SYNTHESIS OF 4- (4-SUBSTITUTED)-1-(3- SUBSTITUTED- 5, 6-DIHYDRO- [1, 2, 4] TRIAZOLO [3, 4-A] PHTHALAZIN-6-YLAMINO) AZETIDIN-2-ONE DERIVATIVES AS ANTIDIABETIC AGENTS

SYNTHESIS OF 4- (4-SUBSTITUTED)-1-(3- SUBSTITUTED- 5, 6-DIHYDRO- [1, 2, 4] TRIAZOLO [3, 4-A] PHTHALAZIN-6-YLAMINO) AZETIDIN-2-ONE DERIVATIVES AS ANTIDIABETIC AGENTS

Smita Singh *and Pranjal Kumar Singh

R. M. Modinagar College of Pharmacy, SRM Institute of Science and Technology, Delhi NCR Campus, Delhi Meerut Road, Modinagar, Uttar Pradesh, India.

ABSTRACT: In this research work, numerous molecules that have substituted triazole phthalazine derivatives were obtained using phthalic anhydride as a starting material. It was taken as starting material that gave reaction in the precence of different conditions with different substituted benzoyl chloride that yielded 6 chloro-3 substituted  6a, 10 a-dihydro-[1, 2, 4] triazolo [3, 4-a] phthalazine derivatives (I-V). These intermediates further reacted with substituted benzaldehyde and yielded 4-2-3-Substituted - 6a, 10 a-dihydro-[1, 2, 4] triazolo [3, 4-a] phthalazin-6-yl) substituted hydrazinyl derivatives (VI-X) which were further react with triethyl amine and acetyl chloride yields (XXI-XXX). The antidiabetic effect was investigated using oral glucose tolerance test in normal and non-insulin-dependent diabetes mellitus (NIDDM) in STZ-rat model. In this model Roziglitazone taken as a standard drug for this pharmacological activity.

Keywords: STZ-rat model, Roziglitazone, Triazolophthalazine, Antidiabetic activity, Phthalic anhydride

INTRODUCTION: Heterocyclic nitrogen-containing compounds have received great attention due to their various applications in different fields, especially as therapeutically active drugs. Examples of nitrogen heterocycles that have exciting biological properties are pyridazine and phthalazine derivatives. They constitute the structural profile for certain biologically active compounds and are thus known to be essential primary elements. Several studies have focused on the pharmacological benefits of derivatives of phthalazine derivatives and on a wide variety of contributions in different areas of interest.

In organic chemistry, these structures are used extensively as intermediates for the synthesis of various compounds. In the other hand, derivatives of phthalazine as bioactive compounds have been thoroughly studied. They possess as prescribed extraordinary biological behaviour ¹. They are commonly known as flexible scaffolds for a range of pharmacological practises, such as analgesic, anti-inflammatory, antimicrobial, anti-depressant, diuretic, anti-hypertensive, anti-tuberculosis, and anti-HIV, as well as several other useful activities ^2-4.

Phtalazines are the medicinally essential Versatile Pharmacophore and have drawn the interest of medicinal chemists due to their diverse pharmacological activities across the last decade. The basic functionalization of different ring locations makes them an appealing synthetic building block for new drug design and synthesis. A wide variety of pharmacological results arise from the insertion of this versatile, biologically recognized pharmacophore into existing medicinally active molecules. A significant group of compounds is pyridazinones and phtalazines, many of which have widespread pharmacological properties such as antihypertensive, inhibitory platelet aggregation, and cardiotonic activities. Some are also well known for their use their marked analgesic, anti-inflammatory, antinociceptive and anti-ulcer activity. Phtalazines have also been identified currently as agents as antidiabetics, anticonvulsants, antiasthmatics, antimicrobials, etc. These positive studies suggest that the medicinal advantages of this enriched skeleton should be comprehensively studied ⁵. Azoles, precisely 1,2,4-triazoles, are well known as well tolerated antidiabetic agents, displaying urease inhibition action ^6-10. In the continuation of our research work on the synthesis of various heterocyclic ring systems ^11-14 the current study was conducted to establish new triazolophthalazine derivatives containing triazolophthalazine substitutions at 3^rd and 6^th positions and to examine their antidiabetic function. The target compounds Fig. 1 were designed and synthesized and a comparative study of their antidiabetic activity were done using a rat model.

FIG. 1:

METHODS:

Source of Animals: The experiment was achieved using male Wistar albino rats (200-250 gm), housed in animal facilities that had free access to rat chow and water. The rats were kept under a controlled environment for about 1 week for adaptation and acclimatization before the experimental work was started. The procedures of this work were approved by the animal ethics committee of the Kalka Group of Institutions, Meerut (Regn.No.1902/PO/Re/S/16/CPCSEA) for animal experiments and animal taken from the Kalka Group of Institutions, Meerut (Regn.No.1902/PO/Re/S/16/CPCSEA) for animal experiments. Animal were owned by Kalka Group of Institutions, Meerut (Regn. No. 1902/PO/Re/S/16/CPCSEA). They are obtained from the Kalka Group of Institutions, Meerut (Regn.No.1902/PO/Re/S/16/CPCSEA) for animal activity. Concent letter number is Regn. No. 1902/PO/Re/S/16/CPCSEA. I released animals after experimental work. There is no use of euthanasia and anaes during the experimental procedure.

General Synthetic Procedure: The parent novel 4- (4-substituted)-1-(3- substituted- 5, 6-dihydro- [1, 2, 4] triazolo [3, 4-a] phthalazin-6-ylamino) azetidin-2-one derivatives (XXI-XXX) were obtained using a phthalic anhydride with dimethyl formamide, triethylamine and diaxane taken as reacting material for the synthesis of 1, 4 dichloro phthalazine. After this 1, 4 dichloro phthalazine reacts with substituted benzoyl chloride to give numbers of derivatives. These derivatives were further reacted phosphorus oxychloride and then with hydrazine hydrate to give the hydrazine derivatives. These derivatives are treated in dry benzene, triethylamine, and chloro acetyl chloride at low temperatures (below 5^oC). (Scheme 1) ^15-16.

Reaction Scheme 1-:

R₁: SUBSTITUTED BENZOYL CHLORIDE, R₂=SUBSTITUTED ALDEHYDE

Step-1 Synthesis of 6 chloro -3-phenyl-[1, 2, 4] triazolo [3, 4-a] phthalazine: 4-hydrazine 1-chlorophthalazine (2gm), dioxin (20ml), Triethylamine (1.46mol) and benzoyl chloride (0.91 ml) mixed in round bottom flask (RBF). This reaction mixture was stirred for 2 h at room temperature on a magnetic stirrer. The reaction mixture was refluxed for 14 h at 50-55 °C, after completion of reaction precipitate was collected and recrystallized by methanol.

Step-2 Synthesis of 1-(3substituted- -[1, 2, 4] triazolo [3, 4-a] phthalazin-6yl) hydrazine: Previous step derivatives (6 chloro -3-phenyl-[1, 2, 4] triazolo [3, 4-a] phthalazine) taken (5 gm) and react with tetra hydro furan (THF) (60 ml) was added drop wise to a solution mixture of NHNH₂.2H₂O (hydrazine hydrate) (6.28 gm) in tetra hydro furan (THF) 10 ml, at normal temp. Both reaction mixtures were stirred and heated at 60 °C for 60 min by magnetic stirrer. Then 50% of the organic solvent was evaporated under reduced pressure. Solution was treated with petroleum ether and kept it below 0 °C. Purity of compounds was checked by analytical spectrometry methods.

Step-3 Synthesis of 4-(2-(3-substituted [1, 2, 4] triazolo [3, 4-a] phthalazin-6-yl)hydrazinyl) substituted derivatives: Reaction mixture of VI (0.01 mol),  with chloro benzaldehyde (0.01 mol) in equimolar amount in the presence of triethyl amine (12 ml) and acetyl chloride refluxed for 1 h. Reaction was monitored by TLC. At the end of process, the entire product was collected after filtration. Solid obtained was recrystallized with suitable solvent.

Step-4 Synthesis of 4-(-Substituted)-1-(3-phenyl-5, 6-dihydro-[1, 2, 4] triazolo [3, 4-a] phthalazine-6-yl amino) azetidin-2- one: Compounds was obtained from the previous step prepared were taken in solution 0.3 mol, in 30 ml of dry benzene added to stirred mixture of triethylamine 0.16 mol and acetyl chloride 0.16mol, at room temperature. The resulting materials were filtered and recrystallized with the proper ratio of solvent chloroform-methanol (1:1).

Experimental: The structures of the newly synthesized compounds were elucidated based on their IR, 1H-NMR, 13C-MR, MS spectral data and elemental analyses. The IR spectra of the obtained compounds exhibited the presence of 3020 (Ar-CH)_, 1635 (C=N), 1595(C=C), 1384(C-N); 662 1092(OCH₃) 1634 (-NH); 2983(-CH alkyl); 1726 (C=O); 1115(C-O). In addition to the expected aromatic protons signals, the 1H-NMR spectra revealed the appearance of new singlet for δ: 7.93, 7.85 (d, Ar-H, 2H), 7.48, 7.32, 7.22 (m, Ar-H, 4H), 7.38(d, Ar-H, 2-H); 8.14 (d, Ar-H, 2-H); 3.49.3.24 (d, C-H, 2-H), 4.7 (s, N-H, 1H). 13C-NMR spectra of the obtained compounds showed the appearance of new signals at range δ ¹³C NMR: CH for benzene, (140, 136, 69,149, 120, 126, 127,128), C for triazole, (148,128), C for chain C (128, 129, 134, 173, 55). Moreover, the MS of compound 3g showed a molecular ion peak at m/z 424-511 (M+-1, 0.22%).

In-vitro Antidiabetic Study-

Inhibition of α-amylase Enzyme: Starch solution (0.1%) was prepared by dissolving 0.1 g of starch in 100 mL of sodium acetate buffer (pH = 4.8, 16 mM). An enzyme solution was prepared by dissolving 27.5 mg of α-amylase in 100 mL of deionized H₂O. A colorimetric reagent was prepared by dissolving 1 g of 3,5-dinitro salicylic acid in deionized H₂O (20 mL) and 0.16 g sodium hydroxide (in 10 mL deionized H₂O) and 4 g of sodium potassium tartrate was added gradually to the mixture. The mixture was mixed well and the volume was made up to 100mL using deionized H₂O. Both control (100 μL) and the sulfonylurea or TZD derivatives (100 μL) were separately mixed with the starch solution (100 μL) and left for 30 minutes to react with the α-amylase solution (under alkaline conditions at 25°C).

The action was recorded after 5 min. The liberated maltose was measured quantitatively by the reduction of 3,5-dinitro salicylic acid to 3-amino-5-nitrosalicylic acid. This reaction was measured at 540 nm ^{17, 18, 19}.

In-vivo Antidiabetic Study:

Animals: The experiment was achieved using male Wistar albino rats (200-250 g), housed in animal facilities that had free access to rat chow and water. The rats were kept under a controlled environment for about 1 week for adaptation and acclimatization before the experimental work was started. The animal ethics committee approved the procedures of this work of the Kalka Group of Institutions, Meerut (Regn. No. 1902/PO/Re/S/16/CPCSEA) for animal experiments.

Dose Determination: Rosiglitazone was applied as a standard antidiabetic drug at a 4 mg/kg dose in 1% Arabic gum and was administered orally ²⁰. Equivalent weights of the tested compounds were used since it is critical to determine the suitable dose for each compound at equivalent doses basis.

Sucrose-loaded model: The male Wistar rats were fasted overnight. Blood was collected, and then the test triazolophthalazine derivatives were given to the corresponding groups (each group consists of 3 rats) orally.

A sucrose load of (10 g/ kg) body weight was given to each rat after 30 minutes post-treatment. Blood samples were collected after 30, 60, 90 and 120 min from the sucrose treatment. The percentage (%) reduction in blood glucose level was determined according to the AUC protocol ²¹.

Streptozotocin-induced Diabetes: Male Wistar rats were fasted overnight and were injected intraperitoneally with streptozotocin (STZ, 65 mg/kg body weight) dissolved in a citrate buffer (pH 4.5, 50 mM). These rats were given access to a sucrose solution (15 g/100 mL) to prevent hypoglycemia. STZ was purchased from (Sigma-Aldrich, Co., St. Louis, USA. Catalog number: 1001062761) ^{22, 23}.

Experimental Design: Twenty rats (four groups of 5 rats each, n = 5) were used to investigate the antihyperglycemic effect of triazolophthalazine derivatives. Group 1 was the control untreated group; Group 2 was a diabetic control group; Group 3 was treated with the reference antidiabetic drug (rosigilitazone, 100 mg/Kg). Group 4 was given the various triazolophthalazine derivatives (XI-XX, 100 mg/Kg). The treated groups administered the rosigilitazone and the different derivatives orally.

METHODS: For each group, blood glucose was determined at 0, 1, 2, 4, and 6 hours after the oral administration of compounds using a glucometer (Kalka Group of Institutions, Meerut), and the obtained results are shown in Table I.Values were expressed as mean± SEM. Compared with the Barferoni ANOVA test, data was evaluated by measurement of variance as well as group means.

Effects of Triazolophthalazine Derivatives on Fasting Blood Glucose Levels: During the experiment, fasting blood glucose levels in normal and diabetic control rats remain unchanged. However, the blood glucose levels were increased significantly in the case of untreated rats compared with the normal control. In contrast, a drop in the high blood glucose levels was observed in the diabetic rats when treated with compounds XXII, XXV, XXVII, and XXX rosiglitazone. By the completion of the experiment (after 4 weeks), 100 mg/Kg dose of compound XXV reduced the level of blood glucose by 49.2%, whereas the rosiglitazone treatment decreased the blood glucose levels by 54.4%. Furthermore, no significant blood glucose-lowering effect was observed for compounds XXI, XXIII, XXIV, XXVI, XXVIII and XXIX.

RESULT & DISCUSSION: The structures of the newly synthesized compounds were elucidated based on their IR, 1H-NMR, 13C-MR, MS spectral data, and elemental analyses. The IR spectra of the obtained compounds exhibited the presence of 3020 (Ar-CH), 1635 (C=N), 1595(C=C), 1384(C-N); 662 1092(OCH3) 1634 (-NH); 2983(-CH alkyl); 1726 (C=O); 1115(C-O). In addition to the expected aromatic protons signals, the 1H-NMR spectra revealed the appearance of new singlet for δ: 7.93, 7.85 (d, Ar-H, 2H), 7.48, 7.32, 7.22 (m, Ar-H, 4H), 7.38(d, Ar-H, 2-H); 8.14 (d, Ar-H, 2-H); 3.49.3.24 (d, C-H, 2-H), 4.7 (s, N-H, 1H). 13C-NMR spectra of the obtained compounds showed the appearance of new signals at range δ 13C NMR: CH for benzene, (140, 136, 69,149, 120, 126, 127,128), C for triazole, (148,128), C for chain C (128, 129, 134, 173, 55). Moreover, the MS of compound XXV showed a molecular ion peak at m/z 424-511 (M+-1, 0.22%). The synthesized triazolophthalazine derivatives showed significant activity (80.0%, 76.56%, and 75.43%) against α-amylase enzyme at different concentrations. The results of the experimental works are summarized in Table 1 and Fig. 2.

TABLE 1: PHYSICOCHEMICAL PARAMETER OF COMPOUNDS4- (4-SUBSTITUTED)-1-(3- SUBSTITUTED- 5, 6-DIHYDRO- [1, 2, 4] TRIAZOLO [3, 4-A] PHTHALAZIN-6-YLAMINO) AZETIDIN-2-ONE DERIVATIVES. (XXI-XXX)

Note: Solvents system: ethyyl acetate: chloroform

FIG. 2: EFFECT OF SYNTHETIC COMPOUNDS (XXI-XXX) ON BLOOD GLUCOSE LEVEL OF RAT

The synthesized triazolophthalazine derivatives showed a significant reduction in blood glucose level in the Sucrose-loaded model.

No significant blood glucose-lowering effect was observed for compounds XXII, XXV, XXVII and XXX Table 2.

TABLE 2: EFFECT OF ROSIGLITAZONE AND THE SELECTED 4-(-SUBSTITUTED)-1-(3-PHENYL-5, 6-DIHYDRO-[1, 2, 4] TRIAZOLO [3, 4-A] PHTHALAZINE-6-YL AMINO) AZETIDIN-2- ONE DERIVATIVE (XXI-XXX) ON FASTING BLOOD GLUCOSE LEVELS OF NORMAL DIABETIC AND TREATED RATS

Note: All determinations were carried out in a triplicate manner and values are expressed as the mean ± SD. Values are expressed as mean ± SEM (n=6),*** p<0.001,**p<0.01, *p<0.05, compare to diabetic control, Rosiglitazone was used as standard drug.

DISCUSSION: In this research work, numerous molecules that have substituted triazole phthalazine derivatives were obtained by using 4-hydrazine-1 chlorophthalazine as reacting molecule and different substituted benzoyl chloride that yielded 6 chloro-3 substituted  6a,10 a-dihydro-[1, 2, 4] triaolo [3, 4-a] phthalazine derivatives (I-V). These intermediates were treated with hydrazine hydrate to yield 6 hydrazine-3 substituted 6a, 10a-dihydro-[1, 2, 4] triaolo [3, 4-a] phthalazine derivatives (VI-X). These intermediates further reacted with substituted benzaldehyde and yielded 4-2-3-Substituted-6a, 10 a-dihydro-[1, 2, 4] triazolo [3, 4-a] phthalazin-6-yl) substituted hydrazinyl derivatives (XI-XX). These intermediate further treated with thioglycollic acid and yielded (XXI-XXX). 4-2-3-Substituted-6a, 10 a-dihydro-[1, 2, 4] triazolo [3, 4-a] phthalazin-6-yl) substituted hydrazinyl derivatives (XXI-XXX). Structures of all synthesized molecules were confirmed by using IR, ¹HNMR, MASS and elemental analysis spectroscopic techniques.

Antidiabetic Activity: All the synthesized compounds were screened in-vivo for their antidiabetic activity by a streptozotocin-induced diabetic model in albino rats. From the series XXII**, XXV**, XVII**, XXX**only some compounds had shown a significant reduction in blood glucose as compared to control diabetic rats. Those compounds having electron-donating substituents, i.e. XXII**, XXV**, XXVII** and XXX**, showed a significant increase in antidiabetic activity. it was interesting to note that compound XVIII, XIX, XXIX, having both electron donating at different position and electron with drawing group at different position of the phenyl ring showed increase in antidiabetic activity.

ACKNOWLEDGEMENT: Authors are grateful to Prof. Ranjeet Singh, Director of Pharmacy Department (Shobhit University), and Prof. Vijay Kumar Sharma, Director of Pharmacy Department (K.N. ModiInstitute of Pharmaceutical Education and Research) for supporting and motivating of completion of my research work.

CONFLICTS OF INTEREST: This research work does not have any conflict of interest because all work is done by me individual work all funding resources are self-funding by me.

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    How to cite this article:

    Singh S and Singh PK: Synthesis of 4- (4-substituted)-1-(3- substituted- 5, 6-dihydro- [1, 2, 4] triazolo [3, 4-a] phthalazin-6-ylamino) azetidin-2-one derivatives as antidiabetic agents. Int J Pharm Sci & Res 2022; 13(9): 3543-49. doi: 10.13040/IJPSR.0975-8232.13(9).3543-49.

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