Synthesis and Reactions of Some New Heterocyclic Carbohydrazides and Related Compounds as Potential Anticancer Agents

Abstract

Acylation of 3-hydrazino-5,6-diphenyl-1,2,4-triazine (2) and hydrazine hydrate (7) with 4-aryl-1,3,7-triphenyl-8-oxa-1,2,6-triazaspiro[4.4]nona-2,6-dien-9-ones 5a,b gave the corresponding heterocyclic carbohydrazides 6a,b and 8a,b respectively. Conversion of compounds 8a,b into the versatile carbohydrazide derivatives 9a-g, 10, 13 and the related oxadiazoles 11, 12a,b was undertaken. A primary in vitro test of compound 8a (concentration 10^-4 M) showed activity against leukemia cell lines (CCRF-CEM, K-256, MOLT-4, PRMI-8226, SR).

Introduction

Hydrazides and related compounds have been described as useful building blocks for the assembly of various heterocyclic rings [1]. A large number of aliphatic, alicyclic, aromatic and heterocyclic carbohydrazides, their derivatives and related compounds are reported to present a plethora of biological activities [2,3,4,5,6,7,8,9,10,11,12,13,14,15]. Thus, different carbohydrazides were found to be useful as medicaments especially in the treatment of inflammatory and autoimmune diseases, osteoarthritis, respiratory diseases, tumors, cachexia, cardiovascular diseases, fever, hemorrhage and sepsis [11]. Carbohydrazides and related compounds exhibited antifungal [2], antiviral [14], bacteriostatic [2,7,9,14], antiparasite [2,10], antituberculous [3,4,5,6], psychotropic [2], and insecticidal [15] activities. Some heterocyclic carbohydrazides are useful as antifertility agents in rats and pigeons [13]. Other carbohydrazides were reported to be components of deodorant compositions that can be used for removal of offensive odor components [16]. The 1,3,4-oxadiazoles have been reported to be biologically versatile compounds having bactericidal, fungicidal, analgesic, antiproteolytic, hypoglycemic, tranquilizing and CNS depressant properties [2]. All these facts encouraged us to synthesize some new 2-pyrazolin-3-carbohydrazides 8a,b, their derivatives 9a-g, 10, 13 and some related oxadiazoles 11, 12a,b in anticipation of expected interesting biological activities.

Results and discussion

Acylation of 3-hydrazino-5,6-diphenyl-1,2,4-triazine (2) with 4-arylidene-2-phenyl-oxazol-5(4H)-ones (1a-d) has been previously reported [17] to give the corresponding N-(5,6-diphenyl-1,2,4-triazin-3-yl)-carbohydrazides 3a-d (Scheme 1).

Scheme 1.

Scheme 1.

We have now studied the acylation of both compound 2 and hydrazine hydrate (7) with the 4-aryl-1,3,7-triphenyl-8-oxa-1,2,6-triazaspiro[4.4]nona-2,6-dien-9-ones 5a,b. Some chemical transformations leading to new functionalities have also been achieved (Scheme 2). For example, acylation of 3-hydrazino-5,6-diphenyl-1,2,4-triazine (2) with the spiro compounds 5a,b [19,20] gave the corresponding novel N-(5,6-diphenyl-1,2,4-triazin-3-yl)-1,3-diphenyl-4-aryl-5-benzoylamino-2-pyrazolin-5-carbohydrazides 6a,b. The structure of compounds 6a,b was assigned based on analytical and spectral data. Thus, the IR spectra of these compounds showed bands at 3405-3396, 3277-3267 (NH stretching), 3063-3059, 3038-3028 (aromatic CH stretching), 1709 (hydrazide C=O stretching ), 1685-1682 (amide C=O stretching), 1627 (C=N stretching) and 1601-1597 cm^-1 (aromatic C=C stretching).

Scheme 2.

Scheme 2.

Also, the ¹H-NMR spectra of compounds 6a,b revealed signals at δ 11.31-10.28 (2s, hydrazide NHNH), 7.97-7.72 (s, amide NH), 7.61-6.50 (m, ArH's), 5.87-5.64 (s, pyrazolinyl CH). Moreover, the ¹³C-NMR of compounds 6a,b showed signals consistent with their structures (cf. Experimental). Similarly, acylation of hydrazine hydrate (7) with the spiro compounds 5a,b afforded the corresponding 4-aryl-5-benzoylamino-1,3-diphenyl-2-pyrazoline-5-carbohydrazides 8a,b. The structure of compounds 8a,b was established chemically and spectroscopically. Thus, the ¹H-NMR spectra of these compounds not only showed the presence of the pyrazolinyl proton at δ 5.59-5.32, but also revealed the presence of NH₂ protons at δ 4.61-4.54 [s, 2H (exchangeable)]. The mass spectra of compounds 8a,b, also gave their correct parent ion peaks at m/z 475 (M⁺, 1.3%), and 505 (M⁺, 0.4%), respectively.

Condensation of compounds 8a,b with aryl aldehydes and/or acetylation of compound 8a with acetic acid was found to proceed concurrently with the elimination of a benzamide molecule to give the corresponding N-arylidene and/or N-acetoxy-4-aryl-1,3-diphenyl-pyrazole-5-carbohydrazides 9a-g and/or 10 respectively. The structures of these compounds were inferred from their analytical and spectral data. Thus, the IR spectra of compounds 9a-g showed only one carbonyl function (hydrazide C=O) at 1722-1670 cm^-1 and that of compound 10 showed a carbonyl function at 1672 cm^-1(hydrazide C=O overlapped with acetyl C=O). The ¹H-NMR spectra of 9a-g and 10 not only showed the absence of both the pyrazolinyl proton at δ 5.59-5.32 and the NH₂ protons at δ 4.61-4.54, but also the presence of the N=CH in compounds 9a-g (δ 8.30-7.65) and the acetyl protons of compound 10 (δ 1.86). The IR spectra of compounds 9a-g as well as their ¹H-NMR spectra (relative proton integration ratio) showed the presence of both hydrazide (25-63.3%) and hydrazole (36.7-75%) tautomeric structures. The mass spectra of compounds 9a,c gave their correct parent ion peaks at m/z 442 (M⁺, 13.7%) and 456 (M⁺, 12%), respectively.

Treatment of compound 8a with benzoic acid and phosphorous oxychloride was found to proceed via concurrent cyclocondensation and elimination of a benzamide molecule to give the 5-phenyl-2-(1,3,4-triphenylpyrazol-5-yl)-1,3,4-oxadiazole (11). The mass spectrum of compound 11 showed its correct parent ion peak at m/z 440 (M⁺, 49.9%).

Compounds 8a,b reacted with carbon disulfide in ethanolic KOH to yield the corresponding 2-(4-aryl-1,3-diphenyl-5-benzoylamino-2-pyrazolin-5-yl)-1,3,4-oxadiazole-5(4H)-thiones (12a,b). The absence of the characteristic weak S-H stretching bands at 2600-2550 and the appearance of the strong C=S stretching bands at 1069-1064 cm^-1 in the IR spectra of compounds 12a,b confirmed their thione form and excluded the tautomeric thiol structure. The IR spectra of compounds 12a,b showed also bands at 1199-1019 cm^-1 (=C-O-C= stretching). The ¹H-NMR spectra revealed the presence of the NH oxadiazolyl proton at δ 14.60-14.52 and the CH pyrazolinyl proton at δ 6.32-5.90.

Reaction of compound 8b with phenyl isothiocyanate gave N-(N-phenylthiocarbamoyl)-5-benzoylamino-1,3-diphenyl-4-(2-methoxyphenyl)-2-pyrazolin-5-carbohydrazide (13). Elemental and spectral data are consistent with the structure assigned to this compound (cf. Experimental).

Biological Evaluation

A primary in vitro test of compound 8a (concentration 10^-4 M) showed activity against Leukemia cell lines (CCRF-CEM, K-562, MOLT-4, PRMI-8226, SR). Further investigation is in progress.

Experimental

General

All melting points are uncorrected. IR spectra (KBr disks) were recorded on a Perkin-Elmer 1430 spectrometer. The abbreviations str. and bend. are used to indicate stretching and bending bands, respectively . ¹H-NMR and ¹³C-NMR were measured with a Varian GEMINI 200 spectrometer (200 MHz for ¹H-NMR; 50MHz for ¹³C-NMR). The abbreviation exch. is used to indicate exchangeable protons. Mass spectra were recorded on a GCMS - QP 1000 EX (70EV) spectrometer. Elemental analyses were carried out at the Microanalytical Center, Cairo University. Anticancer screening of compound 8a was carried out at the National Cancer Institute – National Institutes of Health, Bethesda, Maryland, United States of America. The starting materials 3-hydrazino-5,6-diphenyl-1,2,4-triazine (2) [18] and 4-aryl-1,3,7-triphenyl-8-oxa-1,2,6-triazaspiro-[4.4]nona-2,6-dien-9-ones 5a,b [19,20] were prepared as reported.

General procedure for the preparation of N-(5,6-diphenyl-1,2,4-triazin-3-yl)-4-aryl-5-benzoylamino-1,3-diphenyl-2-pyrazoline-5-carbohydrazides (6a,b).

Each of compounds 5a,b (1 mmol) was added to a solution of compound 2 (1 mmol) in toluene (10 mL). The reaction mixture was then heated under reflux for 1¹/₂ hour, concentrated, and diluted with petroleum ether (bp. 40-60 °C). After decantation, the residue obtained was boiled in ethanol (5 mL), filtered, and cooled. The formed precipitate was collected by filtration and recrystallized from ethanol giving colorless crystals of 6a,b.

N-(5,6-Diphenyl-1,2,4-triazin-3-yl)-5-benzoylamino-1,3,4-triphenyl-2-pyrazoline-5-carbohydrazide (6a). Using the general procedure, 5a gave 6a (73%); mp. 218-219°C; IR (cm^-1): 3405, 3277 (NH str.), 3063, 3038 (aromatic CH str.), 2922, 2866, 2855 (pyrazolinyl aliphatic CH str.), 1709 (hydrazide C=O str.), 1685 (amide C=O str.), 1627 (C=N str.), 1601 (aromatic C=C str.), 1505, 1480 (NH bend.), 1365, 1312, 1283, 1251 (C-N str.), 762, 697 (aromatic CH bend.); ¹H-NMR (DMSO-d₆) δ 11.31, 10.31 [2s, 2H (exch.), hydrazide NHNH], 7.72 [s, 1H (exch.), amide NH], 7.57-6.82 (m, 30H, ArH's), 5.64 (s, 1H, pyrazolinyl CH); ¹³C-NMR (DMSO-d₆) δ 171.5, 164.8 (C=O), 157, 152, 146.5, 142.5 (C=N), 136.2, 134.6, 132.2, 131.5 (aromatic C), 130.5, 129.5, 129.4, 128.7, 128.6, 128.5, 128.2, 127.6, 127.3, 127.2, 127.0. 126.2 (aromatic CH), 81.6 (pyrazolinyl C), 63.5 (pyrazolinyl CH); Anal. for C₄₄H₃₄N₈O₂ Calcd.: C, 74.77; H, 4.85; N, 15.85. Found: C, 74.60; H, 5.00, N, 15.70.

N-(5,6-Diphenyl-1,2,4-triazin-3-yl)-5-benzoylamino-1,3-diphenyl-4-(2-methoxyphenyl)-2-pyrazoline-5-carbohydrazide (6b). Using the general procedure, 5b gave 6b (41%); mp. 210-212°C; IR (cm^-1): 3396, 3267 (NH str.), 3059, 3028 (aromatic CH str.), 2964, 2932, 2883, 2833 (OCH₃ and pyrazolinyl aliphatic CH str.), 3059, 3028, 2997 (aromatic CH str.), 1709 (hydrazide C=O str.), 1682 (amide C=O str.), 1597(aromatic C=C str.), 1495, 1473, 1445 (NH bend.), 1358, 1331, 1290, 1252 (C-N str.), 1067, 1028 (C-O str. of OCH₃), 762, 692 (aromatic CH bend.); ¹H-NMR (DMSO-d₆) δ 11.23, 10.28 [2 brs, 2H (exch.), hydrazide NHNH], 7.97 [s, 1H (exch.), amide NH] 7.61-6.50 (m, 29H, ArH's), 5.87 (s, 1H, pyrazolinyl CH), 3.60 (s, 3H, OCH₃); ¹³C-NMR (DMSO-d₆) δ 171.64, 164.30, (C=O), 157.28, 146.84, 142.78, 136.41 (C=N), 135.95, 134.76, 132.74, 132.49, 132.45, 132.41, 131.46 (aromatic C), 130.54, 129.70. 129.31, 129.20, 128.74, 128.64, 128.40, 128.29, 126.86, 126.08, 125.89, 121.68, 120.33, 115.15, 115.09, 114.99 (aromatic CH), 110.04 (pyrazolinyl C), 80.55 (pyrazolinyl CH), 55.04 (OCH₃); Anal. for C₄₅H₃₆N₈O₃ Calcd.: C, 73.35; H, 4.92; N, 15.21. Found: C, 73.50; H, 5.00; N, 15.40.

General procedure for the preparation of 4-aryl-5-benzoylamino-1,3-diphenyl-2-pyrazoline-5-carbohydrazides (8a,b). To a suspension of each of compounds 5a,b (1 mmol) in methanol (20 mL) was added 80% hydrazine hydrate (0.5 mL). While the reaction mixture of compound 8a was shaken for ten minutes at room temperature, that of compound 8b was heated under reflux for one hour. The reaction mixtures of each compound were then left overnight at room temperature. The colorless precipitate formed was collected by filtration and recrystallized from methanol to give colorless crystals of 8a,b.

5-Benzoylamino-1,3,4-triphenyl-2-pyrazoline-5-carbohydrazide (8a). Using the general procedure, 5a gave 8a (73%); mp. 214-215°C; IR (cm^-1): 3400, 3325 (NH, NH₂ str.), 3065, 3034 (aromatic CH str.), 2930 (pyrazolinyl CH str.), 1669 (C=O str.), 1625 (C=N str.), 1601 (aromatic C=C str.), 1503, 1480 (NH bend.), 1374, 1321, 1280, 1243 (C-N str.), 750, 696 (aromatic CH bend.); ¹H-NMR (DMSO-d₆) δ 10.05 [s, 1H (exch.), hydrazide NH], 8.07 [s, 1H (exch.), amide NH], 7.60-6.86 (m, 20H, ArH's), 5.32 (s, 1H, pyrazolinyl CH), 4.54[s, 2H (exch.), NH₂]; MS m/z 475 (M⁺, 1.3%); Anal. for C₂₉H₂₅N₅O₂ Calcd.: C, 73.24; H, 5.30; N, 14.73. Found: C, 73.20; H, 5.25; N, 14.60.

5-Benzoylamino-1,3-diphenyl-4-(2-methoxyphenyl)-2-pyrazoline-5-carbohydrazide (8b). Using the general procedure, 5b gave 8b (74%); mp. 230°C; IR (cm^-1): 3384, 3334,3284 (NH, NH₂ str.), 3061, 3025 (aromatic CH str.), 2954, 2942, 2901, 2835 (OCH₃ and pyrazolinyl aliphatic CH str.), 1684 (hydrazide C=O str.), 1672 (amide C=O str.), 1636 (C=N str.), 1604 (aromatic C=C str.), 1497, 1475 (NH bend.), 1375, 1294, 1250 (C-N str.), 1167, 1028 (C-O str. of OCH₃), 750, 692 (aromatic CH bend.); ¹H-NMR (DMSO-d₆) δ 10.25 [s, 1H (exch.), hydrazide NH], 8.18 [s, 1H (exch.), amide NH], 7.56-6.49 (m, 19H, ArH's), 5.59 (s, 1H, pyrazolinyl CH), 4.61[s, 2H (exch.), NH₂], 3.82 (s, 3H, OCH₃); MS m/z 505 (M⁺, 0.4%); Anal. for C₃₀H₂₇N₅O₃ Calcd.: C, 71.27; H, 5.38; N, 13.85. Found: C, 71.30; H, 5.50; N, 14.00.

N-Arylidene-4-aryl-1,3-diphenylpyrazole-5-carbohydrazides (9a-g).

General Procedure A: To a solution of each of compounds 8a,b (1 mmol) in either acetic acid (12 mL) or n-butanol (20 mL) was added the appropriate aryl aldehyde (1 mmol) and the reaction mixture was then heated under reflux for a time as shown as in Table 1. The crystalline colorless precipitates of compounds 9a-d,f were collected by filtration, washed with methanol, and recrystallized from the appropriate solvent. Pure 9e,g were obtained from their reaction mixtures via dilution with water, collection of the formed precipitate by filtration, and recrystallization from the appropriate solvent.

Table 1.

9	Reaction Solvent	Reflux Time	Recrystallization Solvent
a	n-Butanol	3 hours	EtOH
b	Acetic acid	20 minutes	n-Butanol
c	Acetic acid	11/2 hour	Acetic acid
d	Acetic acid	11/2 hour	Acetic acid
e	Acetic acid	2 hours	Ethanol
f	Acetic acid	11/4 hour	Ethanol
g	Acetic acid	2 hours	Ethanol

Table 1.

9	Reaction Solvent	Reflux Time	Recrystallization Solvent
a	n-Butanol	3 hours	EtOH
b	Acetic acid	20 minutes	n-Butanol
c	Acetic acid	11/2 hour	Acetic acid
d	Acetic acid	11/2 hour	Acetic acid
e	Acetic acid	2 hours	Ethanol
f	Acetic acid	11/4 hour	Ethanol
g	Acetic acid	2 hours	Ethanol

General Procedure B: To compound 8a (1 mmol) was added 4-methylbenzaldehyde (1 mmol) and 3 drops of piperidene. The reaction mixture was then heated (oil bath) at 120 °C till complete dissolution which was followed by an immediate resolidification. The reaction mixture was allowed to cool to room temperature, diluted with methanol, and the formed colorless crystalline product was collected by filtration and recrystallized from ethanol giving colorless crystals of 9c, identical with the product 9c obtained from general procedure A (mp. and mixed mp. as well as analytical and spectral data).

N-Benzylidene-1,3,4-triphenylpyrazole-5-carbohydrazide (9a). Using general procedure A, 8a gave 9a (34%); mp. 229-230°C; IR (cm^-1): 3584-3291 (OH str. of hydrazole tautomer), 3213 (NH str.), 3066, 3028 (aromatic CH str.), 1674 (hydrazide C=O str.) 1655 (C=N str.), 1597 (aromatic C=C str.), 1556, 1500 (NH bend.), 1365, 1313, 1275, 1246 (C-N str.), 760, 692 (aromatic CH bend.); ¹H-NMR (CDCl₃) δ 10.03, 8.43 [ 2brs,1H (exch.), hydrazide (53.7%) - hydrazole (46.3%) tautomeric proton], 7.73-7.07 (m, 21H, ArH's, N=CH); Ms m/z 442 (M⁺, 13.7%); Anal. for C₂₉H₂₂N₄O Calcd.: C, 78.71; H, 5.01; N, 12.66. Found: C, 78.80; H, 5.20; N, 12.80.

N-(2-Hydroxybenzylidene)-1,3,4-triphenylpyrazole-5-carbohydrazide (9b). Using general procedure A, 8a gave 9b (88%); mp.283-285°C; IR (cm^-1): 3200-2500 (OH str.), 3178 (NH str.), 3055, 3007 (aromatic CH str.), 1722 (hydrazide C=O str.), 1651(C=N str.), 1601 (aromatic C=C str.), 1545, 1499 (NH bend.), 1367, 1331, 1313, 1292, 1277, 1250, 1186, 1184, 1149 [C-N, C-O (phenolic) str.], 758, 692 (aromatic CH bend.); ¹H-NMR (DMSO-d₆) δ 12.36 [s, 1H (exch.), 2-(OH)-C₆H₄] 10.70, 9.96 [2s, 1H (exch.), hydrazide (63.3%) - hydrazole (36.7%) tautomeric proton], 8.30 (s, 1H, N=CH), 7.72-6.73 (m, 19H, ArH's); Anal. for C₂₉H₂₂N₄O₂ Calcd.: C, 75.97; H, 4.83; N, 12.22. Found: C, 76.00; H, 4.76; N, 12.00.

N-(4-Methylbenzylidene)-1,3,4-triphenylpyrazole-5-carbohydrazide (9c). Using the general procedures A and/or B, 8a gave 9c (67%) and / or (70%), respectively; mp. 222-223°C; IR (cm^-1): 3342-2400 (OH str. of hydrazole tautomer), 3197 (NH str.), 3052, 3000 (aromatic CH str.), 2947, 2919 (CH str. of CH₃), 1672 (hydrazide C=O str.) 1653 (C=N str.), 1603 (aromatic C=C str.), 1564, 1500 (NH bend.), 1372, 1335, 1322, 1311, 1292, 1279, 1256, 1211-1027 [C-O (of hydrazole tautomer), C-N str.], 765,757, 702, 684 (aromatic CH bend.); ¹H-NMR (CDCl₃) δ 10.45, 8.50 [2s, 1H (exch.), hydrazide (61.0%) - hydrazole (39.0%) tautomeric proton], 7.65-7.08 (m, 20H, ArH's, N=CH), 2.33 (s, 3H, CH₃); MS m/z 456 (M⁺, 12.0%); Anal. for C₃₀H₂₄N₄O Calcd.: C, 78.92; H, 5.30; N, 12.27. Found: C, 78.90; H, 5.40; N, 12.40.

N-(4-Methoxybenzylidene)-1,3,4-triphenylpyrazole-5-carbohydrazide (9d). Using general procedure A, 8a gave 9d (83%); mp. 245-247°C; IR (cm^-1): 3713-2555 (OH str.of hydrazole tautomer), 3194 (NH str.), 3055, 3006 (aromatic CH str.), 2967, 2927, 2838 (CH str. of OCH₃), 1673 (hydrazide C=O str.), 1651 (C=N str.), 1604 (aromatic C=C str.), 1565, 1506 (NH bend.), 1369, 1306, 1251, 1172-1028 [C-O, C-N str.), 762,701 (aromatic CH bend.); ¹H-NMR (CDCl₃) δ 9.93, 8.40 [2s, 1H (exch.), hydrazide (52.2%) - hydrazole (47.8%) tautomeric proton], 7.69-6.83 (m, 20H, ArH's, N=CH), 3.84 (s, 3H, OCH₃); Anal. for C₃₀H₂₄N₄O₂ Calcd.: C, 76.25; H, 5.12; N, 11.86. Found: C, 76.40; H, 5.08; N, 12.00.

N-Benzylidene-1,3-diphenyl-4-(2-methoxyphenyl)-pyrazole-5-carbohydrazide (9e). Using general procedure A, 8b gave 9e (80%); mp. 175-176°C; IR (cm^-1): 3200-2500 (OH str. of hydrazole tautomer), 3196 (NH str.), 3067 (aromatic CH str.), 2987, 2930, 2856 (CH str. of OCH₃), 1670 (hydrazide C=O str.) 1651 (C=N str.), 1612, 1595 (aromatic C=C str.), 1556, 1499 (NH bend.), 1364, 1273,1242-1074 (C-O, C-N str.), 760, 700, 692 (aromatic CH bend.); ¹H-NMR (CDCl₃) δ 9.83, 9.43 [2s, 1H (exch.), hydrazide (27.8%) - hydrazole (72.2%) tautomeric proton], 7.72-6.95 (m, 20H, ArH's, N=CH), 3.85 (s, 3H, OCH₃); Anal. for C₃₀H₂₄N₄O₂ Calcd.: C, 76.25; H, 5.12; N, 11.86. Found: C, 76.40; H, 5.10; N, 11.60.

N-(2-Hydroxybenzylidene)-1,3-diphenyl-4-(2-methoxyphenyl)-pyrazole-5-carbohydrazide (9f). Using general procedure A, 8b gave 9f (81%); mp. 207-208°C; ¹H-NMR (CDCl₃): δ 10.69 [s, 1H (exch.), OH], 9.37 [s, 1H (exch.), NH], 7.89 (s, 1H, N=CH), 7.67-6.84 (m, 18H, ArH's), 3.84 (s, 3H, OCH₃); Anal. for C₃₀H₂₄N₄O₃ Calcd.: C, 73.75; H, 4.95; N, 11.47. Found: C, 73.80; H, 5.00; N, 11.62.

N-(4-Methoxybenzylidene)-1,3-diphenyl-4-(2-methoxyphenyl)-pyrazole-5-carbohydrazide (9g). Using general procedure A, 8b gave 9g (85%); mp. 178-180°C; IR (cm^-1): 3645-3266 (OH str. of hydrazole tautomer), 3175 (NH str.), 3068, 3005 (aromatic CH str.), 2962, 2933, 2902, 2837(CH str. of OCH₃), 1685 (hydrazide C=O str.) 1650 (C=N str.), 1603 (aromatic C=C str.), 1547, 1509 (NH bend.), 1366, 1307,1254 , 1170-1026 (C-O, C-N str.) 758, 694 (aromatic CH bend.); ¹H-NMR (CDCl₃): δ 9.74, 9.34 [2s,1H (exch.), hydrazide (25.0%) - hydrazole (75.0%) tautomeric proton], 7.72-6.86 (m, 19H, ArH's, N=CH), 3.83(s, 6H, OCH₃); Anal. for C₃₁H₂₆N₄O₃ Calcd.: C, 74.08; H, 5.21; N, 11.15. Found: C, 74.12; H, 5.10; N, 11.60.

N-Acetyl-1,3,4-triphenylpyrazole-5-carbohydrazide (10). To compound 8a (1 mmol) was added acetic acid (15 mL) and the reaction mixture was heated under reflux for 1¹/₄ hour. After cooling, the reaction mixture was poured onto water and the formed precipitate was collected by filtration and recrystallized from ethanol as colorless crystals of 10 (83%); mp. 237-238°C; IR (cm^-1): 3194 (NH str.), 3055, 3009 (aromatic CH str.), 2968, 2914, 2839 (CH str. of CH₃), 1672 (C=O str.), 1651 (C=N str.), 1605 (aromatic C=C str.), 1564, 1512, 1500 (NH bend.), 1371, 1306, 1279, 1250 (C-N str.), 772, 768, 704, 690 (aromatic CH bend.); ¹H-NMR (DMSO-d₆): δ 10.76, 9.98 [2s, 2H (exch.), hydrazide NHNH], 7.97-7.26 (m, 15H, ArH's), 1.85 (s, 3H, CH₃CO); Anal. for C₂₄H₂₀N₄O₂ Calcd.: C, 72.71; H, 5.08; N, 14.13. Found: C, 72.80; H, 5.10; N, 14.50.

2-(1,3,4-Triphenylpyrazol-5-yl)-5-phenyl-1,3,4-oxadiazole (11). A mixture of compound 8a (1 mmol), benzoic acid (1 mmol), and phosphororus oxychloride (1 mmol) was heated under reflux for 1¹/₂ hour. After cooling to room temperature, the reaction mixture was poured onto crushed ice, stirred, decanted and diluted with water. The residue obtained after a second decantation was boiled with methanol. The solidified residue obtained on cooling was collected by filtration and recrystallized from N,N-dimethylformamide as colorless crystals of 11 (23%); mp.185°C; ¹H-NMR (DMSO-d₆): δ 7.69-7.34 (m, ArH's); MS m/z 440 (M⁺, 49.9); Anal. for C₂₉H₂₀N₄O Calcd.: C, 79.07; H, 4.57; N, 12.72. Found: C, 79.10; H, 4.62; N, 12.69.

General procedure for the preparation of 2-(4-Aryl-5-benzoylamino-1,3-diphenyl-2-pyrazolin-5-yl)-1,3,4-oxadiazole-5(4H)-thiones (12a,b). To a solution containing 95% ethanol (5 mL) and potassium hydroxide (1 mmol, dissolved in the least amount of water), were added compounds 8a,b (1 mmol) followed by carbon disulfide (1.5 mmol). The reaction mixture was heated under reflux for 3 hours till all the evolution of hydrogen sulfide ceased. After decantation, the supernatant solution was evaporated, diluted with water (while a milky solution was obtained), and acidified with hydrochloric acid containing ice. The reaction mixture was allowed to stand at room temperature for 15 minutes, filtered, and the solid obtained was washed well with water and dried at room temperature. The crude products were then recrystallized from ethanol as colorless crystals of 12a,b.

2-(5-Benzoylamino-1,3,4-triphenyl-2-pyrazolin-5-yl)-1,3,4-oxadiazole-5(4H)-thione (12a). Using the general procedure, 8a gave 12a (81%); mp. 236-237°C; IR (cm^-1): 3421, 3157 (NH str.), 3063, 3030 (aromatic CH str.), 2945, 2926, 2852 (pyrazolinyl CH str.), 1683 (amide C=O str.), 1600 (aromatic C=C str.), 1507, 1489, 1469 (NH bend.), 1331, 1286, 1255 (C-N str.), 1199, 1153,1019 (=C-O-C= str.), 1064 (C=S str.), 761, 649 (aromatic CH bend.); ¹H-NMR (DMSO-d₆): δ 14.60 [brs, 1H (exch.), oxadiazolyl NH], 9.85 [s, 1H (exch.), amide NH], 7.83-7.10 (m, 20H, ArH's), 5.90 (s, 1H, pyrazolinyl CH); Anal. for C₃₀H₂₃N₅O₂S Calcd.: C, 69.61; H, 4.48; N, 13.53; S,6.19. Found: C, 69.50; H, 4.50; N, 13.59; S, 6.15.

2-[5-Benzoylamino-1,3,-diphenyl-4-(2-methoxyphenyl)-2-pyrazolin-5-yl]-1,3,4-oxadiazole-5(4H)-thione (12b). Using the general procedure, 8b gave 12b (81%); mp. 140°C; IR ((cm^-1): 3375, 3139 (NH str.), 3067 (aromatic CH str.), 2938, 2836 (OCH₃ and pyrazolinyl aliphatic CH str.), 1682 (amide C=O str.), 1602 (aromatic C=C str.), 1498, 1470, 1446 (NH bend.), 1343, 1328, 1293, 1253 (C-N str.), 1190, 1149, 1106, 1027 (=C-O-C= str., C-O str. of OCH₃), 1069 (C=S str.), 759, 699 (aromatic CH bend.); ¹H-NMR (DMSO-d₆): δ 14.52 [brs, 1H (exch.), oxadiazolyl NH], 9.69 [s, 1H (exch.), amide NH], 7.78-6.78 (m,19H, ArH's), 6.32 (s, 1H, pyrazolinyl CH), 3.85 (s, 3H, OCH₃); Anal. for C₃₁H₂₅N₅O₃S Calcd.: C, 67.99; H, 4.60; N, 12.79; S,5.85. Found: C, 68.12 H, 4.62; N, 12.69; S,5.82.

N-(N-Phenylthiocarbamoyl)-5-benzoylamino-1,3-diphenyl-4-(2-methoxyphenyl)-2-pyrazoline-5-carbo-hydrazide (13). To a suspension of 8b (1 mmol) in absolute ethanol (25 mL) was added phenyl isothiocyanate (1.01 mmol), and the mixture was heated under reflux for 2¹/₂ hours (all materials went into solution after 45 minutes of heating under reflux). The reaction mixture was concentrated, allowed to cool, and upon scratching, the product precipitated as colorless crystals. The crude product was collected by filtration and recrystallized from ethanol as colorless crystals of 13 (75%) mp.145-146°C; IR (cm^-1): 3371, 3327, 3150, 3110 (NH str.), 3059,3029 (aromatic CH str.), 2964, 2923, 2880, 2842 (OCH₃ and pyrazolinyl aliphatic CH str.), 1718 (hydrazide C=O str.), 1678 (amide C=O str.), 1651, 1625 (C=N str.), 1599 (aromatic C=C str.), 1543,1497, 1473, 1442 (NH bend.), 1380, 1357, 1320, 1291, 1252 (C-N str.), 1210-1025 (C-O str.), 1070 (C=S str.), 758, 692 (aromatic CH bend.); ¹H-NMR (DMSO-d₆): δ 10.79, 9.92, 9.34, 9.15 [3s, 1brs, 4H (exch.), 4NH], 7.80-6.55 (m, 24H, ArH's), 6.23 (s, 1H, pyrazolinyl CH), 3.76 (s, 3H, OCH₃); Anal. for C₃₇H₃₂N₆O₃S Calcd.: C, 69.35; H, 5.03; N, 13.11; S, 5.04. Found: C, 69.1, H, 5.30; N, 13.00; S, 5.10