Synthesis and molecular structure of novel 2-(alkylthio)-4-chloro-N-(4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-5-methylbenzenesulfonamides with potential anticancer activity

Jarosław Sławiński; Beata Żołnowska; Czesława Orlewska; Jarosław Chojnacki

doi:10.1007/s00706-012-0849-7

. 2012 Sep 25;143(12):1705–1718. doi: 10.1007/s00706-012-0849-7

Synthesis and molecular structure of novel 2-(alkylthio)-4-chloro-N-(4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-5-methylbenzenesulfonamides with potential anticancer activity

Jarosław Sławiński ^1,^✉, Beata Żołnowska ¹, Czesława Orlewska ¹, Jarosław Chojnacki ²

PMCID: PMC4495025 PMID: 26166861

Abstract

A series of novel 4-chloro-N-(4,5-dihydro-5-oxo-1-R²-1H-1,2,4-triazol-3-yl)-5-methyl-2-(R¹-methylthio)benzenesulfonamide derivatives have been synthesized as potential anticancer agents. The in vitro antitumor activity of some compounds was evaluated in the US National Cancer Institute (NCI) against the NCI-60 cell line panel. The most prominent compound showed remarkable activity against 13 human tumor cell lines representing lung, colon, CNS, melanoma, ovarian, renal, prostate, and breast at low micromolar GI₅₀ level in the range of 1.9–3.0 μM.

Graphical Abstract

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Electronic supplementary material

The online version of this article (doi:10.1007/s00706-012-0849-7) contains supplementary material, which is available to authorized users.

Keywords: Sulfonamide, Anticancer, Isocyanate, Cyclization, Triazolone

Introduction

The aryl- and heteroarylsulfonamides are widely described compounds revealing a broad spectrum of applications in biological and pharmacological areas [1]. For many years, 2-mercaptobenzenesulfonamide derivatives (MBSAs) have been of interest because of the various biological properties including antitumor [2–10], antimicrobial [11, 12], and antiviral activities [13, 14], and inhibition of carbonic anhydrase [15–17].

It has been known that aryl/heteroarylsulfonamides may act as antitumor agents through a variety of mechanisms such as cell cycle perturbation in the G1 phase, disruption of microtubules, angiogenesis inhibition, and functional suppression of the transcriptional activator NF-Y. The most prominent mechanism was the inhibition of carbonic anhydrase isozymes [18–22]. Recently, a host of structurally novel arylsulfonamide derivatives have been reported to show substantial anticancer activities in vitro and/or in vivo [23–26]. We have reported the synthesis and anticancer activity of 2-mercaptobenzenesulfonamides and subsequently extended our study to analogues with various heterocyclic ring systems attached to the benzenesulfonamide scaffold [4–6, 8, 10, 15] (Fig. 1 structure A [4–6, 8, 15], B [8], C [10]).

Fig. 1 — General structures of 2-mercaptobenzenesulfonamides A, B, C, and D

In this article we investigated new sulfonamide derivatives containing a triazolone ring in their structure. Triazolones are described in the literature as biologically active compounds, including anti-inflammatories [27], Nk_i antagonists [28], inhibitors of tumor necrosis factor-α-converting enzyme (TACE) [29], checkpoint kinase-1 inhibitor [30], anti-tumor agents [31–34], and molecular chaperone Hsp90 inhibitor, which is currently in clinical trials for a number of human cancers [35]. Taking into account the interesting properties of triazolones, we have synthesized novel compounds of general structure D (Fig. 1).

Results and discussion

Chemistry

The main goal of this study was to synthesize and investigate the anticancer activity of the new 2-(alkylthio)benzenesulfonamides containing diverse substituted 1,2,4-triazol-5-one moieties. Thus, we propose a synthetic route leading to the target 2-(alkylthio)-4-chloro-N-(4,5-dihydro-5-oxo-1-R²-1H-1,2,4-triazol-3-yl)-5-methylbenzenesulfonamides as shown in Scheme 1.

Starting 3-aminobenzodithiazine 1 could be readily converted to the corresponding dipotassium 2 and potassium salts 3 and 4, according to the reported procedure for preparation of N-(phenylsulfonyl)cyanamide potassium salts [36]. Novel potassium salts 5–10 were prepared by the reaction of 2 with the corresponding halomethyl electrophiles such as aryl/cycloalkyl/methyl chlorides in methanol or ethanol. Subsequent reaction of salts 3–10 with either hydrazine monohydrochloride, methylhydrazine, p-toluenesulfonyl hydrazide, or various 4-substituted phenylhydrazine hydrochlorides led to the formation of the desired 3-(R²-amino)-1-[4-chloro-5-methyl-2-(R¹-methylthio)phenylsulfonyl]guanidine derivatives 11–25 as depicted in Scheme 1. It is pertinent to know, however, that aminoguanidine 15 was chosen for the synthesis in two different ways (route A and B in Scheme 1). This was supposed to explain some arising synthetic aspects: whether the usefulness of the potassium salt, i.e., 3 with tosyl hydrazide (route A), is higher than the reaction of aminoguanidine 11 with tosyl chloride (TsCl, route B), and whether the reaction proceeds on the N-terminal nitrogen atom of the sulfonylhydrazide moiety or on the second nitrogen atom neighboring the sulfonyl group. As it turned out, both methods products 15 were identical, with structures (IR, NMR) having a N’-substituted sulfonylhydrazide fragment and obtained in almost equal yields.

Many methods are known for the synthesis of 1,2,4-triazol-5-ones. Triazol-5-ones can be prepared for instance by the reaction of the corresponding nitriles via imidates with semicarbazide [37], from 4-substituted semicarbazides under alkaline conditions [32], by heating of N ¹,N ⁴-substituted hydrazinecarboxamides in alkaline media [38], by cyclization of semicarbazide with an excess of phosgene [39], from the reaction of N-acylureas with arylhydrazines [40], N-acylurethanes with phenylhydrazines as an Einhorn–Brunner reaction extension, as well as from C-halobenzylidenephenylhydrazones via nitrilimines with phenyl isocyanates [41, 42].

In the present study we utilized a new method for the synthesis of 1,2,4-triazol-5-ones in the reaction of the corresponding aminoguanudines 11–25 with an excess of p-toluenesulfonyl isocyanate (TsNCO, Scheme 1). The isocyanates are well known as carbonyl precursors [43] and electrophilic agents whose reactions with hydrazines lead to intramolecular cyclization to five-membered heterocyclic rings [44] or reagents in cycloaddition reactions with various compounds having C=N bonds [45].

Our experiments demonstrated that the proposed synthetic route was an efficient way to prepare the desired N-(4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzenesulfonamides 26–40 when an excess of three molar equivalents of tosyl isocyanate was applied in the reaction with the corresponding aminoguanidines 11–25 in anhydrous tetrahydrofuran (THF) for at least 9 h at reflux. It is noteworthy, however, when 2 equivalents of tosyl isocyanate were used, no cyclization product was observed and a complex mixture of products was formed, even after considerable extending of the reaction time.

The structure of the new compounds was confirmed by elemental analyses (C, H, N) and spectral (NMR, IR, MS) data presented in the experimental section. Moreover, X-ray analysis was undertaken to confirm proposed structures on the representative compound 31, which crystallized as pyridinium salt (further specified as 31Pyr, Figs. 2 and 3).

Fig. 2 — Molecular structure of **31Pyr** showing the atom-labeling scheme. Displacement ellipsoids drawn at the 50 % probability level, with the solvating water molecule omitted

Fig. 3 — Hydrogen bonds in structure of **31Pyr**. *Blue lines* represent hydrogen bonds; transparent *yellow* balls denote inversion centers in the crystal (generated using Mercury CSD 2.4 [46])

Molecular structure

Details on data collection, structure solution, and refinement are given in Table 1. Compound 31Pyr crystallizes in the monoclinic space group C2/c with (typical for this symmetry) eight molecules in the unit cell. The molecule, being a secondary benzenesulfonamide, is deprotonated at the N1 atom and in the crystal structure is present in the anionic form (Fig. 2). The proton is accepted by pyridine so a pyridinium ion acts as a counterion. Additionally the solid contains solvating molecules of water that reside on twofold rotation axes, and these positions are not fully occupied by them (s.o.f. = 0.079). Actually, only ca. 1/8 of the H₂O molecules suffice to fit to the observed electron density in this region.

Table 1.

Crystal data and structure refinement for compound 31Pyr

Empirical formula	C₂₀H₂₀ClN₄O₅S₂·C₅H₆N·0.08(O)
Formula weight	577.42
Temperature/K	120(2)
Wavelength/Å	0.71073
Crystal system	Monoclinic
Space group	C2/c
Unit cell dimensions
a/Å	14.1490(3)
b/Å	14.0574(4)
c/Å	28.1211(6)
α/°	90
β/°	102.107(2)
γ/°	90
Volume/Å³	5,468.8 (2)
Z	8
Density (calculated)/mg m⁻³	1.403
Absorption coefficient/mm⁻¹	0.338
F(000)	2405
Crystal size/mm³	0.20 × 0.13 × 0.10
θ range for data collection/°	2.3–26.0
Index ranges	−17 ≤ h ≤ 17, −12 ≤ k ≤ 17, −25 ≤ l ≤ 34
Reflections collected	12,491
Independent reflections	5,374 [R(int) = 0.02]
Completeness to θ = 26.0°	99.6 %
Absorption correction	Numerical
Refinement method	Full-matrix least-squares on F ²
Data/restraints/parameters	5,374/0/349
Goodness-of-fit on F ²	1.04
Final R indices [I > 2σ(I)]	R ₁ = 0.0405, wR ² = 0.1015
R indices (all data)	R ₁ = 0.0469, wR ² = 0.1074
Largest diff. peak and hole/e·Å⁻³	0.43 and −0.31

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The two ions are linked by a charge-assisted hydrogen bond of the (+)NH···N(−) type; pyridinium N(5) is a donor, and sulfonamide N(1) is an acceptor. Bonds N(4)–H(4) interact with carbonyl oxygen atoms O5 from the triazolone moiety of the neighboring molecules forming intermolecular hydrogen bonds NH···O. These interactions arranged in pairs can be described by the R²₂(8) motifs situated about local inversion centers (see Fig. 3). Detailed information on hydrogen bonds is given in Table 2. Packing of molecules in the solid state is reinforced also by π–π stacking interactions between adjacent aromatic rings C5–C10 whose centers of gravity (Cg or centroids) are distant at 3.8513(10) Å. The geometry of the interaction is more precisely characterized in Table 3.

Table 2.

Hydrogen bond geometry in crystal structure of 31Pyr

D–H···A	D–H/Å	H···A/Å	D···A/Å	D–H···A/°
N4–H4···O5ⁱ	0.88	1.89	2.765 (2)	171
N5–H5···N1	0.88	1.90	2.767 (2)	169

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Symmetry code: (i) −x + 1/2, −y + 1/2, −z

Table 3.

Main π–π stacking interaction geometry in crystal structure of 31Pyr

Cg(1)···Cg(1ⁱⁱ)^a/Å	α ^b/°	β ^c/°	Perp.^d
3.8513(10)	17	15.5	3.7104(7)

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Ring (1) is composed from C5–C10 carbon atoms

Symmetry code: (ii) −x, y, 1/2−z

^aDistance between centroids

^bDihedral angle between the rings

^cAngle between the vector span on the centroids and normal to ring(1)

^dPerpendicular distance of Cg(I) on the other ring

Biological assay

Compounds 27, 28, and 30–39 were initially tested at a single dose (10⁻⁵ M) in the full NCI-60 cell panel, and the results are shown in Table 4. The methodology of the in vitro cancer screen is described at the website http://www.dtp.nci.nih.gov/branches/btb/ivclsp.html.

Table 4.

Inhibition growth percent (IGP [%]). One-dose screening data of in vitro tumor growth inhibition for compounds 27, 28, 30–39 at a dose of 10 μM

Panel	Cell line	Compound
Panel	Cell line	27	28	30	31	32	33	34	35	36	37	38	39
Non-small cell	A549/ATCC	26	62	*	*	3	*	2	3	58	*	5	*
Lung cancer	NCI-H522	46	69	71	84	NT	5	5	*	NT	*	83	*
Lung cancer	HOP-92	21	6	29	18	NT	NT	20	NT	NT	5	19	NT
Leukemia	RPMI-8226	36	45	45	39	NT	7	13	11	NT	7	*	*
	SR	7	28	57	31	NT	NT	19	NT	NT	NT	78	NT
	HL-60(TB)	19	13	27	26	*	15	*	NT	91	*	*	22
	MOLT-4	2	10	22	16	*	7	7	22	52	*	21	17
	K-562	14	17	49	37	NT	NT	*	NT	NT	9	66	NT
Renal cancer	RXF 393	2	46	*	1	*	*	*	*	73	2	16	*
Renal cancer	UO-31	15	18	14	26	3	3	11	10	36	24	23	11
CNS cancer	SNB-75	23	*	15	18	7	2	12	10	61	4	19	*
	SF-295	*	*	*	*	*	4	1	2	77	8	3	*
	SF-539	*	*	*	*	*	*	*	*	49	*	*	*
Colon cancer	HCC-2998	1	*	*	*	*	*	*	*	41	*	66	4
	HCT-116	3	6	6	*	*	1	*	4	75	*	62	*
	HCT-15	4	*	7	*	*	5	*	4	65	1	38	2
	HT29	*	*	4	*	*	*	1	*	88	*	53	*
	SW-620	1	*	9	5	*	6	4	*	68	2	55	*
	COLO 205	*	*	*	*	*	NT	*	NT	71	*	NT	NT
	KM12	*	*	5	*	*	*	*	*	79	*	1	*
Breast cancer	MCF7	*	*	38	*	2	*	2	*	83	3	51	*
	T-47D	8	3	20	9	*	*	*	1	31	6	41	1
	MDA-MB-468	NT	NT	NT	NT	*	NT	3	NT	3^a	NT	61	*
	HS 578T	11	*	24	5	*	NT	2	NT	46	12	*	NT
Ovarian cancer	OVCAR-3	*	1	8	*	*	*	1	*	5^a	*	65
Ovarian cancer	NCI/ADR-RES	NT	NT	NT	NT	*	2	5	9	64	*	32
Melanoma	UACC-257	*	33	*	*	*	*	4	*	21	*	21	*
	UACC-62	3	7	15	7	*	10	*	7	55	4	*	9
	MALME-3M	5	NT	5	*	*	12	13	4	43	16	25	2
	SK-MEL-2	*	*	*	9	*	*	19	*	26	*	NT	*
	MDA-MB-435	NT	NT	NT	NT	1	9	*	1	29^a	*	69	*
Prostate cancer	PC-3	9	6	16	8	5	8	5	12	59	*	7	6

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Data obtained from NCI-60 DTP human tumor cell line screening

NT not tested

* Not active

^aCytotoxic effect (lethality)

The relatively highest sensitivity to the compounds described here was found for the cell lines of non-small cell lung cancer NCI-H522 cell line to compounds 27, 28, 31, and 38 (46 % < IGP < 84 %), leukemia RPMI-8226 to compounds 27, 28, 30, and 31 (36 % < IGP < 45 %), HL-60(TB) to 30, 31, 36, and 39 (22 % < IGP < 91 %), and K-562 to compounds 30, 31, and 38 (37 % < IGP < 66 %) as well as breast MCF7 to 30, 36, and 38 (38 % < IGP < 83 %) (Table 4).

The following conclusions can be drawn from the structure–activity relationship study (Table 4):

The susceptibility of the non-small cell lung NCI-H522 cell line against 2-(benzylthio)-N-(2,5-dihydro-5-oxo-1-R²-1H-1,2,4-triazol-3-yl)benzenesulfonamide derivatives (27, 28, 30) was remarkable and increased when the methyl group (R² = Me, 27, IGP = 46 %) was replaced by aromatic moieties such as phenyl (R² = Ph, 28, IGP = 69 %) or tosyl (R² = 4-MePhSO₂, 30, IGP = 71 %). The compounds mentioned above showed similar potency for RPMI-8226 (27, IGP = 36 %; 28, IGP = 45 %; 30, IGP = 45 %) and SR (27, IGP = 7 %; 28, IGP = 28 %; 30, IGP = 57 %) lines of leukemia. It should be noted, moreover, that replacement of R² = Ph (28) for R² = 4-MePhSO₂ (30) caused loss of activity against non-small cell lung cancer (A549/ATCC) and renal (RXF 393) cell lines.
For the series of N-(4,5-dihydro-5-oxo-1-phenyl-1H-1,2,4-triazol-3-yl)-2-(R¹-methylthio)benzenesulfonamides the substituent at the sulfur atom S-2 at the 2-position of benzenesulfonamide has an impact on the antiproliferative activity against some cancer cell lines: exchange for instance of R¹ = 1-naphthyl in 36 into R¹ = Ph (28), 1,3-dioxolan-1-yl (32), 3-CF₃Ph (34), 4-CF₃Ph (35), and 1,2-dihydro-2-oxoquinolin-4-yl (39) decreased activity against the leukemia HL-60(TB) cell line, as well as the leukemia MOLT-4 cell line; replacing R¹ = 1-naphthyl or Ph for R¹ = 3-CF₃Ph, 4-CF₃Ph or 1,2-dihydro-2-oxoquinolin-4-yl resulted in loss of activity against cell lines non-small cell lung A549/ATCC and renal RXF 393.
The significant susceptibility of almost the entire colon cancer subpanel against N-(4,5-dihydro-5-oxo-1-R²-1H-1,2,4-triazol-3-yl)-2-(naphthalen-1-ylmethylthio)benzenesulfonamides 36 and 38 should be pointed out. Moreover, the exchange of R² = Ph (36) or 4-MePhSO₂ (38) for 4-ClPh (37) led to a lack of susceptibility of HCC-2998, HTC-116, HTC-15, HT29, and SW-620.

Further anticancer evaluation was performed at five-dose assay on the distinctive compound 36. The anticancer activity of the tested compound was reported for each cell line by the parameters GI₅₀ (molar concentration of the compounds that inhibit 50 % net cell growth), TGI (molar concentration of the compounds leading to total inhibition), and LC₅₀ (molar concentration of the compounds causing 50 % net cell death). The susceptibility of individual subpanels indicates the following order: prostate, colon, CNS, leukemia, ovarian, non-small cell lung, melanoma, renal, and breast cancer (Table 5). As shown in Table 5, compound 36 exhibited remarkable activity at low GI₅₀ level <11.2 μM (MID GI₅₀ = 4.2 μM) over a number of cancer cell lines, acting effectively against 13 human tumor cell lines with GI₅₀ values in the low micromolar range of 1.9–3.0 μM with selectivity toward melanoma MDA-MB-435 (GI₅₀ = 1.9 μM, TGI = 5.5) and renal A498 (GI₅₀ = 1.9 μM, TGI = 10.5) cell lines. It is worth mentioning that lines HL-60(TB), NCI-H522, COLO 205, SF-539, MDA-MB-435, OVCAR-3, A498, RXF 393, DU-145, and MDA-MB-468 were characterized by the relatively low parameters GI₅₀ (1.9–3.2 μM), TGI (4.9–12.3 μM), and LC₅₀ below 58.7 μM.

Table 5.

The in vitro tumor growth inhibition data for compound 36

Panel	Cell line	GI^a₅₀/μM	TGI^b/μM	LC^c₅₀/μM
Leukemia	CCRF-CEM	3.2	13.2	>100
	HL-60(TB)	3.1	9.2	58.7
	K-562	3.6	13.9	>100
	MOLT-4	5.7	37.2	>100
	RPMI-8226	3.6	28.1	>100
Non-small cell lung cancer	A549/ATCC	4.4	27.8	>100
	EKVX	4.6	23.3	>100
	HOP-62	7.1	20.8	49.3
	HOP-92	7.5	23.0	57.0
	NCI-H226	3.6	16.1	53.0
	NCI-H23	3.1	11.7	42.8
	NCI-H322M	8.3	32.9	>100
	NCI-H460	2.8	11.7	>100
	NCI-H522	2.5	8.3	44.1
Colon cancer	COLO 205	2.3	4.9	11.1
	HCC-2998	3.5	12.6	40.0
	HCT-116	3.4	12.6	43.0
	HCT-15	4.0	15.3	47.8
	HT29	3.5	11.7	41.9
	KM12	3.2	12.5	46.1
	SW-620	4.6	18.6	48.9
CNS cancer	SF-268	3.7	15.5	48.2
	SF-295	3.0	13.9	>100
	SF-539	3.2	9.4	44.1
	SNB-19	4.8	23.5	95.3
	SNB-75	2.9	15.5	85.1
	U251	5.3	19.9	54.9
Melanoma	LOX IMVI	4.8	18.3	48.8
	MALME-3 M	8.9	29.4	92.2
	M14	3.2	11.5	64.9
	MDA-MB-435	1.9	5.5	32.0
	SK-MEL-2	5.8	20.7	60.2
	SK-MEL-28	6.0	20.1	54.2
	SK-MEL-5	3.6	13.1	36.6
	UACC-257	7.9	33.6	>100
	UACC-62	4.0	16.1	48.5
Ovarian cancer	IGROV1	4.9	21.9	97.0
	OVCAR-3	2.4	6.2	23.6
	OVCAR-4	4.2	16.5	55.1
	OVCAR-5	6.3	19.4	46.8
	OVCAR-8	5.0	33.0	>100
	NCI/ADR-RES	2.7	8.6	>100
	SK-OV-3	3.9	18.1	>100
Renal cancer	786-0	7.9	22.0	54.3
	A498	1.9	10.5	38.0
	ACHN	5.8	21.9	68.7
	CAKI-1	4.2	25.9	>100
	RXF 393	2.5	7.6	32.2
	SN12C	4.6	18.2	52.7
	TK-10	10.3	24.2	56.8
	UO-31	5.5	18.7	45.9
Prostate cancer	PC-3	3.6	17.1	73.7
Prostate cancer	DU-145	2.9	8.6	32.6
Breast cancer	MCF7	3.8	15.3	>100
	MDA-MB-231/ATCC	5.6	20.5	60.4
	HS 578T	2.9	19.6	>100
	BT-549	11.2	26.0	60.4
	T-47D	6.1	35.9	>100
	MDA-MB-468	3.0	12.3	49.9

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Data obtained from NCI-60 DTP human tumor cell line screening

^aGI₅₀: molar concentration that inhibits 50 % net cell growth

^bTGI: molar concentration giving total growth inhibition

^cLC₅₀: molar concentration causing 50 % net cell death

A COMPARE [47] analysis at the NCI of compound 36 showed a moderate Pearson’s correlation coefficient (PCC = 0.473–0.425) with agents disrupting microtubule formation such as maytansine and rhizoxin [48].

Conclusion

We have developed a new method for the synthesis of a series of 2-(alkylthio)-4-chloro-N-(4,5-dihydro-5-oxo-1-R²-1H-1,2,4-triazol-3-yl)-5-methylbenzenesulfonamides 26–40. The prominent compound 36 showed high (GI₅₀ = 1.9–3.0 μM) activity against 13 of the tumor cell lines and reasonable activity at level GI₅₀ <11.2 μM (MID GI₅₀ = 4.2 μM) over a number cell lines, suggesting that 36 may be a useful lead compound for the search for more powerful anticancer agents with low toxicity against normal cells.

Experimental

The following instruments and parameters were used: melting points: Boetius apparatus; IR spectra: KBr pellets, 400–4,000 cm⁻¹, Thermo Mattson Satellite FTIR spectrometer; ¹H NMR and ¹³C NMR: Varian Gemini 200 apparatus or Varian Unity Plus 500 MHz, chemical shifts are expressed as δ values relative to Me₄Si as standard; LC–MS analyses: Shimadzu LCMS-IT-TOF LC-20A mass spectrometer with an electrospray ionization, capillary voltage in positive ion mode +4.5 kV, column: Jupiter 4 u Proteo 90 Å, 4.0 × 150 mm, 4 μm, mobile phase: A—water with 0.1 % formic acid, B—0.1 % formic acid in acetonitrile, linear gradient 50–100 % B in 45 min, flow rate: 0.2 cm³ min⁻¹. The results of elemental analyses for C, H, and N were in agreement with the calculated values within ±0.3 % range. Thin-layer chromatography (TLC) was performed on Merck Kieselgel 60F254 plates and visualized with UV. N-(5-Methylphenylsulfonyl)cyanamide potassium salts 3, 4 and aminoguanidines 11–14 and 16 were obtained in accordance with the previously described procedures [2, 36].

N-[4-Chloro-2-(1,3-dioxolan-2-ylmethylthio)-5-methylphenylsulfonyl]cyanamide potassium salt (5, C₁₂H₁₂ClKN₂O₄S₂)

To a suspension of 3.05 g 5-chloro-2-(cyanoaminosulfonyl)-4-methylthiophenolate dipotassium salt (2, 9 mmol) in 9 cm³ methanol 2.4 cm³ 2-(bromomethyl)-1,3-dioxolane (23 mmol) was added dropwise for 5 min. The reaction mixture was stirred at 65 °C for 6.5 h, then 12 h at room temperature. The precipitate was collected by filtration. The filtrate was evaporated to dryness, and the residue was triturated with 90 cm³ diethyl ether to give a second fraction of precipitate. The product was extracted from the combined fractions of solid with hot ethanol to give 2.99 g (86 %) 5. M.p.: 224–225 °C; TLC: R _f = 0.74 (CHCl₃:MeOH = 3:1); IR (KBr): Inline graphic = 2,924 (CH₃, CH₂), 2,854 (CH₃, CH₂), 2,179 (C≡N), 1,339, 1,145 (SO₂) cm⁻¹; ¹H NMR (200 MHz, DMSO-d ₆): δ = 2.31 (s, 3H, CH₃), 3.21 (d, 2H, S–CH₂), 3.79–4.00 (m, 4H, CH₂–O), 5.11 (t, 1H, CH–O), 7.46 (s, 1H, H-3), 7.77 (s, 1H, H-6) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.22, 36.04, 64.96, 102.34, 117.50, 127.42, 130.74, 131.36, 135.75, 135.97, 140.86 ppm.

General procedure for the preparation of N-[4-chloro-5-methyl-2-(R¹-methylthio)phenylsulfonyl]cyanamide potassium salts 6–10

To a suspension of 3.05 g 5-chloro-2-(cyanoaminosulfonyl)-4-methylthiophenolate dipotassium salt (2, 9 mmol) in methanol or ethanol the appropriate halomethyl electrophile was added. The reaction mixture was stirred at room temperature or at 65 °C. The precipitate was collected by filtration. The product was separated from inorganic salts by extraction with 200 cm³ hot ethanol.

N-[4-Chloro-5-methyl-2-[3-(trifluoromethyl)benzylthio]phenylsulfonyl]cyanamide potassium salt (6, C₁₆H₁₁ClF₃KN₂O₂S₂)

Starting from 2 in 45 cm³ ethanol and 1.3 cm³ 3-(trifluoromethyl)benzyl chloride (9 mmol) for 2 h at room temperature, compound 6 was obtained. Yield: 3.46 g (84 %); m.p.: 158–160 °C; TLC: R _f = 0.87 (CHCl₃:MeOH = 2:1); IR (KBr): Inline graphic = 2,924 (CH₃, CH₂), 2,174 (C≡N), 1,332, 1,132 (SO₂) cm⁻¹; ¹H NMR (200 MHz, DMSO-d ₆): δ = 2.31 (s, 3H, CH₃), 4.41 (s, 2H, S–CH₂), 7.41 (s, 1H, H-3), 7.58-7.62 (m, 2H, Ar), 7.76–7.81 (m, 3H, H-6, Ar) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.23, 35.73, 117.46, 124.12, 124.20, 125.95, 126.03, 127.78, 129.77, 130.85, 131.89, 133.49, 134.82, 135.94, 138.57, 141.12 ppm.

N-[4-Chloro-5-methyl-2-[4-(trifluoromethyl)benzylthio]phenylsulfonyl]cyanamide potassium salt (7, C₁₆H₁₁ClF₃KN₂O₂S₂)

Starting from 2 in 45 cm³ ethanol and 1.3 cm³ 4-(trifluoromethyl)benzyl chloride (9 mmol) for 4 h at room temperature, compound 7 was obtained. Yield: 3.64 g (88 %); m.p.: 177–178 °C; TLC: R _f = 0.69 (ethyl acetate:isopropanol = 2:1); IR (KBr): Inline graphic = 2,921 (CH₃, CH₂), 2,176 (C≡N), 1,327, 1,137 (SO₂) cm⁻¹; ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.29 (s, 3H, CH₃), 4.38 (s, 2H, S–CH₂), 7.38 (s, 1H, H-3), 7.66 (d, 2H, Ar), 7.68 (d, 2H, Ar), 7.73 (s, 1H, H-6) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.23, 35.78, 117.50, 125.41, 125.49, 125.56, 127.57, 130.13, 130.87, 131.84, 134.93, 135.96, 141.06, 142.02 ppm.

N-[4-Chloro-5-methyl-2-(naphthalen-1-ylmethylthio)phenylsulfonyl]cyanamide potassium salt (8, C₁₉H₁₄ClKN₂O₂S₂)

Starting from 2 in 10 cm³ ethanol and 1.3 cm³ 1-(chloromethyl)naphthalene (9 mmol) for 1 h at room temperature, compound 8 was obtained. Yield: 3.09 g (78 %); m.p.: 223–225 °C; TLC: R _f = 0.63 (ethyl acetate:isopropanol = 2:1); IR (KBr): Inline graphic = 2,922 (CH₃, CH₂), 2,175 (C≡N), 1,341, 1,140 (SO₂) cm⁻¹; ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.32 (s, 3H, CH₃), 4.72 (s, 2H, S–CH₂), 7.44–7.47 (m, 1H, Ar), 7.51 (s, 1H, H-3), 7.52–7.59 (m, 2H, Ar), 7.61 (d, 1H, Ar), 7.76 (s, 1H, H-6), 7.87 (d, 1H, Ar), 7.95 (d, 1H, Ar), 8.24 (d, 1H, Ar) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.29, 34.68, 117.49, 124.62, 125.78, 126.20, 126.52, 127.76, 128.20, 128.36, 128.76, 130.80, 131.60, 131.71, 132.20, 133.68, 136.04, 136.15, 140.76 ppm.

N-[4-Chloro-2-(1,2-dihydro-2-oxoquinolin-4-ylmethylthio)-5-methylphenylsulfonyl]cyanamide potassium salt (9, C₁₈H₁₃ClKN₃O₃S₂)

Starting from 2 in 42 cm³ ethanol and 2.1 g 4-(bromomethyl)quinolin-2(1H)-one (9 mmol) for 4 h at room temperature, compound 9 was obtained. Yield: 3.60 g (88 %); m.p.: 199–201 °C; TLC: R _f = 0.61 (ethyl acetate:isopropanol:acetic acid = 1:1:0.02); IR (KBr): Inline graphic = 2,922 (CH₃, CH₂), 2,181 (C≡N), 1,668 (CO), 1,341, 1,142 (SO₂) m⁻¹; ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.31 (s, 3H, CH₃), 4.52 (s, 2H, S-CH₂), 6.57 (s, 1H, Ar), 7.21 (t, 1H, Ar), 7.32 (d, 1H, Ar), 7.40 (s, 1H, H-3), 7.51 (t, 1H, Ar), 7.77 (s, 1H, H-6), 7.93 (d, 1H, Ar), 11.74 (s, 1H, NH) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.30, 33.33, 115.88, 117.50, 118.47, 121.99, 122.08, 125.42, 128.14, 130.82, 132.21, 134.60, 136.04, 139.22, 141.24, 146.29, 161.59 ppm.

N-[4-Chloro-2-(2,3-dihydrobenzo[b][1,4]dioxin-2-ylmethylthio)-5-methylphenylsulfonyl]cyanamide potassium salt (10, C₁₇H₁₄ClKN₂O₄S₂)

Starting from 2 in 23 cm³ methanol and 1.7 cm³ 2-(bromomethyl)-1,4-benzodioxane (12 mmol) for 6 h at 65 °C, compound 10 was obtained. Yield: 3.2 g (78 %); m.p.: 98–100 °C; TLC: R _f = 0.86 (CHCl₃:pentane:acetone = 1:1:0.5); IR (KBr): Inline graphic = 2,923 (CH₃, CH₂), 2,176 (C≡N), 1,343, 1,143 (SO₂) cm⁻¹; ¹H NMR (200 MHz, DMSO-d ₆): δ = 2.33 (s, 3H, CH₃), 3.34 (d, 2H, S–CH₂), 4.04–4.13 (m, 2H, CH₂–O), 4.29–4.43 (m, 1H, CH–O), 6.80–6.91 (m, 4H, Ar), 7.57 (s, 1H, H-3), 7.78 (s, 1H, H-6) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.30, 32.96, 66.34, 71.91, 107.38, 117.23, 117.37, 121.61, 121.79, 128.34, 130.85, 132.24, 134.60, 136.20, 141.72, 142.81, 143.13 ppm.

General procedure for the preparation of 1-[4-chloro-5-methyl-2-(R¹-methylthio)phenylsulfonyl]-3-(R²-amino)guanidines 15, 17–25

To a suspension of the appropriate N-(phenylsulfonyl)cyanamide potassium salt (3, 5–10, 3.5 mmol) in dry toluene was added the corresponding phenylhydrazine hydrochloride derivative (3.5 mmol) or p-toluenesulfonyl hydrazide (3.5 mmol) in the presence of p-toluenesulfonic acid monohydrate (PTSA, 3.5 mmol). The reaction mixture was stirred at reflux for 1–8 h, and left overnight at 0 °C. The precipitate was filtered off, and dried, then treated with 20 cm³ of water. After vigorously stirring for 30 min the precipitate was collected by filtration, dried, and crystallized from ethanol (15, 17, 19, 21-23, 25), ethyl acetate/hexane (18), or ethyl acetate (20, 24).

1-[2-(Benzylthio)-4-chloro-5-methylphenylsulfonyl]-3-(4-methylphenylsulfonylamino)guanidine (15, C₂₂H₂₃ClN₄O₄S₃)

Method A. According to the general procedure, starting from 1.37 g 3, 0.65 g p-toluenesulfonyl hydrazide, and 0.66 g PTSA in 40 cm³ of dry toluene for 1 h, the title compound 15 was obtained. Yield: 1.62 g (86 %); m.p.: 242–244 °C; TLC: R _f = 0.38 (CHCl₃:pentane:acetone = 1:1:0.5); IR (KBr): Inline graphic = 3,469, 3,361 (NH), 2,922, 2,832 (CH₃, CH₂), 1,384, 1,340, 1,172, 1,141 (SO₂) cm⁻¹; ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.30 (s, 3H, CH₃), 2.39 (s, 3H, CH₃), 4.29 (s, 2H, S–CH₂), 7.18 (brs, 1H, NH=), 7.25–7.28 (m, 1H, Ar), 7.32–7.38 (m, 4H, Ar), 7.42–7.43 (m, 4H, H-3, NH, Ar), 7.66 (d, 2H, Ar), 7.79 (s, 1H, H-6), 9.23 (s, 1H, N–NHSO₂), 9.89 (s, 1H, SO₂NH) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.20, 21.35, 36.60, 127.51, 128.04, 128.15, 128.74, 129.41, 129.89, 130.58, 132.09, 134.71, 135.86, 136.48, 136.74, 139.64, 144.17, 158.47 ppm.

Method B. To a cooled mixture of 1.35 g 11 (3.5 mmol) in 5 cm³ dry pyridine was added 0.67 g tosyl chloride (3.5 mmol). The ice bath was removed and the mixture was stirred at room temperature for 4 h, then at 60–65 °C for 5 h. After standing overnight, the mixture was added dropwise to 12 cm³ slush and vigorously stirred for 2 h. The solid was filtered off, washed with water (5 × 20 cm³), 1 % HCl (2 × 20 cm³), water (2 × 20 cm³) and dried. Purification from MeOH yielded 15 (86 %); m.p. 242–244 °C (dec.); IR and ¹H NMR spectra were identical with an authentic sample of 15.

1-[4-Chloro-2-(1,3-dioxolan-2-ylmethylthio)-5-methylphenylsulfonyl]-3-(phenylamino)guanidine (17, C₁₈H₂₁ClN₄O₄S₂)

Starting from 1.36 g 5 and 0.51 g phenylhydrazine hydrochloride in 5 cm³ dry toluene for 1 h, the title compound 17 was obtained. Yield: 0.80 g (50 %); m.p.: 173–175 °C; TLC: R _f = 0.59 (CHCl₃:pentane:acetone = 1:1:0.5); IR (KBr): Inline graphic = 3,447 (NH), 2,923 (CH₃, CH₂), 1,393, 1140 (SO₂) cm⁻¹; ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.32 (s, 3H, CH₃), 3.28 (d, 2H, S-CH₂), 3.79–3.85 (m, 2H, CH₂–O), 3.92–3.98 (m, 2H, CH₂–O), 5.14 (t, 1H, CH–O), 6.69 (d, 2H, Ar), 6.79 (t, 1H, Ar), 7.02 (s, 1H, NH=), 7.17 (t, 2H, Ar), 7.38 (s, 1H, NH-Ph), 7.56 (s, 1H, H-3), 7.86 (s, 1H, H-6), 7.88 (s, 1H, NH-NH-Ph), 9.07 (s, 1H, NHSO₂) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.22, 36.44, 65.06, 102.35, 112.99, 120.01, 128.16, 129.09, 130.56, 132.04, 136.00, 136.64, 140.28, 148.23, 159.25 ppm.

1-[4-Chloro-5-methyl-2-[3-(trifluoromethyl)benzylthio]phenylsulfonyl]-3-(phenylamino)guanidine (18, C₂₂H₂₀ClF₃N₄O₂S₂)

Staring from 1.61 g 6 and 0.50 g phenylhydrazine hydrochloride in 11 cm³ dry toluene for 1 h, the title compound 18 was obtained. Yield: 1.26 g (68 %); m.p.: 184–185 °C; TLC: R _f = 0.67 (CHCl₃:pentane:acetone = 1:1:0.5); IR (KBr): Inline graphic = 3,444 (NH), 2,925 (CH₃, CH₂), 1,330, 1,120 (SO₂) cm⁻¹; ¹H NMR (200 MHz, DMSO-d ₆): δ = 2.30 (s, 3H, CH₃), 4.46 (s, 2H, S–CH₂), 6.66 (d, 2H, Ar), 6.77 (t, 1H, Ar), 7.04 (s, 1H, NH=), 7.13 (t, 2H, Ar), 7.40 (s, 1H, NH-Ph), 7.47 (s, 1H, H-3), 7.55–7.68 (m, 2H, Ar), 7.74 (s, 1H, H-6), 7.97 (s, 1H, NH-NH-Ph), 7.88–7.97 (m, 2H, Ar), 9.08 (s, 1H, NHSO₂) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.22, 35.90, 112.94, 119.97, 124.20, 124.27, 126.01, 126.08, 128.42, 129.05, 129.89, 130.77, 132.49, 133.44, 134.90, 136.59, 138.39, 140.47, 148.16, 159.19 ppm.

1-[4-Chloro-5-methyl-2-[3-(trifluoromethyl)benzylthio]phenylsulfonyl]-3-(4-methylphenylsulfonylamino)guanidine (19, C₂₃H₂₂ClF₃N₄O₄S₃)

Starting from 1.61 g 6, 0.65 g p-toluenesulfonyl hydrazide, and 0.66 g PTSA in 40 cm³ dry toluene for 1.5 h, the title compound 19 was obtained. Yield: 1.49 g (70 %); m.p.: 190–191 °C; TLC: R _f = 0.65 (CHCl₃:MeOH = 16:3); IR (KBr): Inline graphic = 3,459, 3,360, 3,310 (NH), 2,926 (CH₃, CH₂), 1,635 (C=N), 1,333, 1,174, 1,126 (SO₂) cm⁻¹; ¹H NMR (200 MHz, DMSO-d ₆): δ = 2.29 (s, 3H, CH₃), 2.38 (s, 3H, CH₃), 4.40 (s, 2H, S–CH₂), 7.24 (brs, 1H, NH), 7.36 (d, 2H, Ar tosyl), 7.43 (s, 1H, NH), 7.50–7.77 (m, 7H, Ar, Ar tosyl), 7.78 (s, 1H, H-6), 9.22 (s, 1H, SO₂NH), 9.90 (s, 1H, SO₂NH) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.22, 21.32, 36.01, 124.31, 124.39, 126.00, 126.08, 128.13, 128.89, 129.51, 129.89, 130.59, 132.68, 133.46, 134.69, 134.73, 136.69, 138.41, 140.23, 144.18, 158.46 ppm.

1-[4-Chloro-5-methyl-2-[4-(trifluoromethyl)benzylthio]phenylsulfonyl]-3-(phenylamino)guanidine (20, C₂₂H₂₀ClF₃N₄O₂S₂)

Starting from 1.61 g 7 and 0.51 g phenylhydrazine hydrochloride in 13 cm³ dry toluene for 2 h, the title compound 20 was obtained. Yield: 1.04 g (56 %); m.p.: 161–164 °C; TLC: R _f = 0.71 (CHCl₃:pentane:acetone = 1:1:0.5); IR (KBr): Inline graphic = 3,433 (NH), 2,924 (CH₃, CH₂), 1,325, 1,129 (SO₂) cm⁻¹; ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.29 (s, 3H, CH₃), 4.46 (s, 2H, S–CH₂), 6.65 (d, 2H, Ar), 6.76 (t, 1H, Ar), 7.04 (s, 1H, NH=), 7.11 (t, 2H, Ar), 7.40 (s, 1H, NH-Ph), 7.46 (s, 1H, H-3), 7.62–7.72 (m, 4H, H-6, Ar, NH-NH-Ph), 7.89 (d, 2H, Ar), 9.06 (s, 1H, NHSO₂) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.21, 35.81, 112.94, 119.96, 125.48, 125.56, 125.63, 128.03, 129.04, 130.12, 130.79, 132.39, 135.04, 136.65, 140.29, 141.74, 148.15, 159.21 ppm.

1-[4-Chloro-5-methyl-2-(naphthalen-1-ylmethylthio)phenylsulfonyl]-3-(phenylamino)guanidine (21, C₂₅H₂₃ClN₄O₂S₂)

Starting from 1.54 g 8 and 0.5 g phenylhydrazine hydrochloride in 10 cm³ dry toluene for 1 h, the title compound 21 was obtained. Yield: 0.82 g (40 %); m.p.: 145–150 °C; TLC: R _f = 0.71 (CHCl₃:pentane:acetone = 1:1:0.5); IR (KBr): Inline graphic = 3,331 (NH), 2,922 (CH₃, CH₂), 1,391, 1,137 (SO₂) cm⁻¹; ¹H NMR (200 MHz, DMSO-d ₆): δ = 2.33 (s, 3H, CH₃), 4.79 (s, 2H, S–CH₂), 6.62 (d, 2H, Ar), 6.75 (t, 1H, Ar), 6.96 (s, 1H, NH=), 7.07–7.10 (m, 2H, Ar), 7.33 (s, 1H, NH-Ph), 7.43–7.46 (m, 1H, Ar), 7.52–7.61 (m, 4H, H-3, Ar), 7.84–7.96 (m, 4H, H-6, Ar, NH-NH-Ph), 8.25 (d, 1H, Ar), 9.05 (s, 1H, NHSO₂) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.28, 34.82, 112.92, 119.97, 124.50, 125.82, 126.24, 126.60, 128.22, 128.41, 128.80, 128.89, 129.06, 130.73, 131.71, 132.00, 132.24, 133.69, 136.19, 136.72, 140.13, 148.13, 159.19 ppm.

1-[4-Chloro-5-methyl-2-(naphthalen-1-ylmethylthio)phenylsulfonyl]-3-(4-chlorophenylamino)guanidine (22, C₂₅H₂₂Cl₂N₄O₂S₂)

Starting from 1.54 g 8 and 0.63 g 4-chlorophenylhydrazine hydrochloride in 10 cm³ dry toluene for 3 h, the title compound 22 was obtained. Yield: 1.34 g (70 %); m.p.: 148–149 °C; TLC: R _f = 0.68 (CHCl₃:pentane:acetone = 1:1:0.5); IR (KBr): Inline graphic = 3,448, 3,318 (NH), 2,923 (CH₃, CH₂), 1,340, 1,140 (SO₂) cm⁻¹; ¹H NMR (200 MHz, DMSO-d ₆): δ = 2.33 (s, 3H, CH₃), 4.80 (s, 2H, S–CH₂), 6.60 (d, 2H, Ar), 6.98 (s, 1H, NH=), 7.07 (d, 2H, Ar), 7.35–7.64 (m, 6H, Ar, NH), 7.84–8.10 (m, 4H, Ar, NH), 8.50 (d, 1H, Ar), 9.05 (s, 1H, NHSO₂) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.27, 34.77, 114.35, 123.23, 124.51, 125.81, 126.25, 126.60, 128.27, 128.45, 128.78, 130.72, 131.73, 131.98, 132.22, 133.68, 136.22, 136.77, 139.97, 147.18, 159.01 ppm.

1-[4-Chloro-5-methyl-2-(naphthalen-1-ylmethylthio)phenylsulfonyl]-3-(4-methylphenylsulfonylamino)guanidine (23, C₂₆H₂₅ClN₄O₄S₃)

Starting from 1.54 g 8, 0.65 g p-toluenesulfonyl hydrazide, and 0.66 g PTSA in 70 cm³ dry toluene for 2.5 h, the title compound 23 was obtained. Yield: 1.61 g (78 %); m.p.: 203–206 °C; TLC: R _f = 0.32 (CHCl₃:pentane:acetone = 1:1:0.5); IR (KBr): Inline graphic = 3,475, 3,370, 3,310 (NH), 2,923 (CH₃, CH₂), 1633 (C=N), 1,339, 1,172, 1,146 (SO₂) cm⁻¹; ¹H NMR (200 MHz, DMSO-d ₆): δ = 2.33 (s, 3H, CH₃), 2.36 (s, 3H, CH₃), 4.74 (s, 2H, S–CH₂), 7.20 (brs, 1H, NH), 7.31 (d, 2H, Ar tosyl), 7.44 (s, 1H, NH), 7.48–7.74 (m, 6H, Ar naphth, tosyl), 7.66 (s, 1H, H-3), 7.82 (s, 1H, H-6), 7.84–8.02 (m, 2H, Ar naphth), 8.24 (d, 1H, Ar naphth), 9.20 (s, 1H, SO₂NH), 9.86 (s, 1H, SO₂NH) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.28, 21.33, 34.97, 124.49, 125.79, 126.24, 126.58, 128.12, 128.22, 128.41, 128.80, 128.96, 129.86, 130.57, 131.67, 132.07, 132.46, 133.68, 134.65, 135.97, 136.79, 139.94, 144.13, 158.45 ppm.

1-[4-Chloro-2-(1,2-dihydro-2-oxoquinolin-4-ylmethylthio)-5-methylphenylsulfonyl]-3-(phenylamino)guanidine (24, C₂₄H₂₂ClN₅O₃S₂)

Starting from 1.6 g 9 and 0.51 g phenylhydrazine hydrochloride in 15 cm³ dry toluene for 8 h, the title compound 24 was obtained. Yield: 1.06 g (58 %); m.p.: 171–173 °C; TLC: R _f = 0.70 (CHCl₃:MeOH = 16:3); IR (KBr): Inline graphic = 3,343 (NH), 2,922 (CH₃, CH₂), 1,663 (CO), 1,386, 1,143 (SO₂) cm⁻¹; ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.31 (s, 3H, CH₃), 4.62 (s, 2H, S–CH₂), 6.66 (d, 2H, Ar), 6.69 (s, 1H, Ar), 6.76 (t, 1H, Ar), 7.00 (s, 1H, NH =), 7.13 (t, 2H, Ar), 7.22 (t, 1H, Ar), 7.32 (d, 1H, Ar), 7.39 (s, 1H, NH-Ph), 7.50 (t, 1H, Ar), 7.52 (s, 1H, H-3), 7.88 (s, 1H, H-6), 7.90 (s, 1H, NH-NH-Ph), 7.94 (d, 1H, Ar), 9.14 (s, 1H, NHSO₂), 11.78 (s, 1H, NH-quinol) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.03, 33.16, 112.69, 115.69, 118.31, 119.75, 121.67, 121.83, 125.01, 128.46, 128.85, 130.51, 130.61, 132.64, 134.39, 136.49, 138.90, 140.48, 146.08, 147.88, 158.91, 161.55 ppm.

1-[4-Chloro-2-(2,3-dihydrobenzo[b][1,4]dioxin-2-ylmethylthio)-5-methylphenylsulfonyl]-3-(phenylamino)guanidine (25, C₂₃H₂₃ClN₄O₄S₂)

Starting from 1.57 g 10 and 0.53 g phenylhydrazine hydrochloride in 8 cm³ dry toluene for 1 h, the title compound 25 was obtained. Yield: 1.12 g (62 %); m.p.: 175–177 °C; TLC: R _f = 0.70 (CHCl₃:pentane:acetone = 1:1:0.5); IR (KBr): Inline graphic = 3,442 (NH), 2,923 (CH₃, CH₂), 1,399, 1,145 (SO₂) cm⁻¹; ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.33 (s, 3H, CH₃), 3.32-3.48 (m, 2H, S–CH₂), 4.06–4.10 (m, 1H, CH–O), 4.37 (d, 2H, CH₂–O), 6.68 (d, 2H, Ar), 6.77 (t, 1H, Ar), 6.81–6.87 (m, 4H, Ar), 7.03 (s, 1H, NH=), 7.15 (t, 2H, Ar), 7.41 (s, 1H, NH-Ph), 7.64 (s, 1H, H-3), 7.88 (s, 1H, H-6), 7.90 (s, 1H, NH-NH-Ph), 9.09 (s, 1H, NHSO₂) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.29, 33.19, 66.32, 72.02, 112.96, 117.23, 117.41, 120.03, 121.66, 121.83, 128.87, 129.11, 130.74, 132.78, 134.89, 136.86, 140.95, 142.77, 143.10, 148.19, 159.23 ppm.

General procedure for the preparation of 4-chloro-5-methyl-2-(R¹-methylthio)-N-(1-R²-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzenesulfonamide derivatives 26–40

The reaction was carried out in a two-neck round-bottom flask (capacity 5 cm³) with drying tube protection. To the cooled (0 °C) mixture of the corresponding aminoguanidines 11–25 (1 mmol) in dry THF, 0.46 cm³ TsNCO (3 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 1 h, then at reflux for 8–36 h. After cooling (0 °C, overnight) the reaction product was isolated in precipitate state (27–31, 34–40) or in oil form (26, 32, and 33) and purified by crystallization from ethanol (26-31, 33–39), ethyl acetate (32), or acetonitrile (40).

2-(Benzylthio)-4-chloro-N-(4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-5-methylbenzenesulfonamide (26, C₁₆H₁₅ClN₄O₃S₂)

Starting from 0.385 g 11 (1 mmol) in 1.5 cm³ THF, the reaction mixture was refluxed for 8 h. After cooling to room temperature, the oily solution was treated with 30 cm³ diethyl ether. The ether solution was decanted from the solid, evaporated to dryness, and the residue crystallized from ethanol to obtain 0.065 g (16 %) of 26. The deposit after decantation was treated with 20 cm³ diethyl ether, filtered off, and purified by crystallization from ethanol to give 0.123 g (30 %) as a second fraction of 26. M.p.: 278–279 °C; TLC: R _f = 0.44 (benzene:EtOH = 2:1); IR (KBr): Inline graphic = 3,346 (NH), 2,929 (CH₃, CH₂), 1,688 (CO), 1,355, 1,161 (SO₂) cm⁻¹; ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.32 (s, 3H, CH₃), 4.36 (s, 2H, S–CH₂), 7.26 (t, 1H, Ar), 7.32 (t, 2H, Ar), 7.43 (d, 2H, Ar), 7.54 (s, 1H, H-3), 7.86 (s, 1H, H-6), 11.19 (s, 1H, NH), 11.50 (s, 1H, NH) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.29, 36.81, 125.89, 127.63, 128.73, 129.49, 132.02, 132.78, 136.05, 136.29, 138.29, 154.50 ppm; LC–MS (IT-TOF): m/z = 410 (M⁺), t _R = 5 min.

2-(Benzylthio)-4-chloro-N-(4,5-dihydro-1-methyl-5-oxo-1H-1,2,4-triazol-3-yl)-5-methylbenzenesulfonamide (27, C₁₇H₁₇ClN₄O₃S₂)

Starting from 0.399 g 12 (1 mmol) in 1.5 cm³ THF, the reaction mixture was refluxed for 8 h. The product was purified to give 0.263 g (62 %) of 27. M.p.: 226–228 °C; TLC: R _f = 0.22 (benzene:EtOH = 2:1); IR (KBr): Inline graphic = 3,102 (NH), 2,924 (CH₃, CH₂), 1,764 (CO), 1,319, 1,131 (SO₂) cm⁻¹; ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.31 (s, 3H, CH₃), 3.19 (s, 3H, CH₃), 4.32 (s, 2H, S–CH₂), 7.25 (t, 1H, Ar), 7.31 (t, 2H, Ar), 7.37 (d, 2H, Ar), 7.51 (s, 1H, H-3), 7.94 (s, 1H, H-6), 11.75 (brs, 1H, NH) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.21, 32.66, 36.38, 127.51, 128.04, 128.71, 129.20, 130.93, 132.18, 135.60, 136.67, 136.84, 139.58, 147.70, 152.49 ppm; LC–MS (IT-TOF): m/z = 424 (M⁺), t _R = 6 min.

2-(Benzylthio)-4-chloro-N-(4,5-dihydro-5-oxo-1-phenyl-1H-1,2,4-triazol-3-yl)-5-methylbenzenesulfonamide (28, C₂₂H₁₉ClN₄O₃S₂)

Starting from 0.461 g 13 (1 mmol) in 1.5 cm³ THF, the reaction mixture was refluxed for 9 h. The product was purified to give 0.362 g (74 %) of 28. M.p.: 212–214.5 °C; TLC: R _f = 0.61 (benzene:EtOH = 2:1); IR (KBr): Inline graphic = 3,240 (NH), 2,923 (CH₃, CH₂), 1,702 (CO), 1,354, 1,173 (SO₂) cm⁻¹; ¹H NMR (200 MHz, DMSO-d ₆): δ = 2.36 (s, 3H, CH₃), 4.34 (s, 2H, S–CH₂), 7.12–7.24 (m, 4H, Ar), 7.30–7.44 (m, 4H, Ar), 7.58 (s, 1H, H-3), 7.66 (d, 2H, Ar), 7.98 (s, 1H, H-6), 11.98 (s, 1H, NH) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.21, 36.70, 117.66, 124.74, 127.60, 128.49, 128.63, 129.19, 129.44, 132.80, 133.21, 135.55, 135.85, 136.71, 137.91, 138.92, 139.52, 151.52 ppm; LC–MS (IT-TOF): m/z = 486 (M⁺), t _R = 13 min.

2-(Benzylthio)-4-chloro-N-[4,5-dihydro-1-(4-nitrophenylsulfonyl)-5-oxo-1H-1,2,4-triazol-3-yl]-5-methylbenzenesulfonamide (29, C₂₂H₁₈ClN₅O₇S₃)

Starting from 0.596 g 14 (1 mmol) in 2 cm³ THF, the reaction mixture was refluxed for 9 h. The product was purified to give 0.30 g (50 %) of 29. M.p.: 211–214 °C; TLC: R _f = 0.59 (benzene:ethanol = 2:1); IR (KBr): Inline graphic = 3,429, 3,269 (NH), 1,764 (CO), 1,536, 1,350 (NO₂), 1,403, 1,391, 1,184, 1,167 (SO₂) cm⁻¹; ¹H NMR (200 MHz, DMSO-d ₆): δ = 2.32 (s, 3H, CH₃), 4.28 (s, 2H, S–CH₂), 7.10–7.21 (m, 3H, Ar), 7.30 (d, 2H, Ar), 7.50 (s, 1H, H-3), 7.78 (d, 2H, J = 8.8 Hz, Ar), 7.89 (s, 1H, H-6), 8.24 (d, 2H, J = 8.8 Hz, Ar) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.19, 36.41, 124.92, 127.42, 128.30, 128.40, 128.47, 128.82, 129.16, 132.48, 133.47, 135.98, 136.15, 138.37, 141.76, 144.95, 150.91, 151.71 ppm; LC–MS (IT-TOF): m/z = 596 (M⁺), t _R = 15 min.

2-(Benzylthio)-4-chloro-N-[4,5-dihydro-1-(4-methylphenylsulfonyl)-5-oxo-1H-1,2,4-triazol-3-yl]-5-methylbenzenesulfonamide (30, C₂₃H₂₁ClN₄O₅S₃)

Starting from 0.539 g 15 (1 mmol) in 1.5 cm³ THF, the reaction mixture was refluxed for 8 h. The product was purified to give 0.405 g (72 %) of 30. M.p.: 202–204 °C; TLC: R _f = 0.60 (benzene:EtOH = 2:1); IR (KBr): Inline graphic = 3,371 (NH), 2,922 (CH₃, CH₂), 1,755 (CO), 1,387, 1,191, 1,176 (SO₂) cm⁻¹; ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.34 (s, 3H, CH₃), 2.37 (s, 3H, CH₃), 4.28 (s, 2H, S–CH₂), 7.20 (t, 1H, Ar), 7.26 (d, 2H, Ar), 7.33 (d, 2H, Ar), 7.36 (d, 2H, Ar), 7.51 (d, 2H, Ar), 7.54 (s, 1H, H-3), 7.89 (s, 1H, H-6), 11.93 (s, 1H, NH) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.23, 21.46, 36.67, 127.32, 127.60, 128.52, 128.66, 129.32, 130.18, 132.69, 133.33, 133.95, 135.42, 135.86, 136.42, 138.77, 143.34, 145.82, 151.67 ppm; LC–MS (IT-TOF): m/z = 564 (M⁺), t _R = 12 min.

4-Chloro-N-[4,5-dihydro-1-(4-methylphenyl)-5-oxo-1H-1,2,4-triazol-3-yl]-2-(ethoxycarbonylmethylthio)-5-methylbenzenesulfonamide (31, C₂₀H₂₁ClN₄O₅S₂)

Starting from 0.471 g 16 (1 mmol) in 1.5 cm³ THF, the reaction mixture was refluxed for 8 h. The precipitate of by-products was filtered off. The filtrate was evaporated to dryness under reduced pressure and purified to give 0.343 g (69 %) of 31. M.p.: 190–191 °C; TLC: R _f = 0.42 (benzene:EtOH = 2:1); IR (KBr): Inline graphic = 3,255 (NH), 2,978, 2,801 (CH₃, CH₂), 1,726 (CO), 1,336, 1,171 (SO₂) cm⁻¹; ¹H NMR (200 MHz, DMSO-d ₆): δ = 1.04 (t, 3H, CH₃), 2.26 (s, 3H, CH₃), 2.38 (s, 3H, CH₃), 3.97-4.08 (m, 4H, S–CH₂, CH₂), 7.18 (d, 2H, Ar), 7.52 (d, 2H, Ar), 7.60 (s, 1H, H-3), 8.01 (s, 1H, H-6), 11.98 (s, 1H, NH) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 14.10, 19.23, 20.66, 35.15, 61.43, 117.76, 129.14, 129.54, 133.20, 133.51, 133.90, 135.33, 135.51, 136.11, 138.90, 139.23, 151.40, 168.89 ppm; LC–MS (IT-TOF): m/z = 496 (M⁺), t _R = 12 min.

4-Chloro-N-(4,5-dihydro-5-oxo-1-phenyl-1H-1,2,4-triazol-3-yl)-2-(1,3-dioxolan-2-ylmethylthio)-5-methylbenzenesulfonamide (32, C₁₉H₁₉ClN₄O₅S₂)

Starting from 0.458 g 17 (1 mmol) in 3 cm³ THF, the reaction mixture was refluxed for 5 h. After cooling to room temperature, the oily residue was treated with diethyl ether to obtain a white solid. The crude product was purified to give 0.159 g (33 %) of 32. M.p.: 214–217 °C; TLC: R _f = 0.36 (benzene:EtOH = 2:1); IR (KBr): Inline graphic = 3,414 (NH), 2,972 (CH₃, CH₂), 1,716 (CO), 1,382, 1,165 (SO₂) cm⁻¹; ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.37 (s, 3H, CH₃), 3.28 (d, 2H, S–CH₂), 3.71-3.75 (m, 2H, CH₂–O), 3.83–3.88 (m, 2H, CH₂–O), 5.05 (t, 1H, CH–O), 7.13 (t, 1H, Ar), 7.36 (t, 2H, Ar), 7.64 (d, 2H, Ar), 7.68 (s, 1H, H-3), 7.97 (s, 1H, H-6), 11.97 (s, 1H, NH) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.22, 36.70, 64.96, 102.10, 117.69, 124.73, 129.18, 129.31, 129.83, 132.98, 136.13, 136.74, 137.89, 138.87, 139.64, 151.54 ppm; LC–MS (IT-TOF): m/z = 482 (M⁺), t _R = 9 min.

4-Chloro-N-(4,5-dihydro-5-oxo-1-phenyl-1H-1,2,4-triazol-3-yl)-5-methyl-2-[3-(trifluoromethyl)benzylthio]benzenesulfonamide (33, C₂₃H₁₈ClF₃N₄O₃S₂)

Starting from 0.506 g 18 (1 mmol) in 1 cm³ THF, the reaction mixture was refluxed for 9 h. After cooling to room temperature, the oily residue was treated with diethyl ether to obtain a white solid. The crude product was purified to give 0.210 g (38 %) of 33. M.p.: 195–198 °C; TLC: R _f = 0.45 (benzene:EtOH = 2:1); IR (KBr): Inline graphic = 3,425 (NH), 2,924 (CH₃, CH₂), 1,702 (CO), 1,334, 1,170 (SO₂) cm⁻¹; ¹H NMR (200 MHz, DMSO-d ₆): δ = 2.36 (s, 3H, CH₃), 4.48 (s, 2H, S-CH₂), 7.14 (t, 1H, Ar), 7.27–7.58 (m, 4H, Ar), 7.58 (s, 1H, H-3), 7.62–7.76 (m, 4H, Ar), 7.98 (s, 1H, H-6), 12.00 (s, 1H, NH) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.20, 36.05, 117.62, 124.20, 124.29, 124.71, 126.08, 126.16, 128.93, 129.14, 129.32, 129.56, 133.24, 133.33, 133.43, 135.44, 136.33, 137.85, 138.81, 139.48, 151.49 ppm; LC–MS (IT-TOF): m/z = 554 (M⁺), t _R = 17 min.

4-Chloro-N-[4,5-dihydro-1-(4-methylphenylsulfonyl)-5-oxo-1H-1,2,4-triazol-3-yl]-5-methyl-2-[3-(trifluoromethyl)benzylthio]benzenesulfonamide (34, C₂₄H₂₀ClF₃N₄O₅S₃)

Starting from 0.607 g 19 (1 mmol) in 2 cm³ THF, the reaction mixture was refluxed for 36 h. The product was purified to give 0.443 g (71 %) of 34. M.p.: 99–100 °C; TLC: R _f = 0.62 (benzene:EtOH = 2:1); IR (KBr): Inline graphic = 3,284 (NH), 2,924 (CH₃, CH₂), 1,716 (CO), 1,331, 1,347, 1,170, 1,194 (SO₂) cm⁻¹; ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.32 (s, 3H, CH₃), 2.34 (s, 3H, CH₃), 4.38 (s, 2H, S–CH₂), 7.30 (d, 2H, Ar), 7.43–7.52 (m, 4H, Ar), 7.55–7.69 (m, 3H, Ar), 7.86 (s, 1H, H-6), 11.90 (brs, 1H, NH) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.24, 21.36, 36.03, 127.34, 127.79, 129.03, 129.78, 129.85, 130.14, 133.12, 133.29, 133.98, 135.36, 136.18, 136.55, 137.83, 138.61, 143.63, 144.62, 145.77, 148.09, 151.75 ppm; LC–MS (IT-TOF): m/z = 632 (M⁺), t _R = 20 min.

4-Chloro-N-(4,5-dihydro-5-oxo-1-phenyl-1H-1,2,4-triazol-3-yl)-5-methyl-2-[4-(trifluoromethyl)benzylthio]benzenesulfonamide (35, C₂₃H₁₈ClF₃N₄O₃S₂)

Starting from 0.529 g 20 (1 mmol) in 1 cm³ THF, the reaction mixture was refluxed for 9 h. The product was purified to give 0.29 g (52 %) of 35. M.p.: 208–210 °C; TLC: R _f = 0.40 (benzene:EtOH = 2:1); IR (KBr): Inline graphic = 3,253 (NH), 2,923 (CH₃, CH₂), 1,701 (CO), 1,327, 1,127 (SO₂) cm⁻¹; ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.35 (s, 3H, CH₃), 4.46 (s, 2H, S–CH₂), 7.14 (t, 1H, Ar), 7.36 (t, 2H, Ar), 7.50 (d, 2H, Ar), 7.56 (d, 2H, Ar), 7.59 (s, 1H, H-3), 7.63 (d, 2H, Ar), 7.97 (s, 1H, H-6), 11.99 (s, 1H, NH) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.21, 35.92, 117.62, 124.70, 125.36, 125.43, 127.76, 129.15, 129.83, 130.11, 133.17, 133.25, 135.78, 135.97, 137.88, 138.89, 139.63, 144.53, 151.51 ppm; LC–MS (IT-TOF): m/z = 554 (M⁺), t _R = 17 min.

4-Chloro-N-(4,5-dihydro-5-oxo-1-phenyl-1H-1,2,4-triazol-3-yl)-5-methyl-2-(naphthalen-1-ylmethylthio)benzenesulfonamide (36, C₂₆H₂₁ClN₄O₃S₂)

Starting from 0.513 g 21 (1 mmol) in 1 cm³ THF, the reaction mixture was refluxed for 9 h. After cooling to room temperature, the reaction mixture was treated with petroleum ether to obtain a white solid. The crude product was purified to give 0.166 g (31 %) of 36. M.p.: 214–216 °C; TLC: R _f = 0.55 (CHCl₃:MeOH = 16:3); IR (KBr): Inline graphic = 3,258 (NH), 2,922 (CH₃, CH₂), 1,720 (CO), 1,349, 1,168 (SO₂) cm⁻¹; ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.39 (s, 3H, CH₃), 4.80 (s, 2H, S–CH₂), 7.15 (t, 1H, Ar), 7.32–7.42 (m, 3H, Ar), 7.51–7.53 (m, 3H, Ar), 7.62–7.73 (m, 3H, H-3, Ar), 7.83 (d, 1H, Ar), 7.92 (d, 1H, Ar), 8.00 (s, 1H, H-6), 8.20 (d, 1H, Ar), 11.90 (s, 1H, NH) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.26, 35.02, 117.70, 124.41, 124.78, 125.69, 126.25, 126.62, 128.44, 128.58, 128.78, 129.21, 129.56, 131.43, 131.61, 132.95, 133.11, 133.64, 135.66, 137.08, 137.91, 138.95, 139.51, 151.50 ppm; LC–MS (IT-TOF): m/z = 536 (M⁺), t _R = 18 min.

4-Chloro-N-[1-(4-chlorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl]-5-methyl-2-(naphthalen-1-ylmethylthio)benzenesulfonamide (37, C₂₆H₂₀Cl₂N₄O₃S₂)

Starting from 0.545 g 22 (1 mmol) in 2 cm³ THF, the reaction mixture was refluxed for 9 h. The product was purified to give 0.224 g (39 %) of 37. M.p.: 205–206 °C; TLC: R _f = 0.59 (benzene:EtOH = 2:1); IR (KBr): Inline graphic = 3,251 (NH), 2,924 (CH₃, CH₂), 1,722 (C=O), 1,352, 1,166 (SO₂) cm⁻¹; ¹H NMR (200 MHz, DMSO-d ₆): δ = 2.39 (s, 3H, CH₃), 4.81 (s, 2H, S-CH₂), 7.31–7.58 (m, 6H, Ar), 7.62–7.72 (m, 3H, Ar), 7.80–7.94 (m, 2H, Ar), 8.01 (s, 1H, H-6), 8.20 (d, 1H, Ar), 11.99 (s, 1H, NH) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.27, 34.99, 119.09, 124.41, 125.89, 126.24, 126.61, 128.41, 128.56, 128.77, 129.17, 129.56, 131.43, 131.60, 132.96, 133.09, 133.64, 135.59, 136.76, 137.08, 138.98, 139.92, 142.10, 151.42 ppm; LC–MS (IT-TOF): m/z = 570 (M⁺), t _R = 22 min.

4-Chloro-N-[4,5-dihydro-1-(4-methylphenylsulfonyl)-5-oxo-1H-1,2,4-triazol-3-yl]-5-methyl-2-(naphthalen-1-ylmethylthio)benzenesulfonamide (38, C₂₇H₂₃ClN₄O₅S₃)

Starting from 0.589 g 23 (1 mmol) in 2 cm³ THF, the reaction mixture was refluxed for 11 h. The product was purified to give 0.438 g (70 %) of 38. M.p.: 118–120 °C; TLC: R _f = 0.60 (benzene:EtOH = 2:1); IR (KBr): Inline graphic = 3,530 (NH), 2,973 (CH₃, CH₂), 1,726 (CO), 1,388, 1,370, 1,193, 1,177 (SO₂) cm⁻¹; ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.31 (s, 3H, CH₃), 2.37 (s, 3H, CH₃), 4.70 (s, 2H, S–CH₂), 7.32 (d, 2H, Ar), 7.38 (t, 1H, Ar), 7.48–7.53 (m, 5H, Ar), 7.63 (s, 1H, H-3), 7.84 (d, 1H, Ar), 7.90 (s, 1H, H-6), 7.94 (d, 1H, Ar), 8.08 (d, 1H, Ar), 11.90 (brs, 1H, NH) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.29, 21.42, 35.06, 124.28, 125.76, 126.27, 126.64, 127.37, 128.27, 128.56, 128.79, 128.96, 130.19, 131.38, 131.59, 132.90, 133.27, 133.64, 133.91, 135.68, 136.75, 138.77, 143.56, 145.85, 151.78 ppm; LC–MS (IT-TOF): m/z = 614 (M⁺), t _R = 23 min.

4-Chloro-N-(4,5-dihydro-5-oxo-1-phenyl-1H-1,2,4-triazol-3-yl)-2-(1,2-dihydro-2-oxoquinolin-4-ylmethylthio)-5-methylbenzenesulfonamide (39, C₂₅H₂₀ClN₅O₄S₂)

Starting from 0.528 g 24 (1 mmol) in 3 cm³ THF, the reaction mixture was refluxed for 9 h. The product was purified to give 0.161 g (29 %) of 39. M.p.: 185–188 °C; TLC: R _f = 0.12 (CHCl₃:MeOH = 16:3), R _f = 0.19 (CHCl₃:MeCN:AcOH = 2:1:0.05); IR (KBr): Inline graphic = 3,467 (NH), 2,923 (CH₃, CH₂), 1,692, 1,655 (CO), 1,383, 1,127 (SO₂) cm⁻¹; ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.37 (s, 3H, CH₃), 4.59 (s, 2H, S–CH₂), 6.58 (s, 1H, Ar), 7.10 (t, 1H, Ar), 7.16 (t, 1H, Ar), 7.30 (d, 1H, Ar), 7.34 (t, 2H, Ar), 7.49 (t, 1H, Ar), 7.55 (s, 1H, H-3), 7.65 (d, 2H, Ar), 7.88 (d, 1H, Ar), 8.01 (s, 1H, H-6), 11.73 (s, 2H, NH-quinolin, NH-triazolone) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.27, 33.74, 115.88, 117.75, 118.29, 121.90, 122.48, 124.75, 125.28, 129.17, 129.46, 130.83, 133.17, 133.53, 135.51, 136.33, 137.84, 138.90, 139.23, 139.47, 145.59, 151.51, 161.49 ppm; LC–MS (IT-TOF): m/z = 554 (M⁺), t _R = 17 min.

4-Chloro-2-(2,3-dihydrobenzo[b][1,4]dioxin-2-ylmethylthio)-N-(4,5-dihydro-5-oxo-1-phenyl-1H-1,2,4-triazol-3-yl)-5-methylbenzenesulfonamide (40, C₂₄H₂₁ClN₄O₅S₂)

Starting from 0.519 g 25 (1 mmol) in 3 cm³ THF, the reaction mixture was refluxed for 9 h. The product was purified to give 0.262 g (48 %) of 40. M.p.: 185–188 °C; TLC: R _f = 0.53 (benzene:ethanol = 2:1); IR (KBr): Inline graphic = 3,311 (NH), 2,922 (CH₃, CH₂), 1,697 (CO), 1,334, 1,165 (SO₂) cm⁻¹; ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.38 (s, 3H, CH₃), 3.36 (dd, 1H, S–CH₂), 3.46 (dd, 1H, S–CH₂), 4.00 (dd, 1H, O–CH₂), 4.26 (dd, 1H, O–CH₂), 4.31–4.35 (m, 1H, O–CH), 6.70–6.81 (m, 4H, Ar), 7.12 (t, 1H, Ar), 7.34 (t, 2H, Ar), 7.64 (d, 2H, Ar), 7.76 (s, 1H, H-3), 8.01 (s, 1H, H-6), 12.01 (s, 1H, NH) ppm; ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.29, 33.64, 66.26, 72.02, 117.15, 117.29, 117.69, 121.61, 121.70, 124.74, 129.14, 129.83, 133.09, 133.61, 135.83, 136.62, 137.83, 139.12, 139.50, 142.61, 142.99, 151.54 ppm; LC–MS (IT-TOF): m/z = 545 (M⁺), t _R = 21 min.

X-ray structure determination

Experimental diffraction data were collected on a KM4 CCD kappa-geometry diffractometer (Oxford diffraction), equipped with a Sapphire2 CCD detector. An enhanced X-ray Mo Kα radiation source with a graphite monochromator was used. Determination of the unit cell and diffraction data collection were carried out at 120 K in a stream of dry nitrogen (Oxford CryoSystems). All calculations (data reduction, structure solution, and refinement) were carried out using CrysAlisPro [49] package. The structure was solved by direct methods, and all non-hydrogen atoms were refined with anisotropic thermal parameters by full-matrix least squares procedure based on F ². Final refinements were carried out using the SHELX-97 package [50], run under control of WinGX program [51].

All hydrogen atoms were refined using isotropic model with U _iso (H) values fixed to be 1.2 times U _eq of C atoms for CH and CH₂ and 1.5 times U _eq for CH₃. Bond lengths C–H were fixed at 0.98 Å for methyl groups, and 0.95 Å for methylene and methine groups; distances N–H were set to 0.88 Å. Solvating water molecules generated an electron density peak of ca. 1.7 e Å⁻³. Because the electron density maximum is placed at a special position (½, y, ¼) localization of hydrogen atoms is additionally uncertain so we did not attempt to find H atoms. The occupation factor of oxygen atom O10 was refined freely to obtain 0.079. One incorrect reflection (−1 1 17) was omitted.

Crystallographic data for the structure of 31Pyr reported in this article have been deposited with the Cambridge Crystallographic Data Center as supplementary publication no. CCDC868805. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax: (+44) 1223-336-033; email: deposit@ccdc.cam.ac.uk].

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 157 kb)^{(157.5KB, pdf)}

Acknowledgments

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

Open Access

This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary material 1 (PDF 157 kb)^{(157.5KB, pdf)}

[CR1] 1.Negwer M. Organic-chemical drugs and their synonyms. Berlin: Akademie Verlag; 1994. [Google Scholar]

[CR2] 2.Sławiński J, Bednarski P, Grünert R, Reszka P. Polish J Chem. 2003;77:53. [Google Scholar]

[CR3] 3.Sławiński J, Bednarski P, Reszka P. Polish J Chem. 2004;78:369. [Google Scholar]

[CR4] 4.Sławiński J. Eur J Med Chem. 2004;39:179. doi: 10.1016/j.ejmech.2003.09.013. [DOI] [PubMed] [Google Scholar]

[CR5] 5.Sławiński J, Gdaniec M. Eur J Med Chem. 2005;40:377. doi: 10.1016/j.ejmech.2004.11.014. [DOI] [PubMed] [Google Scholar]

[CR6] 6.Sławiński J, Brzozowski Z. Eur J Med Chem. 2006;41:1180. doi: 10.1016/j.ejmech.2006.05.008. [DOI] [PubMed] [Google Scholar]

[CR7] 7.Brzozowski Z, Sławiński J. Polish J Chem. 2007;81:1419. [Google Scholar]

[CR8] 8.Brzozowski Z, Sączewski F, Sławiński J. Eur J Med Chem. 2007;42:1218. doi: 10.1016/j.ejmech.2007.01.020. [DOI] [PubMed] [Google Scholar]

[CR9] 9.Brzozowski Z, Sączewski F, Sławiński J, Bednarski PJ, Grünert R, Gdaniec M. Bioorg Med Chem. 2007;15:2560. doi: 10.1016/j.bmc.2007.01.052. [DOI] [PubMed] [Google Scholar]

[CR10] 10.Sławiński J, Brożewicz K, Fruziński A, Główka ML. Heterocycles. 2011;83:1093. doi: 10.3987/COM-11-12164. [DOI] [Google Scholar]

[CR11] 11.Brzozowski Z, Sławiński J, Kędzia A, Kwapisz E. J Heterocycl Chem. 2009;46:1396. doi: 10.1002/jhet.272. [DOI] [Google Scholar]

[CR12] 12.Sławiński J, Żołnowska B, Pirska D, Kędzia A, Kwapisz E. J Enzyme Inhib Med Chem. 2011 doi: 10.3109/14756366.2011.625024. [DOI] [PubMed] [Google Scholar]

[CR13] 13.Kuo CL, Assefa H, Brzozowski Z, Sławiński J, Sączewski F, Buolamwini IK, Neamati N. J Med Chem. 2004;47:385. doi: 10.1021/jm030378i. [DOI] [PubMed] [Google Scholar]

[CR14] 14.Brzozowski Z, Sławiński J, Sączewski F, Sanchez T, Neamati N. Eur J Med Chem. 2008;43:1188. doi: 10.1016/j.ejmech.2007.08.013. [DOI] [PubMed] [Google Scholar]

[CR15] 15.Sączewski F, Sławiński J, Kornicka A, Brzozowski Z, Pomarnacka E, Innocenti A, Scozzafava A, Supuran CT. Bioorg Med Chem Lett. 2006;16:4846. doi: 10.1016/j.bmcl.2006.06.064. [DOI] [PubMed] [Google Scholar]

[CR16] 16.Sączewski F, Innocenti A, Brzozowski Z, Sławiński J, Pomarnacka E, Kornicka A, Scozzafava A, Supuran CT. J Enzyme Inhib Med Chem. 2006;21:563. doi: 10.1080/14756360600648146. [DOI] [PubMed] [Google Scholar]

[CR17] 17.Sączewski F, Innocenti A, Sławiński J, Kornicka A, Brzozowski Z, Pomarnacka E, Scozzafava A, Supuran CT. Bioorg Med Chem. 2008;16:3933. doi: 10.1016/j.bmc.2008.01.034. [DOI] [PubMed] [Google Scholar]

[CR18] 18.Casini A, Scozzafava A, Mastrolorenzo A, Supuran CT. Curr Cancer Drug Targets. 2002;2:55. doi: 10.2174/1568009023334060. [DOI] [PubMed] [Google Scholar]

[CR19] 19.Supuran CT, Scozzafava A, Casini A. Med Res Rev. 2003;23:146. doi: 10.1002/med.10025. [DOI] [PubMed] [Google Scholar]

[CR20] 20.Kivela AJ, Kivela J, Saarnio J, Parkkila J. World J Gastroenterol. 2005;11:155. doi: 10.3748/wjg.v11.i2.155. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR21] 21.Supuran CT, Scozzafava A. Bioorg Med Chem. 2007;15:4336. doi: 10.1016/j.bmc.2007.04.020. [DOI] [PubMed] [Google Scholar]

[CR22] 22.Supuran CT. Nat Rev Drug Discov. 2008;7:168. doi: 10.1038/nrd2467. [DOI] [PubMed] [Google Scholar]

[CR23] 23.Supuran CT, Casini A, Mastrolorenzo A, Scozzafava A. Mini Rev Med Chem. 2004;4:625. doi: 10.2174/1389557043403792. [DOI] [PubMed] [Google Scholar]

[CR24] 24.Abbate F, Casini A, Owa T, Scozzafava A, Supuran CT. Bioorg Med Chem Lett. 2004;14:217. doi: 10.1016/j.bmcl.2003.09.062. [DOI] [PubMed] [Google Scholar]

[CR25] 25.Rostom SA. Bioorg Med Chem. 2006;14:6475. doi: 10.1016/j.bmc.2006.06.020. [DOI] [PubMed] [Google Scholar]

[CR26] 26.Chen J, Liu T, Wu R, Lou J, Cao J, Dong X, Yang B, He Q, Hu Y. Bioorg Med Chem. 2010;18:8478. doi: 10.1016/j.bmc.2010.10.047. [DOI] [PubMed] [Google Scholar]

[CR27] 27.Mullican MD, Wilson MW, Connor DT, Kostlan CR, Schrier DJ, Dyer RD. J Med Chem. 1993;36:1090. doi: 10.1021/jm00060a017. [DOI] [PubMed] [Google Scholar]

[CR28] 28.Elipe MV, Huskey SE, Zhu B. J Pharm Biomed Anal. 2003;30:1431. doi: 10.1016/S0731-7085(01)00715-4. [DOI] [PubMed] [Google Scholar]

[CR29] 29.Sheppeck JE, Gilmore JL, Tebben A, Xue CB, Liu RQ, Decicco CP, Duan JJ. Bioorg Med Chem Lett. 2007;17:2769. doi: 10.1016/j.bmcl.2007.02.076. [DOI] [PubMed] [Google Scholar]

[CR30] 30.Oza V, Ashwell S, Brassil P, Breed J, Ezhuthachan J, Deng C, Grondine M, Horn C, Liu D, Lyne P, Newcombe N, Pass M, Read J, Su M, Toader D, Yu D, Yu Y, Zabludoff S. Bioorg Med Chem Lett. 2012;22:2330. doi: 10.1016/j.bmcl.2012.01.043. [DOI] [PubMed] [Google Scholar]

[CR31] 31.Demirbaş N, Ugurluoglu R, Demirbaş A. Bioorg Med Chem. 2002;10:3717. doi: 10.1016/S0968-0896(02)00420-0. [DOI] [PubMed] [Google Scholar]

[CR32] 32.Pomarnacka E, Koźlarska-Kędra I. Il Farmaco. 2003;58:423. doi: 10.1016/S0014-827X(03)00071-5. [DOI] [PubMed] [Google Scholar]

[CR33] 33.Adams ND, Aquino CJ, Chaudhari AM, Ghergurovich JM, Kiesow TJ, Parrish CA, Reif AJ, Wiggall K (2011) Triazolones as fatty acid synthase inhibitors. WO patent 2011103546, 25 Aug 2011

[CR34] 34.Adams ND, Aquino CJ, Chaudhari AM, Ghergurovich JM, Kiesow TJ, Parrish CA, Reif AJ, Wiggall K. Chem Abstr. 2011;155:380343. [Google Scholar]

[CR35] 35.Ying W, Du Z, Sun L, Foley KP, Proia DA, Blackman RK, Zhou D, Inoue T, Tatsuta N, Sang J, Ye S, Acquaviva J, Ogawa LS, Wada Y, Barsoum J, Koya K. Mol Cancer Ther. 2012;11:475. doi: 10.1158/1535-7163.MCT-11-0755. [DOI] [PubMed] [Google Scholar]

[CR36] 36.Sławiński J. Pol J Chem. 2001;75:1309. [Google Scholar]

[CR37] 37.Sheppeck JE, Gilmore JL, Tebben A, Xue CHB, Liu RQ, Decicco CP, Duan JJW. Bioorg Med Chem Lett. 2007;17:2769. doi: 10.1016/j.bmcl.2007.02.076. [DOI] [PubMed] [Google Scholar]

[CR38] 38.Shalini M, Yogeeswari P, Sriram D, Stables JP. Biomed Pharmacother. 2009;63:187. doi: 10.1016/j.biopha.2006.04.002. [DOI] [PubMed] [Google Scholar]

[CR39] 39.Brown RJ, Annis G, Casalnuovo A, Chan D, Shapiro R, Marshall WJ. Tetrahedron. 2004;60:4361. doi: 10.1016/j.tet.2004.03.056. [DOI] [Google Scholar]

[CR40] 40.Brenner M, Bechtel WD, Palluk R, Wienrich M, Weiser NO (2002) Pharmaceutical compositions containing triazolones and methods of treating neurodegenerative disease using triazolones. US patent 6,492,407 B2, 10 Dec 2002

[CR41] 41.Huisgen R (1961) Proc Chem Soc 357

[CR42] 42.Galishev VA, Chistoklevtov UN, Petrov AA. Russ Chem Res. 1980;49:880. doi: 10.1070/RC1980v049n09ABEH002513. [DOI] [Google Scholar]

[CR43] 43.Kuninobu Y, Nishimura S, Takai K. Org Biomol Chem. 2006;4:203. doi: 10.1039/b516916j. [DOI] [PubMed] [Google Scholar]

[CR44] 44.Tsuge O, Kanemasa S, Tashiro M. Tetrahedron. 1968;24:5205. doi: 10.1016/S0040-4020(01)88431-3. [DOI] [Google Scholar]

[CR45] 45.Tsuge O, Kanemasa S. Bull Chem Soc Jpn. 1972;45:2877. doi: 10.1246/bcsj.45.2877. [DOI] [Google Scholar]

[CR46] 46.Macrae CF, Bruno IJ, Chisholm JA, Edgington PR, McCabe P, Pidcock E, Rodriguez-Monge L, Taylor R, van de Streek J, Wood PA. J Appl Crystallogr. 2008;41:466. doi: 10.1107/S0021889807067908. [DOI] [Google Scholar]

[CR47] 47.Boyd RM, Paull KD. Drug Dev Res. 1995;34:91. doi: 10.1002/ddr.430340203. [DOI] [Google Scholar]

[CR48] 48.Amos LA. Semin Cell Dev Biol. 2011;22:916. doi: 10.1016/j.semcdb.2011.09.014. [DOI] [PubMed] [Google Scholar]

[CR49] 49.Oxford Diffraction (2005) CrysAlis CCD and CrysAlis RED, Version 1.171. Oxford Diffraction Ltd, Abingdon, England

[CR50] 50.Sheldrick GM. Acta Crystallogr A. 2008;64:112. doi: 10.1107/S0108767307043930. [DOI] [PubMed] [Google Scholar]

[CR51] 51.Farrugia LJ. J Appl Crystallogr. 1999;32:837. doi: 10.1107/S0021889899006020. [DOI] [Google Scholar]

PERMALINK

Synthesis and molecular structure of novel 2-(alkylthio)-4-chloro-N-(4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-5-methylbenzenesulfonamides with potential anticancer activity

Jarosław Sławiński

Beata Żołnowska

Czesława Orlewska

Jarosław Chojnacki

Abstract

Abstract

Graphical Abstract

Electronic supplementary material

Introduction

Fig. 1.

Results and discussion

Chemistry

Scheme 1.

Fig. 2.

Fig. 3.

Molecular structure

Table 1.

Table 2.

Table 3.

Biological assay

Table 4.

Table 5.

Conclusion

Experimental

N-[4-Chloro-2-(1,3-dioxolan-2-ylmethylthio)-5-methylphenylsulfonyl]cyanamide potassium salt (5, C12H12ClKN2O4S2)

General procedure for the preparation of N-[4-chloro-5-methyl-2-(R1-methylthio)phenylsulfonyl]cyanamide potassium salts 6–10

N-[4-Chloro-5-methyl-2-[3-(trifluoromethyl)benzylthio]phenylsulfonyl]cyanamide potassium salt (6, C16H11ClF3KN2O2S2)

N-[4-Chloro-5-methyl-2-[4-(trifluoromethyl)benzylthio]phenylsulfonyl]cyanamide potassium salt (7, C16H11ClF3KN2O2S2)

N-[4-Chloro-5-methyl-2-(naphthalen-1-ylmethylthio)phenylsulfonyl]cyanamide potassium salt (8, C19H14ClKN2O2S2)

N-[4-Chloro-2-(1,2-dihydro-2-oxoquinolin-4-ylmethylthio)-5-methylphenylsulfonyl]cyanamide potassium salt (9, C18H13ClKN3O3S2)

N-[4-Chloro-2-(2,3-dihydrobenzo[b][1,4]dioxin-2-ylmethylthio)-5-methylphenylsulfonyl]cyanamide potassium salt (10, C17H14ClKN2O4S2)

General procedure for the preparation of 1-[4-chloro-5-methyl-2-(R1-methylthio)phenylsulfonyl]-3-(R2-amino)guanidines 15, 17–25

1-[2-(Benzylthio)-4-chloro-5-methylphenylsulfonyl]-3-(4-methylphenylsulfonylamino)guanidine (15, C22H23ClN4O4S3)

1-[4-Chloro-2-(1,3-dioxolan-2-ylmethylthio)-5-methylphenylsulfonyl]-3-(phenylamino)guanidine (17, C18H21ClN4O4S2)

1-[4-Chloro-5-methyl-2-[3-(trifluoromethyl)benzylthio]phenylsulfonyl]-3-(phenylamino)guanidine (18, C22H20ClF3N4O2S2)

1-[4-Chloro-5-methyl-2-[3-(trifluoromethyl)benzylthio]phenylsulfonyl]-3-(4-methylphenylsulfonylamino)guanidine (19, C23H22ClF3N4O4S3)

1-[4-Chloro-5-methyl-2-[4-(trifluoromethyl)benzylthio]phenylsulfonyl]-3-(phenylamino)guanidine (20, C22H20ClF3N4O2S2)

1-[4-Chloro-5-methyl-2-(naphthalen-1-ylmethylthio)phenylsulfonyl]-3-(phenylamino)guanidine (21, C25H23ClN4O2S2)

1-[4-Chloro-5-methyl-2-(naphthalen-1-ylmethylthio)phenylsulfonyl]-3-(4-chlorophenylamino)guanidine (22, C25H22Cl2N4O2S2)

1-[4-Chloro-5-methyl-2-(naphthalen-1-ylmethylthio)phenylsulfonyl]-3-(4-methylphenylsulfonylamino)guanidine (23, C26H25ClN4O4S3)

1-[4-Chloro-2-(1,2-dihydro-2-oxoquinolin-4-ylmethylthio)-5-methylphenylsulfonyl]-3-(phenylamino)guanidine (24, C24H22ClN5O3S2)

1-[4-Chloro-2-(2,3-dihydrobenzo[b][1,4]dioxin-2-ylmethylthio)-5-methylphenylsulfonyl]-3-(phenylamino)guanidine (25, C23H23ClN4O4S2)

General procedure for the preparation of 4-chloro-5-methyl-2-(R1-methylthio)-N-(1-R2-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzenesulfonamide derivatives 26–40

2-(Benzylthio)-4-chloro-N-(4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-5-methylbenzenesulfonamide (26, C16H15ClN4O3S2)

2-(Benzylthio)-4-chloro-N-(4,5-dihydro-1-methyl-5-oxo-1H-1,2,4-triazol-3-yl)-5-methylbenzenesulfonamide (27, C17H17ClN4O3S2)

2-(Benzylthio)-4-chloro-N-(4,5-dihydro-5-oxo-1-phenyl-1H-1,2,4-triazol-3-yl)-5-methylbenzenesulfonamide (28, C22H19ClN4O3S2)

2-(Benzylthio)-4-chloro-N-[4,5-dihydro-1-(4-nitrophenylsulfonyl)-5-oxo-1H-1,2,4-triazol-3-yl]-5-methylbenzenesulfonamide (29, C22H18ClN5O7S3)

2-(Benzylthio)-4-chloro-N-[4,5-dihydro-1-(4-methylphenylsulfonyl)-5-oxo-1H-1,2,4-triazol-3-yl]-5-methylbenzenesulfonamide (30, C23H21ClN4O5S3)

4-Chloro-N-[4,5-dihydro-1-(4-methylphenyl)-5-oxo-1H-1,2,4-triazol-3-yl]-2-(ethoxycarbonylmethylthio)-5-methylbenzenesulfonamide (31, C20H21ClN4O5S2)

4-Chloro-N-(4,5-dihydro-5-oxo-1-phenyl-1H-1,2,4-triazol-3-yl)-2-(1,3-dioxolan-2-ylmethylthio)-5-methylbenzenesulfonamide (32, C19H19ClN4O5S2)

4-Chloro-N-(4,5-dihydro-5-oxo-1-phenyl-1H-1,2,4-triazol-3-yl)-5-methyl-2-[3-(trifluoromethyl)benzylthio]benzenesulfonamide (33, C23H18ClF3N4O3S2)

4-Chloro-N-[4,5-dihydro-1-(4-methylphenylsulfonyl)-5-oxo-1H-1,2,4-triazol-3-yl]-5-methyl-2-[3-(trifluoromethyl)benzylthio]benzenesulfonamide (34, C24H20ClF3N4O5S3)

4-Chloro-N-(4,5-dihydro-5-oxo-1-phenyl-1H-1,2,4-triazol-3-yl)-5-methyl-2-[4-(trifluoromethyl)benzylthio]benzenesulfonamide (35, C23H18ClF3N4O3S2)

4-Chloro-N-(4,5-dihydro-5-oxo-1-phenyl-1H-1,2,4-triazol-3-yl)-5-methyl-2-(naphthalen-1-ylmethylthio)benzenesulfonamide (36, C26H21ClN4O3S2)

4-Chloro-N-[1-(4-chlorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl]-5-methyl-2-(naphthalen-1-ylmethylthio)benzenesulfonamide (37, C26H20Cl2N4O3S2)

4-Chloro-N-[4,5-dihydro-1-(4-methylphenylsulfonyl)-5-oxo-1H-1,2,4-triazol-3-yl]-5-methyl-2-(naphthalen-1-ylmethylthio)benzenesulfonamide (38, C27H23ClN4O5S3)

4-Chloro-N-(4,5-dihydro-5-oxo-1-phenyl-1H-1,2,4-triazol-3-yl)-2-(1,2-dihydro-2-oxoquinolin-4-ylmethylthio)-5-methylbenzenesulfonamide (39, C25H20ClN5O4S2)

4-Chloro-2-(2,3-dihydrobenzo[b][1,4]dioxin-2-ylmethylthio)-N-(4,5-dihydro-5-oxo-1-phenyl-1H-1,2,4-triazol-3-yl)-5-methylbenzenesulfonamide (40, C24H21ClN4O5S2)

X-ray structure determination

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N-[4-Chloro-2-(1,3-dioxolan-2-ylmethylthio)-5-methylphenylsulfonyl]cyanamide potassium salt (5, C₁₂H₁₂ClKN₂O₄S₂)

General procedure for the preparation of N-[4-chloro-5-methyl-2-(R¹-methylthio)phenylsulfonyl]cyanamide potassium salts 6–10

N-[4-Chloro-5-methyl-2-[3-(trifluoromethyl)benzylthio]phenylsulfonyl]cyanamide potassium salt (6, C₁₆H₁₁ClF₃KN₂O₂S₂)

N-[4-Chloro-5-methyl-2-[4-(trifluoromethyl)benzylthio]phenylsulfonyl]cyanamide potassium salt (7, C₁₆H₁₁ClF₃KN₂O₂S₂)

N-[4-Chloro-5-methyl-2-(naphthalen-1-ylmethylthio)phenylsulfonyl]cyanamide potassium salt (8, C₁₉H₁₄ClKN₂O₂S₂)

N-[4-Chloro-2-(1,2-dihydro-2-oxoquinolin-4-ylmethylthio)-5-methylphenylsulfonyl]cyanamide potassium salt (9, C₁₈H₁₃ClKN₃O₃S₂)

N-[4-Chloro-2-(2,3-dihydrobenzo[b][1,4]dioxin-2-ylmethylthio)-5-methylphenylsulfonyl]cyanamide potassium salt (10, C₁₇H₁₄ClKN₂O₄S₂)

General procedure for the preparation of 1-[4-chloro-5-methyl-2-(R¹-methylthio)phenylsulfonyl]-3-(R²-amino)guanidines 15, 17–25

1-[2-(Benzylthio)-4-chloro-5-methylphenylsulfonyl]-3-(4-methylphenylsulfonylamino)guanidine (15, C₂₂H₂₃ClN₄O₄S₃)

1-[4-Chloro-2-(1,3-dioxolan-2-ylmethylthio)-5-methylphenylsulfonyl]-3-(phenylamino)guanidine (17, C₁₈H₂₁ClN₄O₄S₂)

1-[4-Chloro-5-methyl-2-[3-(trifluoromethyl)benzylthio]phenylsulfonyl]-3-(phenylamino)guanidine (18, C₂₂H₂₀ClF₃N₄O₂S₂)

1-[4-Chloro-5-methyl-2-[3-(trifluoromethyl)benzylthio]phenylsulfonyl]-3-(4-methylphenylsulfonylamino)guanidine (19, C₂₃H₂₂ClF₃N₄O₄S₃)

1-[4-Chloro-5-methyl-2-[4-(trifluoromethyl)benzylthio]phenylsulfonyl]-3-(phenylamino)guanidine (20, C₂₂H₂₀ClF₃N₄O₂S₂)

1-[4-Chloro-5-methyl-2-(naphthalen-1-ylmethylthio)phenylsulfonyl]-3-(phenylamino)guanidine (21, C₂₅H₂₃ClN₄O₂S₂)

1-[4-Chloro-5-methyl-2-(naphthalen-1-ylmethylthio)phenylsulfonyl]-3-(4-chlorophenylamino)guanidine (22, C₂₅H₂₂Cl₂N₄O₂S₂)

1-[4-Chloro-5-methyl-2-(naphthalen-1-ylmethylthio)phenylsulfonyl]-3-(4-methylphenylsulfonylamino)guanidine (23, C₂₆H₂₅ClN₄O₄S₃)

1-[4-Chloro-2-(1,2-dihydro-2-oxoquinolin-4-ylmethylthio)-5-methylphenylsulfonyl]-3-(phenylamino)guanidine (24, C₂₄H₂₂ClN₅O₃S₂)

1-[4-Chloro-2-(2,3-dihydrobenzo[b][1,4]dioxin-2-ylmethylthio)-5-methylphenylsulfonyl]-3-(phenylamino)guanidine (25, C₂₃H₂₃ClN₄O₄S₂)

General procedure for the preparation of 4-chloro-5-methyl-2-(R¹-methylthio)-N-(1-R²-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzenesulfonamide derivatives 26–40

2-(Benzylthio)-4-chloro-N-(4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-5-methylbenzenesulfonamide (26, C₁₆H₁₅ClN₄O₃S₂)

2-(Benzylthio)-4-chloro-N-(4,5-dihydro-1-methyl-5-oxo-1H-1,2,4-triazol-3-yl)-5-methylbenzenesulfonamide (27, C₁₇H₁₇ClN₄O₃S₂)

2-(Benzylthio)-4-chloro-N-(4,5-dihydro-5-oxo-1-phenyl-1H-1,2,4-triazol-3-yl)-5-methylbenzenesulfonamide (28, C₂₂H₁₉ClN₄O₃S₂)

2-(Benzylthio)-4-chloro-N-[4,5-dihydro-1-(4-nitrophenylsulfonyl)-5-oxo-1H-1,2,4-triazol-3-yl]-5-methylbenzenesulfonamide (29, C₂₂H₁₈ClN₅O₇S₃)

2-(Benzylthio)-4-chloro-N-[4,5-dihydro-1-(4-methylphenylsulfonyl)-5-oxo-1H-1,2,4-triazol-3-yl]-5-methylbenzenesulfonamide (30, C₂₃H₂₁ClN₄O₅S₃)

4-Chloro-N-[4,5-dihydro-1-(4-methylphenyl)-5-oxo-1H-1,2,4-triazol-3-yl]-2-(ethoxycarbonylmethylthio)-5-methylbenzenesulfonamide (31, C₂₀H₂₁ClN₄O₅S₂)

4-Chloro-N-(4,5-dihydro-5-oxo-1-phenyl-1H-1,2,4-triazol-3-yl)-2-(1,3-dioxolan-2-ylmethylthio)-5-methylbenzenesulfonamide (32, C₁₉H₁₉ClN₄O₅S₂)

4-Chloro-N-(4,5-dihydro-5-oxo-1-phenyl-1H-1,2,4-triazol-3-yl)-5-methyl-2-[3-(trifluoromethyl)benzylthio]benzenesulfonamide (33, C₂₃H₁₈ClF₃N₄O₃S₂)

4-Chloro-N-[4,5-dihydro-1-(4-methylphenylsulfonyl)-5-oxo-1H-1,2,4-triazol-3-yl]-5-methyl-2-[3-(trifluoromethyl)benzylthio]benzenesulfonamide (34, C₂₄H₂₀ClF₃N₄O₅S₃)

4-Chloro-N-(4,5-dihydro-5-oxo-1-phenyl-1H-1,2,4-triazol-3-yl)-5-methyl-2-[4-(trifluoromethyl)benzylthio]benzenesulfonamide (35, C₂₃H₁₈ClF₃N₄O₃S₂)

4-Chloro-N-(4,5-dihydro-5-oxo-1-phenyl-1H-1,2,4-triazol-3-yl)-5-methyl-2-(naphthalen-1-ylmethylthio)benzenesulfonamide (36, C₂₆H₂₁ClN₄O₃S₂)

4-Chloro-N-[1-(4-chlorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl]-5-methyl-2-(naphthalen-1-ylmethylthio)benzenesulfonamide (37, C₂₆H₂₀Cl₂N₄O₃S₂)

4-Chloro-N-[4,5-dihydro-1-(4-methylphenylsulfonyl)-5-oxo-1H-1,2,4-triazol-3-yl]-5-methyl-2-(naphthalen-1-ylmethylthio)benzenesulfonamide (38, C₂₇H₂₃ClN₄O₅S₃)

4-Chloro-N-(4,5-dihydro-5-oxo-1-phenyl-1H-1,2,4-triazol-3-yl)-2-(1,2-dihydro-2-oxoquinolin-4-ylmethylthio)-5-methylbenzenesulfonamide (39, C₂₅H₂₀ClN₅O₄S₂)

4-Chloro-2-(2,3-dihydrobenzo[b][1,4]dioxin-2-ylmethylthio)-N-(4,5-dihydro-5-oxo-1-phenyl-1H-1,2,4-triazol-3-yl)-5-methylbenzenesulfonamide (40, C₂₄H₂₁ClN₄O₅S₂)