Synthesis of Trisubstituted s-Triazine derivatives

 

 Umang A Gosalia², Sonika Jain², Pankaj Jain¹*, Jaya Dwivedi²

¹Department of Pharmacy, Banasthali University, Banasthali, Rajasthan- 304022, India

²Department of Chemistry, Banasthali University, Banasthali, Rajasthan- 304022, India

 

ABSTRACT:

Oxoketene dithioacetals 2(a-d) of 2-(N-amino methyl substituted isatin-3-hydrazinyl)-4-(N₁-substituted-4’-amino benzene sulphonamidyl)-6-(8’-amino-4’-carbazolyl)-1,3,5-triazine derivatives 1(a-d) have been synthesized on their reaction with carbon disulphide and methyl iodide by well established procedure. Pyrazoles, isoxazoles 3(a-d), pyrimidine derivatives 4(a-d) and benzodiazepines derivatives 5(a-d) were synthesized.
Structure of all the compounds have been established by elemental analysis, IR, ¹H NMR and Mass spectral data.

 

 

 

INTRODUCTION:

The development of efficient methodologies to facilitate the preparation of compound libraries from molecules having proven record of bio-efficacy is an intense area of research in medicinal chemistry^1-6. Literature is replete with the examples showing that pyrazole, isoxazole, pyrimidine, and their fused derivatives are incorporated into drugs designed for antiviral,⁷ antimicrobial,⁸ antitumor,⁹ antifungal,¹⁰ pesticidal,¹¹ anticonvulsant,¹² antihistaminic,¹³ antibiotic,¹⁴ antidepressant,¹⁵ CNS regulant¹⁶ etc. These heterocyclic moieties also form the core of nucleic acid and bases.

 

s-Triazine is associated with unique property that it is highly active and on the other hand all the three chlorine atoms of s-triazine can be replaced by temperature dependent fashion¹⁷. By using this unique property 2,4,6-trisubstituted-s-triazine derivatives, namely; 2-(N-amino methyl substituted isatin-3-hydrazinyl)-4-(N₁-substituted-4′-amino benzenesulfonamidyl)-6-(8′-amino-4′-oxo-N-benzylazacarbazolyl)-1,3,5-triazine have been prepared and reported in acceptable yields¹⁸.

 

Some time incorporation of bioactive moieties to bioactive pharmacophores enhance the overall activity of the molecue.^19-26 Inspired by this fact in the present work we aimed to synthesize five, six and seven membered heterocyclic ring annulated s-triazine derivatives.

 

MATERIAL AND METHODS:

Chemicals and reagents:

The entire chemicals were purchased from Aldrich Chemical Company (USA) and were used after purification by distillation. The reactions were monitored by precoated aluminium silica gel 60F 254 thin layer plates procured from Merck (Germany). All melting points were measured by capillary apparatus and are uncorrected. All the compounds were routinely checked by IR, ¹H-NMR and mass spectrometries. IR spectra were recorded in KBr on a Perkin-Elmer model 8201 FTIR spectrophotometer. ¹H-NMR spectra were recorded at ambient temperature using a Brucker spectroscopin DPX-300 MHz spectrophotometer in DMSO. The following abbreviations were used to indicate the peak multiplicity s-singlet, d-doublet, t-triplet, m-multiplet. FAB mass spectra were recorded on a JEOL SX102 mass spectrometer using Argon/Xenon (6 kV, 10 mB) gas. Column chromatography was performed on silica gel (Merck). Anhydrous sodium sulfate was used as a drying agent for the organic phase.

 

General procedure for the preparation of compounds

Synthesis of 4-(4-(2-(bis(methylthio)methylene)-1-oxo-2,3,4,9-tetrahydro -1H-carbazol-6-ylamino)-6-(2-(1 (morpholinomethyl)-2-oxoindolin-3-ylidene) hydrazinyl)-1,3,5-triazin-2-ylamino)-N-(thiazol-2-yl) benzenesulfonamide (2a):

A mixture of (1a) (1.9g, 0.005mol) and CS₂ (0.4ml, 0.005mol) was added to well stirred and cooled suspension of t BuOK (1.2g,0.01mol) in dry benzene (15ml) and DMF (10ml). The reaction mixture was allowed to stand at room temperature for 4hr. Methyliodide (1.4ml, 0.01ml) was gradually added to above solution with stirring and external cooling (exothermic reaction). The reaction mixture was allowed to stand for further 4 hr at room temperature with occasionally shaking. It was then refluxed on a water bath for 3 hr. The mixture was poured on crushed ice and the benzene layer was separated. The aqueous portion was extracted with benzene and combined extracts were washed, dried on anhydrous sodium sulphate to give 2a.

 

Compounds 2b, 2c, 2d were also prepared by using similar method using appropriate reactant and by changing required time for completion of reaction.

 

Synthesis of 4-(4-(3-(methylthio)-1,4,5,10-tetrahydropyrazolo[3,4-a] carbazol-7-ylamino)-6-(2-(1-(morpholinomethyl)-2-oxoindolin-3-ylidene) hydrazinyl)-1,3,5-triazin-2-ylamino)-N-(thiazol-2-yl) benzenesulfonamide (3a)

Hydrazine hydrate (0.05ml, 0.01mol) and (2a) (2.4g, 0.005mol) were taken in 10 ml of ethanol and refluxed for 3 hr. The solvent was removed and the residue was extracted with 20 ml of chloroform. On removal of the solvent 3a, was obtained as crystalline solid.

 

Synthesis of (Z)-N-(6-methylpyrazin-2-yl)-4-(4-(3-(methylthio)-5,10-dihydro-4H-isoxazolo[5,4-a]carbazol-7-ylamino)-6-(2-(2-oxo-1-(piperidin-1-ylmethyl)indolin-3-ylidene)hydrazinyl)-1,3,5-triazin-2-ylamino)benzenesulfonamide (3b)

To hydroxylamine hydrochloride (2.78g, 0.04mole) was added sodium methoxide (3.24g, 0.06mole) in absolute methanol (30ml) and stirred for 10 minutes. To this solution, 2b (1.58g, 0.004mole) was added and the mixture was refluxed for 5 hours. Most of the methanol was evaporated under reduced pressure and the remaining mixture was poured into ice cold water. The solid separated was filtered, washed with diethyl ether, dried and recrystallized from ethanol to give analytically pure product 3b

 

4-(4-(3-(methylthio)-1,4,5,10-tetrahydropyrazolo[3,4-a]carbazol-7-ylamino)-6-(2-(2-oxo-1-(pyrrolidin-1-ylmethyl)indolin-3-ylidene)hydrazinyl)-1,3,5-triazin-2-ylamino)-N-(oxazol-2-yl)benzenesulfonamide (3c)

Hydrazine hydrate (0.05ml, 0.01 mol) and (2c) (2.4g, 0.005mol) were taken in 10 ml of ethanol and refluxed for 3 hr. The solvent was removed and the residue was extracted with 20 ml of chloroform. On removal of the solvent 3c, was obtained as crystalline solid.

 

N-(5,6- dimethylpyrazin-2-yl) -4-(4-(2-(1-((4-methylpiperazin-1-yl)methyl)- 2-oxoindolin-3-ylidene) hydrazinyl)- 6-(3-(methylthio)-5,10-dihydro-4H-isoxazolo[5,4-a] carbazol-7-ylamino)-1,3,5-triazin-2-ylamino) benzenesulfonamide (3d)

To hydroxylamine hydrochloride (2.78g, 0.04mole) was added sodium methoxide (3.24g, 0.06mole) in absolute methanol (30ml) and stirred for 10 minutes. To this solution, 2d (1.58g, 0.004mole) was added and the mixture was refluxed for 5 hours. Most of the methanol was evaporated under reduced pressure and the remaining mixture was poured into ice cold water. The solid separated was filtered, washed with diethylether, dried and recrystallized from ethanol to give analytically pure product 3d

 

Synthesis of 4-(4-(2-hydroxy-4-(methylthio)-6,11-dihydro-5H-pyrimido [4,5-a]carbazol-8-ylamino)-6-(2-(1-(morpholinomethyl)-2-oxoindolin-3-ylidene)hydrazinyl)-1,3,5-triazin-2-ylamino)-N-(thiazol-2-yl) benzenesulfonamide (4a)

To a mixture of urea (3g, 0.005mol) and sodium ethoxide (2.6g, 0.00 mol) in ethanol (15ml) was added to (2a) (2.4g, 0.005mol) and the reaction mixture was refluxed for 10-14 hr. The solvent was removed by distillation and the residue was treated with glacial acetic acid (7-10ml) just enough to dissolve sodium salt of pyrimidine and refluxed for 15 min. The reaction mixture was poured on crushed ice and the precipitate obtained was purified by recrystallization with ethanol to give (4a)

 

Compounds 4b, 4c, 4d were also prepared by using similar method using appropriate reactant and by changing required time for completion of reaction.

 

Synthesis of 4-(4-(3-(methylthio)-1H-benzo-[b][1,4]diazepine[3,4-a] carbazol-7-ylamino)-6-(2-(1-(morpholinomethyl)-2-oxoindolin-3-ylidene) hydrazinyl)-1,3,5-triazin-2-ylamino)-N-(thiazol-2-yl)benzenesulfonamide (5a)

To a mixture of o-phenylenediamine (1.08 g, 0.01mole), and 2a (2.4g, 0.005mol) was added ethanol and refluxed for 4-5 hours. The solvent was distilled under reduced pressure and the residue was quenched in crushed ice. It was extracted with chloroform, washed with water and dried over anhydrous sodium sulphate to give 5.083. 0.11 g, (yield 20 %), m. p. 385-386 ^oC

 

Other compounds 5b, 5c, 5d were also prepared in a likewise manner by changing in the reagents and refluxing time.

 

Physical and Analytical characterization of the compounds

4-(4-(2-(bis (methylthio)methylene)-1-oxo-2,3,4,9-tetrahydro -1H-carbazol-6-ylamino)-6-(2-(1-(morpholinomethyl)- 2-oxoindolin-3-ylidene) hydrazinyl)-1,3,5-triazin-2-ylamino)-N-(thiazol-2-yl) benzenesulfonamide (2a)

1.3 g (yield 45%). m.p. 298-299^oC., IR (KBr) cm^-1 1320 ,1157 (S=O), 3300 (NH of pyrrole ring), 1715 (C=O), 3140 (C-H str. Ar-H), 1610 (C=C str. Ar-H), 1270 (C-N str.). 2853 ,1465 (-CH₂-).¹H-NMR (DMSO) δ 12.64(1H,s,NH), 12.5(1H,s,NH), 11.34(1H,s,NH), 10.67(1H,s,NH), 9.44(1H,s,NH), 8.91(1H,s,NH), 7.86-7.22(13H,m,Ar-H), 4.03(2H,s,CH₂), 3.65(4H,t,CH₂, J=1.2 Hz), 2.93(2H,t,CH₂, J=1.4 Hz), 2.87(2H,t,CH₂), 2.53(3H,s,CH₃), 2.50(4H,t,CH₂), MS (ESI) m/z Calcd for C₄₀H₃₈N₁₂O₅S₄ (M) 895.07; Anal. Calcd for C₄₀H₃₈N₁₂O₅S₄: N=18.78, S=14.33Found: N=18.68 S=14.23

 

4-(4-(2-(bis(methylthio)methylene)-1-oxo-2,3,4,9-tetrahydro-1H-carbazol-6-ylamino)-6-(2-(2-oxo-1-(piperidin-1-ylmethyl)indolin-3-ylidene)hydrazinyl)-1,3,5-triazin-2-ylamino)-N-(6-methylpyrazin-2-yl)benzenesulfonamide (2b)

1.5 g Yield (42 %), m.p. 305-306^oC, IR (KBr) cm^-1  1320, 1157 (S=O), 3300 (NH of pyrrole ring), 1715(C=O), 3140(C-H str. Ar-H), 1610 (C=C str. Ar-H), 1270 (C-N str.). 2853,1465 cm^-1 (-CH₂-).¹H-NMR (DMSO) δ 11.75(1H,s,NH), 11.34(1H,s,NH), 10.67(1H,s,NH), 9.44(1H,s,NH), 8.91(1H,s,NH), 8.11-7.20(13H,m,Ar-H), 4.03(2H,s,CH₂), 2.93(2H,t,CH₂, J=1.1 Hz), 2.87(2H,t,CH₂), 2.53(3H,s,CH₃), 2.50(4H,t,CH₂, J=1.3 Hz), 2.33(3H,s,CH₃), 1.59(2H,q,CH₂), 1.53(4H,m,CH₂), MS (ESI) m/z Calcd for C₄₃H₄₃N₁₃O₄S₃ (M) 901.27; Anal. Calcd for C₄₃H₄₃N₁₃O₄S₃: N=20.19, S=10.66 Found: N=20.21S=10.71

 

4-(4-(2-(bis(methylthio)methylene)-1-oxo-2,3,4,9-tetrahydro-1H-carbazol-6-ylamino)-6-(2-(2-oxo-1-(pyrrolidin-1-ylmethyl)indolin-3-ylidene)hydrazinyl)-1,3,5-triazin-2-ylamino)-N-(oxazol-2-yl)benzenesulfonamide (2c)

1.0 g Yield (40 %), m.p. 284-285^oC, IR (KBr) cm^-1 1320, 1157(S=O), 3300 (NH of pyrrole ring), 1715 (C=O), 3140 (C-H str. Ar-H), 1610 (C=C str. Ar-H), 1270 (C-N str.). 2853 1465 cm^-1 (-CH₂-).¹H-NMR (DMSO) δ 12.5(1H,s,NH), 11.63(1H,s,NH), 11.34(1H,s,NH), 10.67(1H,s,NH), 9.44(1H,s,NH), 8.91(1H,s,NH), 7.86-7.22(13H,m,Ar-H), 2.93(2H,t,CH₂, J=1.1 Hz), 2.87(2H,t,CH₂, J=1.3 Hz), 2.53(6H,s,CH₃), 2.50(4H,t,CH₂, J=0.8 Hz), 1.68(4H,m,CH₂), MS (ESI) m/z Calcd for C₄₀H₃₈N₁₂O₅S₃ (M) 863.00; Anal. Calcd for C₄₀H₃₈N₁₂O₅S₃: N=19.48, S=11.15 Found: N=19.38 S=11.25

4-(4-(2-(bis(methylthio)methylene)-1-oxo-2,3,4,9-tetrahydro-1H-carbazol-6-ylamino)-6-(2-(1-((4-methylpiperazin-1-yl)methyl)-2-oxoindolin-3-ylidene)hydrazinyl)-1,3,5-triazin-2-ylamino)-N-(5,6-dimethylpyrazin-2-yl)benzenesulfonamide (2d)

0.8 g Yield (38 %), m.p. 300-301^oC, IR (KBr) cm^-1 1130, 1150 (S=O), 1615 (C=O), 3120 (C-H str. Ar-H), 1610 (C=C str. Ar-H), 1270 (C-N str.), 2653 ,1445 cm^-1 (-CH₂-). ¹H-NMR (DMSO) δ 11.63(1H,s,NH), 11.27 (1H,s,NH), 10.67 (1H,s,NH), 9.44(1H,s,NH), 8.91 (1H,s,NH), 7.93-7.20 (16H,m,Ar-H), 4.03(2H,s,CH₂), 3.03 (2H,t,CH₂), 2.83(2H,t,CH₂), 2.75(6H,s,2CH₃), 2.53(3H,s,CH₃), 2.35(8H,t,CH_2, J=1.2 Hz), 2.26 (3H,s,CH₃), MS (ESI) m/z Calcd for C₄₄H₄₆N₁₄O₄S₃ (M) 931.12; Anal. Calcd for C₄₄H₄₆N₁₄O₄S₃ : N=21.06, S=10.33 Found: N=21.16 S=10.43

 

Synthesis of 4-(4-(3-(methylthio)-1,4,5,10-tetrahydropyrazolo[3,4-a] carbazol-7-ylamino)-6-(2-(1-(morpholinomethyl)-2-oxoindolin-3-ylidene) hydrazinyl)-1,3,5-triazin-2-ylamino)-N-(thiazol-2-yl) benzenesulfonamide (3a)

1.5g, (yield 30%) m.p. 375-376 ^oC IR (KBr) cm^-1 1320, 1157(S=O), 3300 (NH of pyrrole ring), 1715 (C=O), 3140 (C-H str. Ar-H), 1610 (C=C str. Ar-H), 1270 (C-N str.). 2853,1465 (-CH₂-) . ¹H-NMR (DMSO) δ12.64(1H,s,NH), 12.5(1H,s,NH), 11.34(1H,s,NH), 10.67(1H,s,NH), 9.44(1H,s,NH), 8.91(1H,s,NH), 7.86-7.22(13H,m,Ar-H), 4.03(2H,s,CH₂), 3.65(4H,t,CH_2, J=1.1 Hz), 2.93(2H,t,CH₂, J=1.2 Hz), 2.87(2H,t,CH₂, J=1.4 Hz), 2.53(3H,s,CH₃), 2.50(4H,t,CH₂), MS (ESI) m/z Calcd for C₃₉H₃₆N₁₄O₄S₃ (M) 860.99 ; Anal. Calcd for C₃₉H₃₆N₁₄O₄S₃ : N=22.78, S=11.17 Found: N=22.98 S=11.21

 

Synthesis of (Z)-N-(6-methylpyrazin-2-yl)-4-(4-(3-(methylthio)-5,10-dihydro-4H-isoxazolo[5,4-a]carbazol-7-ylamino)-6-(2-(2-oxo-1-(piperidin-1-ylmethyl)indolin-3-ylidene)hydrazinyl)-1,3,5-triazin-2-ylamino)benzenesulfonamide (3b)

(0.92g, yield-26%), m.p. 350-351^oC. IR (KBr) cm^-1 1320, 1157 (S=O), 3300 (NH of pyrrole ring), 1715 (C=O), 3140 (C-H str. Ar-H), 1610 (C=C str. Ar-H), 1270 (C-N str.), 2853,1465 (-CH₂-). ¹H-NMR (DMSO) 11.75(1H,s,NH), 11.34(1H,s,NH), 10.67(1H,s,NH), 9.44(1H,s,NH), 8.91(1H,s,NH), 8.11-7.20(13H,m,Ar-H), 4.03(2H,s,CH₂), 2.93(2H,t,CH₂, J=1.5 Hz), 2.87(2H,t,CH₂), 2.53(3H,s,CH₃), 2.50(4H,t,CH₂, J=0.9 Hz), 2.33(3H,s,CH₃), 1.59(2H,q,CH₂), 1.53(4H,m,CH₂), MS (ESI) m/z Calcd for C₄₂H₄₀N₁₄O₄S₂ (M) 868.99; Anal. Calcd for C₄₂H₄₀N₁₄O₄S₂ : N=22.56, S=7.38 Found: N=22.86 S=7.48

 

4-(4-(3-(methylthio)-1,4,5,10-tetrahydropyrazolo[3,4-a]carbazol-7-ylamino)-6-(2-(2-oxo-1-(pyrrolidin-1-ylmethyl)indolin-3-ylidene)hydrazinyl)-1,3,5-triazin-2-ylamino)-N-(oxazol-2-yl)benzenesulfonamide (3c)

0.72g Yield (20 %), m.p. 390-391^oC,IR (KBr) cm^-1 1320,1157(S=O), 3300 (NH of pyrrole ring), 1715(C=O), 3140 (C-H str. Ar-H), 1610 (C=C str. Ar-H), 1270 (C-N str.). 2853 ,1465 cm^-1 (-CH₂-). ¹H-NMR (DMSO) 12.5 (1H,s,NH), 11.63 (1H,s,NH), 11.34 (1H,s,NH), 10.67 (1H,s,NH), 9.44 (1H,s,NH), 8.91 (1H,s,NH), 7.86-7.22 (13H,m,Ar-H), 2.93(2H,t,CH₂), 2.87 (2H,t,CH₂, J=1.4 Hz), 2.53 (3H,s,CH₃), 2.50 (4H,t,CH₂, J=1.2 Hz), 1.68(4H,m,CH₂), MS (ESI) m/z Calcd for C₃₉H₃₆N₁₄O₄S₂ (M) 828.93 ; Anal. Calcd for C₃₉H₃₆N₁₄O₄S₂ : N=23.56, S=7.74 Found: N=23.75 S=7.84

 

N-(5,6-dimethylpyrazin-2-yl)-4-(4-(2-(1-((4-methylpiperazin-1-yl)methyl)-2-oxoindolin-3-ylidene)hydrazinyl)-6-(3-(methylthio)-5,10-dihydro-4H-isoxazolo[5,4-a]carbazol-7-ylamino)-1,3,5-triazin-2-ylamino)benzenesulfonamide (3d)

0.82g Yield (24 %), m.p. 355-356^oC, IR (KBr) cm^-11320, 1157 (S=O), 3300 (NH of pyrrole ring), 1715 (C=O), 3140 (C-H str. Ar-H), 1610 (C=C str. Ar-H), 1270 (C-N str.). 2853 , 1465 cm^-1 (-CH₂-).¹H-NMR (DMSO) 11.75 (1H,s,NH), 11.34(1H,s,NH), 10.67 (1H,s,NH), 9.44 (1H,s,NH), 8.91(1H,s,NH), 7.86-7.22(12H,m,Ar-H), 4.03 (2H,s,CH₂), 2.93(2H,t,CH_2, J=0.8 Hz), 2.87 (2H,t,CH₂), 2.75(6H,s,2xCH₃), 2.53 (3H,s,CH₃), 2.35 (8H,t,CH₂), 2.26 (3H,s,CH₃), MS (ESI) m/z Calcd for C₄₃H₄₃N₁₅O₄S₂ (M) 898.03 ; Anal. Calcd for C₄₃H₄₃N₁₅O₄S₂ : N=23.40, S=7.14 Found: N=22.84 S=7.24

 

Synthesis of 4-(4-(2-hydroxy-4-(methylthio)-6,11-dihydro-5H-pyrimido [4,5-a]carbazol-8-ylamino)-6-(2-(1-(morpholinomethyl)-2-oxoindolin-3-ylidene)hydrazinyl)-1,3,5-triazin-2-ylamino)-N-(thiazol-2-yl) benzenesulfonamide (4a)

0.75 g (yield 25%), m.p. 370-371 ^oC. IR (KBr) cm^-1 1130, 1150 (S=O), 1615 (C=O),3120 (C-H str. Ar-H), 1610 (C=C str. Ar-H), 1270 (C-N str.), 2653 ,1445 cm^-1 (-CH₂-) . ¹H-NMR (DMSO) 12.64 (1H,s,NH), 11.34 (1H,s,NH), 11.24(1H,s,OH), 10.67 (1H,s,NH), 9.44 (1H,s,NH), 8.91(1H,s,NH), 7.86-7.22(13H,m,Ar-H), 4.03 (2H,s,CH₂), 3.65(4H,t,CH_2, J=2.2 Hz), 2.93 (2H,t,CH₂), 2.87 (2H,t,CH₂, J=1.9 Hz), 2.53(3H,s,CH₃), 2.50(4H,t,CH₂), MS (ESI) m/z Calcd for C₄₀H₃₆N₁₄O₅S₃ (M) 889 ; Anal. Calcd for C₄₀H₃₆N₁₄O₅S₃ : N=22.06, S=10.60 Found: N=21.97 S=10.70

 

4-(4-(2-mercapto-4-(methylthio)-6,11-dihydro-5H-pyrimido[4,5-a]carbazol-8-ylamino)-6-(2-(2-oxo-1-(piperidin-1-ylmethyl)indolin-3-ylidene)hydrazinyl)-1,3,5-triazin-2-ylamino)-N-(6-methylpyrazin-2-yl)benzenesulfonamide (4b)

0.45 g Yield (38 %), m.p. 377-378^oC, IR (KBr) cm^-11130, 1150 (S=O), 1615 (C=O), 3120 (C-H str. Ar-H), 1610 (C=C str. Ar-H), 1270(C-N str.), 2653 ,1445 cm^-1 (-CH₂-).¹H-NMR (DMSO) 12.15(1H,s,NH), 11.75 (1H,s,NH), 11.34 (1H,s,NH), 10.67(1H,s,NH), 9.44 (1H,s,NH), 8.91(1H,s,NH), 8.11-7.20(13H,m,Ar-H), 4.03 (2H,s,CH₂), 2.93 (2H,t,CH_2, J=0.75 Hz), 2.87 (2H,t,CH₂), 2.53 (3H,s,CH₃), 2.45(4H,m,CH₂), 2.33 (3H,s,CH₃), 1.59 (2H,m,CH₂), 1.53(4H,m,CH₂), MS (ESI) m/z Calcd for C₄₃H₄₁N₁₅O₃S₃ (M) 912.08 ; Anal. Calcd for C₄₃H₄₁N₁₅O₃S₃ : N=23.03, S=10.41Found: N=23.24 S=10.51

 

4-(4-(2-hydroxy-4-(methylthio)-6,11-dihydro-5H-pyrimido[4,5-a]carbazol-8-ylamino)-6-(2-(2-oxo-1-(pyrrolidin-1-ylmethyl)indolin-3-ylidene)hydrazinyl)-1,3,5-triazin-2-ylamino)-N-(oxazol-2-yl)benzenesulfonamide (4c)

0.32 g Yield (28 %), m.p. 384-385^oC, IR (KBr) cm^-11130 ,1150 (S=O), 1615 (C=O), 3120 (C-H str. Ar-H), 1610 (C=C str. Ar-H), 1270 (C-N str.), 2653 ,1445 cm^-1 (-CH₂-). ¹H-NMR (DMSO) 11.34(1H,s,NH), 11.14 (1H,s,NH), 10.67(1H,s,NH),10.14(1H,s,NH), 9.44 (1H,s,NH), 8.91 (1H,s,NH), 7.86-7.22(13H,m,Ar-H), 4.03 (2H,s,CH₂), 2.93(2H,t,CH_2, J=3.4 Hz), 2.87 (2H,t,CH₂), 2.53(3H,s,CH₃), 2.50(4H,t,CH₂, J=4.2 Hz), 1.68(4H,t,CH₂), MS (ESI) m/z Calcd for C₄₀H₃₆N₁₄O₅S₂ (M) 856.93; Anal. Calcd for C₄₀H₃₆N₁₄O₅S₂ : N=22.88, S=7.48 Found: N=23.05 S=7.58

 

N-(5,6-dimethylpyrazin-2-yl)-4-(4-(2-mercapto-4-(methylthio)-6,11-dihydro-5H-pyrimido[4,5-a]carbazol-8-ylamino)-6-(2-(1-((4-methylpiperazin-1-yl)methyl)-2-oxoindolin-3-ylidene)hydrazinyl)-1,3,5-triazin-2-ylamino)benzenesulfonamide (4d)

0.25 g Yield (22 %), m.p. 345-346^oC, IR (KBr) cm^-11130, 1150(S=O), 1615 (C=O), 3120 (C-H str. Ar-H), 1610 (C=C str. Ar-H), 1270 (C-N str.), 2653, 1445 cm^-1 (-CH₂-).¹H-NMR (DMSO) 12.15(1H,s,NH), 11.75 (1H,s,NH), 11.34(1H,s,NH), 10.67(1H,s,NH), 9.44 (1H,s,NH), 8.91(1H,s,NH), 7.86-7.22(12H,m,Ar-H), 4.03 (2H,s,CH₂), 2.93 (2H,t,CH₂, J=3.2 Hz), 2.87 (2H,t,CH₂), 2.75 (6H,s,2xCH₃), 2.53(3H,s,CH₃), 2.35 (8H,t,CH₂), 2.26(3H,s,CH₃), MS (ESI) m/z Calcd for C₄₄H₄₄N₁₆O₃S₃ (M) 941.12 ; Anal. Calcd for C₄₄H₄₄N₁₆O₃S₃ : N=23.18, S=10.22 Found: N=22.44 S=10.72

 

(Z)-4-((4-((6-(methylthio)-7,8,13,14-tetrahydrobenzo[2,3][1,4]diazepino[5,6-a]carbazol-10-yl)amino)-6-(2-(1-(morpholinomethyl)-2-oxoindolin-3-ylidene)hydrazineyl)-1,3,5-triazin-2-yl)amino)-N-(thiazol-2-yl)benzenesulfonamide (5a)

0.25 g Yield (20 %), m.p. 385-386^oC, IR (KBr) cm^-11230 cm-1, 1166 (S=O), 1710 (C=O), 3120, 1610, 1270, 2653 ¹H-NMR (DMSO) 12.64(1H,s,NH), 11.63 (1H,s,NH), 10.67(1H,s,NH), 9.44(1H,s,NH), 8.91 (1H,s,NH), 7.86-6.75(17H,m,Ar-H), 4.03(2H,s,CH₂), 3.65 (4H,t,CH₂), 3.03(2H,t,CH₂), 2.83(2H,t,CH₂), 2.53 (3H,s,CH₃), 2.50 (4H,t,CH₂)., MS (ESI) m/z Calcd for C₄₅H₄₀N₁₄O₄S₃ (M) 936.25 (100%), 937.26(49.3%), 938.25(17.5%).; Anal. Calcd for C₄₅H₄₀N₁₄O₄S₃ : N=20.93, S=10.29 Found: N=20.71 S=10.39

 

(Z)-N-(6-methylpyrazin-2-yl)-4-((4-((6-(methylthio)-7,8,13,14-tetrahydro-14l3-benzo[2,3][1,4]thiazepino[7,6-a]carbazol-10-yl)amino)-6-(2-(2-oxo-1-(piperidin-1-ylmethyl)indolin-3-ylidene)hydrazineyl)-1,3,5-triazin-2-yl)amino)benzenesulfonamide (5b)

0.25 g Yield (15 %), m.p. 360-361^oC, IR (KBr) cm^-11230 cm-1, 1166 (S=O), 1710 (C=O), 3120, 1610, 1270, 2653 ¹H-NMR (DMSO) 11.63(1H,s,NH), 11.27 (1H,s,NH), 10.67 (1H,s,NH), 9.44 (1H,s,NH), 8.91 (1H,s,NH), 8.11-7.20 (17H,m,Ar-H), 4.03(2H,s,CH₂), 3.09 (2H,t,CH₂), 2.83 (2H,t,CH₂), 2.53 (3H,s,CH₃), 2.45 (4H,t,CH₂), 2.33(3H,s,CH₃), MS (ESI) m/z Calcd for C₄₈H₄₅N₁₄O₃S₃ (M) 936.25(100%), 937.26(49.3%), 938.25 (17.5%).; Anal. Calcd for C₄₈H₄₅N₁₄O₃S₃ : N=20.41, S=10.00 Found: N=20.31 S=10.15

 

(Z)-4-((4-((6-(methylthio)-7,8,13,14-tetrahydrobenzo[2,3][1,4]diazepino[5,6-a]carbazol-10-yl)amino)-6-(2-(2-oxo-1-(pyrrolidin-1-ylmethyl)indolin-3-ylidene)hydrazineyl)-1,3,5-triazin-2-yl)amino)-N-(oxazol-2-yl)benzenesulfonamide (5c)

0.25 g Yield (20 %), m.p. 385-386^oC, IR (KBr) cm^-11230 cm-1, 1166 (S=O), 1710 (C=O), 3120, 1610, 1270, 2653 ¹H-NMR (DMSO) 11.67(1H,s,NH), 11.47(1H,s,NH), 11.10(1H,s,NH), 10.67(1H,s,NH), 9.44 (1H,s,NH), 8.91(1H,s,NH), 7.86-7.09(17H,m,Ar-H), 4.03 (2H,s,CH₂), 3.03(2H,t,CH₂), 2.83(2H,t,CH₂), 2.51 (4H,t,CH₂), 1.68 (4H,t,CH₂). MS (ESI) m/z Calcd for C₄₅H₄₀N₁₄O₄S₂ (M) 905.05 (100%), 937.26(49.3%), 938.25(17.5%).; Anal. Calcd for C₄₅H₄₀N₁₄O₄S₂ : N=21.67, S=7.09 Found: N=21.87 S=7.19

 

(Z)-N-(5,6-dimethylpyrazin-2-yl)-4-((4-(2-(1-((4-methylpiperazin-1-yl)methyl)-2-oxoindolin-3-ylidene)hydrazineyl)-6-((6-(methylthio)-7,8,13,14-tetrahydro-14l3-benzo[2,3][1,4]thiazepino[7,6-a]carbazol-10-yl)amino)-1,3,5-triazin-2-yl)amino)benzenesulfonamide (5d)

0.25g Yield (20 %), m.p. 385-386^oC, IR (KBr) cm^-11230 cm-1, 1166 (S=O), 1710 (C=O), 3120, 1610, 1270, 2653 ¹H-NMR (DMSO) 11.63(1H,s,NH), 11.27 (1H,s,NH), 10.67 (1H,s,NH), 9.44(1H,s,NH), 8.91 (1H,s,NH), 7.93-7.20 (16H,m,Ar-H), 4.03(2H,s,CH₂), 3.03 (2H,t,CH₂), 2.83(2H,t,CH₂), 2.75(6H,s,2CH₃), 2.53 (3H,s,CH₃), 2.35 (8H,t,CH₂), 2.26(3H,s,CH₃). MS (ESI) m/z Calcd for C₄₉H₄₈N₁₅O₃S₃ (M) 991.20 (100%), 937.26(49.3%), 938.25 (17.5%).; Anal. Calcd for C₄₉H₄₈N₁₅O₃S₃ : N=21.20, S=9.70 Found: N=22.70 S=9.75

 

RESULTS AND DISCUSSION:

As a part of an ongoing endeavour to create novel heterocyclic scaffolds of anticipated biological activity from easily accessible starting materials, we report herein, the preliminary results of our studies on the synthesis of isoxazole, pyrazole, pyrimidine, annulated analogue of carbazolo, sulphonamido, isatinimino substituted s-triazine derivatives 3(a-d) scheme-2, 4(a-d) Scheme-3, from oxoketene dithioacetals 2(a-d). ) A perusal of literature on the potential of oxoketenedithioacetals in synthesis demonstrated that these were readily formed base catalyzed condensation of carbonyl species containing an active methylene group with CS₂+ MeI.²⁷ Application of this strategy on 1(a-d) afforded the intermediates 2(a-d) in moderate to good yield (scheme-1). Oxoketene dithioacetals have been extensively employed in the synthesis of a wide variety of heterocyclic compounds because of their accessibility through the reaction with bidentate nucleophiles such as hydrazine, hydroxylamine, and urea to give the pyrazole, isoxazole, pyrimidine derivatives respectively.

 

The characterization of synthesized compounds was done by using various spectral techniques such as IR, ¹H NMR, ¹³C NMR spectra, MS analysis and elemental analysis. Compounds 2(a-d) were characterized by observing a sharp peak of S-Me at δ 2.53 and a sharp singlet of 6 protons of two S-Me was also observed. Formation of compound 3(a-d) was confirmed by disappearing peak of carbonyl functionality and also singlet for six protons has been changed to singlet for 3 protons which indicates that cyclization has been taken place. Similarly compound 4(a-d) also exhibited singlet for 3 protons and singlet for OH, singlet for SH. Presence of OH was also confirmed by deuterium exchange.

 

Scheme-1

1(a-d)                                                     2(a-d)

 

Scheme-2

R₁ =    R₂ =

 

1a, 2a, R₁=morpholinyl, R₂= thiazolyl, 1b, 2b, R₁=piperidinyl, R₂=methylpyrimidinyl

 

1c, 2c, R₁= pyrazolyl, R₂= oxazolyl, 1d, 2d, R₁=N-methyl piperazinyl, R₂= dimethyl pyrimidinyl

 

  2(a-d)                                   3(a-d)

 

R₁ =      R₂ =

 

3a, R₁= morpholinyl, R₂= thiazolyl, Y=NH, 3b, R₁=piperidinyl, R₂=methylpyrimidinyl Y=O

3c, R₁= pyrazolyl, R₂= oxazolyl Y=NH, 3d, R₁₌N-methyl piperazinyl, R₂ = dimethyl pyrimidinyl Y=O

 

2(a-d)                                                         4(a-d)

 

Scheme-3

R₁ =          R₂ =

 

4a, R₁= morpholinyl, R₂= thiazolyl, X=O, 4b, R₁=piperidinyl, R₂=methylpyrimidinyl X=S

4c, R₁= pyrazolyl, R₂= oxazolyl X=O, 4d, R₁₌N-methyl piperazinyl, R₂= dimethyl pyrimidinyl X=S

 

Scheme-4

5a, R₁= morpholinyl, R₂= thiazolyl, X=N, 5b, R₁=piperidinyl, R₂=methylpyrimidinyl Z=N

5c, R₁= pyrazolyl, R₂= oxazolyl X=S, 5d, R₁₌N-methyl piperazinyl, R₂= dimethyl pyrimidinyl Z=S

 

CONCLUSION:

Synthesis of heterocycles is a continous process and great need for the beneficial of human in modern time. Five, six and seven memebered ring heterocycles contributes greatly in synthetic chemistry and have many biological importanat activities.Synthesis of these very prominent bioactive pharmacophores should be done very economically and environment friendly manner. For this purpose new methods need to be explore. In this paper we have reported a easy and versatile method of the synthesis of pyrazole, isooxazole, pyrimidine derivatives annulated with s-triazine scaffold. Biological activity of these compounds are under investigation.

 

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

 

ACKNOWLEDGEMENT:

Authors thanks to the Vice-Chancellor of Banasthali University, Rajasthan, India for support provided by him to complete this work.

 

REFERENCES:

1.     Gaudino EC, Tagliapietra S, Martina K, et al. Recent advances and perspectives in the synthesis of bioactive coumarins. RSC Advances. 6; 2016: 46394-46405.

2.     Bala S, Sharma N, Kajal A, et al. Mannich bases: An important pharmacophore in present scenario. International Journal of Medicinal Chemistry. 2014: 1-15.

3.     Jain S, Dwivedi J, Jain P, et al. Use of 2,4,6-trichloro-1,3,5-triazine (TCT) as organic catalyst in organic synthesis. Synthetic communications. 46(14); 2016:1155–1174.

4.     Ehsan S, Khan B. Conventional and microwave-assisted synthesis of 5-halogeno-(X) 2, 4-(1H, 3H) pyrimidinedione and their biological evaluation. Asian Journal of Research Chemistry. 3(4); 2010:1103-1106.

5.     Divekar K, Hardik J, Brahmani PS. Synthesis and biological evaluation of some novel pyrimidine derivatives. Asian Journal of Research Chemistry. 4(1); 2011:64-67.

6.     Srinath N, Prasad RY, Mukkanti K. Synthesis and antimicrobial activity of some new 2, 4, 6 -trisubstituted pyrimidines. Asian Journal of Research Chemistry. 4(2); 2011:329-333.

7.     El-Sabbagh OI, Baraka MM, Ibrahim SM, et al. Synthesis and antiviral activity of new pyrazole and thiazole derivatives. European Journal of Medicinal Chemistry. 44; 2008:3746–53.

8.     Ahsan MJ, Saini V. Design and synthesis of 3-(4-aminophenyl)-5-(4- methoxyphenyl)-4,5-dihydro-1H-pyrazole-1- carboxamide/ carbothioamide analogues as antitubercular agents. Journal of Basic Applied Sciences. 4; 2015: 41–6.

9.     Liu  JJ, Zhao  MY, Zhang  X. Pyrazole derivatives as antitumor, anti-inflammatory and antibacterial agents, Mini Reviews in Medicinal Chemistry. 13; 2013: 1957-66.

10.   Shehry MFE, Swellem RH, Abu-Bakr SM, et al. Synthesis and molluscicidal evaluation of some new pyrazole, isoxazole, pyridine, pyrimidine, 1,4-thiazine and 1,3,4-thiadiazine derivatives incorporating benzofuran moiety, European Journal of Medicinal Chemistry. 45; 2010: 4783-4787.

11.   Kendre BV, Landge MG, Bhusare SR, Synthesis of some pyrazole, isoxazole, benzoxazepine and benzothiazepine derivatives as anti-inflammatory and antimicrobial agents. American Journal of Pharmacetical Technology Research. 2; 2012: 490–500.

12.   Padmaja A, Payani T, Reddy GD.  Synthesis, antimicrobial and antioxidant activities of substituted pyrazoles, isoxazoles, pyrimidine and thioxopyrimidine derivatives. European Journal of Medicinal Chemistry. 44; 2009: 4557–4566.

13.   Naidu KM, Suresh A, Subbalakshmi J, et al. Design, synthesis and antimycobacterial activity of various 3-(4-(substitutedsulfonyl) piperazin-1-yl)benzo[d]isoxazole derivatives, European Journal of Medicinal Chemistry. 87; 2014: 71-78.

14.   Kumar RS, Arif IA, Ahamed A. Anti-inflammatory and antimicrobial activities of novel pyrazole analogues, Saudi Journal of Biological Sciences 23; 2016: 614–620.

15.   Patil PO, Bari SB. Synthesis and antidepressant activity of some new 5-(1h-indol-3-yl)-3-(substituted aryl)-4,5-dihydroisoxazoline derivatives. Journal of Chemistry 2013: (2013).

16.   Abu-Hashem AA, Youssef MM, Hussein HAR. Synthesis, antioxidant, antituomer activities of some new thiazolo pyrimidines, pyrrolothiazolo pyrimidines and triazolo pyrrolothiazolo pyrimidines derivatives. Journal of the Chinese Chemical Society. 58(1); 2011: 41–48.

17.   Kumar GJ, Kumar SN, Thummuri D, et al. Synthesis and characterization of new s-triazine bearing benzimidazole and benzothiazole derivatives as anticancer agents, Medicinal Chemistry Research. 24; 2015: 3991–4001.

18.   Jain S, Sharma A, Agrawal M, et al. synthesis and antimicrobial evaluation of some novel trisubstituted s-triazine derivatives based on isatinimino, sulphonamido, and azacarbazole. Journal of Chemistry. 2013 (2013): 1-9.

19.   Khanage SG, Mohite PB, Raju SA. Synthesis, anticancer and antibacterial activity of some novel 1, 2, 4-triazole derivatives containing pyrazole and tetrazole rings. Asian Journal of Research Chemistry. 4(4); 2011: 567-573.

20.   Moid A, Nikhat F, Purohit MG. Synthesis, characterization and anti-microbial evaluation of substituted isoxazole derivatives. Asian Journal of Research Chemistry. 4(7); 2011: 1158-1160.

21.   Singh S, Sharma PK, Dudhe R. Synthesis of pyrazolopyrimidine derivatives and their antibacterial activity. Asian Journal of Research Chemistry. 4(10); 2011: 1594-1599.

22.   Parmar K, Kundariya K, Prajapati S. Synthesis and spectral studies of 1, N-acetyl-3-aryl-5-(1’,N-phenyl-3’-o-methoxyphenyl-pyrazole-4’-yl)-pyrazoline derivatives and their expected biological activity. Asian Journal of Research Chemistry. 5(5); 2012: 571-575.

23.   Lachoriya NP, Indorkar D, Shrivastava SP, et al. Synthesis of 3-(4'-Bromo phenyl)-5-(aryl substituted) isoxazolines Compounds computational studies and Biological activity. Asian Journal of Research Chemistry. 5(9); 2012: 1095-1098.

24.   Rashmi P, Laxmivenkatesh G. Synthesis, spectral studies and evaluation of 4-(5-substituted- [1,3,4] oxadiazol-2-ylmethoxy)-thieno[2,3-d]pyrimidines as novel antimicrobials. Asian Journal of Research Chemistry. 6(4); 2013: 354-359.

25.   Modi V, Shah RS. Synthesis of some biological active pyrazole derivatives. Asian Journal of Research Chemistry. 6(11); 2013: 1060-1064.

26.   Roopa HR, Saravanan J, Mohan S. Synthesis, Characterization and anti-inflammatory activity of some schiff bases of 4-amino-5,6-dimethyl thieno [2,3-d] pyrimidines. Asian Journal of Research Chemistry. 8(3); 2015: 213-217.

27.   Agrawal M, Jain S, Agarwal A, et al. Application of novel precursors derived from carbazolo condensed azepinones to the direct single step synthesis of corresponding isoxazole and pyrazole annulated analogues of medicinal importance. Oriental Pharmacy and Experimental Medicine. 12; 2012:141–150.

 

 

Received on 27.02.2020         Modified on 13.04.2020

Accepted on 28.05.2020         © RJPT All right reserved