New substituted aryl esters and aryl amides of 3,4-dihydro-2 H -1,2,4-benzothiadiazine 1,1-dioxides as positive allosteric modulators of AMPA receptors

Gaëlle Dintilhac; Deniz Arslan; Sébastien Dilly; Laurence Danober; Iuliana Botez; Pierre Lestage; Bernard Pirotte; Pascal de Tullio

doi:10.1039/C1MD00069A

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DOI: 10.1039/C1MD00069A (Concise Article) Med. Chem. Commun., 2011, 2, 509-523

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New substituted aryl esters and aryl amides of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides as positive allosteric modulators of AMPA receptors

Gaëlle Dintilhac *^a, Deniz Arslan ^a, Sébastien Dilly ^a, Laurence Danober ^b, Iuliana Botez ^b, Pierre Lestage ^b, Bernard Pirotte† ^a and Pascal de Tullio† ^a
^aDrug Research Center, Laboratory of Medicinal Chemistry, University of Liège, Av. de l'hôpital, 1, 4000, Liège, Belgium. E-mail: G.Dintilhac@ulg.ac.be; Fax: +32 4 366 43 62; Tel: +32 4 366 43 68
^bInstitut de recherches Servier, 125, chemin de ronde, 78290, Croissy-sur-Seine, France

Received 3rd March 2011 , Accepted 3rd March 2011

First published on 24th March 2011

Abstract

AMPA receptor potentiators belonging to 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides have been found to be of great interest as cognitive enhancers. Previous structure–activity relationships have demonstrated the importance for activity of the nature of the substituent at the 7-position of the heterocycle. This work aims to explore the impact on AMPA potentiation of the introduction of different aryl and aralkyl ester or aryl amide groups at the 7-position. The new synthesized compounds were evaluated as AMPA receptor potentiators by examining their effect on rat brain primary cell cultures on AMPA-evoked membrane depolarisation using fluorescent membrane potential dyes and on imaging-based plate reader. The most potent compound of this series was 2-methylphenyl 4-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide 16c which provoked a strong potentiation of AMPA current with a potency close to that reported for the best reference compounds of the benzothiadiazine class (i.ecyclothiazide). This work also revealed that only the ortho-substitution of the phenyl group of 1,2,4-benzothiadiazine-7-carboxylate esters provided potent AMPA receptor potentiators opening the way to further chemical exploration.

Abbreviations

GABA	γ-aminobutyric acid
AMPA	α-amino-3-hydroxy-5-methylisoxazole-4-propionate
AMPApam	positive allosteric modulators of the AMPA receptors
CDI	1,1′-carbonyldiimidazole
DMF	N,N′-dimethylformamide
BOP	benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate
TLC	thin layer chromatography
DMSO	dimethylsufoxide
FDSS	functional drug screening system
ACN	acetonitrile
PBS	phosphate buffered saline
BBB	blood-brain barrier

1. Introduction

Glutamate is, with GABA and glycine, the main neurotransmitter belonging to the amino-acid family. Its activity, together with other transmitters, maintains an equilibrium between neuronal excitation and inhibition.

Two types of receptors are associated with glutamate and are located in the central nervous system : the ionotropic and the metabotropic receptors. The first class of receptors could be classified in three main subtypes according to their affinity for different exogenous agonists : the KA (kainate), the NMDA (N-methyl-D-aspartate) and the AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionate) receptors. Among these, the AMPA receptors are involved in several important biological processes such as the expression and the maintenance of long-term potentiation (LTP), the development of the central nervous system¹ (CNS), synaptic plasticity, learning and memory processes.^2,3 It has been proven that a disorder in the stimulation of these receptors could have negative consequences, as their excessive stimulation is linked to excitotoxicity⁴ and leads to several disorders such as epilepsy and neurogenerative disorders (i.e. : Huntington's and Alzheimer's diseases). On the contrary, a decrease of glutamate stimulation plays an important role in the cognition deficits. AMPA agonists have been proposed as possible therapeutic agents but they induce a marked excitotoxicity and remain simply as valuable pharmacological tools. Due to lower risk of toxicity in case of overdose, positive allosteric modulators of the AMPA receptors (AMPApams) have been developed.^5–7 This latter approach seems better than a direct stimulation since positive allosteric modulators need the presence of the endogenous neurotransmitter to be active and to amplify the AMPA signals. They are therefore less toxic than the agonists. Beside their great interest as cognitive enhancers, AMPA receptor potentiators could also be important candidates for the treatment of schizophrenia or depression.⁶ The most important family of AMPApams include the 1,2,4-benzothiadiazine 1,1-dioxides with compounds 1, 2 and 3 as reference drugs.^8,9 Among these drugs, cyclothiazide (1) and the other benzothiadiazines, such as IDRA-21 (3), have been shown to bind and to act differently on the AMPA receptors, suggesting mechanistic differences in this series.^10,11 Many synthetic developments have been made around this family leading to the discovery of very potent pyrido- and benzothiadiazine dioxides such as 4,¹²5,¹²6,¹³7 (S18986)¹⁴ and 8 (Fig. 1).¹⁵ These compounds are structurally characterised by a saturated thiadiazine ring substituted at the 4-position by a small alkyl group.^13,15,16 In the benzenic series, the 7-position seems to be critical for activity and several small groups have been introduced at this position but little has been done to enhance the steric hindrance (in this position). The present work aims at continuing the exploration of the impact on the AMPA receptor potentiation by the introduction of different aryl and aralkyl ester or aryl amide groups at the 7-position (with 9 as a general structure) while keeping a short alkyl chain at the 4-position like a methyl or an ethyl chain.


	Fig. 1 Chemical structure of some positive allosteric modulators of AMPA receptors (1–8) and the general structure of the newly synthetized 1,2,4-benzothiadiazine 1,1-dioxides.

2. Chemistry

The synthetic pathways used to prepare the different products in the 3,4-dihydro-2H-benzothiadiazine 1,1-dioxide series are described in Schemes 1, 2 and 3.


	Scheme 1 Reagents and conditions : (i) H₂SO₄ 50%, Δ; (ii) CH(OCH₂CH₃)₃, Δ; (iii) KMnO₄, water, Δ; (iv) appropriate phenol, CDI, DMF, Δ; (v) NaH, DMF, R⁴-I; (vi) NaBH₄, 2-propanol, Δ.


	Scheme 2 Reagents and conditions : (i) benzyl alcohol or phenethyl alcohol, CDI, DMF, Δ; (ii) K₂CO₃, DMF, CH₃CH₂I, Δ; (iii) NaBH₄, 2-propanol, Δ.


	Scheme 3 Reagents and conditions : (i) appropriate aniline, BOP, NaHCO₃, DMF; (ii) K₂CO₃, DMF, R⁴-I, Δ; (iii) NaBH₄, 2-propanol, Δ.

7-Methyl-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide 10 was submitted to ring opening in acidic conditions to give the corresponding aminobenzenesulfonamide 11. The latter reacted with triethyl orthoformate to give intermediate 12 by ring closure. Oxidation of the methyl group of 12 was then accomplished by action of KMnO₄. Esterification of compound 13 was achieved on the 7-carboxylic acid function by using the appropriate phenol in the presence of CDI. The resulting benzothiadiazines 14 were then alkylated at the 4-position by the appropriate alkyl iodide. The last step was the saturation of the double bond at the 2,3-positions. This was achieved by action of sodium borohydride leading to the final products 16 (Scheme 1).

For the synthesis of compounds bearing a benzyloxy- or phenethyloxycarbonyl group, esterification occurred on the carboxylic acid function 13 with the corresponding benzyl alcohol or phenethyl alcohol in the presence of CDI. The benzothiadiazines 17 were then alkylated by ethyl iodide in the presence of potassium carbonate. The reduction with sodium borohydride in 2-propanol gave the final products 19 (Scheme 2).

Concerning 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides substituted at the 7-position by a phenylaminocarbonyl group, the amide link was introduced starting from compound 13. The reaction was achieved by using BOP in presence of NaHCO₃. The expected products 20 were then alkylated with the appropriate alkyl iodide. Finally, compounds of general formula 21 were converted into their saturated counterparts by reduction with sodium borohydride (Scheme 3).

3. Pharmacology

The diversely 7-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides were tested as AMPA receptor potentiators. The functional assay consisted of examining the effect of the AMPA receptor potentiators on AMPA-evoked membrane depolarisation, measured by fluorescent membrane potential dyes and imaging based plate reader (FDSS), on rat brain primary cell cultures. Results are reported in Table 1, 2 and 3 and compared to the activity of compounds 1^8,9 and 4¹² used as reference.

Table 1 The effects of 7-phenoxycarbonyl-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides on AMPA-evoked membrane depolarisation, measured by fluorescence membrane potential dyes and an imaging-based plate reader (FDSS) on rat brain primary cell cultures


Cmpd	o	m	p	R⁴	EC_2X^a (μM)	EC₅₀^b (μM)	Max increase^c (%)
a Concentration of drug evoking a 2-fold increase of all AMPA-mediated responses (between 3–100 μM AMPA; mean ± SEM; n ≥ 2). b Concentration of compound evoking 50% of the maximal effect of the compound. c Maximum effect of the drug on the AMPA-evoked current (expressed in % of the current evoked by AMPA, taken as 100%). d nd : not determined. e Compound described in the ref.¹⁵ and tested as AMPA receptor potentiator using voltage-clamp recordings of AMPA-induced currents on XenopusOocytes.
16a	H	H	H	Me	3.66 ± 0.16	3.65 ± 0.34	550
16b ^e	H	H	H	Et	32.36 ± 1.15	nd^d	>670
16c	Me	H	H	Me	0.94 ± 0.15	1.72 ± 0.29	410
16d	Me	H	H	Et	3.48 ± 0.29	3.91 ± 0.59	330
16e	H	Me	H	Me	>100	nd^d	<200
16f	H	Me	H	Et	>100	nd^d	<200
16g	H	H	Me	Et	>100	nd^d	<200
16h	Et	H	H	Me	>100	nd^d	<200
16i	Et	H	H	Et	>100	nd^d	<200
16j	Pr	H	H	Et	>100	nd^d	<200
16k	H	H	Pr	Et	>100	nd^d	<200
16l	OMe	H	H	H	>100	nd^d	<200
16m	OMe	H	H	Me	6.40 ± 0.47	7.27 ± 2.30	410
16n	OMe	H	H	Et	10.63 ± 9.10	nd^d	380
16o	H	OMe	H	Et	>35	nd^d	200
16p	H	H	OMe	Et	>100	nd^d	<200
16q	OEt	H	H	Me	7.08 ± 1.99	nd^d	>360
16r	OEt	H	H	Et	21.57 ± 8.04	nd^d	>270
16s	OBz	H	H	Me	>100	nd^d	<200
16t	OBz	H	H	Et	>100	nd^d	<200
16u	H	OBz	H	Et	>100	nd^d	<200
1 ^e				H	1.7 ± 0.4	7.1 ± 0.7	844
4 ^e				Et	7.9 ± 2.2	22 ± 12	1478

Table 2 The effects of 7-benzyloxy or 7-phenethyloxycarbonyl-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides on AMPA-evoked membrane depolarisation, measured by fluorescence membrane potential dyes and an imaging-based plate reader (FDSS), on rat brain primary cell cultures


Cmpd	n	EC_2X^a (μM)	EC₅₀^b (μM)	Max increase^c (%)
a Concentration of drug evoking a 2-fold increase of all AMPA-mediated responses (between 3–100 μM AMPA; mean ± SEM; n ≥ 3). b Concentration of compound evoking 50% of the maximal effect of the compound. c Maximum effect of the drug on the AMPA-evoked current (expressed in % of the current evoked by AMPA, taken as 100%). d nd : not determined.
19a	1	>100	nd^d	<200
19b	2	>100	nd^d	<200

Table 3 The effects of 7-phenylaminocarbonyl-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides on AMPA-evoked membrane depolarisation, measured by fluorescence membrane potential dyes and an imaging-based plate reader (FDSS), on rat brain primary cell cultures


Cmpd	R⁴	R	EC_2X^a (μM)	EC₅₀^b (μM)	Max increase^c (%)
a Concentration of drug evoking a 2-fold increase of all AMPA-mediated responses (between 3–100 μM AMPA; mean ± SEM; n ≥ 2). b Concentration of compound evoking 50% of the maximal effect of the compound. c Maximum effect of the drug on the AMPA-evoked current (expressed in % of the current evoked by AMPA, taken as 100%). d nd : not determined.
22a	Me	H	>100	nd^d	<200
22b	Me	Me	>100	nd^d	<200
22c	Me	Et	>100	nd^d	<200
22d	Et	H	>100	nd^d	<200

4. Results and discussion

Contrary to previously described results demonstrating the weak activity of compounds substituted at the 7-position by a carboxylic group or its methyl ester or amide counterparts, the introduction of a phenoxycarbonyl group at the 7-position led to potent AMPA receptor potentiators (16a, 16c, 16d, 16m and 16q). These results are quite surprising because, in all the benzothiadiazine series that we developed around IDRA-21 structure, the presence of hindered groups on the benzenic or on the thiadiazine rings provoked a strong decrease of affinity for AMPA receptors.

The nature of the substituent at the 4-position also seemed to be important for activity. Indeed, in all series, 4-methyl derivatives were more potent than the 4-ethyl counterparts (compare 16a with 16b, 16c with 16d, 16m with 16n and 16q with 16r). These results were rather different to the results previously described^12,15 but underline the fact that the steric hindrance on the thiadiazine ring have a great influence on activity. However, the absence of a substituent in this position (16l) led to a drastic decrease in AMPA current potentiation.

The introduction of small electron donating groups (Me and OMe) in the ortho-, meta- and para-position of the phenyl group was realized in order to identify the best position for a putative substitution (Table 1).

Examination of the results obtained with methyl, methoxy or ethoxy groups demonstrated that only ortho substitution of 4-methyl-substituted compounds allowed the maintenance of a marked AMPA potentiation (16a, 16c, 16m and 16q).

Indeed, all meta or para substituted derivatives appeared to be less active or inactive in the chosen pharmacological model (16e, 16f, 16g, 16k, 16o, 16p and 16u).

Moreover, an increase of the size of the ortho (Et and Pr) substituent led also to a rapid loss of potency (16h, 16i, 16j, 16s and 16t).

These results highlight the negative impact of the steric hindrance on activity and confirm the very sensitive cut-off that links activity and substitution of the thiadiazine ring system in our series. The data underline also the poor steric latitude at some crucial positions of the thiadiazine ring or the phenyl ester group.

Concerning the maximum increase of the AMPA current observed with the most active compounds (see Table 1) it can be noticed that these derivatives seems to exhibit lower maximal effect than cyclothiazide and 4 but enhance both significantly and potently the current induced by AMPA.

Since the lead compounds are aryl esters expected to show some sensitivity to hydrolysis, it was important to appreciate their chemical stability in aqueous solution. Thus, a degradation experiment of compound (16a) was realized in aqueous medium under neutral (pH = 7.4) and acidic (pH = 1) conditions and monitored by HPLC. The results indicated no significant degradation of this product on both conditions even after 24 h at 25 °C.

Table 2, indicates that by separating the phenyl ring with one or two carbon atoms from the ester function at the 7-position, a complete loss of activity was observed (compare 19a and 19b with 16b).

Replacement of an ester function by an amide function also seemed to be unfavourable to activity, whether the nitrogen atom was or was not substituted (22a, 22b, 22c and 22d) (Table 3). These compounds were prepared with the aim of providing analogues of the active ester exhibiting a greater metabolic stability. This loss of activity could be due to the change of the conformation between the ester and the amide function including a change in the phenyl ring orientation.

By comparing our SAR data to those of cyclothiazide and its analogues on AMPA receptors, we can expect that our compounds are not able to occupy the same binding sites. Indeed, the absence of a hindered substituent at the 3-position and the absence of a hydrogen atom at the 4-position (which seem to be required for cyclothiazide activity and its binding to the GluR2 ligand-binding domain^10,11) prohibited the same interactions between our molecules and the iGluR2 subunits. So, in spite of an evident structural analogy, the SAR deduced from cyclothiazide analogues could not be applied to our derivatives. The new compounds show closer analogy to IDRA-21 suggesting a similar positioning in the binding pocket. However, because an aryl ester function appears to be required in order to maintain a high level of activity, the phenyl group probably enters into a specific hydrophobic pocket of restricted size and capacity. It is tempting to speculate that our molecules could probably have a binding mode between that of cyclothiazide and IDRA-21.

As AMPA receptors are located in the CNS, it seems important to evaluate the ability of our lead compounds to cross the blood-brain barrier (BBB). It is well described that some physicochemical properties such as acidity (pK_a) or lipophilicity (i.e. log P) constants greatly influence this penetration. As the 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide ring are known to exhibit estimated or measured pK_a values >9,¹⁶ it could be postulated that cyclothiazide, IDRA-21 and our compounds are poorly or not ionized at the physiological pH which is an important requirement for CNS drugs. Concerning lipophilicity, it is generally admitted that log P values between 2 and 4 are favourable to a BBB crossing. We have estimated the log P values of cyclothiazide, IDRA-21 and 16a, 16c and 16m using ClogP programme¹⁷ (Biobyte Corp. 201 W. Fourth Street, Suite ≠ 204 Claremont, CA 91711-4707; USA). Calculated log P value of cyclothiazide was found to be equal to 1.97 which is very close to the described measured value (lit. : 1.95).¹⁸ Despite of this value, cyclothiazide is reported to not readily cross the BBB.¹⁹IDRA-21 has the same calculated log P value than cyclothiazide (2.07) but is decribed to have in vivo effect in memory tests suggesting a penetration in the brain.²⁰ Compared to the references, our lead compounds (16a, 16c and 16m) show an interesting increase of lipophilicity value with an estimated log P value ≥3 (respectively 3.27, 3.77 and 2.94). Taking into account pK_a and calculated log P values we can postulate that our drugs could present physicochemical properties compatible with CNS required drug like profile.

5. Conclusions

A series of 7-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides were synthesised and evaluated as positive allosteric modulators of the AMPA receptors. The biological results obtained with the new molecules showed that the modulation of the nature of the substituent at the 7-position had a marked effect on in vitro activity. Among the new described products, compounds bearing a phenoxycarbonyl group at the 7-position, and more specifically a 2-methylphenoxycarbonyl group (compound 16c), appeared to possess a very interesting in vitro activity on the AMPA receptors. From a general point of view, it appears that the introduction of a methyl chain on the nitrogen atom at the 4-position is better for the activity than an ethyl chain. In the same way, the presence of a short alkyl or O-alkyl group at the ortho-position of the phenyloxycarbonyl group is also favorable for activity. The rank order of potency is as follows Me > OMe > OEt. If the same alkyl or O-alkyl group was bore on the meta or para-position, a decrease or a loss of activity was observed. The same observation was made when the benzene ring was separated from the carboxylic group by one or two carbon atoms. Finally, it appeared that the replacement of the ester group by an amido group at the 7-position conducted to a loss of activity. This work indicates that the introduction at the 7-position of bulky groups such as a phenoxycarbonyl group can provide very potent AMPA receptor potentiators even if modulation of the substitution on the phenyl ring seems to have a marked affect on the activity of the AMPA receptors. In particular, ortho-substitution of the ester aromatic ring appears to be quite interesting for the AMPA current modulation and opens new perspectives that could allow for the improvement of pharmacodynamic and pharmacokinetic parameters in this promising series.

This series of compounds could be placed between cyclothiazide and IDRA-21 in terms of structure but demonstrated that the presence of a hydrogen atom at the 4-position and a hindered group at the 3-position are not required to maintain an interesting activity. This opens new perspectives for the development of more bulky and probably more subunit selective AMPA receptor potentiators in the benzothiadiazine family.

6. Experimental protocols

6.1. Chemistry

Melting points were determined on a Stuart SMP3 capillary apparatus and are uncorrected. IR spectra were recorded as KBr pellets on a Perkin Elmer 1000 FTIR-spectrophotometer. The ¹H NMR spectra were taken on a Bruker Advance 500 (500 MHz) instrument in DMSO-d6 with TMS as an internal standard; chemical shifts are reported in δ values (ppm) relative to internal TMS. The abbreviation s = singlet, d = doublet, t = triplet, q = quadruplet, dd = doublet of doublet, td = triplet of doublet, m = multiplet, b = broad and Cq = quaternary carbon are used throughout. Elemental analyses (C, H, N, S) were realized on a FlashEA 1112 series (Thermo-Interscience) and where within ±0.4% of the theoretical values. All reactions were routinely checked by TLC on silica gel Merck 60F254.

2-Amino-5-methylbenzenesulfonamide (11). A solution of 7-methyl-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide (10, 10 g, 47,12 mmol) in sulfuric acid 50% (150 mL) was refluxed until complete dissolution of the suspension. At the end of the reaction, the solution was adjusted to pH 7 with an aqueous solution of concentrated NaOH. The solvent was removed by distillation under reduced pressure. The residue was triturated with methanol and the salts were eliminated by filtration. The filtrate was concentrated to dryness under reduced pressure and the residue was triturated in water (a minimum). The resulting precipitate was collected by filtration, washed with water and dried (6.58 g, 75%); mp 113–121 °C; (Found: C, 45.23; H, 5.40; N, 15.03; S, 17.30. Calc. for C₇H₁₀N₂O₂S: C, 45.14; H, 5.41; N, 15.04; S, 17.21%); ν/cm⁻¹ 3440, 3395, 3361, 3287, 1536, 1500, 1315, 1141; δ_H (500 MHz, DMSO-d₆, Me₄Si) 2.17 (s, 3H, CH₃), 5.63 (s, 2H, NH₂), 6.71 (d, 1H, J = 8.3 Hz, 3-H), 7.06 (dd, 1H, J = 1.8 Hz and 8.3 Hz, 4-H), 7.14 (s, 2H, SO₂NH₂), 7.35 (d, 1H, J = 1.8 Hz, 6-H).

7-Methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide (12). 2-Amino-5-methylbenzenesulfonamide (11, 6 g, 32,21 mmol) was heated in triethyl orthoformiate (30 mL) to reflux for 20 min. After cooling on an ice bath, the title compound was collected by filtration, washed with diethyl ether and dried (6 g, 95%); mp > 300 °C; (Found: C, 49.08; H, 4.14; N, 14.31; S, 16.19. Calc. for C₈H₈N₂O₂S: C, 48.97; H, 4.11; N, 14.28; S, 16.34%); δ_H (500 MHz, DMSO-d₆, Me₄Si) 2.38 (s, 3H, CH₃), 7.23 (d, 1H, J = 8.4 Hz, 5-H), 7.50 (dd, 1H, J = 1.4 Hz and 8.4 Hz, 6-H) 7.62 (d, 1H, J = 1.4 Hz, 8-H), 7.94 (s, 1H, CH [double bond, length as m-dash]

N), 12.19 (bs, 1H, 4-NH).

4H-1,2,4-Benzothiadiazine-7-carboxylic acid 1,1-dioxide (13). 7-Methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide (12, 3,9 g, 19,9 mmol) was heated at 70 °C in water (60 mL). A solution of NaOH 10% was added dropwise to the mixture until dissolution of the suspension. Potassium permanganate (11,7 g, 74,1 mmol) was added portionwise and the mixture was kept at 70 °C for 4 h. At the end of the reaction, the insoluble material was removed by filtration and the filtrate was treated with charcoal. After the elimination of charcoal, the solution was adjusted to pH 1 with concentrated HCl and the resulting precipitate was collected by filtration, washed with water and dried (1.89 g, 42%); mp > 300 °C; (Found: C, 42.06; H, 2.74; N, 12.18; S, 13.78. Calc. for C₈H₆N₂O₄S: C, 42.48; H, 2.67; N, 12.38; S, 14.17%); δ_H (500 MHz, DMSO-d₆, Me₄Si) 7.44 (d, 1H, J = 8.6 Hz, 5-H), 8.07 (s, 1H, CH [double bond, length as m-dash]

N), 8.18 (dd, 1H, J = 1.8 Hz and 8.6 Hz, 6-H) 8.25 (d, 1H, J = 1.8 Hz, 8-H), 12.61 (bs, 1H, 4-NH), 13.41 (bs, 1H, COOH).

General procedure for the synthesis of compounds 14 and 17. A mixture of 4H-1,2,4-benzothiadiazine-7-carboxylic acid 1,1-dioxide (13, 2,2 mmol), DMF (5 mL) and CDI (4,4 mmol) was heated at 60 °C for 2 h. The appropriate phenol or alcohol (3,33 mmol) was added and the solution was heated at 60 °C for 1 h. The solvent was removed by distillation under reduced pressure. The residue was treated with water (20 mL) and extracted 3-fold (3 × 20 mL) with ethyl acetate. The combined organic layers were dried over MgSO₄ and filtered. The filtrate was concentrated to dryness under reduced pressure and the residue of the title compound was recrystallized in methanol–water 1/3.

Phenyl 4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (14a). (0.28 g, 41%); mp 252–255 °C; δ_H (500 MHz, DMSO-d₆, Me₄Si) 7.33 (m, 3H, p-H and o-H), 7.49 (m, 2H, m–H), 7.53 (d, 1H, J = 8.5 Hz, 5-H), 8.12 (s, 1H, CHN), 8.35 (d, 1H, J = 8.5 Hz, 6-H), 8.45 (s, 1H, 8-H), 12.78 (bs, 1H, 4-NH).

2-Methylphenyl 4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (14b). (0.22 g, 31%); mp 199–204 °C; δ_H (500 MHz, DMSO-d₆, Me₄Si) 2.17 (s, 3H, 2′-CH₃), 7.27 (m, 4H, 3′-H, 4′-H, 5′-H and 6′-H), 7.54 (d, 1H, J = 8.9 Hz, 5-H), 8.11 (s, 1H, CHN), 8.38 (dd, 1H, J = 1.8 Hz and 8.9 Hz, 6-H), 8.46 (d, 1H, J = 1.8 Hz, 8-H), 12.65 (bs, 1H, 4-NH).

3-Methylphenyl 4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (14c). (0.23 g, 65%); mp 240–242 °C; δ_H (500 MHz, DMSO-d₆, Me₄Si) 2.35 (s, 3H, 3′-CH₃), 7.34 (m, 4H, 2′-H, 4′-H, 5′-H and 6′-H), 7.51 (d, 1H, J = 8 Hz, 5-H), 8.11 (s, 1H, CHN), 8.34 (dd, 1H, J = 1.7 Hz and 8 Hz, 6-H), 8.43 (d, 1H, J = 1.7 Hz, 8-H), 12.72 (bs, 1H, 4-NH).

4-Methylphenyl 4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (14d). (0.45 g, 64%); δ_H (500 MHz, DMSO-d₆, Me₄Si) 2.32 (s, 3H, 4′-CH₃), 7.20 (d, 2H, J = 9 Hz, 2′H and 6′H or 3′H and 5′H), 7.28 (d, 2H, J = 9 Hz, 2′H and 6′H or 3′H and 5′H), 7.52 (d, 1H, J = 8.7 Hz, 5-H), 8.12 (s, 1H, CHN), 8.35 (dd, 1H, J = 0.9 Hz and 8.7 Hz, 6-H), 8.43 (d, 1H, J = 0.9 Hz, 8-H), 12.76 (bs, 1H, 4-NH).

2-Ethylphenyl 4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (14e). (0.22 g, 20%); mp 161–165 °C; δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.13 (t, 3H, J = 7.5 Hz, 2′-CH₂CH₃), 2.54 (q, 2H, J = 7.5 Hz, 2′-CH₂CH₃), 7.28 (m, 3H, 3′-H or 6′-H, 4′-H and 5′-H), 7.38 (d, 1H, J = 6.9 Hz, 3′-H or 6′-H), 7.54 (d, 1H, J = 8.7 Hz, 5-H), 8.11 (s, 1H, CHN), 8.38 (dd, 1H, J = 1.9 Hz and 8.7 Hz, 6-H), 8.45 (d, 1H, J = 1.9 Hz, 8-H), 12.67 (bs, 1H, 4-NH).

2-Propylphenyl 4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (14f). (0.2 g, 26%); mp 203–205 °C; δ_H (500 MHz, DMSO-d₆, Me₄Si) 0.84 (t, 3H, J = 7.3 Hz, 2′-CH₂CH₂CH3), 1.55 (m, 2H, J = 7.3 Hz, 2′-CH₂CH₂CH₃), 2.51 (t, 2H, J = 7.3 Hz, 2′-CH₂CH₂CH₃), 7.31 (m, 4H, 3′-H, 4′-H, 5′-H and 6′-H), 7.54 (d, 1H, J = 8.5 Hz, 5-H), 8.10 (s, 1H, CHN), 8.36 (dd, 1H, J = 1.6 Hz and 8.5 Hz, 6-H), 8.44 (d, 1H, 8-H), 12.68 (bs, 1H, 4-NH).

4-Propylphenyl 4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (14g). (0.58 g, 71%); mp 219–221 °C; δ_H (500 MHz, DMSO-d₆, Me₄Si) 0.91 (t, 3H, J = 7.5 Hz, 4′-CH₂CH₂CH3), 1.62 (m, 2H, J = 7.5 Hz, 4′-CH₂CH₂CH₃), 2.59 (t, 2H, J = 7.5 Hz, 4′-CH₂CH₂CH₃), 7.22 (d, 2H, J = 8.2 Hz, 2′-H and 6′-H or 3′-H and 5′-H), 7.29 (d, 2H, J = 8.2 Hz, 2′-H and 6′-H or 3′-H and 5′-H), 7.52 (d, 1H, J = 8.8 Hz, 5-H), 8.11 (s, 1H, CHN), 8.34 (dd, 1H, J = 1.7 Hz and 8.8 Hz, 6-H), 8.43 (d, 1H, J = 1.7 Hz, 8-H), 12.68 (bs, 1H, 4-NH).

2-Methoxyphenyl 4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (14h). (0.51 g, 69%); δ_H (500 MHz, DMSO-d₆, Me₄Si) 3.77 (s, 3H, 2′-OCH₃), 7.03 (td, 1H, J = 1.1 Hz and 8.2 Hz, 4′-H or 5′-H), 7.20 (dd, 1H, J = 1.1 Hz and 8.2 Hz, 3′-H or 6′-H), 7.29 (td, 1H, J = 1.1 Hz and 8.2 Hz, 4′-H or 5′-H), 7.32 (dd, 1H, J = 1.1 Hz and 8.2 Hz, 3′-H or 6′-H), 7.53 (d, 1H, J = 8.7 Hz, 5-H), 8.12 (s, 1H, CHN), 8.34 (dd, 1H, J = 1.9 Hz and 8.7 Hz, 6-H), 8.42 (d, 1H, J = 1.9 Hz, 8-H), 12.71 (bs, 1H, 4-NH).

3-Methoxyphenyl 4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (14i). (1.12 g, 76%); mp 226–229 °C; δ_H (500 MHz, DMSO-d₆, Me₄Si) 3.79 (s, 3H, 3′-OCH₃), 6.91 (d, 2H, J 8.3 Hz, 4′-H and 6′-H), 6.97 (s, 1H, 2′-H), 7.38 (t, 1H, J = 8.3 Hz, 5′-H), 7.52 (d, 1H, J = 8.7 Hz, 5-H), 8.10 (s, 1H, CHN), 8.33 (dd, 1H, J = 1.5 Hz and 8.7 Hz, 6-H), 8.44 (d, 1H, J = 1.5 Hz, 8-H), 12.68 (bs, 1H, 4-NH).

4-Methoxyphenyl 4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (14j). (0.27 g, 36%); δ_H (500 MHz, DMSO-d₆, Me₄Si) 3.79 (s, 3H, 4′-OCH₃), 7.01 (d, 2H, J = 9 Hz, 2′-H and 6′-H or 3′-H and 5′-H), 7.26 (d, 2H, J = 9 Hz, 2′-H and 6′-H or 3′-H and 5′-H), 7.52 (d, 1H, J = 8.7 Hz, 5-H), 8.11 (s, 1H, CHN), 8.34 (dd, 1H, J = 1.6 Hz and 8.7 Hz, 6-H), 8.43 (d, 1H, J = 1.6 Hz, 8-H), 12.70 (bs, 1H, 4-NH).

2-Ethoxyphenyl 4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (14k). (0.92 g, 80%); mp 191–193 °C; δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.19 (t, 3H, J = 6.9 Hz, 2′-OCH₂CH₃), 4.05 (q, 2H, J = 6.9 Hz, 2′-OCH₂CH₃), 7.01 (t, 1H, J = 8 Hz, 4′-H or 5′-H), 7.18 (d, 1H, J = 8 Hz, 3′-H or 6′-H), 7.27 (d, 1H, J = 8 Hz, 3′-H or 6′-H), 7.29 (t, 1H, J = 8 Hz, 4′-H or 5′-H), 7.53 (d, 1H, J = 8.6 Hz, 5-H), 8.11 (s, 1H, CHN), 8.34 (dd, 1H, J = 1.7 Hz and 8.6 Hz, 6-H), 8.42 (d, 1H, J = 1.7 Hz, 8-H), 12.69 (bs, 1H, 4-NH).

2-Benzyloxyphenyl 4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (14l). (0.55 g, 60%); mp 206–210 °C; δ_H (500 MHz, DMSO-d₆, Me₄Si) 5.15 (s, 2H, OCH₂), 7.04 (t, 1H, J = 7.5 Hz, H-aromatic), 7.28 (m, 8H, H-aromatic), 7.51 (d, 1H, J = 8.7 hz, 5-H), 8.11 (s, 1H, CHN), 8.34 (dd, 1H, J = 1.8 Hz and 8.7 Hz, 6-H), 8.45 (d, 1H, J = 1.8 Hz, 8-H), 12.63 (bs, 1H, 4-NH).

3-Benzyloxyphenyl 4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (14m). (0.96 g, 53%); mp 146–150 °C; δ_H (500 MHz, DMSO-d₆, Me₄Si) 5.12 (s, 2H, OCH₂), 6.92 (d, 1H, J = 8.1 Hz, 4′-H or 6′-H), 6.98 (d, 1H, J = 8.1 Hz, 4′-H or 6′-H), 7.06 (s, 1H, 2′-H), 7.40 (m, 7H, 5-H, 5′-H and H-aromatic), 7.96 (s, 1H, CHN), 8.26 (dd, 1H, J = 1.7 Hz and 8.7 Hz, 6-H), 8.41 (d, 1H, J = 1.7 Hz, 8-H), 12.70 (bs, 1H, 4-NH).

Benzyl 4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (17a). (0.33 g, 53%); δ_H (500 MHz, DMSO-d₆, Me₄Si) 5.38 (s, 2H, OCH₂), 5.43 (m, 6H, 5-H and H-aromatic), 8.08 (s, 1H, CHN), 8.22 (dd, 1H, J = 1.9 Hz and 8.6 Hz, 6-H), 8.29 (d, 1H, J = 1.9 Hz, 8-H), 12.68 (bs, 1H, 4-NH).

Phenethyl 4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (17b). (0.26 g, 88%); δ_H (500 MHz, DMSO-d₆, Me₄Si) 3.06 (t, 2H, J = 6.8 Hz, OCH₂CH₂), 4.51 (t, 2H, J = 6.8 Hz, OCH₂CH₂), 7.28 (m, 5H, H-aromatic), 7.44 (d, 1H, J = 8.8 Hz, 5-H), 8.05 (s, 1H, CHN), 8.14 (dd, 1H, J = 1.9 Hz and 8.8 Hz, 6-H), 8.23 (d, 1H, J = 1.9 Hz, 8-H), 12.62 (bs, 1H, 4-NH).

General procedure for the synthesis of compounds 15. A mixture of the appropriate 7-substituted 4H-1,2,4-benzothiadiazine 1,1-dioxide (14, 2 mmol) and DMF (5 mL) was stirred at room temperature. Sodium hydride at 60% in dispersion in mineral oil (2,2 mmol) was added all at once and the solution was stirred at room temperature for 30 min. The appropriate alkyl iodide (10 mmol) was then added and the stirring was maintained for 2 h. Water was added to the solution and the resulting insoluble material was collected by filtration, washed with water and dried.

Phenyl 4-methyl-4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (15a). (0.36 g, 86%); δ_H (500 MHz, DMSO-d₆, Me₄Si) 3.69 (s, 3H, NCH₃), 7.34 (d, 2H, J = 7.9 Hz, 2′-H and 6′-H), 7.36 (t, 1H, J = 7.9 Hz, 4′-H), 7.50 (t, 2H, J = 7.9 Hz, 3′-H and 5′-H), 7.71 (d, 1H, J = 7.9 Hz, 5-H), 8.21 (s, 1H, CHN), 8.43 (dd, 1H, J = 1.6 Hz and 9 Hz, 6-H), 8.49 (d, 1H, J = 1.6 Hz, 8-H).

2-Methylphenyl 4-methyl-4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (15c). (0.15 g, 65%); δ_H (500 MHz, DMSO-d₆, Me₄Si) 2.18 (s, 3H, 2′-CH₃), 3.71 (s, 3H, NCH₃), 7.29 (m, 4H, 3′-H, 4′-H, 5′-H and 6′-H), 7.72 (d, 1H, J = 8.8 Hz, 5-H), 8.20 (s, 1H, CHN), 8.48 (dd, 1H, J = 2 Hz and 8.8 Hz, 6-H), 8.51 (d, 1H, J = 2 Hz, 8-H).

2-Methylphenyl 4-ethyl-4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (15d). (0.18 g, 82%); mp 208–214 °C; δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.36 (t, 3H, J = 7 Hz, NCH₂CH₃), 2.18 (s, 3H, 2′-CH₃), 4.23 (q, 2H, J = 7 Hz, NCH₂CH₃), 7.31 (m, 4H, 3′-H, 4′-H, 5′-H and 6′-H), 7.83 (d, 1H, J = 9.2 Hz, 5-H), 8.27 (s, 1H, CHN), 8.45 (dd, 1H, J = 1.9 Hz and 9.2 Hz, 6-H), 8.51 (d, 1H, J = 1.9 Hz, 8-H).

3-Methylphenyl 4-methyl-4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (15e). (0.19 g, 82%); mp 161–165 °C; δ_H (500 MHz, DMSO-d₆, Me₄Si) 2.39 (s, 3H, 3′-CH₃), 3.69 (s, 3H, NCH₃), 7.16 (m, 2H, 4′-H and 6′-H), 7.18 (s, 1H, 2′-H), 7.38 (t, 1H, J = 8.2 Hz, 5′-H), 7.71 (d, 1H, J = 8.8 Hz, 5-H), 8.20 (s, 1H, CHN), 8.42 (dd, 1H, J = 1.8 Hz and 8.8 Hz, 6-H), 8.48 (d, 1H, J = 1.8 Hz, 8-H).

3-Methylphenyl 4-ethyl-4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (15f). (0.3 g, 68%); mp 149–152 °C; δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.34 (t, 3H, J = 7.2 Hz, NCH₂CH₃), 2.37 (s, 3H, 3′-CH₃), 4.23 (q, 2H, J = 7.2 Hz, NCH₂CH₃), 7.39 (m, 4H, 3′-H, 4′-H, 5′-H and 6′-H), 7.81 (d, 1H, J = 8.9 Hz, 5-H), 8.28 (s, 1H, CHN), 8.41 (dd, 1H, J = 1.9 Hz and 8.9 Hz, 6-H), 8.49 (d, 1H, J = 1.9 Hz, 8-H).

4-Methylphenyl 4-ethyl-4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (15g). (0.23 g, 72%); δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.36 (t, 3H, J = 6.9 Hz, NCH₂CH₃), 2.35 (s, 3H, 4′-CH₃), 4.23 (q, 2H, J = 6.9 Hz, NCH₂CH₃), 7.25 (m, 4H, 3′-H, 4′-H, 5′-H and 6′-H), 7.81 (d, 1H, J = 8.9 Hz, 5-H), 8.26 (s, 1H, CHN), 8.40 (dd, 1H, J = 2 Hz and 8.9 Hz, 6-H), 8.48 (d, 1H, J 2 Hz, 8-H).

2-Ethylphenyl 4-methyl-4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (15h). (0.2 g, 85%); mp 165–169 °C; δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.13 (t, 3H, J = 7.8 Hz, 2′-CH₂CH₃), 2.55 (q, 2H, J = 7.8 Hz, 2′-CH₂CH₃), 3.71 (s, 3H, NCH₃), 7.34 (m, 4H, 3′-H, 4′-H, 5′-H and 6′-H), 7.73 (d, 1H, J = 8.7 Hz, 5-H), 8.21 (s, 1H, CHN), 8.47 (dd, 1H, J = 2 Hz and 8.7 Hz, 6-H), 8.49 (d, 1H, J = 2 Hz, 8-H).

2-Ethylphenyl 4-ethyl-4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (15i). (0.16 g, 66%); mp 89–94 °C; δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.13 (t, 3H, J = 7.7 Hz, 2′-CH₂CH₃), 1.36 (t, 3H, J = 6.9 Hz, NCH₂CH₃), 2.55 (q, 2H, J = 7.7 Hz, 2′-CH₂CH₃), 4.23 (q, J = 6.9 Hz, 2H, NCH₂CH₃), 7.34 (m, 4H, 3′-H, 4′-H, 5′-H and 6′-H), 7.83 (d, 1H, J = 8.8 Hz, 5-H), 8.27 (s, 1H, CHN), 8.44 (dd, 1H, J = 1.9 Hz and 8.8 Hz, 6-H), 8.50 (d, 1H, J = 1.9 Hz, 8-H).

2-Propylphenyl 4-ethyl-4H-1,2,4-benzothiadiazine 1,1-dioxide-7-carboxylate (15j). (0.17 g, 78%); δ_H (500 MHz, DMSO-d₆, Me₄Si) 0.85 (t, 3H, J = 7.2 Hz, 2′-CH₂CH₂CH3), 1.37 (t, 3H, J = 6.9 Hz, NCH₂CH₃), 1.56 (m, 2H, J = 7.2 Hz, 2′-CH₂CH₂CH₃), 2.52 (t, 2H, J = 7.2 Hz, 2′-CH₂CH₂CH₃), 4.24 (q, 2H, J = 6.9 Hz, NCH₂CH₃), 7.34 (m, 4H, 3′-H, 4′-H, 5′-H and 6′-H), 7.84 (d, 1H, J = 8.9 Hz, 5-H), 8.27 (s, 1H, CHN), 8.44 (dd, 1H, J = 1.8 Hz and 8.9 Hz, 6-H), 8.50 (d, 1H, 8-H).

4-Propylphenyl 4-ethyl-4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (15k). (0.16 g, 74%); mp 143–146 °C; δ_H (500 MHz, DMSO-d₆, Me₄Si) 0.92 (t, 3H, J = 7.3 Hz, 4′-CH₂CH₂CH3), 1.36 (t, 3H, J = 7 Hz, NCH₂CH3), 1.62 (m, 2H, J = 7.3 Hz, 4′-CH₂CH₂CH₃), 2.60 (t, 2H, J = 7.3 Hz, 4′-CH₂CH₂CH₃), 4.23 (q, 2H, J = 7 Hz, NCH₂CH₃), 7.24 (d, 2H, J = 8.2 Hz, 2′-H and 6′-H or 3′-H and 5′-H), 7.29 (d, 2H, J = 8.2 Hz, 2′-H and 6′-H or 3′-H and 5′-H), 7.81 (d, 1H, J = 9 Hz, 5-H), 8.26 (s, 1H, CHN), 8.40 (dd, 1H, J = 2 Hz and 9 Hz, 6-H), 8.48 (d, 1H, J = 2 Hz, 8-H).

2-Methoxyphenyl 4-methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide-7-carboxylate (15l). (0.09 g, 61%); δ_H (500 MHz, DMSO-d₆, Me₄Si) 3.70 (s, 3H, NCH₃), 3.77 (s, 3H, 2′-OCH₃), 7.03 (t, 1H, J = 7.7 Hz, 4′-H or 5′-H), 7.21 (d, J = 7.7 Hz, 1H, 3′-H or 6′-H), 7.31 (d, 1H, J = 7.7 Hz, 3′-H or 6′-H), 7.32 (t, 1H, J = 7.7 Hz, 4′-H or 5′-H), 7.71 (d, 1H, J = 8.9 Hz, 5-H), 8.21 (s, 1H, CHN), 8.42 (dd, 1H, J = 2 Hz and 8.9 Hz, 6-H), 8.46 (d, 1H, J = 2 Hz, 8-H).

2-Methoxyphenyl 4-ethyl-4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (15m). (0.18 g, 68%); mp 156–158 °C; δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.36 (t, 3H, J = 7 Hz, NCH₂CH3), 3.77 (s, 3H, 2′-OCH₃), 4.23 (q, 2H, J = 7 Hz, NCH₂CH₃), 7.03 (t, 1H, J = 7.7 Hz, 4′-H or 5′-H), 7.21 (d, 1H, J = 7.7 Hz, 3′-H or 6′-H), 7.30 (d, 1H, J = 7.7 Hz, 3′-H or 6′-H), 7.32 (t, 1H, J = 7.7 Hz, 4′-H or 5′-H), 7.82 (d, 1H, J = 8.9 Hz, 5-H), 8.27 (s, 1H, CHN), 8.40 (dd, 1H, J = 1.8 Hz and 8.9 Hz, 6-H), 8.47 (d, 1H, J = 1.8 Hz, 8-H).

3-Methoxyphenyl 4-ethyl-4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (15n). (0.24 g, 44%); mp 166–168 °C; δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.36 (t, 3H, J = 6.9 Hz, NCH₂CH3), 3.79 (s, 3H, 3′-OCH₃), 4.23 (q, 2H, J = 6.9 Hz, NCH₂CH₃), 6.91 (m, 2H, 4′-H and 6′-H), 6.98 (s, 1H, 2′-H), 7.38 (t, 1H, J = 8.5 Hz, 5′-H), 7.81 (d, 1H, J = 8.9 Hz, 5-H), 8.26 (s, 1H, CHN), 8.40 (dd, 1H, J = 2.1 Hz and 8.9 Hz, 6-H), 8.48 (d, 1H, J = 2.1 Hz, 8-H).

4-Methoxyphenyl 4-ethyl-4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (15o). (0.23 g, 84%). This compound was used without further purification in the next step of synthesis.

2-Ethoxyphenyl 4-methyl-4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (15p). (0.18 g, 88%); δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.18 (t, 3H, J = 6.7 Hz, 2′-OCH₂CH₃), 3.70 (s, 3H, NCH₃), 4.06 (q, 2H, J = 6.7 Hz, 2′-OCH₂CH₃), 7.01 (t, 1H, J = 7.9 Hz, 4′-H or 5′-H), 7.19 (d, 1H, J = 7.9 Hz, 3′-H or 6′-H), 7.29 (d, 1H, J = 7.9 Hz, 3′-H or 6′-H), 7.31 (t, 1H, J = 7.9 Hz, 4′-H or 5′-H), 7.71 (d, 1H, J = 8.9 Hz, 5-H), 8.20 (s, 1H, CHN), 8.42 (dd, 1H, J = 1.7 Hz and 8.9 Hz, 6-H), 8.47 (d, 1H, J = 1.7 Hz, 8-H).

2-Ethoxyphenyl 4-ethyl-4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (15q). (0.18 g, 73%); mp 161–164 °C; δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.18 (t, 3H, J = 7 Hz, 2′-OCH₂CH₃), 1.38 (t, 3H, J = 7.4 Hz, NCH₂CH₃), 4.06 (q, 2H, J = 7 Hz, 2′-OCH₂CH₃), 4.23 (q, 2H, J = 7.4 Hz, NCH₂CH₃), 7.01 (t, 1H, J = 7.7 Hz, 4′-H or 5′-H), 7.20 (d, 1H, J = 7.7 Hz, 3′-H or 6′-H), 7.30 (m, 2H, 3′-H or 6′-H and 4′-H or 5′-H), 7.81 (d, 1H, J = 8.9 Hz, 5-H), 8.27 (s, 1H, CHN), 8.40 (dd, 1H, J = 2 Hz and 8.9 Hz, 6-H), 8.49 (d, 1H, J = 2 Hz, 8-H).

2-Benzyloxyphenyl 4-methyl-4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (15r). (0.07 g, 34%). This compound was used without further purification in the next step of synthesis.

2-Benzyloxyphenyl 4-ethyl-4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (15s). (0.13 g, 48%); δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.36 (t, 3H, J = 7.1 Hz, NCH₂CH₃), 4.23 (q, 2H, J = 7.1 Hz, NCH₂CH₃), 5.16 (s, 2H, OCH₂), 7.05 (t, 1H, J = 7.5 Hz, H-aromatic), 7.27 (m, 8H, H-aromatic), 7.80 (d, 1H, J = 8.6 Hz, 5-H), 8.27 (s, 1H, CHN), 8.40 (dd, 1H, J = 2 Hz and 8.6 Hz, 6-H), 8.49 (d, 1H, J = 2 Hz, 8-H).

3-Benzyloxyphenyl 4-ethyl-4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (15t). (0.35 g, 81%); δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.38 (t, 3H, J = 7.1 Hz, NCH₂CH₃), 4.22 (q, 2H, J = 7.1 Hz, NCH₂CH₃), 5.14 (s, 2H, OCH₂), 6.94 (d, 1H, J = 8.6 Hz, H-aromatic), 7.01 (d, 1H, J = 8.2 Hz, H-aromatic), 7.08 (s, 1H, H-aromatic), 7.41 (m, 6H, H-aromatic), 7.82 (d, 1H, J = 9 Hz, 5-H), 8.27 (s, 1H, CHN), 8.41 (dd, 1H, J = 1.9 Hz and 9 Hz, 6-H), 8.49 (d, 1H, J = 1.9 Hz, 8-H).

General procedure for the synthesis of compounds 16, 19 and 22. A mixture of the appropriate 7-substituted 4-alkyl-4H-1,2,4-benzothiadiazine 1,1-dioxide (15, 18 and 21, 3 mmol) in 2-propanol (3 mL) was supplemented under stirring with sodium borohydride (6 mmol). After stirring at 30 °C for 10 min, the solvent was removed by distillation under reduced pressure and the residue was suspended in water. The alkaline suspension was adjusted to pH 7 with 0.1 N HCl and extracted 3-fold with methylene chloride (3 × 20 mL). The combined organic layers were dried over MgSO₄ and filtered. The filtrate was concentrated to dryness under reduced pressure and the residue of the title compound was recrystallized in methanol–water 1/3.

Phenyl 4-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (16a). (0.25 g, 71%); mp 171–174 °C; (Found: C, 56.56; H, 4.40; N, 8.94; S, 9.32. Calc. for C₁₅H₁₄N₂O₄S: C, 56.59; H, 4.43; N, 8.80; S, 10.07%); ν/cm⁻¹ 3443, 3208, 3361, 1731, 1609, 1524, 1394, 1244, 1148 cm⁻¹; δ_H (500 MHz, DMSO-d₆, Me₄Si) 3.08 (s, 3H, NCH₃), 4.79 (d, 2H, J = 8.1 Hz, 3-CH₂), 7.01 (d, 1H, J = 8.9 Hz, 5-H), 7.27 (d, 2H, J = 7.5 Hz, 2′-H and 6′-H), 7.32 (t, 1H, J = 7.5 Hz, 4′-H), 7.45 (t, 2H, J = 7.5 Hz, 3′-H and 5′-H), 8.07 (dd, 1H, J = 2.1 Hz and 8.9 Hz, 6-H), 8.19 (d, 1H, J = 2.1 Hz, 8-H), 8.29 (t, 1H, J = 8.1 Hz, 2-NH); δ_C (500 MHz, DMSO-d₆, Me₄Si) 36.22 (1C, NCH₃), 62.19 (1C, 3-CH₂), 113.58 (1C, 5-CH), 115.16 (1Cq), 121.63 (1Cq), 121.94 (2C, 2′-CH and 6′-CH or 3′-CH and 5′-CH), 125.81 (1C, 4′-CH), 126.17 (1C, 8-CH), 129.50 (2C, 2′-CH and 6′-CH or 3′-CH and 5′-CH), 134.29 (1C, 6-CH), 147.36 (1Cq), 150.63 (1Cq), 163.53 (1Cq).

2-Methylphenyl 4-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (16c). (0.11 g, 74%); mp 162–163 °C; (Found: C, 57.98; H, 5.06; N, 8.58 S, 9.91. Calc. for C₁₆H₁₆N₂O₄S: C, 57.82; H, 4.85; N, 8.43; S, 9.65%); ν/cm⁻¹ 3207, 2922, 1693, 1605, 1524, 1335, 1241, 1173 cm⁻¹; δ_H (500 MHz, DMSO-d₆, Me₄Si) 2.14 (s, 3H, 2′-CH₃), 3.07 (s, 3H, NCH₃), 4.83 (s, 2H, 3-CH₂), 7.01 (d, 1H, J = 8.9 Hz, 5-H), 7.18 (d, 1H, J = 7.6 Hz, 3′-H or 6′-H), 7.21 (t, 1H, J = 7.6 Hz, 4′-H or 5′-H), 7.28 (t, 1H, J = 7.6 Hz, 4′-H or 5′-H), 7.34 (d, 1H, J = 7.6 Hz, 3′-H or 6′-H), 8.09 (dd, 1H, J = 2.2 Hz and 8.9 Hz, 6-H), 8.20 (d, 1H, J = 2.2 Hz, 8-H), 8.28 (bs, 1H, 2-NH); δ_C (500 MHz, DMSO-d₆, Me₄Si) 15.67 (1C, 2′-CH₃), 36.23 (1C, NCH₃), 62.20 (1C, 3-CH₂), 113.63 (1C, 5-CH), 114.95 (1Cq), 121.69 (1Cq), 122.24 (1C, 3′-CH or 4′-CH or 5′-CH or 6′-CH), 125.98 (1C, 3′-CH or 4′-CH or 5′-CH or 6′-CH), 126.10 (1C, 8-CH), 127.00 (1C, 3′-CH or 4′-CH or 5′-CH or 6′-CH), 129.93 (1Cq), 130.93 (1C, 3′-CH or 4′-CH or 5′-CH or 6′-CH), 134.29 (1C, 6-CH), 147.37 (1Cq), 149.19 (1Cq), 163.22 (1Cq).

2-Methylphenyl 4-ethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (16d). (0.11 g, 75%); mp 136–140 °C; (Found: C, 59.00; H, 5.32; N, 8.18; S, 9.57. Calc. for C₁₇H₁₈N₂O₄S: C, 58.94; H, 5.24; N, 8.09; S, 9.25%); ν/cm⁻¹ 3290, 2972, 1726, 1604, 1519, 1337, 1220, 1162 cm⁻¹; δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.16 (t, 3H, J = 7 Hz, NCH₂CH₃), 2.18 (s, 3H, 2′-CH₃), 3.58 (q, 2H, J = 7 Hz, NCH₂CH₃), 4.82 (d, 2H, J = 7.7 Hz, 3-CH₂), 7.08 (d, 1H, J = 9 Hz, 5-H), 7.19 (d, 1H, J = 7.6 Hz, 3′-H or 6′-H), 7.22 (t, 1H, J = 7.6 Hz, 4′-H or 5′-H), 7.28 (t, 1H, J = 7.65 Hz, 4′-H or 5′-H), 7.36 (d, 1H, J = 7.6 Hz, 3′-H or 6′-H), 8.09 (dd, 1H, J = 2.2 Hz and 9 Hz, 6-H), 8.21 (d, 1H, J = 2.2 Hz, 8-H), 8.26 (d, 1H, J = 7.7 Hz, 2-NH); δ_C (500 MHz, DMSO-d₆, Me₄Si) 11.58 (1C, NCH₂CH₃), 15.72 (1C, 2′-CH₃), 43.25 (1C, NCH₂CH₃), 60.56 (1C, 3-CH₂), 113.43 (1C, 5-CH), 114.63 (1Cq), 121.52 (1Cq), 122.21 (1C, 3′-CH or 4′-CH or 5′-CH or 6′-CH), 125.97 (1C, 3′-CH or 4′-CH or 5′-CH or 6′-CH), 126.52 (1C, 8-CH), 127.00 (1C, 3′-CH or 4′-CH or 5′-CH or 6′-CH), 129.93 (1Cq), 130.94 (1C, 3′-CH or 4′-CH or 5′-CH or 6′-CH), 134.26 (1C, 6-CH), 146.24 (1Cq), 149.19 (1Cq), 163.18 (1Cq).

3-Methylphenyl 4-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (16e). (0.13 g, 85%); mp 152–154 °C; (Found: C, 58.03; H, 4.93; N, 8.45; S, 9.12. Calc. for C₁₆H₁₆N₂O₄S: C, 57.82; H, 4.85; N, 8.43; S, 9.65%); ν/cm⁻¹ 3238, 2923, 1731, 1609, 1525, 1297, 1234, 1142 cm⁻¹; δ_H (500 MHz, DMSO-d₆, Me₄Si) 2.34 (s, 3H, 3′-CH₃), 3.07 (s, 3H, NCH₃), 4.83 (s, 2H, 3-CH₂), 7.00 (d, 1H, J = 9 Hz, 5-H), 7.05 (d, 1H, J = 7.9 Hz, 4′-H or 6′-H), 7.09 (s, 1H, 2′-H), 7.11 (d, 1H, J = 7.9 Hz, 4′-H or 6′-H), 7.33 (t, 1H, J = 7.9 Hz, 5′-H), 8.06 (dd, 1H, J = 2.2 Hz and 9 Hz, 6-H), 8.18 (d, 1H, J = 2.2 Hz, 8-H), 8.29 (bs, 1H, 2-NH); δ_C (500 MHz, DMSO-d₆, Me₄Si) 20.90 (1C, 3′-CH₃), 36.20 (1C, NCH₃), 62.10 (1C, 3-CH₂), 113.57 (1C, 5-CH), 115.23 (1Cq), 118.99 (1C, 4′-CH or 6′-CH), 121.65 (1Cq), 122.42 (1C, 2′-CH), 126.13 (1C, 8-CH), 126.51 (1C, 4′-CH or 6′-CH), 129.22 (1C, 5′-CH), 134.31 (1C, 6-CH), 139.23 (1Cq), 147.30 (1Cq), 150.62 (1Cq), 163.61 (1Cq).

3-Methylphenyl 4-ethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (16f). (0.21 g, 86%); mp 147–150 °C; (Found: C, 59.07; H, 5.32; N, 8.27; S, 9.21. Calc. for C₁₇H₁₈N₂O₄S: C, 58.94; H, 5.24; N, 8.09; S, 9.25%); ν/cm⁻¹ 3254, 2975, 1716, 1607, 1523, 1334, 1230, 1162 cm⁻¹; δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.12 (t, 3H, J = 7 Hz, NCH₂CH₃), 2.36 (s, 3H, 3′-CH₃), 3.52 (q, 2H, J = 7 Hz, NCH₂CH₃), 4.83 (s, 2H, 3-CH₂), 7.06 (d, 1H, J = 9 Hz, 5-H), 7.12 (m, 3H, 2′-H, 4′-H and 6′-H), 7.35 (t, 1H, J = 7.8 Hz, 5′-H), 8.03 (dd, 1H, J = 2.1 Hz and 9 Hz, 6-H), 8.19 (d, 1H, J = 2.1 Hz, 8-H), 8.29 (bs, 1H, 2-NH); δ_C (500 MHz, DMSO-d₆, Me₄Si) 11.57 (1C, NCH₂CH₃), 20.77 (1C, 3′-CH₃), 43.24 (1C, NCH₂CH₃), 60.57 (1C, 3-CH₂), 113.37 (1C, 5-CH), 114.83 (1Cq), 118.91 (1C, 2′-CH or 4′-CH or 6′-CH), 121.54 (1Cq), 121.60 (1C, 2′-CH or 4′-CH or 6′-CH), 122.35 (1C, 5′-CH), 126.51 (1C, 8-CH), 129.17 (1C, 2′-CH or 4′-CH or 6′-CH), 134.22 (1C, 6-CH), 139.22 (1Cq), 146.19 (1Cq), 150.58 (1Cq), 163.53 (1Cq).

4-Methylphenyl 4-ethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (16g). (0.16 g, 71%); mp 176–180 °C; (Found: C, 58.84; H, 5.25; N, 8.30; S, 9.36. Calc. for C₁₇H₁₈N₂O₄S: C, 58.94; H, 5.24; N, 8.09; S, 9.25%); ν/cm⁻¹ 3181, 2980, 1733, 1609, 1521, 1296, 1180, 1159 cm⁻¹; δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.14 (t, 3H, J = 7.1 Hz, NCH₂CH₃), 2.31 (s, 3H, 4′-CH₃), 3.54 (q, 2H, J = 7.1 Hz, NCH₂CH₃), 4.88 (d, 2H, J = 8.2 Hz, 3-CH₂), 7.07 (d, 1H, J = 9.2 Hz, 5-H), 7.13 (d, 2H, J = 8.3 Hz, 2′-H and 6′-H or 3′H and 5′-H), 7.26 (d, 2H, J = 8.3 Hz, 2′-H and 6′-H or 3′-H and 5′-H), 8.02 (dd, 1H, J = 2 Hz and 9.2 Hz, 6-H), 8.19 (d, 1H, J = 2 Hz, 8-H), 8.29 (t, 1H, J = 8.2 Hz, 2-NH); δ_C (500 MHz, DMSO-d₆, Me₄Si) 11.60 (1C, NCH₂CH₃), 20.41 (1C, 4′-CH₃), 43.27 (1C, NCH₂CH₃), 60.55 (1C, 3-CH₂), 113.33 (1C, 5-CH), 114.86 (1Cq), 121.48 (1Cq), 121.60 (2C, 2′-CH and 6′-CH or 3′-CH and 5′-CH), 126.50 (1C, 8-CH), 129.81 (2C, 2′-CH and 6′-CH or 3′-CH and 5′-CH), 134.30 (1C, 6-CH), 134.95 (1Cq), 146.18 (1Cq), 148.42 (1Cq), 163.67 (1Cq).

2-Ethylphenyl 4-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (16h). (0.13 g, 85%); mp 208–210 °C; (Found: C, 58.83; H, 5.28; N, 8.14; S, 8.83. Calc. for C₁₇H₁₈N₂O₄S: C, 58.94; H, 5.24; N, 8.09; S, 9.25%); ν/cm⁻¹ 3289, 2945, 1715, 608, 1525, 1337, 1235, 1171 cm⁻¹; δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.12 (t, 3H, J = 7.6 Hz, 2′-CH₂CH₃), 2.51 (q, 2H, J = 7.6 Hz, 2′-CH₂CH₃), 3.07 (s, 3H, NCH₃), 4.83 (s, 2H, 3-CH₂), 7.01 (d, 1H, J = 9.2 Hz, 5-H), 7.18 (d, 1H, J = 7.2 Hz, 3′-H or 6′-H), 7.26 (m, 2H, 4′-H and 5′-H), 7.36 (d, 1H, J = 7.2 Hz, 3′-H or 6′-H), 8.09 (dd, 1H, J = 2.3 Hz and 9.2 Hz, 6-H), 8.20 (d, 1H, J = 2.3 Hz, 8-H), 8.28 (bs, 1H, 2-NH); δ_C (500 MHz, DMSO-d₆, Me₄Si) 14.26 (1C, 2′-CH₂CH₃), 22.77 (1C, 2′-CH₂CH₃), 36.19 (1C, NCH₃), 62.29 (1C, 3-CH₂), 113.73 (1C, 5-CH), 114.94 (1Cq), 121.69 (1Cq), 122.60 (1C, 3′-CH or 6′-CH), 126.07 (1C, 4′-CH or 5′-CH), 126.17 (1C, 8-CH), 126.98 (1C, 4′-CH or 5′-CH), 129.42 (1C, 3′-CH or 6′-CH), 134.29 (1C, 6-CH), 135.56 (1Cq), 147.36 (1Cq), 148.67 (1Cq), 163.51 (1Cq).

2-Ethylphenyl 4-ethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (16i). (0.07 g, 44%); mp 115–116 °C; (Found: C, 60.16; H, 5.65; N, 7.82; S, 9.08. Calc. for C₁₈H₂₀N₂O₄S: C, 59.98; H, 5.59; N, 7.77; S, 8.89%); ν/cm⁻¹ 3242, 2973, 1706, 1607, 1530, 1336, 1235, 1168 cm⁻¹; δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.12 (t, 3H, J = 7.4 Hz, 2′-CH₂CH₃), 1.16 (t, 3H, J = 7 Hz, NCH₂CH₃), 2.51 (q, 2H, J = 7.4 Hz, 2′-CH₂CH₃), 3.54 (q, 2H, J = 7 Hz, NCH₂CH₃), 4.84 (s, 2H, 3-CH₂), 7.07 (d, 1H, J = 9.1 Hz, 5-H), 7.18 (d, 1H, J = 7.5 Hz, 3′-H or 6′-H), 7.26 (m, 2H, 4′-H and 5′-H), 7.35 (d, 1H, J = 7.5 Hz, 3′-H or 6′-H), 8.06 (dd, 1H, J = 2.1 Hz and 9.1 Hz, 6-H), 8.20 (d, 1H, J = 2.1 Hz, 8-H), 8.23 (bs, 1H, 2-NH); δ_C (500 MHz, DMSO-d₆, Me₄Si) 11.60 (1C, NCH₂CH₃), 14.29 (1C, 2′-CH₂CH₃), 22.78 (1C, 2′-CH₂CH₃), 43.28 (1C, NCH₂CH₃), 60.56 (1C, 3-CH₂), 113.52 (1C, 5-CH), 114.66 (1Cq), 121.53 (1Cq), 122.61 (1C, 3′-CH or 6′-CH), 126.20 (1C, 4′-CH or 5′-CH), 126.50 (1C, 8-CH), 127.03 (1C, 4′-CH or 5′-CH), 129.49 (1C, 3′-CH or 6′-CH), 134.27 (1C, 6-CH), 135.64 (1Cq), 146.28 (1Cq), 148.73 (1Cq), 163.50 (1Cq).

2-Propylphenyl 4-ethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (16j). (0.09 g, 56%); mp 86–90 °C; (Found: C, 61.43; H, 6.07; N, 7.27; S, 7.90. Calc. for C₁₉H₂₂N₂O₄S: C, 61.83; H, 6.23; N, 7.21; S, 8.25%); ν/cm⁻¹ 3237, 2960, 1725, 1607, 1521, 1334, 1241, 1168 cm⁻¹; δ_H (500 MHz, DMSO-d₆, Me₄Si) 0.83 (t, 3H, J = 7.4 Hz, 2′-CH₂CH₂CH3), 1.17 (t, 3H, J = 6.9 Hz, NCH₂CH₃), 1.54 (m, 2H, j = 7.4 Hz, 2′-CH₂CH₂CH₃), 2.44 (t, 2H, J = 7.4 Hz, 2′-CH₂CH₂CH₃), 3.56 (q, 2H, J = 6.9 Hz, NCH₂CH₃), 4.87 (s, 2H, 3-CH₂), 7.08 (d, 1H, J = 9.2 Hz, 5-H), 7.19 (d, 1H, J = 7.4 Hz, 3′-H or 6′-H), 7.25 (t, 1H, J = 7.4 Hz, 4′-H or 5′-H), 7.29 (t, 1H, J = 7.4 Hz, 4′-H or 5′-H), 7.36 (d, 1H, J = 7.4 Hz, 3′-H or 6′-H), 8.07 (dd, 1H, J = 1.9 Hz and 9.2 Hz, 6-H), 8.21 (d, 1H, J = 1.9 Hz, 8-H), 8.23 (bs, 1H, 2-NH); δ_C (500 MHz, DMSO-d₆, Me₄Si) 11.58 (1C, NCH₂CH₃), 13.68 (1C, 2′-CH₂CH₂CH₃), 22.84 (1C, 2′-CH₂CH₂CH₃), 31.68 (1C, 2′-CH₂CH₂CH₃), 43.26 (1C, NCH₂CH₃), 60.56 (1C, 3-CH₂), 113.48 (1C, 5-CH), 114.62 (1Cq), 121.53 (1Cq), 122.67 (1C, 3′-CH or 6′-CH), 125.96 (1C, 4′-CH or 5′-CH), 126.42 (1C, 8-CH), 127.01 (1C, 4′-CH or 5′-CH), 130.24 (1C, 3′-CH or 6′-CH), 133.99 (1Cq), 134.18 (1C, 6-CH), 146.23 (1Cq), 148.801Cq), 163.44 (1Cq).

4-Propylphenyl 4-ethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (16k). (0.1 g, 62%); mp 146–148 °C; (Found: C, 60.66; H, 5.95; N, 7.71; S, 8.50. Calc. for C₁₉H₂₂N₂O₄S: C, 60.94; H, 5.92; N, 7.48; S, 8.56%); ν/cm⁻¹ 3235, 2954, 1705, 1607, 1515, 1337, 1243, 1167 cm⁻¹; δ_H (500 MHz, DMSO-d₆, Me₄Si) 0.91 (t, 3H, J = 7.5 Hz, 4′-CH₂CH₂CH3), 1.16 (t, 3H, J = 7.1 Hz, NCH₂CH₃), 1.61 (m, 2H, J = 7.5 Hz, 4′-CH₂CH₂CH₃), 2.58 (t, 2H, J = 7.5 Hz, 4′-CH₂CH₂CH₃), 3.54 (q, 2H, J = 7.1 Hz, NCH₂CH₃), 4.84 (d, 2H, J = 8.1 Hz, 3-CH₂), 7.06 (d, 1H, J = 9.1 Hz, 5-H), 7.15 (d, 2H, J = 8.4 Hz, 2′-H and 6′-H or 3′-H and 5′-H), 7.26 (d, 2H, J = 8.4 Hz, 2′-H and 6′-H or 3′-H and 5′-H), 8.03 (dd, J = 1.8 Hz and 9.1 Hz, 1H, 6-H), 8.18 (d, J = 1.8 Hz, 1H, 8-H), 8.24 (t, 1H, J = 8.1 Hz, 2-NH); δ_C (500 MHz, DMSO-d₆, Me₄Si) 11.55 (1C, NCH₂CH₃), 13.58 (1C, 4′-CH₂CH₂CH₃), 24.12 (1C, 4′-CH₂CH₂CH₃), 36.55 (1C, 4′-CH₂CH₂CH₃), 43.28 (1C, NCH₂CH₃), 60.54 (1C, 3-CH₂), 113.41 (1C, 5-CH), 114.87 (1Cq), 121.47 (1Cq), 121.59 (2C, 2′-CH and 6′-CH or 3′-CH and 5′-CH), 126.54 (1C, 8-CH), 129.21 (2C, 2′-CH and 6′-CH or 3′-CH and 5′-CH), 134.29 (1C, 6-CH), 139.68 (1Cq), 146.15 (1Cq), 148.56 (1Cq), 163.67 (1Cq).

2-Methoxyphenyl 3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (16l). (0.06 g, 54%); mp 122–123 °C; ν/cm⁻¹ 3338, 2926, 1714, 1606, 1524, 1326, 1294, 1164 cm⁻¹; δ_H (500 MHz, DMSO-d₆, Me₄Si) 3.75 (s, 3H, 2′-OCH₃), 4.74 (s, 2H, 3-CH₂), 6.91 (d, 2H, J = 8.9 Hz, 5-H), 6.99 (t, 1H, J = 7.6 Hz, 4′-H or 5′-H), 7.16 (d, 1H, J = 8.2 Hz, 3′-H or 6′-H), 7.20 (d, 1H, J = 7.6 Hz, 3′-H or 6′-H), 7.27 (t, 1H, J = 8.2 Hz, 4′-H or 5′-H), 7.89 (bs, 1H, 2-NH or 4-NH), 7.93 (dd, 1H, J = 1.8 Hz, and 8.9 Hz, 6-H), 8.11 (bs, 1H, 2-NH or 4-NH), 8.13 (d, 1H, J = 1.8 Hz, 8-H); δ_C (500 MHz, DMSO-d₆, Me₄Si) 54.28 (1C, 3-CH₂), 55.72 (1C, 2′-OCH₃), 112.79 (1C, 3′-CH or 6′-CH), 115.04 (1Cq), 115.86 (1C, 5-CH), 120.60 (2C, 4′-CH or 5′-CH), 123.08 (1C, 3′-CH or 6′-CH), 126.46 (1C, 8-CH), 126.97 (1C, 4′-CH or 5′-CH), 133.78 (1C, 6-CH), 139.37 (1Cq), 147.69 (1Cq), 151.03 (1Cq), 157.71 (1Cq), 163.09 (1Cq).

2-Methoxyphenyl 4-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (16m). (0.06 g, 67%); mp 147–149 °C; (Found: C, 55.34; H, 4.80; N, 7.82; S, 8.74. Calc. for C₁₆H₁₆N₂O₅S: C, 55.16; H, 4.63; N, 8.04; S, 9.20%); ν/cm⁻¹ 3298, 2923, 1710, 1607, 1526, 1335, 1236, 1154 cm⁻¹; δ_H (500 MHz, DMSO-d₆, Me₄Si) 3.07 (s, 3H, NCH₃), 3.75 (s, 3H, 2′-OCH₃), 4.83 (d, 2H, J = 8.2 Hz, 3-CH₂), 6.99 (d, 2H, J = 8.9 Hz, 5-H), 7.01 (t, 1H, J = 7.7 Hz, 4′-H or 5′-H), 7.17 (d, 1H, J = 7.7 Hz, 3′-H or 6′-H), 7.21 (d, 1H, J = 7.7 Hz, 3′-H or 6′-H), 7.28 (t, 1H, J = 7.7 Hz, 4′-H or 5′-H), 8.05 (dd, 1H, J = 1.9 Hz and 8.9 Hz, 6-H), 8.16 (d, 1H, J = 1.9 Hz, 8-H), 8.29 (t, 1H, J = 8.2 Hz, 2-NH); δ_C (500 MHz, DMSO-d₆, Me₄Si) 36.1 (1C, NCH₃), 55.70 (1C, 2′-OCH₃), 62.20 (1C, 3-CH₂), 112.80 (1C, 3′-CH or 6′-CH), 113.70 (1C, 5-CH), 115 (1Cq), 120.60 (2C, 4′-CH or 5′-CH), 121.60 (1Cq), 123 (1C, 3′-CH or 6′-CH), 126.20 (1C, 8-CH), 127 (1C, 4′-CH or 5′-CH), 134.40 (1C, 6-CH), 139.30 (1Cq), 147.30 (1Cq), 151 (1Cq), 163 (1Cq).

2-Methoxyphenyl 4-ethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (16n). (0.12 g, 82%); mp 184–186 °C; (Found: C, 56.28; H, 5.03; N, 7.97; S, 8.60. Calc. for C₁₇H₁₈N₂O₅S: C, 56.34; H, 5.01; N, 7.73; S, 8.85%); ν/cm⁻¹ 3225, 2979, 1708, 1608, 1501, 1333, 1241, 1170 cm⁻¹; δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.16 (t, 3H, J = 6.7 Hz, NCH₂CH₃), 3.54 (q, 2H, J = 6.7 Hz, NCH₂CH₃), 3.75 (s, 3H, 2′-OCH₃), 4.84 (d, 2H, J = 8 Hz, 3-CH₂), 7.00 (t, 1H, J = 7.8 Hz, 4′-H or 5′-H), 7.06 (d, 2H, J = 9.2 Hz, 5-H), 7.16 (d, 1H, J = 7.8 Hz, 3′-H or 6′-H), 7.20 (d, 1H, J = 7.8 Hz, 3′-H or 6′-H), 7.27 (t, 1H, J = 7.8 Hz, 4′-H or 5′-H), 8.02 (dd, 1H, J = 1.8 Hz and 9.2 Hz, 6-H), 8.17 (d, 1H, J = 1.8 Hz, 8-H), 8.23 (t, 1H, J = 8 Hz, 2-NH); δ_C (500 MHz, DMSO-d₆, Me₄Si) 11.60 (1C, NCH₂CH₃), 43.20 (1C, NCH₂CH₃), 55.80 (1C, 2′-OCH₃), 60.60 (1C, 3-CH₂), 112.79 (1C, 3′-CH or 6′-CH), 113.41 (1C, 5-CH), 114.53 (1Cq), 120.59 (1C, 4′-CH or 5′-CH), 121.49 (1Cq), 123.06 (1C, 3′-CH or 6′-CH), 126.54 (1C, 8-CH), 126.99 (1C, 4′-CH or 5′-CH), 134.34 (1C, 6-CH), 139.33 (1Cq), 146.18 (1Cq), 150.95 (1Cq), 162.96 (1Cq).

3-Methoxyphenyl 4-ethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (16o). (0.07 g, 34%); mp 73–98 °C; (Found: C, 56.35; H, 5.01; N, 8.07; S, 8.98. Calc. for C₁₇H₁₈N₂O₅S: C, 56.34; H, 5.01; N, 7.73; S, 8.85%); ν/cm⁻¹ 3229, 2982, 1727, 1606, 1518, 1335, 1229, 1144 cm⁻¹; δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.16 (t, 3H, J = 7 Hz, NCH₂CH₃), 3.54 (q, 2H, J = 7 Hz, NCH₂CH₃), 3.78 (s, 3H, 3′-OCH₃), 4.84 (d, 2H, J = 8.2 Hz, 3-CH₂), 6.83 (d, 2H, J = 8.5 Hz, 4′-H and 6′-H), 6.88 (s, 1H, 2′-H), 7.07 (d, 2H, J = 9.1 Hz, 5-H), 7.35 (t, 1H, J = 8.5 Hz, 5′-H), 8.03 (dd, 1H, J = 2 Hz and 9.1 Hz, 6-H), 8.19 (d, 1H, J = 2 Hz, 8-H), 8.24 (t, 1H, J = 8.2 Hz, 2-NH); δ_C (500 MHz, DMSO-d₆, Me₄Si) 11.60 (1C, NCH₂CH₃), 43.40 (1C, NCH₂CH₃), 55.50 (1C, 3′-OCH₃), 60.60 (1C, 3-CH₂), 108 (1C, 2′-CH), 111.80 (1C, 4′-CH or 6′-CH), 113.40 (1C, 5-CH), 114.20 (1C, 4′-CH or 6′-CH), 114.80 (1Cq), 121.50 (1Cq), 126.51 (1C, 8-CH), 129.86 (1C, 5′-CH), 134.29 (1C, 6-CH), 146.18 (1Cq), 151.62 (1Cq), 160.16 (1Cq), 163.39 (1Cq).

4-Methoxyphenyl 4-ethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (16p). (0.18 g, 90%); mp 187–189 °C; (Found: C, 56.55; H, 5.04; N, 8.08; S, 9.02. Calc. for C₁₇H₁₈N₂O₅S: C, 56.34; H, 5.01; N, 7.73; S, 8.85%); ν/cm⁻¹ 3225, 2976, 1718, 1606, 1519, 1339, 1236, 1193 cm⁻¹; δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.17 (t, 3H, J = 7 Hz, NCH₂CH₃), 3.54 (q, 2H, J = 7 Hz, NCH₂CH₃), 3.78 (s, 3H, 4′-OCH₃), 4.84 (d, 2H, J = 8.3 Hz, 3-CH₂), 6.99 (d, 2H, J = 8.5 Hz, 2′-H and 6′-H or 3′-H and 5′-H), 7.06 (d, 2H, J = 9.2 Hz, 5-H), 7.18 (d, 2H, J = 8.5 Hz, 2′-H and 6′-H or 3′-H and 5′-H), 8.03 (dd, 1H, J = 1.9 Hz and 9.2 Hz, 6-H), 8.18 (d, 1H, J = 1.9 Hz, 8-H), 8.23 (t, 1H, J = 8.3 Hz, 2-NH); δ_C (500 MHz, DMSO-d₆, Me₄Si) 11.63 (1C, NCH₂CH₃), 43.29 (1C, NCH₂CH₃), 55.48 (1C, 4′-OCH₃), 60.57 (1C, 3-CH₂), 113.36 (1C, 5-CH), 114.42 (2C, 2′-H and 6′-H or 3′-H and 5′-H), 114.92 (1Cq), 121.47 (1Cq), 122.75 (2C, 2′-H and 6′-H or 3′-H and 5′-H), 126.50 (1C, 8-CH), 134.27 (1C, 6-CH), 143.95 (1Cq), 146.19 (1Cq), 156.92 (1Cq), 163.86 (1Cq).

2-Ethoxyphenyl 4-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (16q). (0.12 g, 80%); mp 165–167 °C; (Found: C, 56.35; H, 5.03; N, 7.78; S, 8.50. Calc. for C₁₇H₁₈N₂O₅S: C, 56.34; H, 5.01; N, 7.73; S, 8.85%); ν/cm⁻¹ 3296, 2930, 1713, 1607, 1525, 1336, 1236, 1189 cm⁻¹; δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.18 (t, 3H, J = 6.9 Hz, 2′-OCH₂CH₃), 3.07 (s, 3H, NCH₃), 4.03 (q, 2H, J = 6.9 Hz, 2′-OCH₂CH₃), 4.83 (d, 2H, J = 8.2 Hz, 3-CH₂), 6.98 (t, 1H, J = 8.2 Hz, 4′-H or 5′-H), 6.99 (d, 1H, J = 8.8 Hz, 5-H), 7.15 (d, 1H, J = 8.2 Hz, 3′-H or 6′-H), 7.21 (d, 1H, J = 8.2 Hz, 3′-H or 6′-H), 7.25 (t, 1H, J = 8.2 Hz, 4′-H or 5′-H), 8.05 (dd, 1H, J = 2 Hz and 8.8 Hz, 6-H), 8.18 (d, 1H, J = 2 Hz, 8-H), 8.28 (t, 1H, J = 8.2 Hz, 2-NH); δ_C (500 MHz, DMSO-d₆, Me₄Si) 14.53 (1C, NCH₃), 36.25 (1C, 2′-OCH₂CH₃), 62.25 (1C, 3-CH₂), 63.90 (1C, 2′-OCH₂CH₃), 113.64 (1C, 5-CH), 114.01 (1C, 3′-CH or 6′-CH), 115.04 (1Cq), 120.66 (1C, 4′-CH or 5′-CH), 121.51 (1Cq), 122.98 (1C, 3′-CH or 6′-CH), 126.09 (1C, 8-CH), 126.88 (1C, 4′-CH or 5′-CH), 134.27 (1C, 6-CH), 139.82 (1Cq), 147.21 (1Cq), 150.26 (1Cq), 163.07 (1Cq).

2-Ethoxyphenyl 4-ethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (16r). (0.12 g, 80%); mp 211–212 °C; (Found: C, 57.27; H, 5.39; N, 7.41; S, 8.33. Calc. for C₁₈H₂₀N₂O₅S: C, 57.43; H, 5.36; N, 7.44; S, 8.52%); ν/cm⁻¹ 3223, 2979, 1711, 1607, 1544, 1333, 1245, 1167 cm⁻¹; δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.15 (t, 3H, J = 7 Hz, NCH₂CH₃), 1.19 (t, 3H, J = 6.8 Hz, 2′-OCH₂CH₃), 3.54 (q, 2H,J = 7 Hz, NCH₂CH₃), 4.03 (q, 2H, J = 6.8 Hz, 2′-OCH₂CH₃), 4.84 (d, 2H, J = 8.3 Hz, 3-CH₂), 6.99 (t, 1H, J = 7.8 Hz, 4′-H or 5′-H), 7.06 (d, 1H, J = 9 Hz, 5-H), 7.15 (d, 1H, J = 7.8 Hz, 3′-H or 6′-H), 7.21 (d, 1H, J = 7.8 Hz, 3′-H or 6′-H), 7.25 (t, 1H, J = 7.8 Hz, 4′-H or 5′-H), 8.02 (dd, 1H, J = 1.8 Hz and 9 Hz, 6-H), 8.18 (d, 1H, J = 1.8 Hz, 8-H), 8.22 (t, 1H, J = 8.3 Hz, 2-NH); δ_C (500 MHz, DMSO-d₆, Me₄Si) 11.63 (1C, 2′-OCH₂CH₃), 14.58 (1C, NCH₂CH₃), 43.27 (1C, NCH₂CH₃), 60.57 (1C, 3-CH₂), 64.04 (1C, 2′-OCH₂CH₃), 113.38 (1C, 5-CH), 114.02 (1C, 3′-CH or 6′-CH), 114.71 (1Cq), 120.61 (1C, 4′-CH or 5′-CH), 121.42 (1Cq), 122.98 (1C, 3′-CH or 6′-CH), 126.45 (1C, 8-CH), 126.86 (1C, 4′-CH or 5′-CH), 134.20 (1C, 6-CH), 139.82 (1Cq), 146.12 (1Cq), 150.23 (1Cq), 163.01 (1Cq).

2-Benzyloxyphenyl 4-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (16s). (0.02 g, 30%); mp 162–163 °C; (Found: C, 61.95; H, 5.00; N, 6.28; S, 7.11. Calc. for C₂₂H₂₀N₂O₅S: C, 62.25; H, 4.75; N, 6.60; S, 7.55%); ν/cm⁻¹ 3260, 2916, 1720, 1608, 1525, 1332, 1298, 1166 cm⁻¹; δ_H (500 MHz, DMSO-d₆, Me₄Si) 3.07 (s, 3H, NCH₃), 4.83 (d, 2H, J = 8.2 Hz, 3-CH₂), 5.14 (s, 2H, OCH₂), 6.98 (d, 2H, J = 9.7 Hz, 5-H), 7.02 (t, 1H, J = 7.2 Hz, 4′-H or 5′-H), 7.28 (m, 8H, H-aromatic), 8.06 (dd, 1H, J = 1.8 Hz and 9.7 Hz, 6-H), 8.20 (d, 1H, J = 1.8 Hz, 8-H), 8.28 (t, 1H, J = 8.2 Hz, 2-NH); δ_C (500 MHz, DMSO-d₆, Me₄Si) 36.21 (1C, NCH₃), 62.20 (1C, 3-CH₂), 69.70 (1C, OCH₂), 113.63 (1C, 5-CH), 114.49 (1C aromatic), 115.02 (1Cq), 121.04 (1C, 4′-CH or 5′-CH), 121.62 (1Cq), 123.11 (1C aromatic), 126.20 (1C, 8-CH), 126.89 (2C aromatic), 127.64 (1C aromatic), 128.28 (2C aromatic), 134.30 (1C, 6-CH), 136.80 (1Cq), 139.89 (1Cq), 147.24 (1Cq), 149.90 (1Cq), 163.10 (1Cq).

2-Benzyloxyphenyl 4-ethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (16t). (0.09 g, 74%); mp 76–77 °C; (Found: C, 62.60; H, 5.20; N, 6.28; S, 7.15. Calc. for C₂₃H₂₂N₂O₅S: C, 63.00; H, 5.06; N, 6.39; S, 7.31%); ν/cm⁻¹ 3228, 2933, 1727, 1607, 1521, 1333, 1298, 1166 cm⁻¹; δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.15 (t, 3H, J = 6.9 Hz, NCH₂CH₃), 3.53 (q, 2H, J = 6.9 Hz, NCH₂CH₃), 4.84 (s, 2H, 3-CH₂), 5.14 (s, 2H, OCH₂), 7.01 (t, 1H, J = 7.5 Hz, 4′-H or 5′-H), 7.05 (d, 2H, J = 9.2 Hz, 5-H), 7.28 (m, 8H, H-aromatic), 8.03 (dd, 1H, J = 1.8 Hz and 9.2 Hz, 6-H), 8.20 (d, 1H, J = 1.8 Hz, 8-H), 8.25 (bs, 1H, 2-NH); δ_C (500 MHz, DMSO-d₆, Me₄Si) 11.60 (1C, NCH₂CH₃), 43.26 (1C, NCH₂CH₃), 60.62 (1C, 3-CH₂), 69.66 (1C, OCH₂), 113.37 (1C, 5-CH), 114.46 (1C aromatic), 114.62 (1Cq), 121.11 (1C, 4′-CH or 5′-CH), 121.56 (1Cq), 123.10 (1C aromatic), 126.54 (1C, 8-CH), 126.91 (2C aromatic), 127.68 (1C aromatic), 128.29 (2C aromatic), 134.25 (1C, 6-CH), 136.80 (1Cq), 139.92 (1Cq), 146.17 (1Cq), 149.90 (1Cq), 163.11 (1Cq).

3-Benzyloxyphenyl 4-ethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (16u). (0.17 g, 48%); mp 159–163 °C; ν/cm⁻¹ 3225, 2929, 1718, 1610, 1526, 1316, 1238, 1138 cm⁻¹; δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.15 (t, 3H, J = 7.1 Hz, NCH₂CH₃), 3.52 (q, 2H, J = 7.1 Hz, NCH₂CH₃), 4.84 (s, 2H, 3-CH₂), 5.12 (s, 2H, OCH₂), 6.84 (d, 1H, J = 8.3 Hz, 4′-H or 6′-H), 6.95 (d, 1H, J = 8.3 Hz, 4′-H or 6′-H), 6.98 (s, 1H, 2′-H), 7.04 (d, 2H, j = 9.2 Hz, 5-H), 7.39 (m, 6H, 5′-H and H-aromatic), 8.02 (dd, 1H, J = 1.7 Hz and 9.2 Hz, 6-H), 8.17 (d, 1H, J = 1.7 Hz, 8-H), 8.28 (bs, 1H, 2-NH); δ_C (500 MHz, DMSO-d₆, Me₄Si) 11.54 (1C, NCH₂CH₃), 43.21 (1C, NCH₂CH₃), 60.73 (1C, 3-CH₂), 69.48 (1C, OCH₂), 108.77 (1C, 2′-CH), 112.46 (1C, 4′-CH or 6′-CH), 113.31 (1C, 5-CH), 114.39 (1C, 4′-CH or 6′-CH), 114.66 (1Cq), 121.63 (1Cq), 126.49 (1C, 8-CH), 127.76 (2C aromatic), 127.90 (1C aromatic), 128.44 (2C aromatic), 129.90 (1C aromatic), 134.22 (1C, 6-CH), 136.79 (1Cq), 146.24 (1Cq), 151.61 (1Cq), 159.23 (1Cq), 163.43 (1Cq).

Benzyl 4-ethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (19a). (0.13 g, 92%); mp 182–184 °C; (Found: C, 58.73; H, 5.35; N, 8.09; S, 9.32. calc. for C₁₇H₁₈N₂O₄S: C, 58.94; H, 5.24; N, 8.09; S, 9.25%); ν/cm⁻¹ 3228, 2978, 1699, 1609, 1514, 1333, 1241, 1168 cm⁻¹; δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.13 (t, 3H, 7.1 Hz, NCH₂CH₃), 3.50 (q, 2H, J = 7.1 Hz, NCH₂CH₃), 4.80 (d, 2H, J = 8.4 Hz, 3-CH₂), 5.31 (s, 2H, OCH₂), 7.00 (d, 1H, J = 9 Hz, 5-H), 7.35 (t, 1H, J = 7.2 Hz, 4′-H), 7.41 (t, 2H, J = 7.2 Hz, 3′-H and 5′-H), 7.45 (d, 2H, J = 7.2 Hz, 2′-H and 6′-H), 7.93 (dd, 1H, J = 2 Hz and 9 Hz, 6-H), 8.01 (d, 1H, J = 2 Hz, 8-H), 8.17 (t, 1H, J = 8.4 Hz, 2-NH); δ_C (500 MHz, DMSO-d₆, Me₄Si) 11.56 (1C, NCH₂CH₃), 43.19 (1C, NCH₂CH₃), 60.51 (1C, 3-CH₂), 65.88 (1C, OCH₂), 113.24 (1C, 5-CH), 115.59 (1Cq), 121.35 (1Cq), 125.86 (1C, 8-CH), 127.94 (2C aromatic), 128.08 (1C aromatic), 128.50 (2C aromatic), 133.82 (1C, 6-CH), 136.28 (1Cq), 145.81 (1Cq), 164.53 (1Cq).

Phenethyl 4-ethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (19b). (0.11 g, 56%); mp 95–97 °C; (Found: C, 59.98; H, 5.63; N, 7.85; S, 9.38. Calc. for C₁₈H₂₀N₂O₄S: C, 59.98; H, 5.59; N, 7.77; S, 8.89%); ν/cm⁻¹ 3296, 2975, 1708, 1604, 1515, 1340, 1237, 1167 cm⁻¹; δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.12 (t, 3H, J = 7 Hz, NCH₂CH₃), 3.02 (t, 2H, J = 6.7 Hz, OCH₂CH₂), 3.49 (q, 2H, J = 7 Hz, NCH₂CH₃), 4.43 (t, 2H, J = 6.7 Hz, OCH₂CH₂), 4.79 (s, 2H, 3-CH₂), 6.98 (d, 1H, J = 9.2 Hz, 5-H), 7.26 (m, 5H, H-aromatic), 7.84 (dd, 1H, J = 2 Hz and 9.2 Hz, 6-H), 8.02 (d, 1H, J = 2 Hz, 8-H), 8.15 (bs, 1H, 2-NH); δ_C (500 MHz, DMSO-d₆, Me₄Si) 11.59 (1C, NCH₂CH₃), 34.49 (1C, OCH₂CH₂), 43.20 (1C, NCH₂CH₃), 60.55 (1C, 3-CH₂), 64.93 (1C, OCH₂CH₂), 113.21 (1C, 5-CH), 115.81 (1Cq), 121.37 (1Cq), 125.82 (1C, 8-CH), 126.37 (1C aromatic), 128.36 (2C aromatic), 128.91 (2C aromatic), 133.64 (1C, 6-CH), 138.10 (1Cq), 145.71 (1Cq), 164.56 (1Cq).

N-Phenyl-4-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxamide 1,1-dioxide (22a). (0.08 g, 39%); mp 246–249 °C; (Found: C, 56.88; H, 4.74; N, 13.26; S, 10.29. Calc. for C₁₅H₁₅N₃O₃S: C, 56.77; H, 4.76; N, 13.24; S, 10.10%); ν/cm⁻¹ 3339, 3070, 1647, 1610, 1520, 1438, 1308, 1154 cm⁻¹; δ_H (500 MHz, DMSO-d₆, Me₄Si) 3.03 (s, 3H, NCH₃), 4.86 (d, 2H, J = 8.3 Hz, 3-CH₂), 6.95 (d, 1H, J = 9.1 Hz, 5-H), 7.08 (t, 1H, J = 7.5 Hz, 4′-H), 7.33 (t, 2H, J = 7.5 Hz, 3′-H and 5′-H), 7.78 (d, 2H, J = 7.5 Hz, 2′-H and 6′-H), 8.08 (dd, 1H, J = 1.8 Hz and 9.1 Hz, 6-H), 8.19 (t, 1H, J = 8.3 Hz 2-NH), 8.29 (d, 1H, J = 1.8 Hz, 8-H); δ_C (500 MHz, DMSO-d₆, Me₄Si) 36.18 (1C, NCH₃), 62.17 (1C, 3-CH₂), 113.19 (1C, 5-CH), 120.42 (2C, 2′-CH and 6′-CH), 121.27 (1Cq), 121.51 (1Cq), 125.86 (1C, 4′-CH), 124.04 (1C, 8-CH), 128.56 (2C, 3′-CH and 5′-CH), 132.78 (1C, 6-CH), 139.24 (1Cq), 145.93 (1Cq), 163.66 (1Cq).

N-Methyl-N-phenyl-4-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxamide 1,1-dioxide (22b). (0.04 g, 56%); mp 143–144 °C; (Found: C, 57.72; H, 5.15; N, 12.80; S, 9.43. Calc. for C₁₆H₁₇N₃O₃S: C, 57.99; H, 5.17; N, 12.68; S, 9.67%); ν/cm⁻¹ 3104, 2910, 1611, 1523, 1377, 1324, 1158 cm⁻¹; δ_H (500 MHz, DMSO-d₆, Me₄Si) 2.88 (s, 3H, NCH₃), 3.31 (s, 3H, 7-CONCH₃), 4.64 (d, 2H, J = 8.1 Hz, 3-CH₂), 6.60 (d, 1H, J = 9.2 Hz, 5-H), 7.19 (m, 4H, 2′-H, 4′-H, 6′-H and 6-H), 7.32 (t, 2H, J = 7.5 Hz, 3′-H and 5′-H), 7.48 (d, 1H, J = 2 Hz, 8-H), 8.07 (t, 1H, J = 8.1 Hz, 2-NH); δ_C (500 MHz, DMSO-d₆, Me₄Si) 35.98 (1C, NCH₃), 38.36 (1C, 7-CONCH₃), 62.04 (1C, 3-CH₂), 112.30 (1C, 5-CH), 121.23 (1Cq), 122.55 (1Cq), 125.46 (1C, 8-CH), 126.52 (1C, 4′-CH), 126.85 (2C, 2′-CH and 6′-CH), 129.36 (2C, 3′-CH and 5′-CH), 133.66 (1C, 6-CH), 144.44 (1Cq), 144.97 (1Cq), 167.72 (1Cq).

N-Ethyl-N-phenyl-4-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxamide 1,1-dioxide (22c). (0.03 g, 69%); mp 227–229 °C; (Found: C, 58.21; H, 5.49; N, 11.98; S, 9.35. Calc. for C₁₇H₁₉N₃O₃S: C, 59.11; H, 5.54; N, 12.16; S, 9.28%); ν/cm⁻¹ 3107, 2988, 1610, 1586, 1402, 1325, 1166 cm⁻¹; δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.08 (t, 3H, J = 7.1 Hz, 7-CONCH₂CH₃), 2.88 (s, 3H, NCH₃), 3.84 (q, 2H, J = 7.1 Hz, 7-CONCH₂CH₃), 4.64 (s, 2H, 3-CH₂), 6.57 (d, 1H, J = 9.2 Hz, 5-H), 7.16 (d, 2H, J = 8 Hz, 2′-H and 6′-H), 7.19 (dd, 1H, J = 2 Hz and 9.2 Hz, 6-H), 7.21 (t, 1H, J = 8 Hz, 4′-H), 7.33 (t, 2H, J = 8 Hz, 3′-H and 5′-H), 7.48 (d, 1H, J = 2 Hz, 8-H), 8.04 (bs, 1H, 2-NH); δ_C (500 MHz, DMSO-d₆, Me₄Si) 12.52 (1C, 7-CONCH₂CH₃), 35.95 (1C, NCH₃), 45.01 (1C, 7-CONCH₂CH₃), 62.03 (1C, 3-CH₂), 112.28 (1C, 5-CH), 121.19 (1Cq), 122.82 (1Cq), 125.47 (1C, 8-CH), 126.65 (1C, 4′-CH), 127.75 (2C, 2′-CH and 6′-CH), 129.37 (2C, 3′-CH and 5′-CH), 133.57 (1C, 6-CH), 143.15 (1Cq), 144.48 (1Cq), 167.31 (1Cq).

N-Phenyl-4-ethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxamide 1,1-dioxide (22d). (0.1 g, 69%); mp 231–233 °C; (Found: C, 58.05; H, 5.09; N, 12.72; S, 9.64. Calc. for C₁₆H₁₇N₃O₃S: C, 57.99; H, 5.17; N, 12.68; S, 9.67%); ν/cm⁻¹ 3388, 3173, 1649, 1608, 1509, 1331, 1258, 1166 cm⁻¹; δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.12 (t, 3H, J = 6.9 Hz, 7-CONCH₂CH₃), 3.56 (q, 2H, J = 6.9 Hz, 7-CONCH₂CH₃), 4.88 (s, 2H, 3-CH₂), 7.01 (d, 1H, J = 8.8 Hz, 5-H), 7.07 (t, 1H, J = 7.7 Hz, 4′-H), 7.33 (t, 2H, J = 7.7 Hz, 3′-H and 5′-H), 7.75 (d, 2H, J = 7.7 Hz, 2′-H and 6′-H), 8.03 (dd, 1H, J = 2.1 Hz and 8.8 Hz, 6-H), 8.1 (bs, 1H, 2-NH), 8.29 (d, 1H, J = 2.1 Hz, 8-H); δ_C (500 MHz, DMSO-d₆, Me₄Si) 11.66 (1C, NCH₂CH₃), 43.15 (1C, NCH₂CH₃), 60.48 (1C, 3-CH₂), 112.91 (1C, 5-CH), 120.35 (2C, 2′-CH and 6′-CH), 120.84 (1Cq), 121.33 (1Cq), 123.40 (1C, 4′-CH), 124.38 (1C, 8-CH), 128.53 (2C, 3′-CH and 5′-CH), 132.74 (1C, 6-CH), 139.27 (1Cq), 144.76 (1Cq), 163.68 (1Cq).

General procedure for the synthesis of compounds 18 and 21. A mixture of the appropriate 7-substituted 4H-1,2,4-benzothiadiazine 1,1-dioxide (17, 20, 7,6 mmol), potassium carbonate (15,2 mmol) and the appropriate alkyl iodide (38 mmol) in DMF (10 mL) was heated at 60 °C for 2 h. The solvent was removed by distillation under reduced pressure and the residue was suspended in water. The resulting insoluble material was collected by filtration, washed with water and dried.

Benzyl 4-ethyl-4H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide (18a). (0.14 g, 64%); mp 109–111 °C; δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.36 (t, 3H, J = 7.1 Hz, NCH₂CH₃), 4.24 (q, 2H, J = 7.1 Hz, NCH₂CH₃), 5.45 (s, 2H, OCH₂), 7.49 (m, 5H, H-aromatic), 7.72 (d, 1H, J = 8.9 Hz, 5-H), 8.04 (s, 1H, CHN), 8.26 (dd, 1H, 2.1 Hz, and 8.9 Hz, 6-H), 8.33 (d, 1H, J = 2.1 Hz, 8-H).

Phenethyl 4-ethyl-4H-1,2,4-benzothiadiazine 1,1-dioxide-7-carboxylate (18b). (0.19 g, 70%); δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.36 (t, 3H, J = 6.8 Hz, NCH₂CH₃), 3.07 (t, 2H, J = 6.2 Hz, OCH₂CH₂), 4.17 (q, 2H, J = 6.8 Hz, NCH₂CH₃), 4.51 (t, 2H, J = 6.2 Hz, OCH₂CH₂), 7.29 (m, 5H, H-aromatic), 7.73 (d, 1H, J = 9 Hz, 5-H), 8.20 (dd, 1H, J = 1.8 Hz and 9 Hz, 6-H), 8.21 (s, 1H, CHN), 8.29 (d, 1H, J = 1.8 Hz, 8-H).

N-Phenyl-4-methyl-4H-1,2,4-benzothiadiazine-7-carboxamide 1,1-dioxide (21a). (0.15 g, 47%); δ_H (500 MHz, DMSO-d₆, Me₄Si) 3.72 (s, 3H, NCH₃), 7.13 (t, 1H, J = 7.5 Hz, 4′-H), 7.36 (t, 2H, J = 7.5 Hz, 3′-H and 5′-H), 7.65 (d, 1H, J = 8.7 Hz, 5-H), 7.78 (d, 2H, J = 7.5 Hz, 2′-H and 6′-H), 8.15 (s, 1H, CHN), 8.36 (d, 1H, J = 8.7 Hz, 6-H), 8.58 (s, 1H, 8-H), 10.66 (s, 1H, 7-CONH).

N-Methyl-N-phenyl-4-methyl-4H-1,2,4-benzothiadiazine-7-carboxamide 1,1-dioxide (21b). (0.08 g, 50%); mp 262–264 °C; δ_H (500 MHz, DMSO-d₆, Me₄Si) 3.39 (s, 3H, NCH₃), 3.54 (s, 3H, 7-CONCH₃), 7.20 (t, 1H, J = 7.2 Hz, 4′-H), 7.25 (d, 2H, J = 7.2 Hz, 2′-H and 6′-H), 7.30 (t, 2H, J = 7.2 Hz, 3′-H and 5′-H), 7.33 (d, 1H, 9 Hz, 5-H), 7.60 (dd, 1H, J = 1.2 Hz and 9 Hz, 6-H), 7.73 (d, 1H, J = 1.2 Hz, 8-H), 8.02 (s, 1H, CHN).

N-Ethyl-N-phenyl-4-methyl-4H-1,2,4-benzothiadiazine-7-carboxamide 1,1-dioxide (21c). (0.06 g, 20%); mp 263–266 °C; δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.12 (t, 3H, J = 7.1 Hz, 7-CONCH₂CH₃), 3.54 (s, 3H, NCH₃), 3.88 (q, 2H, J = 7.1 Hz, 7-CONCH₂CH₃), 7.22 (m, 3H, H-aromatic), 7.31 (m, 3H, 5-H and H-aromatic), 7.59 (d, 1H, J = 8.7 Hz, 6-H), 8.02 (s, 1H, 8-H).

N-Phenyl-4-ethyl-4H-1,2,4-benzothiadiazine-7-carboxamide 1,1-dioxide (21d). (0.15 g, 45%); δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.35 (t, 3H, J = 6.7 Hz, NCH₂CH₃), 4.21 (q, 2H, j = 6.7 Hz, CONCH₂CH₃), 7.12 (t, 1H, 7.4 Hz, 4′-H), 7.37 (t, 2H, J = 7.4 Hz, 3′-H and 5′-H), 7.75 (d, 1H, J = 9 Hz, 5-H), 7.78 (d, 2H, J = 7.4 Hz, 2′-H and 6′-H), 8.21 (s, 1H, CHN), 8.35 (d, 1H, J = 9 Hz, 6-H), 8.59 (s, 1H, 8-H), 10.56 (s, 1H, 7-CONH).

General procedure for the synthesis of compounds 20. A mixture of 4H-1,2,4-benzothiadiazine-7-carboxylic acid 1,1-dioxide (13, 4,4 mmol), NaHCO₃ (22 mmol), BOP (4,4 mmol), the appropriate benzylamine (4,4 mmol) and DMF (10 mL) was stirred at room temperature over night. The suspension was supplemented with water (20 mL) and extracted 3-fold (3 × 20 mL) with ethyl acetate. The combined layers were dried over MgSO₄ and filtered. The filtrate was concentred to dryness under reduced pressure and the residue of the title compound was recrystallized in methanol–water 1/3.

N-Phenyl-4H-1,2,4-benzothiadiazine-7-carboxamide 1,1-dioxide (20a). (0.94 g, 35%); δ_H (500 MHz, DMSO-d₆, Me₄Si) 7.13 (t, 1H, J = 7.6 Hz, 4′-H), 7.37 (t, 2H, J = 7.6 Hz, 3′-H and 5′-H), 7.46 (d, 1H, J = 8.7 Hz, 5-H), 7.78 (d, 2H, J = 7.6 Hz, 2′-H and 6′-H), 8.07 (s, 1H, CHN), 8.26 (dd, 1H, J = 1.9 Hz and 8.7 Hz, 6-H), 8.54 (d, 1H, J = 1.9 Hz, 8-H), 10.49 (s, 1H, 7-CONH), 12.54 (bs, 1H, 4-NH).

N-Methyl-N-phenyl-4H-1,2,4-benzothiadiazine-7-carboxamide 1,1-dioxide (20b). (0.19 g, 13%); mp 230–236 °C; δ_H (500 MHz, DMSO-d₆, Me₄Si) 3.39 (s, 3H, 7-CONCH₃), 7.14 (d, 1H, J = 8.5 Hz, 5-H), 7.19 (t, 1H, J = 7.6 Hz, 4′-H), 7.23 (d, 2H, J = 7.6 Hz, 2′-H and 6′-H), 7.3 (t, 2H, J = 7.6 Hz, 3′-H and 5′-H), 7.51 (d, 1H, J = 8.5 Hz, 6-H), 7.65 (s, 1H, CHN), 7.94 (s, 1H, 8-H), 12.36 (bs, 1H, 4-NH).

N-Ethyl-N-phenyl-4H-1,2,4-benzothiadiazine-7-carboxamide 1,1-dioxide (20c). (0.5 g, 34%); mp 227–229 °C; δ_H (500 MHz, DMSO-d₆, Me₄Si) 1.11 (t, 3H, J = 7 Hz, 7-CONCH₂CH₃), 3.87 (q, 2H, J = 7 Hz, 7-CONCH₂CH₃), 7.11 (d, 1H, J = 8.6 Hz, 5-H), 7.21 (m, 3H, 2′-H, 4′-H and 6′-H), 7.30 (t, 2H, J = 7.7 Hz, 3′-H and 5′-H), 7.49 (d, 1H, J = 8.6 Hz, 6-H), 7.65 (s, 1H, 8-H), 7.93 (s, 1H, CHN), 12.31 (bs, 1H, 4-NH).

6.2. Biological assay

Effects of the compounds on the AMPA-evoked membrane depolarisation of brain cells. Rat brain cell cultures were prepared from embryonic rat (E17) and were added to poly-D-lysine coated 384-well culture plates for 18 days at 37 °C/5% CO₂ (density 20 000 cells/well). On the day of the experiment, ground media was removed from the cells and was replaced by 20 μL/well of membrane potential dye loading solution (Molecular devices), reconstituted according to the manufacturer's instructions. Plates were incubated for 1 h at room temperature and then directly transferred to the FDSS (fluorescence imaging based plate reader). Baseline fluorescence was monitored for 10 s followed by the addition of AMPA (3–100 μM) for 3 min and then the compound in presence of AMPA for 3 min. Subsequent monitoring of fluorescence changes was performed during these two periods of 3 min. Responses were averaged over the last 15 s of each 3 min-recording period. AMPA concentration-response curves were calculated in absence or presence of different concentrations of the compound. Results were expressed as the area under the curve of AMPA-mediated concentration-response effect in absence or presence of compound. The activities of our compounds were expressed as the EC_2X value which is the concentration of drug evoking a 2-fold increase of all AMPA-mediated responses (between 3–100 μM AMPA). EC₅₀ corresponds to the concentration of compound that evoked 50% of the maximal effect of the compound. Max increase is an arithmetic average which expresses the maximum effect to the drug on the AMPA-evoked current (expressed in the % of the current evoked by AMPA, taken 100%). This value is obtained at the last dose tested.

6.3. Stability assay

The LC separations were carried out on an Agilent 1100 series LC system from Agilent (Waldbronn, Germany) equipped with a quaternary pump, a column thermostat, on autosampler, and a diode array detector. The analyte separations were performed on an Alltech Hypersil BDS C18 column (150 × 4.6 mm, i.d.; particule size = 3 μm) from Alltech (Breda, The Netherlands) using mobile phase A : 90% water and mobile phase B : 10% ACN with a flow rate of 0.8 ml min⁻¹ and the following linear gradient : 0 min, 10% ACN; 24 min, 60% ACN; 27 min, 80% ACN and 32 min, 10% ACN. The column temperature was set to 30 °C.

Stability solution : 99 ml of PBS were added with 1 ml of a solution 1 mM of tested compound in ACN. This solution is incubated at 25 °C and analysed by the method described above at different times from 0 h to 24 h.

Acknowledgements

This study was supported in part by a grant from Servier and the National Fund for Scientific Research (F.N.R.S., Belgium) from which Pascal de Tullio is a Senior Research associate. The technical assistance of Yvette Abrassart and Stéphane Counerotte is gratefully acknowledged.

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Footnote

† Co-supervisors