HETEROCYCLES

Paper | Regular issue | Vol. 81, No. 8, 2010, pp. 1799-1810
Received, 21st April, 2010, Accepted, 21st June, 2010, Published online, 21st June, 2010.
DOI: 10.3987/COM-10-11963

■ 2-Methyl- and 2-Dimethylaminoquino[4,3-e]-1,2,4-thiadiazine 4,4-Dioxides – Synthesis, Structure and N-Methylation

Elwira Chrobak, Michał Wlekliński, Andrzej Maślankiewicz,* Joachim Kusz, Maciej Zubko, and Andrzej Zięba

Department of Organic Chemistry, The Medical University of Silesia, Jagielloñska Str. 4, 41-200 Sosnowiec, Poland

Abstract

Reaction of 4-chloro-3-quinolinesulfonyl chloride (1) with acetamidine or with N,N-dimethyl- and N,N,N'-trimethylquanidine salts led directly or stepwise via 4-chloro-3-quinolinesulfonylguanidine (6a) to the title 2-substituted quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxides (4, 7a, and 8). X-Ray studies proved that 2-methyl derivative 4 exists as the 1H-tautomer while 2-dimethylamino derivative 7a as the 6H-tautomer. Reaction of N-H derivatives 4 and 7a and the pyrido-1,2,4-thiadiazine analog 11a with CH3I/CH3OK/DMF system proceeded at the pyridine-ring nitrogen and led to 6-methylquino derivatives 5 and 7b or the 7-methylpyrido derivative 11b, respectively, as concluded from 2D 1H - 13C NMR data.

INTRODUCTION
Significant biological activities of 1,2,4-benzo- and pyridothiadiazine 1,1-dioxides as potassium channel openers,1-6 AMPA potentiators,7 cytotoxic agents,8 or anti-HIV agents9 has turned medicinal chemists’ attention to search for other areno- and heteroareno- fused 1,2,4-thiadiazine 1,1-dioxides as possible candidates for therapeutic application.
As far as heteroareno derivatives were concerned pyrido-1,2,4-thiadiazine derivatives1,3,5,6,10 were the most studied but synthesis of pyrazo,9 imidazo,7,8 triazolo,11 and thieno9,12 derivatives was also reported. However, no literature data were found for the title quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxides 4, 5, 7a,b, and 8, which, as we describe in this paper, can be accessed from 4-chloro-3-quinolinesulfonyl chloride (1).

RESULTS and DISCUSSION
The 1,2,4-thiadiazine 1,1-dioxide ring system fused to a benzene or heteroarene moiety has usually been formed from ortho-amino-sulfonamide and appropriate cyclization agents. 1,2,3 This approach was preliminarily applied for the synthesis of the title quinothiadiazine (4). The required ortho-amino-sulfonamide, i.e. 4-amino-3-quinolinesulfonamide (3) could be prepared from easily available 4-chloro-3-quinolinesulfonyl chloride (1).14 Cyclization of 4-amino-3-quinolinesulfonamide (3) with acetic anhydride afforded 2-methyl-(1H)-quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (4). The structure of 4 as 1H-tautomer was deduced from X-ray data presented below.
Attempting to shorten the synthetic pathway leading from 4-chloro-3-quinolinesulfonyl chloride (1) to quinothiadiazine (4), 4-chloro-3-quinolinesulfonyl chloride (1) was directely subjected to reaction with acetamidine, or guanidine salts, applying the experimental procedure for sulfonylation of amidines and quanidines.15 Indeed, the reaction with acetamidine hydrochloride led directly to quinothiadiazine 4 in 65 % yield.

However, the reaction of sulfonyl chloride 1 with N,N-dimethylguanidine sulfate stopped at the sulfonylguanidine 6a stage. The structure of 6a as sulfonylimino tautomer was arbitrarily assigned based on literature data15,16 concerning the sulfonylguanidines. Cyclization of N-(4-chloro-3-quinoline sulfonyl)-N',N'-dimethylguanidine (6a) to 2-dimethylamino-(6H)-quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (7a) was performed in boiling phenol applying the amino-de-chlorination procedure for 4-chloroquinolines.14 The structure of 7a in the solid state was deduced from the X-ray study presented below.

The reaction between 4-chloro-3-quinolinesulfonyl chloride (1) and N,N,N'-trimethylguanidine did not proceed in a clean manner, but the major product (ca. 45%) was assigned as 1-methyl derivative 8 as presented below. This assignment was based on NOE experiments summarized in Scheme 2, indicating the spatial proximity of the 1-CH3 group with to the H-10 proton because of irradiation of the N-methyl group protons (singlet, 3H, δ=3.69 ppm) led to enhancement of the H-10 proton signal (dd, δ=8.40 -8.42 ppm) by 15% but irradiation of the H-10 proton led to enhancement of both the N1-CH3 protons signal (δ=3.69 ppm, by 3.8%) and the H-9 signal (m, 1H, m, δ=7.76-7.80 ppm by 11.8%). As concluded from the structure of final product 8, the reaction should start as sulfonylation at the less hindered NH2 group, leaving the NHCH3 group unaffected to produce intermediate compound 6b. The latter was immediately consumed in the amino de-chlorination process to form final product 8.
N-Methylation. In search of biologically active compounds, areno- and heteroareno-fused 1,2,4-thiadiazine 1,1-dioxides were modified by N-alkylation at N-H bonds.3,7,9,10,13 1,2,4-Thiadiazine 1,1-dioxides may exist in the form of N(2)-H and N(4)-H tautomers. However, only 4-alkylation products were isolated for pyrido[2,3-e]-1,2,4-thiadiazine 1,1-dioxide F.7 In the case of compounds A, B, C and G alkylation proceeded at both N(2) and N(4) nitrogens, but for pyrido[2,3-e]-1,2,4-thiadiazine 1,1-dioxides D and E, it occurrred even outside the thiadiazine ring at the pyridine ring endocyclic nitrogen atom.10 (Scheme 3)

Taking into consideration the above, both N-H quinothiadiazine 4,4-dioxides 4 and 7a were subjected to methylation. The required potassium salts of 4 and 7a were prepared in situ using potassium methoxide in DMF medium and then treated with methyl iodide at rt. Unexpectedly, the methylation of the potassium salt of quinothiadiazine 4a proceeded at the pyridine-ring nitrogen atom and led to 2,6-dimethyl-(6H)-quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (5) but not to the expected methylation products at the thiadiazine ring. The structure of 5 was deduced from the NOE study presented in Scheme 1 and also with HMBC experiments as shown in Scheme 4 for compound 7b.
The same methylation approach performed on the potassium salt of 7a also occurred at the pyridine ring to form 6-methyl derivative 7b. The position of the newly-introduced N-CH3 group was concluded from HSQC and HMBC experiments as presented in Scheme 4. The 400 MHz 1H NMR spectrum of 7b reveals three three-proton singlets of N-CH3 groups, well separated multiplets of four benzene ring protons and a singlet of α-quinolinyl, i.e. H-5 proton. In the structure assignment of 7b the key parts are played by the long range proton-carbon correlations between the H-5 proton (s, 1H, δ=9.05 ppm) and three quaternary carbon resonances of pyridine ring carbons accompanied by long range coupling with the N6-methyl group carbon. A connectivity link between the benzene and pyridine parts of the quinothiadiazine molecule could be deduced from the long-range proton-carbon correlations of H-10 proton with C6a and C10b carbons.
Long-range proton-carbon couplings with N6-methyl group protons (s, 3H, δ=4.16 ppm) and C5 and C6a carbons were also observed. Additionally, couplings of protons from dimethylamino group with C2 carbon allowed a complete assignment of the 1H and 13C NMR spectra of 7b and therefore proved the structure of 7b.

To evaluate the unexpected orientation in the methylation of quinothiadiazine 4,4-dioxides 4 and 7a, we returned to 3-dimethylaminopyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide (11a) as des-benzo analog of 7a. For this purpose compound 11a was prepared as presented in Scheme 5. Treatment of 11a with potassium methoxide in DMF solution followed by reaction with methyl iodide at rt also proceeded at the pyridine ring N7-nitrogen and led to the 7-methylderivative 11b.

X-Ray study.
X-Ray data for 2-methyl- and 2-dimethylaminoquinothiadiazine 4,4-dioxides 4 and 7a were presented graphically in the form of ORTEP drawings in figs. 1 and 2. The positions of N-H hydrogen atoms prove the tautomeric preferences for quinothiadiazine dioxide 4 as the 1H-tautomer but for 7a as the 6H-tautomer.

CONCLUSIONS
The title quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxides 4, 5, 7a,b are easily available from reactions of 4-chloro-3-quinolinesulfonyl chloride (1) with acetamidine or N,N-dimethylguanidine salts. Although the 2-methyl derivative 4 exists in the form of a 1H-tautomer and 2-dimethylamino derivative 7a as a 6H-tautomer, the potassium salts of 4 and 7a were methylated outside the thiadiazine ring at the pyridine ring nitrogen, which led to 6-methyl derivatives 5 or 7b, respectively. The same methylation of pyrido-1,2,4-thiadiazine dioxide 11b, reported as NH tautomer at γ-pyridine-ring position,17 also proceeded at the pyridine-ring endocyclic nitrogen to form 7-methyl derivative 11b.

EXPERIMENTAL
Melting points were taken in open capillary tubes and are uncorrected. All NMR spectra were recorded on a Bruker AVANCE 400 spectrometer operating at 400.22 MHz and 100.64 MHz for 1H and 13C nuclei, respectively, in deuterochloroform or in hexadeuterodimethyl sulfoxide solutions with tetramethylsilane (δ 0.0 ppm) as internal standard. NOE experiments were performed for DMSO-d6 solutions of compounds 5 and 8. Two-dimensional 1H-13C HSQC and HMBC experiments were performed using standard Bruker software HSQCGP and HMBCGP, respectively, and the following parameters: the spectral widths in F2 and F1 were ca 5 kHz for 1H and 16.7 kHz for 13C, the relaxation delay was 1.5 s, the refocusing in the HSQC experiment was 1.7 ms and the delay for long-range evolutions was 50 ms in 1H / 13C HMBC. 2D spectra were acquired as 2048 x 1024 hypercomplex files, with 1-4 transients. EI MS spectra were determined on a Finnigan MAT 95 spectrometer at 70 eV.TLC analyses were performed employing Merck’s aluminium oxide 60 F254 neutral (type E) plates and using chloroform as an eluent.
Acetamidine hydrochloride and N,N-dimethylguanidine sulfate were commercial products, N,N,N’-trimethylguanidine sulfate was prepared from N,S-dimethylisothiouronium sulfate and dimethylamine according to the reported method.18 4-Chloro-3-pyridinesulfonyl chloride (9)19 and 4-chloro-3-quinolinesulfonyl chloride (1) were prepared as described previously.14

Synthesis of 2-methyl-(1H)-quino-[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (4) from 4-amino-3-quinolinesulfonamide (3) and acetic anhydride
4-Amino-3-quinolinesulfonamide (3)14 (446 mg, 2 mM) and acetic anhydride (4 mL) was refluxed for 4 h and cooled down to rt. The solid was filtered off and washed with ethanol. It was recrystallized from EtOH to give 374 mg (73%) of 4 semihydrate.
2-Methyl-(1H)-quino-[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (4)
mp 295-297 ºC (ethanol). EI MS (70 eV): m/z(%) = 247 (90.7, M+), 206 (100), 142 (99.8). 1H NMR (DMSO-d6), δ: 2.52 (s, 3H, CH3), 7.84-7.88 (m, 1H, Harom), 7.97-8.01 (m, 1H, Harom), 8.12-8.14 (m, 1H, Harom), 8.73 -8.76 (m, 1H, Harom), 9.11 (s, 1H, H-5), 12.02 (bs, 1H, NH). Anal. Calcd for C11H9N3O2S x ½ H2O: C 51.62, H 3.93, N 16.41. Found: C 51.16, H 3.87, N 16.28.
Reactions of 4-chloro-3-quinolinesulfonyl chloride (1) with acetamidine hydrochloride or with N,N-dimethyl- and N,N,N'-trimethylguanidine sulfates
Solution of 4-chloro-3-quinolinesulfonyl chloride (1) (524 mg, 2 mMol) in 14 mL of acetone was added dropwise within 30 min upon stirring to a mixture of acetamidine hydrochloride (200 mg, ca. 2.1 mMol), 50 % aqueous NaOH (0.4 mL) and acetone (2 mL) at rt. The mixture was stirred for 2 h at rt.
In the same manner were performed reactions with N,N-dimethyl- and N,N,N'-trimethylguanidine sulfates (ca. 1.05 mMol).
The solid was filtered off. In order to isolate chloro derivative 6a, the solid was treated with warm water, cooled down to rt, and crude 6a was filtered off.
Since quinothiadiazines 4 and 8 remained in the acetone filtrates, the filtrates were evaporated to dryness at vacuum with a rotatory evaporator. The semisolid residue was dissolved in 5% aqueous NaOH (2.5 mL) and then neutralized to pH 5-6 with 10% hydrochloric acid. The solid was filtered off, washed with water and dried on air.

Reaction of 4-chloro-3-pyridinesulfonyl chloride (9) with N,N-dimethylguanidine sulfate was carried out in the same way as for treatment of 1 to give N-(4-chloro-3-pyridinesulfonyl)-N',N'-dimethylguanidine (10) with 71% yield.

2-Methyl-(1H)-quino-[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (4)
mp and analytical data – the same as that prepared from 3 and acetic anhydride.
N-(4-Chloro-3-quinolinesulfonyl)-N',N'-dimethylguanidine (6a):
mp 205-207 ºC (EtOH). EIMS (70 eV): m/z(%) = 312 (48.6, M+), 313 [20.3, (M+1)] 314 [19.6, (M+2)], 268 (100). 1H NMR (DMSO-d6), δ: 2.91[s, 6H, N(CH3)2], 7.64-7.68 (bs, 2H, NH2), 7.85-7.88 (m, 1H, Harom), 7.97-8.01 (m, 1H, Harom), 8.15-8.17 (m, 1H, Harom), 8.39-8.41 (m, 1H, Harom), 9.34 (s, 1H, H-2). Anal. Calcd for C12H13ClN4O2S: C 46.08, H 4.19, N 17.91. Found: C 46.09, H 4.27, N 17.42.
N-(4-Chloro-3-pyridinesulfonyl)-N',N'-dimethylguanidine (10):
mp 169-171 ºC (EtOH). EIMS (70 eV): m/z(%) = 262 (75, M+), 264 [(24, (M + 2)+]. 1H NMR (DMSO-d6), δ: 2.87 [s, 6H, N(CH3)2], 7.09 (s, 2H, NH2), 7.64 (d, 3J = 5.6Hz, 1H, H5), 8.61 (d, 3J = 5.6Hz, 1H, H6), 8.99 (s, 1H, H2). Anal. Calcd for C8H11ClN4O2S: C 36.57, H 4.22, N 21.33. Found: C 36.48, H 4.16, N 21.17.
2-Dimethylamino-1-methyl-(1H)-quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (8):
mp 217-219 ºC (EtOH). EIMS (70 eV): m/z(%) = 290 (85, M+), 155 (100). 1H NMR (DMSO-d6), δ: 3.15-3.30 [bs, 6H, N(CH3)2], 3.69 [(s, 3H, CH3N(1)], 7.77-7.80 (m, 1H, H-9), 7.93-7.96 (m, 1H, H-8), 8.14-8.16 (dd, 1H, J=8.4 Hz, J=0.6 Hz, H-7), 8.40-8.42 (dd, 1H, J=8.45 Hz, J=0.7 Hz, H-10), 9.08 (s, 1H, H-5). 1H NMR (CDCl3), δ: 3.28 [bs, 6H, N(CH3)2], 3.69 [(s, 3H, CH3N(1)], 7.68-7.72 (m, 1H, Harom), 7.83-7.88 (m, 1H, Harom), 7.99-8.01 (m, 1H, Harom), 8.22 -8.24 (m, 1H, Harom), 9.30 (s, 1H, H-5). Anal. Calcd for C13H14N4O2S: C 53.78, H 4.86, N 19.30, S 11.04. Found: C 53.61, H 4.82, N 19.10.

Cyclization of N-(4-chloro-3-quinolinesulfonyl)-N',N'-dimethylguanidine (6a) to 2-dimethylamino-(6H)-quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (7a)
A mixture of quinolinesulfonylguanidine 6a (313 mg, 1 mM), NH4Cl (15 mg) and phenol (2 g) was kept in an oil-bath at 190-195 ºC for 2 h. The mixture was cooled down and phenol was removed by steam distillation. The residue was cooled down to rt and filtered off to give crude product 7a. It was dried on air, and recrystallized from EtOH to give quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (7a) (313 mg, 73%).
2-Dimethylamino-(6H)-quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (7a):
mp 313-316 ºC (EtOH). EIMS (70 eV): m/z(%) = 276 (100). 1H NMR (DMSO-d6), δ: 3.31 [s, 6H, N(CH3)2], 7.64-7.68 (m, 1H, Harom), 7.83-7.84 (m, 1H, Harom), 7.87-7.91(m, 1H, Harom), 8.60 -8.63 (m, 1H, Harom), 8.93 (s, 1H, H-5), 13.70 (bs, 1H, NH). Anal. Calcd for C12H12N4O2S: C 52.16, H 4.38, N 20.28. Found: C 51.91, H 4.41, N 19.98.

Cyclization of N-(4-chloro-3-pyridinesulfonyl)-N',N'-dimethylguanidine (10) to 3-dimethylamino-(4H)-pyrido[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (11a)
Cyclization was performed in the same way as for thienothiadiazines, ref.12
A mixture of pyridinesulfonylguanidine 10 (520 mg, 2 mM), cesium carbonate (1 g) and 30 mL of dry butanol was kept in an oil-bath at 110 ºC for 72 h and then concentrated to dryness under vaccum. The residue was dissolved in water (ca. 20 mL) and acidified with formic acid up to pH = 6. The solid was filtered off, dried over anhydrous CaCl2 and boiled with EtOH. Hot solution was decanted off to leave pyrido[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (11a) (320 mg, 71%).
3-Dimethylamino-(4H)-pyrido[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (11a)
mp > 320 ºC, lit.,3 mp > 320 ºC. EIMS (70 eV): m/z (%) = 226 (100). 1H NMR spectrum in DMSO-d6 was identical with the reported data.3
N-Methylation of 2-methyl-(1H)-quino-[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (4) or
2-dimethylamino-(6H)-quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (7a)
Potassium methoxide (0.150 g, ca. 2.1 mM) was added on stirring to the suspension of quinothiadiazine dioxide (2 mMol) in dry DMF (8 mL). The mixture was stirred for 5-10 min until the mixture became clear. Then, a solution of methyl iodide (0.8 mL, ca. 2 mMol) in DMF (2.5 mL) was added dropwise for 15 min and the mixture was stirred at rt for 20 h.
2-Dimethylamino-6-methyl derivative 7b was filtered off and recrystallized from EtOH to give pure 7b (510 mg, 88%). For isolation of compound 5, the mixture was diluted with 60 mL of water. The solid was filtered off, washed with warm water and dried on air. It was recrystallized from EtOH to give 2,6-dimethyl derivative 5 (360 mg, 69%).
Methylation of 3-dimethylaminopyridothiadiazine 4,4-dioxide 1a was performed in the same way as above for 7b to give 3-dimethylamino-7-methyl-(7H)-pyridothiadiazine 4,4-dioxide (11b) with 63% yield.
2,6-Dimethyl-(6H)-quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (5):
mp 286-289 ºC (EtOH). EIMS (70 eV): m/z(%) = 261 (100). 1H NMR (DMSO-d6), δ [δC for carbons from single bond and / long range proton-carbon correlations]: 2.37 [(s, 3H, CH3C); 27.9 (C2)], 4.31 [(s, 3H, CH3N); 42.9 (CH3N) / 138.5 (C6a), 146.0 (C5)], 7.81 [(m, 1H, H9); 128.0 (C9) / 118.5 (C7), 124.1 (C10a)], 8.08 [(m, 1H, H8); 133.9 (C8) / 125.5 (C10), 138.5 (C6a)], 8.13 [(m, 1H, H7); 118.5 (C7) / 124.1 (C10a), 128.0 (C9)], 8.83 [(m, 1H, H10); 125.5 (C10) / 133.9 (C8), 138.5 (C6a), 155.5 (C10b)], 9.47 [(s, 1H, H5); 146.0 (C5) / 42.9 (CH3N), 111.4 (C4a), 138.5 (C6a), 155.5 (C10b)]. Anal. Calcd for C12H11N3O2S: C 55.16, H 4.24, N 16.08. Found: C 55.07, H 4.31, N 16.12.
2-Dimethylamino-6-methyl-(6H)-quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (7b):
mp 283-286 ºC (EtOH). EIMS (70 eV): m/z(%) = 290 (35.7, M+), 183 (100). 1H NMR (DMSO-d6), δ [δC for carbons from single bond and / long range proton-carbon correlations]: 3.10 [(s, 3H, CH3N); 36.62 (CH3N) / 158.6 (C-2)], 3.32 [(s, 3H, CH3N); 36.72 (CH3N / 158.6 (C2)], 4.16 [(s, 3H, N6-CH3); 41.8 (CH3-N6) / 138.6 (C-6a), 143.2 (C-5)], 7.72 [(m, 1H, H-9); 126.9 (C-9) / 118 (C-7), 123.8 (C-10a)], 7.91 [(m, 1H, m, H-8); 133.4 (C-8) / 125.4 (C-10), 138.6 (C-6a)], 7.92 [(m, 1H, m, H-7); 118.0 (C-7) / 123.8 (C-10a), 126.9 (C-9)], 8.71 [(m, 1H, H-10); 125.4 (C-10) / 133.4 (C8), 138.6 (C-6a), 155.7 (C-10b)], 9.05 [(s, 1H, H-5); 143.2 (C-5) / 41.8 (CH3-N6), 111.7 (C-4a), 138.6 (C-6a), 155.7 (C-10b)]. Anal. Calcd for C13H14N4O2S x 2 H2O: C 47.84, H 5.56, N 17.07. Found: C 47.58, H 5.29, N 17.06.
3-Dimethylamino-7-methyl-(7H)-pyrido[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (11b)
mp 261-263 ºC (EtOH). EIMS (70 eV): m/z(%) = 240 (74.1, M+). 1H NMR (DMSO-d6), δ [δC for carbons from single bond and / long range proton-carbon correlations]: 3.08 [(s, 3H, CH3N); 36.6 (CH3N) / 159.5 (C-3)], 3.22 [(s, 3H, CH3N); 36.5 (CH3N / 159.5 (C-3)], 3.99 [(s, 3H, N7-CH3); 44.6 (CH3-N7) / 140.1 (C-8), 142.2 (C-6)], 7.64 [(d, 1H, 3J=7.5 Hz, H-5); 118.7 (C-5) / 119.2 (C-8a), 128.0 (C9), 142.2 (C-6)], 7.79 [(d, 1H, 4J=1.8 Hz, H-8); 140.1 (C-8) / 44.6 (CH3-N7), 142.2 (C-6), 157.0 (C-4a, 8.09 [(dd, 1H, 3J=7.5 Hz, 4J=1.8 Hz, H-6); 142.2 (C-6) / 140.1 (C-8), 157.0 (C-4a)]. Anal. Calcd for C9H12N4O2S: C 44.99, H 5.03, N 23.32. Found: C 44.75, H 4.95, N 23.22.

X-Ray structure analysis
The diffraction data were collected with a four – circle Xcalibur diffractometer with Sapphire3 CCD detector using graphite monochromated Mo Kα radiation. The intensity data were collected and processed using Oxford Diffraction CrysAlis Software.20 The crystal structures were solved by direct methods with the program SHELXS-9721 and refined by full-matrix least-squares method on F2 with SHELXL-97.21
Crystals of 2-methyl-(1H)-quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxide semihydrate C11H9N3O2S · ½ H2O (4) were obtained by slow evaporation of 2-butanone solution at room temperature. Crystal data for 4: monoclinic, space group P21/c, a = 15.6102(2) Å , b = 9.0947(1) Å, c = 16.3347(2) Å, α = 90º, β = 113.469(2)º , γ = 90º, V = 2127.20(4) Å3, Z = 4, dx = 1,600 Mg m-3, T = 100(1) K. Data were collected for a crystal of dimensions 0.40 x 0.38 x 0.13 mm3. Final R indices for 3424 reflections with I > 2σ(I) and 338 refined parameters are R1= 0.0271, wR2= 0.0748, (R1= 0.0297 and wR2= 0.0758, for all 3772 data).
Crystals of 2-dimethylamino-(6H)-quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxide C12H12N4O2S (7a) were grown by slow evaporation from acetone – DMF (10 : 1, v/v) solution at room temperature. Crystal data for (7a): monoclinic, space group P21/c, a = 12.4887(2) Å, b = 14.9486(2) Å, c = 14.2984(2) Å, α = 90º, β = 115.359(2)º, γ = 90º, V = 2412.14(7) Å3, Z = 8, dx = 1,522 Mg m-3, T= 100(1) K. Data were collected for a crystal of dimensions 0.42x 0.23 x 0.14 mm3. Final R indices for 3396 reflections with I > 2σ(I) and 353 refined parameters are R1= 0.0272, wR2= 0.0843, (R1= 0.0352 and wR2= 0.0872, for all 4267 data).
Crystallographic data for compounds 4 and 7a have been deposited with Cambridge Crystallographic Data Centre (CCDC deposition numbers 761849 and 772826, respectively) Copies of the data can be obtained upon request from CCDC, 12 Union road, Cambridge CB2 1EZ, UK).

References

1. B. Pirotte, P. de Tullio, P. Lebrun, M. H. Antoine, J. Fontaine, B. Masereel, M. Schynts, L. Dupont, A. Herchuelz, and J. Delarge, J. Med. Chem., 1993, 36, 3211. CrossRef
2. S. Boverie, M. H. Antoine, F. Somers, B. Becker, S. Sebille, R. Ouedraogo, S. Counerotte, B. Pirotte, P. Lebrun, and P. de Tullio, J. Med. Chem., 2005, 48, 3492. CrossRef
3. P. de Tullio, B. Pirotte, L. Dupont, B. Masereel, D. Laeckmann, T. Podona, O. Diouf, P. Lebrun, and J. Delarge, Tetrahedron, 1995, 51, 3221. CrossRef
4. A. Jahangir and A. Terzic, J. Mol. Cell. Card., 2005, 39, 99. CrossRef
5. B. Pirotte, P. de Tullio, Q.-A. Nguyen, F. Somers, P. Fraikin, X. Florence, P. Wahl, J. B. Hansen, and P. Lebrun, J. Med. Chem., 2010, 53, 147. CrossRef
6. P. Lebrun, B. Becker, N. Morel, P. Ghisdal, M.-H. Antoine, P. de Tullio, and B. Pirotte, Biochem. Pharmacol., 2008, 75, 468. CrossRef
7. P. Francotte, P. de Tullio, T. Podona, O. Diouf, P. Fraikin, P. Lestage, L. Danober, J. Y. Thomas, D. H. Caignard, and B. Pirotte, Bioorg. Med. Chem., 2008, 16, 9948. CrossRef
8. A. Kamal, M. Naseer, A. Khan, K. S. Reddy, S. K. Ahmed, M. S. Kumar, A. Juvekar, S. Sen, and S. Zingde, Bioorg. Med. Chem. Lett., 2007, 17, 5345. CrossRef
9. a) X. Y. Liu, R. Z. Yan, N. G. Chen, and W. F. Xu, Chin. Chem. Lett., 2007, 18, 137; CrossRef b) X. Y. Liu, R. Z. Yan, N. G. Chen, W. F. Xu, M. T. Molina, and S. Vega, Molecules, 2006, 11, 827. CrossRef
10. H. N. Weller, A. V. Miller, R. V. Moquin, K. E. J. Dickinson, S. A. Hedberg, S. Moreland, R. B. Cohen, C. L. Delaney, S. Skwish, and S. Williams, Bioorg. Med. Chem. Lett., 1992, 2, 1115. CrossRef
11. A. Kamal, M. Naseer, A. Khan, K. S. Reddy, K. Rohini, G. N. Sastry, B. Sateesh, and B. Sridhar, Bioorg. Med. Chem. Lett., 2007, 17, 5400. CrossRef
12. F. E. Nielsen, S. Ebdrup, A. Frost Jensen, L. Ynddal, T. B. Bodvarsdottir, C. Stidsen, A. Worsaae, H. C. M. Boonen, P. O. G. Arkhammar, T. Fremming, P. Wahl, H. T. Kornǿ, and J. B. Hansen. J. Med. Chem., 2006, 49, 4127. CrossRef
13. P. de Tullio, B. Becker, S. Boverie, M. Dabrowski, P. Wahl, M. H. Antoine, F. Somers, S. Sebille, R. Ouedraogo, J. B. Hansen, P. Lebrun, and B. Pirotte, J. Med. Chem., 2003, 46, 3342. CrossRef
14. A. Maślankiewicz and L. Skrzypek, Heterocycles, 1994, 38, 1317. CrossRef
15. S.-O. Chua, M. J. Cook, and A. R. Katritzky, J. Chem. Soc., Perkin Trans. II, 1973, 546.
16. G. Albers-Schonberg, H. Joshua, M. B. Lopez, O. D. Hensens, J. P. Springer, J. Chen, S. Ostrove, C. H. Hoffman, A. W. Alberts, and A. A. Patchett, J. Antibiot., 1981, 34, 507. CrossRef
17. P. de Tullio, R. Ouedraogo, L. Dupont, F. Somers, S. Boverie, J. M. Dogne, J. Delarge, and B. Pirotte, Tetrahedron, 1999, 55, 5419. CrossRef
18. R. Pant, Hoppe Seylers’ Z. Physiol. Chem., 1964, 335, 272. CrossRef
19. J. Delarge, Ann. Pharm. Franç., 1973, 31, 467.
20. Oxford Diffraction (2006) CrysAlis CCD and CrysAlis RED. Versions 1.171.32.29. Oxford Diffraction Ltd, Wrocław, Poland.
21. G. M. Sheldrick, Acta Cryst., 2008, A 64, 112.