro-8-indolizinecarboxylate (1c)

(24) To a well stirred solution of NaH (60% in paraffin oil, 115 xmg, 3 mmol) and dry THF (5 mL) (Z)-ethyl 2-(pyrrolidin-2-ylidene)acetate (6a) (155 mg, 1 mmol) was added slowly at 0 C. under argon atmosphere and stirred for 15 min. Then ethyl 2-(acetoxy(3-fluorophenyl)methyl)acrylate (5c) (264 mg, 1 mmol) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (310 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3c as pale yellow solid (229 mg, 73% yield).

(25) .sup.1H NMR (300 MHz, CDCl.sub.3): 7.73 (s, 1H), 7.27-6.85 (m, 4H), 4.29 (q, J=7.1 Hz, 2H), 4.16 (t, J=7.1 Hz, 2H), 3.84 (s, 2H), 3.51 (t, J=7.7 Hz, 2H), 2.26-2.16 (m, 2H); 1.34 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl.sub.3): 164.9, 161.8, 155.4, 137.7, 129.8, 129.7, 128.2, 124.6, 115.6, 113.3, 113.0, 60.7, 49.3, 35.8, 33.7, 20.8, 14.4; MS (ESI): m/z 316 [M+H].sup.+; HRMS (ESI): m/z [M+H].sup.+ calculated for C.sub.18H.sub.19NO.sub.3F: 316.1348; found: 316.1336.

Example 4

(26) ##STR00020##

Ethyl 6-(4-fluorobenzyl)-5-oxo-1,2,3,5-tetrahydro-8-indolizinecarboxylate (1d)

(27) To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) and dry THF (5 mL) (Z)-ethyl 2-(pyrrolidin-2-ylidene)acetate (6a) (155 mg, 1 mmol) was added slowly at 0 C. under argon atmosphere and stirred for 15 min. Then ethyl 2-(acetoxy(4-fluorophenyl)methyl)acrylate (5d) (264 mg, 1 mmol) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (310 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 1d as ash colour solid (238 mg, 76% yield).

(28) .sup.1H NMR (300 MHz, CDCl.sub.3): 7.69 (s, 1H), 7.27-6.91 (m, 4H), 4.28 (q, J=7.1 Hz, 2H), 4.15 (t, J=7.3 Hz, 2H), 3.80 (s, 2H), 3.50 (t, J=7.9 Hz, 2H), 2.26-2.15 (m, 2H), 1.34 (t, J=7.1 Hz, 3H), .sup.13C NMR (75 MHz, CDCl.sub.3): 164.9, 161.8, 155.1, 137.3, 130.4, 130.3, 128.8, 115.2, 114.9, 105.4, 60.6, 49.2, 35.3, 33.6, 20.7, 14.3; MS (ESI): m/z 316 [M+H].sup.+; HRMS (ESI); m/z [M+H].sup.+ calculated for C.sub.18H.sub.19 NO.sub.3F: 316.1348; found: 316.1335.

Example 5

(29) ##STR00021##

Ethyl 6-(2-chlorobenzyl)-5-oxo-1,2,3,5-tetrahydro-8-indolizinecarboxylate (1e)

(30) To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) and dry THF (5 mL) (Z)-ethyl 2-(pyrrolidin-2-ylidene)acetate (6a) (155 mg, 1 mmol) was added slowly at 0 C. under argon atmosphere and stirred for 15 min. Then ethyl 2-(acetoxy(2-chlorophenyl)methyl)acrylate (5e) (280 mg, 1 mmol) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (310 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 1e as ash colour solid (240 mg, 73% yield).

(31) .sup.1H NMR (300 MHz, CDCl.sub.3): 7.61 (s, 1H), 736-7.10 (m, 4H), 4.24 (q, J=6.7 Hz, 2H), 4.15 (t, J=7.5 Hz, 2H), 3.93 (s, 2H), 3.49 (t, J=8.3 Hz, 2H), 2.27-2.16 (m, 2H), 1.31 (t, J=6.7 Hz, 3H); .sup.13C NMR (75 MHz, CDCl.sub.3): 164.9, 161.8, 155.0, 137.7, 136.7, 134.3, 131.4, 129.4, 127.8, 127.0, 126.7, 105.4, 60.6, 49.2, 33.6, 33.5, 20.7, 14.3; MS (ESI): m/z 332 [M+H].sup.+; HRMS (ESI): m/z [M+H].sup.+ calculated for C.sub.18H.sub.19NO.sub.3Cl: 332.1053; found: 332.1038.

Example 6

(32) ##STR00022##

Ethyl 6-(3-chlorobenzyl)-5-oxo-1,2,3,5-tetrahydro-8-indolizinecarboxylate (1f)

(33) To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) and dry THF (5 mL) (Z)-ethyl 2-(pyrrolidin-2-ylidene)acetate (6a) (155 mg, 1 mmol) was added slowly at 0 C. under argon atmosphere and stirred for 15 min. Then ethyl 2-(acetoxy(3-chlorophenyl)methyl)acrylate (5f) (280 mg, 1 mmol) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (310 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 1f as ash colour solid (230 mg, 70% yield).

(34) .sup.1H NMR (300 MHz, CDCl.sub.3): 7.71 (s, 1H), 7.26-7.15 (m, 4H), 4.29 (q, J=7.0 Hz, 2H), 4.15 (t, J=7.3 Hz, 2H), 3.81 (s, 2H), 3.51 (t, J=7.9 Hz, 2H), 2.26-2.16 (m, 2H), 1.35 (t, J=7.0 Hz, 3H); .sup.13C NMR (75 MHz, CDCl.sub.3): 164.9, 161.7, 155.4, 141.5, 137.7, 134.0, 129.6, 128.8, 128.0, 127.2, 126.4, 105.4, 60.7, 49.5, 35.7, 33.7, 20.7, 14.3; MS (ESI): m/z 332 [M+H].sup.+; HRMS (ESI): m/z [M+H].sup.+ calculated for C.sub.18H.sub.19NO.sub.3Cl: 332.1053; found: 332.1045.

Example 7

(35) ##STR00023##

Ethyl 6-(4-chlorobenzyl)-5-oxo-1,2,3,5-tetrahydro-8-indolizinecarboxylate (1g)

(36) To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) and dry THF (5 mL) (Z)-ethyl 2-(pyrrolidin-2-ylidene)acetate (6a) (155 mg, 1 mmol) was added slowly at 0 C. under argon atmosphere and stirred for 15 min. Then ethyl 2-(acetoxy(4-chlorophenyl)methyl)acrylate (5g) (280 mg, 1 mmol) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (310 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, evaporated in vacuo and purified by column chromatography by using silica gel with 30% EtOAc in hexane as eluent to obtained 1g as ash colour solid (267 mg, 81% yield).

(37) .sup.1H NMR (300 MHz, CDCl.sub.3): 7.70 (s, 1H), 7.22 (s, 4H), 4.28 (q, J=6.9 Hz, 2H), 4.14 (t, J=7.3 Hz, 2H), 3.79 (s, 2H), 3.50 (t, J=7.9 Hz, 2H), 2.26-2.15 (m, 2H), 1.34 (t, J=7.1 Hz, 3H); .sup.13C NMR (75 MHz, CDCl.sub.3): 164.9, 161.8, 155.3, 138.0, 137.5, 137.3, 132.0, 130.3, 128.4, 105.4, 60.67, 49.3, 35.5, 33.7, 20.8, 14.3; MS (ESI): 332 [M+H].sup.+; HRMS (ESI): m/z [M+H].sup.+ calculated for C.sub.18H.sub.20NO.sub.3Cl: 332.1053; found: 332.1051.

Example 8

(38) ##STR00024##

Ethyl 6-(2,4-dichlorobenzyl)-5-oxo-1,2,3,5-tetrahydro-8-indolizinecarboxylate (1h)

(39) To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) and THF (5 mL) (Z)-ethyl 2-(pyrrolidin-2-ylidene)acetate (6a) (155 mg, 1 mmol) was added slowly at 0 C. under argon atmosphere and stirred for 15 min. Then ethyl 2-(acetoxy(2,4-dichlorophenyl)methyl)acrylate (5h) (315 mg, 1 mmol) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (310 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 1h as ash colour solid (280 mg, 77% yield).

(40) .sup.1H NMR (500 MHz, CDCl.sub.3): 7.69 (s, 1H), 7.37-7.15 (m, 3H), 4.28 (q, J=7.5 Hz, 2H), 4.16 (t, J=7.5 Hz, 2H), 3.92 (s, 2H), 3.51 (t, J=8.3 Hz, 2H), 2.26-2.16 (m, 2H), 1.33 (t, J=7.5 Hz, 3H); 13C NMR (50 MHz, CDCl.sub.3): 164.5, 161.4, 155.0, 137.7, 135.1, 134.6, 132.4, 131.9, 128.9, 126.7, 126.1, 105.2, 60.4, 49.0, 33.4, 32.9, 20.5, 14.1; MS (ESI): m/z 366 [M+H].sup.+; HRMS (ESI): m/z [M+H].sup.+ calculated for C.sub.18H.sub.18NO.sub.3Cl.sub.2: 366.0663; found: 316.0654.

Example 9

(41) ##STR00025##

Ethyl 6-(2-bromobenzyl)-5-oxo-1,2,3,5-tetrahydro-8-indolizinecarboxylate (1i)

(42) To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) and THF (5 mL) (Z)-ethyl 2-(pyrrolidin-2-ylidene)acetate (6a) (155 mg, 1 mmol) was added slowly at 0 C. under argon atmosphere and stirred for 15 min. Then ethyl 2-(acetoxy(2-bromophenyl)methyl)acrylate (5i) (324 mg, 1 mmol) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (310 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 1i as ash colour solid (291 mg, 78% yield).

(43) .sup.1H NMR (300 MHz, CDCl.sub.3): 7.64 (s, 1H), 7.56-7.05 (m, 4H), 4.25 (q, J=7.1Hz, 2H), 4.18 (t, J=7.5 Hz, 2H), 3.97 (s, 2H), 3.50 (t, J=8.3 Hz, 2H), 2.27-2.16 (m, 2H), 1.31 (t, J=7.1 Hz, 3H); .sup.13C NMR (75 MHz, CDCl.sub.3): 164.9, 161.8, 155.7, 138.4, 137.8, 132.8, 131.4, 128.0, 127.4, 127.0, 124.9, 105.4, 60.6, 49.3, 35.9, 33.6, 20.8, 14.3; MS (ESI): m/z 376 [M+H].sup.+; HRMS (ESI): m/z [M+E].sup.+ calculated for C.sub.18H.sub.19NO.sub.3Br: 376.0548; found: 376.0537.

Example 10

(44) ##STR00026##

Ethyl 6-(3-bromobenzyl)-5-oxo-1,2,3,5-tetrahydro-8-indolizinecarboxylate (1j)

(45) To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) and THF (5 mL) (Z)-ethyl 2-(pyrrolidin-2-ylidene)acetate (6a) (155 mg, 1 mmol) was added slowly at 0 C. under argon atmosphere and stirred for 15 min. Then ethyl 2-(acetoxy(3-bromophenyl)methyl)acrylate (5j) (324 mg, 1 mmol) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (310 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 1j as white solid (280 mg, 75% yield).

(46) .sup.1H NMR (300 MHz, CDCl.sub.3+DMSO-d.sub.6): 7.72 (s, 1H), 7.41-7.11 (m, 4H), 4.29 (q, J=7.1 Hz, 2H), 4.15 (t, J=7.5 Hz, 2H), 3.80 (s, J=7.5 Hz, 2H), 3.51 (t, J=7.5 Hz, 2H), 2.26-2.16 (m, 2H), 1.35 (t, J=7.1 Hz, 3H); .sup.13C NMR (75 MHz, CDCl.sub.3): 164.9, 161.8, 155.5, 141.9, 137.8, 131.8, 129.9, 129.4, 128.1, 127.8, 122.4, 105.4, 60.7, 49.3, 35.8, 33.7, 20.8, 14.4; MS (ESI): m/z 376 [M+H].sup.+; HRMS (ESI): m/z [M+H].sup.+ calculated for C.sub.18H.sub.19NO.sub.3Br: 376.0548; found: 376.0533.

Example 11

(47) ##STR00027##

Ethyl 6-(4-bromobenzyl)-5-oxo-1,2,3,5-tetrahydro-8-indolizinecarboxylate (1k)

(48) To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) and THF (5 mL) (Z)-ethyl 2-(pyrrolidin-2-ylidene)acetate (6a) (155 mg, 1 mmol) was added slowly at 0 C. under argon atmosphere and stirred for 15 min. Then ethyl 2-(acetoxy(4-bromophenyl)methyl)acrylate (5k) (324 mg, 1 mmol) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (310 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 1k as white solid (295 mg, 79% yield).

(49) .sup.1H NMR (300 MHz, CDCl.sub.3): 7.70 (s, 1H), 7.39-7.15 (m, 4H), 4.29 (q, J=7.5 Hz, 2H), 4.14 (t, J=6.9 Hz, 2H), 3.78 (s, 2H), 3.50 (t, J=8.3 Hz, 2H), 2.25-2.15 (m, 2H), 1.34 (t, J=7.5 Hz, 3H); .sup.13C NMR (75 MHz, CDCl.sub.3): 164.9, 161.7, 155.3, 138.5, 137.5, 131.4, 130.7, 128.3, 120.0, 105.4, 60.6, 49.2, 35.6, 33.6, 20.7, 14.3; MS (ESI): 376 [M+H].sup.+; HRMS (ESI): m/z [M+H].sup.+ calculated for C.sub.18H.sub.19NO.sub.3Br: 376.0548; found: 376.0533.

Example 12

(50) ##STR00028##

Ethyl 5-oxo-6-[2-(trifluoromethyl)benzyl]-1,2,3,5-tetrahydro-8-indolizinecarboxylate (1l)

(51) To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) and THF (5 mL) (Z)-ethyl 2-(pyrrolidin-2-ylidene)acetate (6a) (155 mg, 1 mmol) was added slowly at 0 C. under argon atmosphere and stirred for 15 min. Then ethyl 2-(acetoxy(2-(trifluoromethyl)phenyl)methyl)acrylate (5l) (314 mg, 1 mmol) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction Was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (310 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 1l as ash colour solid (258 mg, 71% yield).

(52) .sup.1H NMR (500 MHz, CDCl.sub.3): 7.66-7.25 (m, 5H), 4.24-4.16 (m, 4H), 4.03 (s, 2H), 3.51 (t, J=7.8 Hz, 2H), 2.26-2.20 (m, 2H), 1.29 (t, J=7.8 Hz, 3H): .sup.13C NMR (75 MHz, CDCl.sub.3): 164.8, 161.8, 155.1, 137.9, 137.8, 131.8, 131.5, 127.9, 126.4, 126.0, 125.9, 105.4, 60.5, 49.3, 33.6, 32.0, 20.7, 14.2; MS (ESI): m/z 366 [M+H].sup.+; HRMS (ESI): m/z [M+H].sup.+ calculated for C.sub.19H.sub.19NO.sub.3F.sub.3: 366.1317; found: 366.1308.

Example 13

(53) ##STR00029##

Ethyl 5-oxo-6-[4-(trifluoromethyl)benzyl]-1,2,3,5-tetrahydro-8-indolizinecarboxylate (1m)

(54) To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) and THF (5 mL) (Z)-ethyl 2-(pyrrolidin-2-ylidene)acetate (6a) (155 mg, 1 mmol) was added slowly at 0 C. under argon atmosphere and stirred for 15 min. Then ethyl 2-(acetoxy(4-(trifluoromethyl)phenyl)methyl)acrylate (5m) (314 mg, 1 mmol) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (310 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 1m as ash colour solid (269 mg, 74% yield).

(55) .sup.1H NMR (300 MHz, CDCl.sub.3): 7.74-7.26 (m, 5H), 4.29 (q, J=7.1 Hz, 2H), 4.15 (t, J=7.5 Hz, 2H), 3.88 (s, 2H), 3.51 (t, J=7.9 Hz, 2H), 2.26-2.16 (m, 2H), 1.35 (t, J=7.1 Hz, 3H); .sup.13C NMR (75 MHz, CDCl.sub.3): 164.8, 161.7, 155.5, 143.6, 137.8, 129.1, 128.7, 127.9, 125.3, 125.2, 105.4, 60.7, 49.2, 36.0, 33.7, 20.7, 14.3; MS (ESI): m/z 366 [M+H].sup.+; HRMS (ESI): m/z [M+H].sup.+ calculated for C.sub.19H.sub.19NO.sub.3F.sub.3: 366.1317; found: 366.1311.

Example 14

(56) ##STR00030##

Ethyl 6-(4-methylbenzyl)-5-oxo-1,2,3,5-tetrahydro-8-indolizinecarboxylate (1n)

(57) To a well stirred solution of NaH (60% in paraffin oil 115 mg, 3 mmol) and THF (5 mL) (Z)-ethyl 2-(pyrrolidin-2-ylidene)acetate (6a) (155 mg, 1 mmol) was added slowly at 0 C. under argon atmosphere and stirred for 15 min. Then ethyl 2-(acetoxy(p-tolyl)methyl)acrylate (5n) (260 mg, 1 mmol) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (310 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, evaporated in vacuo and purified by column chromatography using silica gel-with 30% EtOAc in hexane as eluent to obtained 1n as pale yellow solid (241 mg, 78% yield).

(58) .sup.1H NMR (300 MHz, CDCl.sub.3): 7.68 (s, 1H), 7.19-7.06 (m, 4H), 4.27 (q, J=7.1 Hz, 2H), 4.14 (t, J=7.5 Hz, 2H), 3.80 (s, 2H), 3.48 (t, J=8.3 Hz, 2H), 2.30 (s,3H), 2.24 (m, 2H), 1.33 (t, J=7.1 Hz, 3H); .sup.13C NMR (75 MHz, CDCl.sub.3): 165.0, 161.9, 154.9, 137.3, 137.1, 136.4, 135.6, 129.1, 128.8, 105.4, 60.6, 49.2, 35.6, 33.6, 21.0, 20.8, 14.3; MS (ESI): m/z 312 [M+H].sup.+; HRMS (ESI): m/z [M+H].sup.+ calculated for C.sub.19H.sub.22NO.sub.3: 312.1599; found: 312.1614.

Example 15

(59) ##STR00031##

Ethyl 6-(4-ethylbenzyl)-5-oxo-1,2,3,5-tetrahydro-8-indolizinecarboxylate (1o)

(60) To a well stirred solution of NaH (60% in paraffin oil 115 xmg, 3 mmol) and THF (5 mL) (Z)-ethyl 2-(pyrrolidin-2-ylidene)acetate (6a) (155 mg, 1 mmol) was added slowly at 0 C. under argon atmosphere and stirred for 15 min. Then ethyl 2-(acetoxy(4-ethylphenyl)methyl)acrylate (5o) (274 mg, 1 mmol) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (310 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 1o as ash colour (242 mg, 75% yield).

(61) .sup.1H NMR (500 MHz, CDCl.sub.3): 7.68 (s, 1H), 7.20-7.09 (m, 4H), 4.27 (q, J=7.2 Hz, 2H), 4.14 (t, J=7.2 Hz, 2H), 3.80 (s, 2H), 3.48 (t, J=8.2 Hz, 2H), 2.60 (q, J=7.2 Hz, 2H), 2.22-2.16 (m, 2H), 1.32 (t, J=7.2 Hz, 3H), 1.20 (t, J=8.2 Hz, 3H); .sup.13C NMR (75 MHz, CDCl.sub.3): 165.0, 161.9, 154.9, 142.0, 137.3, 136.6, 129.3, 128.9, 127.9, 105.4, 60.6, 49.2, 35.6, 33.6, 28.4, 20.8, 15.6, 14.3; MS (ESI): m/z 326 [M+H].sup.+; HRMS (ESI): m/z [M+H].sup.+ calculated for C.sub.20H.sub.24NO.sub.3: 326.1756; found: 326.1769.

Example 16

(62) ##STR00032##

Ethyl 6-(4-isopropylbenzyl)-5-oxo-1,2,3,5-tetrahydro-8-indolizinecarboxylate (1p)

(63) To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) and THF (5 mL) (Z)-ethyl 2-(pyrrolidin-2-ylidene)acetate (6a) (155 mg, 1 mmol) was added slowly at 0 C. under argon atmosphere and stirred for 15 min. Then ethyl 2-(acetoxy(4-isopropylphenyl)methyl)acrylate (5p) (288 mg, 1 mmol) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (310 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 1p as pale yellow solid (239 mg, 71% yield).

(64) .sup.1H NMR (500 MHz, CDCl.sub.3): 7.68 (s, 1H), 7.21-7.12 (m, 4H), 4.26 (q, J=7.2 Hz, 2H), 4.15 (t, J=7.2 Hz, 2H), 3.80 (s, 2H), 3.48 (t, J=8.2 Hz, 2H), 2.88-2.83 (m, J=7.2 Hz, 1H), 2.22-2.16 (m, 2H), 1.32 (t, J=6.3 Hz, 3H), 1.22 (d, J=6.3 Hz, 6H); .sup.13C NMR (75 MHz, CDCl.sub.3): 165.0, 161.9, 154.9, 146.6, 137.3, 136.7, 129.2, 128.8, 126.4, 105.3, 60.5, 49.2, 35.5, 33.7, 33.6, 23.9, 20.7, 14.2; MS (ESI): m/z 340 [M+H].sup.+; HRMS (ESI): m/z [M+H].sup.+ calculated for C.sub.21H.sub.26NO.sub.3: 340.1912; found: 340.1906.

(65) Pharmacology

(66) Milrinone, a known PDE3 inhibitor, drug has been used as standard for comparison with the inhibitory activity of synthesized new analogues 1a-p. Milrinone is a nonsympathomimetic and nonglycosidic drug that increases myocardial contraction. It increases myocardial cyclic adenosine monophosphate (c-AMP) concentration by selective inhibition of cardiac phosphodiesterase3 (PDE3) enzymes and increases intracellular calcium level, thereby increasing myocardial contractility (Weishaar R E, Quade M M, Schenden J A, Evans D B. Relationship between inhibition of cardiac muscle phosphodiesterase, changes in cyclic nucleotide levels, and contractile response for C1-914 and other novel cardiotonics. (J Cyclic Nucleotide Protein Phosphor Res 1985; 10:551-64). All PDE3 inhibitors has beneficial effects on the acute treatment of congestive heart failure (Bairn D S, McDowell A V, Cherniles J, et al. Evaluation of a new bipyridine inotropic agentmilrinonein patients with severe congestive heart failure. N Engl J Med 1983;309:748-56) and offers an important therapeutic option for left ventricular failure in patients undergoing cardiac surgery because of its unique inodilator effects. PDE3 enzymes are present not only in cardiac muscle but it also present in platelets. In platelets, c-AMP generated from adenosine triphosphate by adenyl cyclase serves as an intracellular second messenger to inhibit the platelet activation at numerous steps (Campbell F W, Addonizo V P Jr. Platelet function alterations during cardiac surgery. In: Ellison N, Jobes D R, ed. Effective hemostasis in cardiac surgery. Philadelphia: W B Saunders, 1988: 93-5). Since abnormal bleeding after cardiopulmonary bypass (CPB) is most often due to an acute acquired defect in platelets (Harker L. Bleeding after cardiopulmonary bypass. N Engl J Med 1986;314:1446-8), preservation of platelet function is critical to maintaining normal hemostasis in patients undergoing cardiac surgery.

(67) The commercially utility of the compounds according to the invention have valuable pharmacological properties. As selective inhibitors of type 3 of cyclic nucleotide phosphodiesterase3 (PDE3), they are suitable for heart failure therapy as well as anti-thrombotic (platelet aggregation-inhibiting) therapy.

(68) Biological Investigations

(69) PDE3 inhibition assay was performed a BIOMOL GREENE Quantizyme Assay System (catalogue No. BML-AK800-0001). The Platelets isolated from human blood were used as a source of PDE3 enzyme. 10 mL blood collected in a vacutainer tube (containing K.sub.3 EDTA) and centrifuged at 190 g for 15 min at room temperature. Top layer (platelet rich plasma) collected, centrifuged at 2500 g for 5 min at 22 C. (Room temp.) The pellet was washed with 2 ml of 50 mM tris buffer (pH-7.4) containing 1 mM MgCl.sub.2 and centrifuged at 2500 g for 5 min. Then 200 l of assay buffer (from PDE kit, Enzo Life Sciences) was added to the pellet and sonicated at 30 s per ml. Pellet was freeze thawed for three times (80 C.) in order to rupture the platelet membrane and release the PDE enzyme. Then the cell homogenate was centrifuged at 2500 rpm for 5 min. Supernatant was collected and used as source for PDE3 enzyme. In 96 well plate (Prod. No. BML-K1101), we added supernatant having PDE3 enzyme, PDE3 assay buffer, cAMP substrate, 5nucleotidase and test or standard compound and incubated for 1 hour at 37 C. The reaction was arrested by the addition 100 l BIOMOL GREEN reagent incubated in room temp for 20 min. The green color developed was measured at 620 nm

(70) Methodology

(71) The in vitro Phosphodiesterase (PDE3) inhibitory activity of compounds 1a-p were measured using a BIOMOL GREEN Quantizyme Assay System (catalogue No. BML-AK8000-0001). The basic principle for this assay is the cleavage of c-AMP or c-GMP into their respective nucleotide by a cyclic nucleotide phosphodiesterase. The nucleotide (AMP or GMP) released is further cleaved into the nucleoside and phosphate by the enzyme 5-nucleotidase. The extent of phosphate released is directly proportional to the PDE activity. In this screening method, the released phosphate by the enzymatic cleavage is quantified using BIOMOL GREEN reagent in a modified malachite green assay. The resulting green colour with max at 620 nm is directly proportional to the released phosphate and then PDE activity. All the compounds-tested in the desired concentrations did not show any significant absorbance at 620 nm under control conditions. Milrinone, a known PDE3 inhibitor drug has been used as a standard compound for comparison with the inhibitory activity of newly synthesized analogues. The concentration with 50% PDE3 activity (IC.sub.50) of all tested compounds was calculated from dose response curves. IC.sub.50 values of all compounds are summarized in Table 1.

(72) TABLE-US-00001 TABLE 1 PDE3 inhibitory activity (IC.sub.50) of Indolizine derivatives. Compound S. No Name IC.sub.50 (PDE3) 1 Milrinone 3300 nM 2 1a 435.20 nM 3 1c 13.500 nM 4 1d 1600 nM 5 1e 129.10 nM 6 1g 108.02 nM 7 1h 576.80 nM 8 1j 11.300 nM 9 1k 67.300 nM
Significance of the Work Carried Out

(73) The novel indolizine based analogues have been synthesized, exhibited potent phosphodiesterase3(PDE3) inhibition activity.

Advantages of the Invention

(74) 1. The present invention provides the synthesis of new indolizine analogues useful as phosphodiesterase3 inhibitory agents.

(75) 2. The present invention provides a process for the preparation of novel indolizine derivatives.

(76) 3. It is an another advantage that Baylis-Hillman adducts used as synthons for the synthesis

(77) of targeted compounds.

(78) 4. It is an another advantage that the synthesized compounds are heterocyclic compound are heterocyclic derivatives.

(79) 5. It is an another advantage that the compounds are useful as cardiotonics.

(80) 6. It is an another advantage that bases utilised for the synthons are simple and base are commercially available.

(81) 7. It is an another advantage that the method used for the synthesis of compounds are novel.