HETEROCYCLES

Paper | Regular issue | Vol. 83, No. 5, 2011, pp. 1093-1109
Received, 3rd February, 2011, Accepted, 14th March, 2011, Published online, 25th March, 2011.
DOI: 10.3987/COM-11-12164

■ Synthesis and Antitumor Activity of Novel N’-(2-Benzylthiobenzenesulfonyl)-1H-pyrazole-1-amidine Derivatives

Jarosław Sławiński,* Kamil Brożewicz, Andrzej Fruziński, and Marek L. Główka

Department of Organic Chemistry, Medical University of Gdańsk, Al. Gen. Hallera 107, 80-416 Gdańsk, Poland

Abstract

A series of N´-(2-benzylthio-4-chlorobenzenesulfonyl)-1H- pyrazole-1-amidines (23-36) were synthesized by the reaction of 3-amino-2-(benzenesulfonyl)guanidines (18-22) with adequate 1,3-diketones. The compounds 23, 24, 26, 30, 31, 34 and 35 were tested in vitro in the full NCI 60 cell panel. The most potent compound in the series (26) showed substantial activity toward some cell lines of leukemia and cancer cells of lung, colon, CNS, melanoma, renal, prostate and breast (GI50 in the range 2.30-9.47 μM).

INTRODUCTION
A number of structurally novel sulfonamide derivatives have recently been reported to show substantial antitumor activity.1,2
Among them the 2-mercaptobenzenesulfonamides (MBSAs) have revealed much attention due to their substantial anticancer3-5 or anti-HIV6-8 activities. Recently, in the course of search for more potent analogues we synthesized a variety of 2-mercaptobenzenesulfonamide derivatives possessing heteroaromatic moieties substituting sulfonamide functionality.9-12 Thus, we found that their anticancer properties strongly depend on the nature of the substituent attached to the sulfonamide nitrogen atom.9-12 Currently, our interest turned to a pyrazole derivatives due to their broad spectrum of biological activity such as CDK4,13 Aurora kinases,14,15 p38-MAP kinase,16,17 TGF-β18 or HIV protease19 inhibition. This prompted us to investigate the chemistry and biological activity of such compounds. Therefore in the present paper we elaborated an efficient method for the synthesis of novel N´-(2-benzylthio-4-chlorobenzenesulfonyl)-1H-pyrazole-1-amidine derivatives.

RESULTS AND DISCUSSION
The starting 7-(azol-2-yl)-1,1-dioxo-1,4,2-benzodithiazine derivatives (5-8) were synthesized in a three-step reaction, as outlined in Scheme 1. At first, starting 6-chloro-3-methylthio-1,1-dioxo-1,4,2-benzodithiazine-7-carboxylic acid (1)20 was converted to the acid chloride (2)21 followed by treatment with two molar equivalents of the appropriate benzhydrazide in dry benzene to give the corresponding N,N'-diaroylhydrazines (3, 4). The latter compounds were converted either to the 1,3,4-oxadiazoles (5, 6) in boiling thionyl chloride or to the corresponding 1,3,4-thiadiazole derivatives (7, 8) in the presence of one molar equivalent of Lawesson’s reagent in toluene.

3-Aminobenzodithiazines (9-12) were in turn obtained by the reaction of the corresponding 3-methylthio derivatives (5-8) with ammonium hydroxide in methanol at ambient temperature for 120 to 190 h (Scheme 1). Subsequent reaction of 3-aminobenzodithiazines (9-12) with an excess of anhydrous K2CO3 in dry tetrahydrofuran in the presence of 1.2 molar equivalent of benzyl chloride furnished the desired novel N-(benzenesulfonyl)cyanamide potassium salts (13-16) in good (68-97%) yields.
The previously described method was employed for the synthesis of aminoguanidine (18)22,23 (Scheme 2). Analogously were synthesized the new 3-amino-2-(benzylthio-4-chlorobenzenesulfonyl)guanidines (19-22). The syntheses of the target N'-(2-benzylthio-4-chlorobenzenesulfonyl)-1H-pyrazole-1-amidine derivatives (23-36) were achieved by reacting the corresponding aminoguanidines (18-22) with adequate 1,3-diketones in refluxing toluene in the presence of catalytic amount (0.05 equiv) of p-toluenesulfonic acid (PTSA).

The structures of the compounds 3-16, 19-22 and the final products 23-36 were confirmed by elemental analyses, IR and NMR spectroscopic data presented in experimental section. It is worth to note that the 1H NMR spectra of the compounds 23-36 in DMSO solution exhibit two signals attributable to the protons of NH2 group in the region δ = 7.88-8.46 and 8.59-9.31 ppm. This fact could be explained by the presence of intramolecular hydrogen bonds (i.e., NH…N and NH…O).
Therefore, X-ray analysis of two representative final compounds 23 and 25 was undertaken (Figure 1). It showed very similar molecular features of the studied structures, resulting from two intramolecular hydrogen bonds (Table 2), namely N-H…N(pyrazole) and N-H…O(sulfonyl).

The bonds define conformation of the N'-sulfonyl-1H-pyrazole-1-amidine fragments in 23 and 25 (Figure 1) In addition, an intermolecular weak hydrogen contact N-H…O(sulfonyl) is observed in structure 25 (Table 2 and Figure 1). It may be of some interest that no other crystal structure comprising N'-sulfonyl-1H- pyrazole-1-amidine frame has been studied until now.24
The compounds 23, 24, 26, 30, 31, 34 and 35 were tested in vitro at the US National Cancer Institute (Bethesda, MD). Primary anticancer assay at concentration of 10-5 M in the full NCI 60 cell panel showed that compounds 30, 31, 34 and 35 were essentially inactive. Thus, it was interesting to find that replacement of methyl group in position 5 of benzene ring (R1) with substituted five-membered heterocyclic rings decreased cytotoxicity considerably. On the other hand the compounds 23, 24 and 26 showed some level of ability to inhibit the growth of human tumor cells. Therefore a secondary screening at five concentrations ranged from 10-8 to 10-4 M was performed for 23 and 26. As shown in Table 3 the compounds 23 and 26 exhibited reasonable anti-proliferative activity (GI50 <25 μM) over 23-29 cell lines. The most potent 26 showed substantial activity toward four to five cell lines of leukemia and cancer cells of lung and breast, and also one or two cell lines of colon, CNS, melanoma, renal and prostate (GI50 in the range 2.30-9.47 μM).

EXPERIMENTAL
Melting points were determined with Boëtius apparatus and are uncorrected. The IR spectra were taken using Thermo Mattson Satellite FTIR spectrophotometer, 1H and 13C NMR were taken with a Varian Gemini 200 MHz or Varian Unity Plus 500 MHz apparatus. Chemical shifts are reported in ppm (δ) and J values in Hz. The results of elemental analyses for C, H and N were in agreement with the calculated values within +/−0.4% range. The starting benzodithiazines 120 and 2,21 N-(benzenesulfonyl)cyanamide potassium salt 1722 and aminoguanidine 1823 were synthesized according to the method described previously.

N′-(6-Chloro-3-methylthio-1,1-dioxo-1,4,2-benzodithiazine-7-carbonyl)benzhydrazide (3)
To a stirred suspension of benzhydrazide (10 mmol, 1.362 g) in dry benzene (20 mL) the solution of 6-chloro-3-methylthio-1,1-dioxo-1,4,2-benzodithiazine-7-carbonyl chloride (5 mmol, 1.711 g) in dry benzene (40 mL) was added dropwise at 5 °C. The resulting suspension was stirred at room temperature for 48 h and concentrated under reduced pressure to dryness. Water was added and the formed precipitate was filtered off and washed with water and 50% EtOH. Crude product was crystallized from EtOH. Yield: 1.888 g, 85%, mp 231-233 °C; IR (KBr) νmax 3385, 3209, 2928, 1700, 1649, 1336, 1168 cm-1; 1H NMR (200 MHz, DMSO-d6) δ 2.73 (s, 3H), 7.54-7.62 (m, 3H), 7.92-7.93 (m, 2H), 8.14 (s, 1H), 8.21 (s, 1H), 10.79 (s, 2H); Anal. Calcd for C16H12ClN3O4S3: C, 43.48; H, 2.74; N, 9.51. Found: C, 43.31; H, 2.69; N, 9.35.

4-Chloro-N′-(6-chloro-3-methylthio-1,1-dioxo-1,4,2-benzodithiazine-7-carbonyl)benzhydrazide (4)
To a stirred suspension of 4-chlorobenzhydrazide (10 mmol, 1.706 g) in dry benzene (20 mL) the solution of 6-chloro-3-methylthio-1,1-dioxo-1,4,2-benzodithiazine-7-carbonyl chloride (5 mmol, 1.711 g) in dry benzene (40 mL) was added dropwise at 5 °C. The resulting suspension was stirred at room temperature for 48 h and concentrated under reduced pressure to dryness. Water was added and the formed precipitate was filtered off and washed with water and 50% EtOH. Crude product was crystallized from EtOH. Yield: 1.833 g, 80%, mp 258-260 °C; IR (KBr) νmax 3379, 3216, 1685, 1654, 1323, 1161 cm-1; 1H NMR (200 MHz, DMSO-d6) δ 2.50 (s, 3H), 7.62-7.64 (m, 2H), 7.95-7.97 (m, 2H), 8.13 (s, 1H), 8.21 (s, 1H), 10.86 (s, 2H); Anal. Calcd for C16H11Cl2N3O4S3: C, 40.34; H, 2.33; N, 8.82. Found: C, 40.11; H, 2.16; N, 8.73.

6-Chloro-7-(5-phenyl-1,3,4-oxadiazol-2-yl)-3-methylthio-1,1-dioxo-1,4,2-benzodithiazine (5)
The suspension of 3 (5 mmol, 2.21 g) in thionyl chloride (25 mL) was stirred for 18 h at room temperature followed by refluxing for 2 h until the reaction mixture clarified. Solution obtained was concentrated under reduced pressure, and ice-water was slowly added. The crude product was granulated by stirring for 30 min, filtered off and washed with cold water, dried and purified by crystallization from DMF. Yield: 1.29 g, 62%, mp 254-255 °C; IR (KBr) νmax 2917, 2841, 1605, 1464, 1337, 1178 cm-1; 1H NMR (200 MHz, DMSO-d6) δ 2.75 (s, 3H), 7.66-7.69 (m, 3H), 8.15-8.16 (m, 2H), 8.36 (s, 1H), 8.71 (s, 1H); Anal. Calcd for C16H10ClN3O3S3: C, 45.33; H, 2.38; N, 9.91. Found: C, 45.22; H, 2.24; N, 9.84.

6-Chloro-7-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-3-methylthio-1,1-dioxo-1,4,2-benzodithiazine (6)
The suspension of 4 (5 mmol, 2.38 g) in thionyl chloride (25 mL) was stirred for 18 h at room temperature followed by refluxing for 3 h until the reaction mixture clarified. Solution obtained was concentrated under reduced pressure, and ice-water was slowly added. The crude product was granulated by stirring for 30 min, filtered off and washed with cold water, dried and purified by crystallization from DMF to give pure 1,3,4-oxadiazoles. Yield: 1.97 g, 87%, mp 266-268 °C; IR (KBr) νmax 2927, 1602, 1436, 1335, 1167 cm-1; 1H NMR (200 MHz, DMSO-d6) δ 2.74 (s, 3H), 7.72-7.74 (m, 2H), 8.15-8.17 (m, 2H), 8.35 (s, 2H), 8.71 (s, 1H); Anal. Calcd for C16H9Cl2N43O3S3: C, 41.93; H, 1.98; N, 9.17. Found: C, 41.88; H, 1.85; N, 9.06.

6-Chloro-7-(5-phenyl-1,3,4-thiadiazol-2-yl)-3-methylthio-1,1-dioxo-1,4,2-benzodithiazine (7)
The suspension of 3 (5 mmol, 2.21 g) and Lawesson’s reagent (5 mmol, 2.03 g) in dry toluene (75 mL) was stirred for 18 h at room temperature followed by refluxing for 2 h until the reaction mixture clarified. Solution obtained was kept at −20 °C for 2 h. The crystalline crude product was filtered off and washed with cold toluene and MeOH. Crystallization from p-dioxane gave pure title compound. Yield: 1.06 g, 48%, mp 246-248 °C; IR (KBr) νmax 3082, 1578, 1532, 1501, 1454, 1334, 1165 cm-1; 1H NMR (200 MHz, DMSO-d6) δ 2.76 (s, 3H), 7.62-7.64 (m, 3H), 8.11-8.12 (m, 2H), 8.37 (s, 1H), 8.84 (s, 1H); Anal. Calcd for C16H10ClN3O2S4: C, 43.68; H, 2.29; N, 9.55. Found: C, 43.55; H, 2.18; N, 9.41.

6-Chloro-7-[5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl]-3-methylthio-1,1-dioxo-1,4,2-benzodithiazine (8)
The suspension of 4 (5 mmol, 2.38 g) and Lawesson’s reagent (5 mmol, 2.03 g) in dry toluene (75 mL) was stirred for 18 h at room temperature followed by refluxing for 2 h until the reaction mixture clarified. Solution obtained was kept at −20 °C for 2 h. The crystalline crude product was filtered off and washed with cold toluene and MeOH. Crystallization from DMF gave pure title compound. Yield: 1.47 g, 62%, mp 285-287 °C; IR (KBr) νmax 3081, 2926, 1580, 1515, 1495, 1329, 1164 cm-1; 1H NMR (200 MHz, DMSO-d6) δ 2.74 (s, 3H), 7.68-7.70 (m, 2H), 8.13-8.15 (m, 2H), 8.37 (s, 1H), 8.83 (s, 1H); Anal. Calcd for C16H9Cl2N3O2S4: C, 40.51; H, 1.91; N, 8.86. Found: C, 40.48; H, 1.86; N, 8.87.

3-Amino-6-chloro-1,1-dioxo-1,4,2-benzodithiazines (9-12). General procedure:
Suspension of the appropriate 3-methylthio derivative 5-8 (3 mmol) in MeOH (5 mL) was cooled to 0 °C and ammonium hydroxide solution (25%, 4 mmol, 0.27 g) was added dropwise. The suspension was stirred at room temperature (120-190 h) until MeSH ceased to evolve (CAUTION: due to a high toxicity, MeSH should be trapped into an aqueous NaOH solution). Precipitated almost pure product was filtered off and crystallized from the appropriate solvent.

3-Amino-6-chloro-7-(5-phenyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-1,4,2-benzodithiazine (9)
Crystallization from 70% DMF/H2O yielded: 0.849 g, 72%, mp 304-306 °C; IR (KBr) νmax 3339, 3294, 3152, 1634, 1590, 1539, 1514, 1483, 1450 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 7.65-7.70 (m, 3H), 8.13-8.14 (m, 2H), 8.28 (s, 1H), 8.60 (s, 1H), 9.41 (br s, 2H); Anal. Calcd for C15H9ClN4O3S2: C, 45.86; H, 2.31; N, 14.26. Found: C, 45.77; H, 2.21; N, 14.16.

3-Amino-6-chloro-7-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-1,4,2-benzodithiazine (10)
Crystallization from DMF yielded: 0.961 g, 75%, mp 301-303 °C; IR (KBr) νmax 3368, 3287, 3155, 3083, 1628, 1605, 1588, 1510, 1482, 1347, 1316, 1168 cm-1; 1H NMR (200 MHz, DMSO-d6) δ 7.70-7.74 (m, 2H), 8.12-8.17 (m, 2H), 8.28 (s, 1H), 8.59 (s, 1H), 9.40 (br s, 2H); Anal. Calcd for C15H8Cl2N4O3S2: C, 42.16; H, 1.89; N, 13.11. Found: C, 42.08; H, 1.81; N, 13.05.

3-Amino-6-chloro-7-(5-phenyl-1,3,4-thiadiazol-2-yl)-1,1-dioxo-1,4,2-benzodithiazine (11)
Crystallization from 70% DMF/H2O yielded: 0.994 g, 81%, mp >320 °C; IR (KBr) νmax 3355, 3290, 3138, 1631, 1584, 1554, 1357, 1308, 1166 cm-1; 1H NMR (200 MHz, DMSO-d6) δ 7.60-7.63 (m, 3H), 8.07-8.12 (m, 2H), 8.27 (s, 1H), 8.74 (s, 1H), 9.38 (br s, 2H); Anal. Calcd for C15H­9ClN4O2S3: C, 44.06; H, 2.22; N, 13.70. Found: C, 43.97; H, 2.05; N, 13.64.

3-Amino-6-chloro-7-[5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl]-1,1-dioxo-1,4,2-benzodithiazine (12)
Crystallization from DMF yielded: 1.157 g, 87%, mp >320 °C; IR (KBr) νmax 3295, 3082, 1582, 1534, 1516, 1495, 1343, 1329, 1165 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 7.69-7.70 (m, 2H), 8.14-8.15 (m, 2H), 8.38 (s, 1H), 8.84 (s, 1H), 9.40 (br s, 2H); Anal. Calcd for C15H8Cl2N4O2S3: C, 40.64; H, 1.82; N, 12.64. Found: C, 40.51; H, 1.77; N, 8.52.

N-(2-Benzylthio-4-chlorobenzenesulfonyl)cyanamide potassium salts (13-16). General procedure:
Suspension of the appropriate 3-amino derivative 9-12 (2 mmol), anhydrous K2CO3 (10 mmol, 1.38 g) and benzyl chloride (2.17 mmol, 0.28 g) in dry THF (15 mL) was heated at reflux for 20-24 h, then cooled in ice-bath and filtered off. The crude product was suspended in 10 mL of water, heated gently to ca. 50 °C, and cooled with vigorous stirring until granular precipitate appeared. Filtering off and washing with cold water and diluted EtOH gave pure potassium salts.

N-[2-Benzylthio-4-chloro-5-(5-phenyl-1,3,4-oxadiazol-2-yl)benzenesulfonyl]cyanamide potassium salt (13)
Yield: 0.709 g, 68%, mp >320 °C; IR (KBr) νmax 3061, 2924, 2170, 1583, 1556, 1526, 1492, 1450, 1297, 1143 cm-1; 1H NMR (200 MHz, DMSO-d6) δ 4.45 (s, 2H), 7.30-7.42 (m, 3H), 7.49-7.52 (m, 2H), 7.63-7.70 (m, 4H), 8.06-8.11 (m, 2H), 8.48 (s, 1H); Anal. Calcd for C22H14ClKN4O3S2: C, 50.71; H, 2.71; N, 10.75. Found: C, 50.63; H, 2.72; N, 10.71.

N-{2-Benzylthio-4-chloro-5-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]benzenesulfonyl}cyanamide potassium salt (14)
Yield: 0.844 g, 76%, mp >320 °C; IR (KBr) νmax 3086, 2167, 1585, 1543, 1524, 1483, 1293, 1140 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 4.46 (s, 2H), 7.31-7.33 (m, 1H), 7.37-7.40 (m, 2H), 7.50-7.52 (m, 2H), 7.71-7.74 (m, 3H), 8.09-8.11 (m, 2H), 8.49 (s, 1H); Anal.Calcd for C22H13Cl2KN4O3S2: C, 47.57; H, 2.36; N, 10.09. Found: C, 47.46; H, 2.29; N, 10.07.

N-[2-Benzylthio-4-chloro-5-(5-phenyl-1,3,4-thiadiazol-2-yl)benzenesulfonyl]cyanamide potassium salt (15)
Yield: 0.838 g, 78%, mp 150-152 °C; IR (KBr) νmax 3059, 2926, 2853, 2173, 1574, 1526, 1494, 1455, 1282, 1140 cm-1; 1H NMR (200 MHz, DMSO-d6) δ 4.43 (s, 2H), 7.30-7.42 (m, 3H), 7.48-7.53 (m, 2H), 7.58-7.61 (m, 3H), 7.70 (s, 1H), 8.06-8.11 (m, 2H), 8.70 (s, 1H); Anal. Calcd for C22H14ClKN4O2S3: C, 49.19; H, 2.63; N, 10.43. Found: C, 49.12; H, 2.45; N, 10.35.

N-{2-Benzylthio-4-chloro-5-[5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonyl}cyanamide potassium salt (16)
Yield: 1.109 g, 97%, mp 237-239 °C; IR (KBr) νmax 2924, 2178, 1626, 1580, 1527, 1497, 1357, 1280, 1138 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 4.42 (s, 2H), 7.28-7.30 (m, 1H), 7.35-7.38 (m, 2H), 7.48-7.49 (m, 2H), 7.64-7.65 (m, 2H), 7.68 (s, 1H), 8.08-8.10 (m, 2H), 8.70 (s, 1H); Anal. Calcd for C22H13Cl2KN4O2S3: C, 46.23; H, 2.29; N, 9.80. Found: C, 46.14; H, 2.18; N, 9.69.

3-Amino-2-(2-benzylthio-4-chlorobenzenesulfonyl)guanidines (19-22). General procedure:
Suspension of the appropriate potassium salt 13-16 (1 mmol) and hydrazine monohydrochloride (2 mmol, 0.137 g) in dry MeCN (10 mL) was stirred at reflux for 18-24 h. The precipitated white solid was filtered off and washed with H2O (1 mL), diluted MeOH (1 mL) and MeCN (1 mL). Crystallization from DMF gave pure title compounds.

3-Amino-2-[2-benzylthio-4-chloro-5-(5-phenyl-1,3,4-oxadiazol-2-yl)benzenesulfonyl]guanidine (19)
Yield: 0.371 g, 72%, mp 278-280 °C; IR (KBr) νmax 3467, 3355, 3213, 2934, 1655, 1620, 1603, 1589, 1554, 1483, 1275, 1119 cm-1; 1H NMR (200 MHz, DMSO-d6) δ 4.47 (s, 2H), 4.55 (s, 2H), 7.08 (s, 2H), 7.31-7.33 (m, 1H), 7.37-7.40 (m, 2H), 7.50-7.51 (m, 2H), 7.64-7.69 (m, 3H), 7.73 (s, 1H), 8.10-8.12 (m, 2H), 8.54 (s, 1H), 8.58 (s, 1H); Anal. Calcd for C22H19ClN6O3S2: C, 51.31; H, 3.72; N, 16.32. Found: C, 51.23; H, 3.68; N, 16.24.

3-Amino-2-{2-benzylthio-4-chloro-5-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]benzenesulfonyl}guanidine (20)
Yield: 0.505 g, 92%, mp 238-239 °C; IR (KBr) νmax 3435, 3362, 3322, 2931, 1652, 1610, 1584, 1482, 1281, 1136 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 4.47 (s, 2H), 4.55 (s, 2H), 7.08 (s, 2H), 7.31-7.32 (m, 1H), 7.37-7.40 (m, 2H), 7.49-7.51 (m, 2H), 7.72-7.74 (m, 3H), 8.10-8.12 (m, 2H), 8.54 (s, 1H), 8.58 (br s, 1H); Anal. Calcd for C22H18Cl2N6O3S2: C, 48.09; H, 3.30; N, 15.30. Found: C, 47.91; H, 3.22; N, 15.18.

3-Amino-2-[2-benzylthio-4-chloro-5-(5-phenyl-1,3,4-thiadiazol-2-yl)benzenesulfonyl]guanidine (21)
Yield: 0.435 g, 82%, mp 272-274 °C; IR (KBr) νmax 3472, 3441, 3342, 3216, 1659, 1605, 1572, 1527, 1494, 1454, 1352, 1275, 1134 cm-1; 1H NMR (200 MHz, DMSO-d6) δ 4.45 (s, 2H), 4.54 (s, 2H), 7.05 (s, 2H), 7.29-7.41 (m, 3H), 7.48-7.51 (m, 2H), 7.59-7.61 (m, 3H), 7.72 (s, 1H),8.05-8.09 (m, 2H), 8.55 (s, 1H), 8.74 (s, 1H); Anal. Calcd for C22H19ClN6O2S3: C, 49.75; H, 3.61; N, 15.82. Found: C, 49.65; H, 3.51; N, 15.78.

3-Amino-2-{2-benzylthio-4-chloro-5-[5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonyl}guanidine (22)
Yield: 0.452 g, 80%, mp 276-278 °C; IR (KBr) νmax 3441, 2924, 2853, 1659, 1606, 1573, 1527, 1495, 1454, 1354, 1293, 1137 cm-1; 1H NMR (200 MHz, DMSO-d6) δ 4.45 (s, 2H), 4.54 (s, 2H), 7.08 (s, 2H), 7.29-7.51 (m, 5H), 7.65-7.69 (m, 2H), 7.69 (s, 1H), 8.08-8.12 (m, 2H), 8.55 (br s, 1H), 8.74 (s, 1H); Anal. Calcd for C22H18Cl2N6O2S3: C, 46.72; H, 3.21; N, 14.86. Found: C, 46.64; H, 3.15; N, 14.71.

N′-(2-Benzylthio-4-chlorobenzenesulfonyl)-1H-pyrazole-1-amidines (23-36). General procedure:
A mixture of the appropriate aminoguanidine 18-22 (1 mmol), adequate 1,3-diketone (1 mmol) and PTSAH2O (0.05 mmol, 0.01 g) in dry toluene (5 mL) was heated at reflux for 7-8 h. By-products were filtered out and the filtrate was left at −20 °C for crystallization. In some cases (29 and 33) mother liquor was evaporated to dryness and then purified by crystallization from MeCN.

N′-(2-Benzylthio-4-chloro-5-methylbenzenesulfonyl)-3,5-dimethyl-1H-pyrazole-1-amidine (23)
Starting from 18 and 2,4-pentanedione (0.100 g) pure compound 23 was obtained after crystallization from MeCN (0.332 g, 74%), mp 168-170 °C; IR (KBr) νmax 3451, 3334, 2981, 2925, 1637, 1580, 1522, 1496, 1346, 1324, 1289, 1129, 1109, 1075 cm-1; 1H NMR (200 MHz, DMSO-d6) δ 2.20 (s, 3H), 2.31 (s, 3H), 2.33 (s, 3H), 4.33 (s, 2H), 6.20 (s, 1H), 7.19-7.22 (m, 5H), 7.58 (s, 1H), 7.88 (br s, 1H), 7.98 (s, 1H), 8.69 (br s, 1H); 13C NMR (50 MHz, DMSO-d6) δ 13.68, 15.34, 19.19, 36.38, 112.10, 127.54, 128.22, 128.64, 129.13, 130.96, 132.59, 136.06, 136.33, 137.78, 138.02, 144.01, 151.45, 151.74; Anal. Calcd for C20H21ClN4O2S2: C, 53.50; H, 4.71; N, 12.48. Found: C, 53.58; H, 4.82; N, 12.61.

N′-(2-Benzylthio-4-chloro-5-methylbenzenesulfonyl)-3,5-diethyl-1H-pyrazole-1-amidine (24)
Starting from 18 and 3,5-heptanedione (0.128 g) pure compound 24 was obtained after crystallization from MeCN (0.367 g, 77%), mp 141-142 °C; IR (KBr) νmax 3455, 3347, 2977, 2934, 1637, 1522, 1315, 1293, 1129 cm-1; 1H NMR (200 MHz, DMSO-d6) δ 0.98 (t, J=7.4 Hz, 3H), 1.78 (t, J=7.6 Hz, 3H), 2.32 (s, 3H), 2.56 (q, J=7.6 Hz, 2H), 2.81 (q, J=7.4 Hz, 3H), 4.31 (s, 2H), 6.26 (s, 1H), 7.17-7.28 (m, 5H), 7.57 (s, 1H), 7.91 (br s, 1H), 7.99 (s, 1H), 8.63 (br s, 1H); 13C NMR (50 MHz, DMSO-d6) δ 12.57, 12.78, 18.91, 21.04, 21.78, 36.11, 108.62, 127.25, 127.80, 128.36, 128.88, 130.75, 132.24, 135.96, 136.03, 137.52, 137.57, 149.90, 151.16, 156.93; Anal. Calcd for C22H25ClN4O2S2: C, 55.39; H, 5.28; N, 11.74. Found: C, 55.46; H, 5.33; N, 12.12.

N′-(2-Benzylthio-4-chloro-5-methylbenzenesulfonyl)-3,5-diphenyl-1H-pyrazole-1-amidine (25)
Starting from 18 and 1,1-dibenzoylmethane (0.224 g) pure compound 25 was obtained after crystallization from MeCN (0.201 g, 35%), mp 116-118 °C; IR (KBr) νmax 3461, 3440, 3348, 3326, 2922, 2855, 1644, 1526, 1343, 1326, 1294, 1284, 1131 cm-1; 1H NMR (200 MHz, DMSO-d6) δ 2.28 (s, 3H), 4.25 (s, 2H), 6.85-6.92 (m, 2H), 7.03-7.31 (m, 9H), 7.47-7.50 (m, 5H), 8.02-8.05 (m, 2H), 8.24 (br s, 1H), 9.18 (br s, 1H); Anal. Calcd for C30H25ClN4O2S2: C, 62.87; H, 4.40; N, 9.78. Found: C, 62.78; H, 4.35; N, 9.74.

N′-(2-Benzylthio-4-chloro-5-methylbenzenesulfonyl)-3,4,5-trimethyl-1H-pyrazole-1-amidine (26)
Starting from 18 and 3-methyl-2,4-pentanedione (0.114 g) pure compound 26 was obtained after crystallization from MeCN/EtOH (0.306 g, 66%), mp 110-111 °C; IR (KBr) νmax 3473, 3361, 2921, 1622, 1522, 1323, 1136 cm-1; 1H NMR (200 MHz, DMSO-d6) δ 1.86 (s, 3H), 2.15 (s, 3H), 2.21 (s, 3H), 2.31 (s, 3H), 4.31 (s, 2H), 7.16-7.21 (m, 5H), 7.58 (s, 1H), 7.80 (br s, 1H), 7.97 (s, 1H), 8.59 (br s, 1H); 13C NMR (50 MHz, DMSO-d6) δ 7.55, 11.97, 13.20, 18.93, 36.10, 117.63, 127.22, 127.95, 128.33, 128.84, 130.67, 132.28, 135.74, 136.15, 137.45, 137.91, 139.22, 151.26, 151.70; Anal. Calcd for C21H23ClN4O2S2: C, 54.48; H, 5.01; N, 12.10. Found: C, 54.56; H, 5.15; N, 12.34.

N′-[2-Benzylthio-4-chloro-5-(5-phenyl-1,3,4-oxadiazol-2-yl)benzenesulfonyl]-3,5-dimethyl-1H-pyrazole-1-amidine (27)
Starting from 19 and 2,4-pentanedione (0.100 g) pure compound 27 was obtained after crystallization from MeCN (0.521 g, 90%), mp 174-175 °C; IR (KBr) νmax 3462, 3324, 2926, 1623, 1586, 1526, 1492, 1326, 1278, 1263, 1139, 1120 cm-1; 1H NMR (200 MHz, DMSO-d6) δ 2.20 (s, 3H), 2.34 (s, 3H), 4.52 (s, 2H), 6.24 (s, 1H), 7.24-7.30 (m, 5H), 7.60-7.68 (m, 3H), 7.88 (s, 1H), 8.06-8.12 (m, 3H), 8.66 (s, 1H), 8.81 (br s, 1H); 13C NMR (50 MHz, DMSO-d6) δ 13.68, 15.38, 35.97, 112.29, 118.35, 123.32, 127.07, 127.80, 128.81, 129.23, 129.29, 129.79, 130.56, 132.57, 135.63, 135.68, 137.93, 143.49, 144.12, 151.59, 151.97, 161.63, 164.61; Anal. Calcd for C27H23ClN6O3S2: C, 56.00; H, 4.00; N, 14.51. Found: C, 55.96; H, 4.05; N, 14.42.

N′-[2-Benzylthio-4-chloro-5-(5-phenyl-1,3,4-oxadiazol-2-yl)benzenesulfonyl]-3,5-diethyl-1H-pyrazole-1-amidine (28)
Starting from 19 and 3,5-heptanedione (0.128 g) pure compound 28 was obtained after crystallization from MeCN (0.474 g, 78%), mp 92-93 °C; IR (KBr) νmax 3427, 3356, 3321, 3083, 2971, 2922, 1633, 1605, 1584, 1538, 1492, 1313, 1298, 1263, 1147 cm-1; 1H NMR (200 MHz, DMSO-d6) δ 1.01 (t, J=7.33 Hz, 3H), 1.19 (t, J=7.53 Hz, 3H), 2.59 (q, J=7,53 Hz, 2H), 2.86 (q, J=7.33 Hz, 2H), 4.51 (s, 2H), 6.30 (s, 1H), 7.24-7.34 (m, 5H), 7.62-7.68 (m, 3H), 7.87 (s, 1H), 8.08-8.13 (m, 3H), 8.67 (s, 1H), 8.75 (br s, 1H); Anal. Calcd for C29H27ClN6O3S2: C, 57.37; H, 4.48; N, 13.84. Found: C, 57.28; H, 4.42; N, 13.68.

N′-[2-Benzylthio-4-chloro-5-(5-phenyl-1,3,4-oxadiazol-2-yl)benzenesulfonyl]-3,5-diphenyl-1H-pyrazole-1-amidine (29)
Starting from 19 and 1,1-dibenzoylmethane (0.224 g) pure compound 29 was obtained. Yield: 0.035 g (5%), mp 196-197 °C; IR (KBr) νmax 3421, 3317, 2924, 1622, 1587, 1566, 1549, 1492, 1466, 1301, 1149 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 4.42 (s, 2H), 6.91-6.93 (m, 2H), 6.96-6.99 (m, 1H), 7.08-7.10 (m, 2H),7.16 (s, 1H), 7.22-7.27 (m, 3H), 7.38-7.39 (m, 2H), 7.44-7.47 (m, 1H), 7.49-7.52 (m, 2H), 7.68-7.71 (m, 3H), 7.76 (s, 1H), 8.04-8.06 (m, 2H), 8.12-8.14 (m, 2H), 8.18 (s, 1H), 8.46 (br s, 1H), 9.31 (br s, 1H); Anal. Calcd for C37H27ClN6O3S2: C, 63.19; H, 3.87; N, 11.95. Found: C, 63.05; H, 3.81; N, 11.89.

N′-[2-Benzylthio-4-chloro-5-(5-phenyl-1,3,4-oxadiazol-2-yl)benzenesulfonyl]-3,4,5-trimethyl-1H-pyrazole-1-amidine (30)
Starting from 19 and 3-methyl-2,4-pentanedione (0.114 g) pure compound 30 was obtained after crystallization from MeCN (0.362 g, 61%), mp 139-140 °C; IR (KBr) νmax 3435, 3329, 2925, 1631, 1586, 1528, 1327, 1144 cm-1; 1H NMR (200 MHz, DMSO-d6) δ 1.89 (s, 3H), 2.17 (s, 3H), 2.25 (s, 3H), 4.51 (s, 2H), 7.26-7.29 (m, 5H), 7.64-7.67 (m, 3H), 7.88 (s, 1H), 7.97 (br s, 1H), 8.08-8.12 (m, 2H), 8.65 (br s, 1H), 8.72 (s, 1H); 13C NMR (50 MHz, DMSO-d6) δ 7.84, 12.25, 13.49, 35.93, 118.11, 118.34, 123.32, 127.06, 127.76, 128.77, 129.21, 129.30, 129.79, 130.52, 132.57, 135.57, 135.77, 138.08, 139.56, 143.45, 151.66, 152.24, 161.64, 164.51; Anal. Calcd for C28H25ClN6O3S2: C, 56.70; H, 4.25; N, 14.17. Found: C, 56.61; H, 4.12; N, 14.03.

N′-{2-Benzylthio-4-chloro-5-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]benzenesulfonyl}-3,5-dimethyl-1H-pyrazole-1-amidine (31)
Starting from 20 and 2,4-pentanedione (0.100 g) pure compound 31 was obtained after crystallization from MeCN (0.485 g, 79%), mp 201-202 °C; IR (KBr) νmax 3464, 3350, 3090, 2925, 1620, 1584, 1525, 1482, 1327, 1142 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 2.21 (s, 3H), 2.34 (s, 3H), 4.53 (s, 2H), 6.25 (s, 1H), 7.27-7.29 (m, 3H), 7.32-7.34 (m, 2H), 7.73-7.74 (m, 2H), 7.89 (s, 1H), 8.06 (s, 1H), 8.11-8.13 (m, 2H), 8.67 (s, 1H), 8.82 (s, 1H); Anal. Calcd for C27H22Cl2N6O3S2: C, 52.86; H, 3.61; N, 13.70. Found: C, 52.72; H, 3.48; N, 13.58.

N′-{2-Benzylthio-4-chloro-5-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]benzenesulfonyl}-3,4,5-trimethyl-1H-pyrazole-1-amidine (32)
Starting from 20 and 3-methyl-2,4-pentanedione (0.114 g) pure compound 32 was obtained after crystallization from MeCN (0.414 g, 66%), mp 199-201 °C; IR (KBr) νmax 3460, 3348, 2925, 1621, 1599, 1586, 1528, 1480, 1327, 1146 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 1.90 (s, 3H), 2.18 (s, 3H), 2.25 (s, 3H), 4.52 (s, 2H), 7.24-7.28 (m, 3H), 7.30-7.34 (m, 2H), 7.72-7.74 (m, 2H), 7.89 (s, 1H), 7.98 (br s, 1H), 8.11-8.13 (m, 2H), 8.66 (s, 1H), 8.82 (br s, 1H); Anal. Calcd for C28H24Cl2N6O3S2: C, 53.59; H, 3.85; N, 13.39. Found: C, 53.41; H, 3.69; N, 13.34.

N′-{2-Benzylthio-4-chloro-5-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]benzenesulfonyl}-4-(2-ethoxycarbonylethyl)-3,5-dimethyl-1H-pyrazole-1-amidine (33)
Starting from 20 and ethyl 4-acetyl-5-oxohexanoate (0.200 g) pure compound 33 was obtained. Yield: 0.557 g (78%), mp 95-97 °C; IR (KBr) νmax 3410, 3282, 2928, 1728, 1626, 1589, 1526, 1482, 1329, 1142 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 1.13 (t, J=6.83 Hz, 3H), 2.21 (s, 3H), 2.29 (s, 3H), 2.44 (t, J=7.33 Hz, 2H), 2.62 (t, J=7.33 Hz, 2H), 4.01 (q, J=6.83 Hz, 2H), 4.52 (s, 2H), 7.26-7.28 (m, 3H), 7.32-7.33 (m, 2H), 7.73-7.74 (m, 2H), 7.89 (s, 1H), 8.00 (br s, 1H), 8.12-8.14 (m, 2H), 8.67 (s, 1H), 8.76 (br s, 1H); 13C NMR (50 MHz, DMSO-d6) δ 1.90, 12.22, 13.42, 14.27, 18.18, 33.88, 36.05, 60.21, 118.20,121.20, 122.21, 127.78, 128.79, 129.28, 129.31, 129.87, 130.56, 135.64, 137.31, 137.95, 140.38, 143.66, 151.60, 151.84, 161.77, 163.85, 172.25; Anal. Calcd for C32H30Cl2N6O5S2: C, 53.86; H, 4.24; N, 11.78. Found: C, 53.71; H, 4.10; N, 11.66.

N′-[2-Benzylthio-4-chloro-5-(5-phenyl-1,3,4-thiadiazol-2-yl)benzenesulfonyl]-3,5-dimethyl-1H-pyrazole-1-amidine (34)
Starting from 21 and 2,4-pentanedione (0.100 g) pure compound 34 was obtained after crystallization from acetone (0.411 g, 69%), mp 197-198 °C; IR (KBr) νmax 3444, 3332, 2926, 1635, 1577, 1524, 1493, 1354, 1297, 1139 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 2.21 (s, 3H), 2.35 (s, 3H), 4.51 (s, 2H), 6.24 (s, 1H), 7.25-7.34 (m, 5H), 7.59-7.62 (m, 2H), 7.89 (s, 1H), 8.06-8.09 (m, 3H), 8.80 (s, 1H), 8.88 (s, 1H); 13C NMR (50 MHz, DMSO-d6) δ 13.69, 15.37, 36.02, 112.27, 124.36, 127.80, 128.04, 128.81, 129.23, 129.45, 129.86, 130.11, 131.94, 135.32, 135.77, 138.22, 142.47, 144.10, 151.58, 151.96, 162.07, 169.43; Anal. Calcd for C27H23ClN6O2S3: C, 54.49; H, 3.90; N, 14.12. Found: C, 54.35; H, 3.67; N, 14.04.

N′-[2-Benzylthio-4-chloro-5-(5-phenyl-1,3,4-thiadiazol-2-yl)benzenesulfonyl]-3,4,5-trimethyl-1H-pyrazole-1-amidine (35)
Starting from 21 and 3-methyl-2,4-pentanedione (0.114 g) pure compound 35 was obtained after crystallization from acetone (0.347 g, 57%), mp 195-197 °C; IR (KBr) νmax 3429, 3322, 2923, 1631, 1602, 1575, 1527, 1480, 1323, 1142 cm-1; 1H NMR (200 MHz, DMSO-d6) δ 1.91 (s, 3H), 2.19 (s, 3H), 2.27 (s, 3H), 4.51 (s, 2H), 7.25-7.31 (m, 5H), 7.61-7.64 (m, 3H), 7.91 (s, 1H), 7.98 (br s, 1H), 8.08-8.11 (m, 2H), 8.72 (br s, 1H), 8.87 (s, 1H); 13C NMR (50 MHz, DMSO-d6) δ 7.86, 12.26, 13.48, 35.98, 118.10, 124.36, 127.76, 128.05, 128.48, 128.78, 129.20, 129.36, 129.46, 129.88, 130.08, 131.96, 135.27, 135.87, 138.37, 138.55, 142.43, 151.65, 152.24, 162.10, 169.45; Anal. Calcd for C28H25ClN6O2S3: C, 55.20; H, 4.14; N, 13.80. Found: C, 55.07; H, 3.98; N, 13.71.

N′-{2-Benzylthio-4-chloro-5-[5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonyl}-3,5-dimethyl-1H-pyrazole-1-amidine (36)
Starting from 22 and 2,4-pentanedione (0.100 g) pure compound 36 was obtained after crystallization from acetone (0.258 g, 41%), mp 194-196 °C; IR (KBr) νmax 3439, 3331, 2925, 2853, 1638, 1578, 1525, 1492, 1332, 1297, 1134 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 2.19 (s, 3H), 2.33 (s, 3H), 4.49 (s, 2H), 6.22 (s, 1H), 7.25-7.32 (m, 3H), 7.65-7.67 (m, 2H), 7.87 (s, 1H), 8.04 (br s, 1H), 8.09-8.11 (m, 2H), 8.78 (br s, 1H), 8.85 (s, 1H); Anal. Calcd for C27H22Cl2N6O2S3: C, 51.51; H, 3.52; N, 13.35. Found: C, 51.42; H, 3.41; N, 13.18.

Crystallography. Selected monocrystals of 23 and 25 were measured with Mo radiation on Bruker SMART APEX diffractometer equipped with CCD area detector at room temperature. The structures were solved by direct methods and refined by full matrix least-square on F2.26 Though all hydrogen atoms were clearly visible at respective difference Fourier syntheses, they were placed at calculated positions and refined at fixed distances with isotropic thermal parameters. Respective crystal data, data collection and final refinement parameters for 23 and 25 are listed in Table 1.
Crystallographic data for the structures reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publications No CCDC 80971 and CCDC 809720. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax: C44 1223 336 033; e-mail: deposit@ccdc.cam.ac.uk].

ACKNOWLEDGEMENTS
The authors are very grateful to Dr. Joel Morris, Chief of Drug Synthesis & Chemistry Branch, National Cancer Institute (Bethesda, MD) for in vitro screening.

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