CA2130095A1 - 2h-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylic acid derivatives used for preparing therapeutic compounds; new products obtained; process for preparing them and therapeutic agents containing the same - Google Patents

Abstract

2130095 9321171 Application of 2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylic acid derivatives of formula (I), a salt of such a compound or a precursor of such a compound to the preparation of NMDA receptor and / or AMPA receptor antagonist drugs, the new compounds of formula (I), their preparation and the drugs containing them.

Description

WO 93/21171 P ~ JFR93 / 00361 21 ~ 00 ~ q ~:.
'"

APPLICATION OF 2H 1,2,4-BENZOT ACID DERIVATIVES ~ IADIAZINE ~ DIOXIDE-3-CARBOXY-LINK TO THE PREPARATION OF ANTAGONIST DRUGS OF NMDAtAMpA ~ RECEPTORS
AS WELL AS NEW PRODUCTS, THEIR PREPARATION AND THE MEDICINES CONTAINING THEM

The present invention relates to the application of 2H- acid derivatives:
1,2,4-benzothiadiazine ~ 3-dioxide-carboxylic of formula:

R2 o ~, O. ''.

R4 ~ N ~ iJ R ~

a salt of such a compound or a precursor of such a compound in the preparation drug antagonists of the NMDA receptor eVou of the AMPA receptor,.
the new compounds of formula (I ~, their preparation and the drugs;
containing them. ~ ~.
-In the formula (1 ~
- R1 represents a carboxy, alkoxy ~ arbonyl, tetrazolyl, -CO-NH2 radical, -CO-NH-alk, -CO-N (alk) ~, -CO-NI IOH, - (: ~ ON (alk) OH, -CO-NH-O-Rs, : 15 -CO-N (alk) -ORs or a group convertible into a carboxy radical in vivo, . "
. ., :: ~ - R2j R3 and R4, identical or different ~ represent a hydrogen atom ~: ~ or halogen or an alkyl radical, - ~
: ~: - Rs represents an alkyl or phenylalkyl radical and ,.
,. ~
alk represents an alkylene or alkyl radical.
: :: 20 ~ lt is understood that the components of ~ vrmule (I) can also be:
find in their tautomeric form:
R
: ~ 12 ~ `S ~ ~"
R3 ~ ~, ~

~, ''''' - '~': ' WO 93/21171 PClr / FR93 / 00361 `

- 2 As groups convertible into a carboxy radical in vivo, mention may be made the radicals -C0-R6 in the ~ uel R6 represents a radical -0-alk-R7, - O-alk-OC O-alk, -O-alk-OC OO alk, -O-alk-OC OR 7, -C) -alk-O H,; ~
- O-alk-C) -alk, -O-alk-S-alk, -O-alk-OR 7, -0-alk-SR 7 -O-alk-C C3 OH, S - O-alk-C OO alk, -O-alk-N R 8 R 9, -N H-alk-OC O-alk, -N ~ l-alk- OC OO alk, -NH-alk-O-CO-R7, -NH-alk-OH, -NH-alk-O-alk, -Nl i-alk-S-alk, -Nl 1-alk-O-R7,; .
-NH-alk-S-R7, -NH-alk-COOH, -NH-alk-COOalk, -NH-alk-NRgP ~ g. ~ ,, In these definitions, alk represents an alkyl or alkyl radical, R
is a radi ~ ai phenyle, P ~ 8 and Rg, identical or different, represent a 10 hydrogen atom or an alkyl, phenyl or phenylalkyl radical or else form with the atom of æote to which they are attached a piperidino eycle,; ~
morpholino or pyrrolidino. -The halogen atoms are the chlorine, bromine, fluorine and iodine.
1 ~ In the definitions which pre ~ edent and those which will be cited below,; -sau ~ corltrary mention, the radicals alkyl, alkoxy and alkylbne and the portions alkyl, alkoxy and aïkyîbne contain 1 has 6 atoms of carbon in chain droi ~ e or rami ~ iée and pr ~ feren ~, ie 1 to 4 carbon atoms.
; ~ ~ The compounds of formula (I) for which either R ~, R3 and R
represent a hydrogen atom and R1 represents a radical c ~ rboxy, alkoxycarbonyl, -C0-NH ~ or -C0-NH-alk; either R4 represents an atom of chlorine or bromine, R2 and R3 ~ represent a hydrogen atom ~ ne and P ~
~ represents a carboxy radical ~, alkoxycarbQnyle, -CO-NH2 or - ~ 0-N! I-alk, either R3 represents; a ~; chlorine or bromine atom ~, R2 and R4 represent a ~ hydrogen atom and; R ~ represents ~ a carboxy, alkoxycarbonyl radical, GO-NH2 or -C0-NH-alk have already been described as diur ~ ticks ~ F ~ ussian Pharmàcol .; and Toxico!., 40, 19-23 (1977 ~; Farm. Zh. (Kiev ~, 2, 62 (1983);
Chem. Abst., 99, 38439g (1983)).
The other Gomposés of formula (i), the salts of these cornposes ~ u IB5 prec ~ rseurs of these compounds are no ~ Jveaux and 0n as such are partia ~ -of the invention. These are the compounds of 10rmule (i) for which: ~ ~

- ~ ~

:,.
:

WO 93/21171 ~ ~ 3 ~ o ~; ~ PCI / FR93 / 003fil

3 ' - R1 represents a carboxy, aicoxycarbonyl, tetrazolyl, -CO-NH2 radical, -CO-NH-alk, -CO-N (alk) 2 -CO-NHOH, -CO-N (alk) OH, -CO-NH-O-Rs, ~
-CO-N (alk) -ORs or -CO-R6 in the ~ uel R6 represents a radical -0-alk-R7 i:.
-O-alk-O-CO-alk, -O-alk-OC: OOalk, -O-alk-O-CO-R7, -O-alk-OH, 5 -O-alk-O-alk, -O-alk-S-alk, -O-alk-O-R7, -0-alk-S-R7, -O-alk-COOH, -O-alk-COOalk, -O-alk-NRgRg, -NH-alk-O-CO-alk, -NH-alk-O-COOalk,: ~:
-NH-alk-Q-CO-R7, -NH-alk-C) H, -NH-alk-O-alk, -Nl l-alk-S-alk, -NH-alk-O-R7,: ^ :
-NH-alk-S-R7, -NH-alk-COOH, -NH-alk-COC) alk, -NH-alk-NRgRg, ~,., ', - R2, R3 and R4, identical or different, each represents an atom of hydrogen or halogen or an alkyl radical,.
- Rs represents an alkyl or phenylalkyl radical, i - R7 represents a phenyl radical, ~:.
- R8 and Rg, identical or different, each represents an atom of hydrogen or an alkyl radical, ~ phenyl or phenylalkyl or else form : ~ ~ 15 with the nitrogen atom ~ which they are attached to a piperidino, morpholino cycle `or pyrrolidinog alk represents an alkylene or alkyl radical, except: ~ compounds for lesqL ~ els that is R2, P ~ 3 and R4 represent a atom ~ of hydrogen and R1 represents a carboxy, alkoxycarbonyl radical, 20 -G (: - NH2 or -GO-NH-alk; ~ either R4 represents ~ nte a chlorine atom or bromej ~ R ~ and R3 ~ represent a hydrQgbne atorne and R1 represents a radlcal carboxy, alkoxycarbonyl,: -CO-NH2 ~ or -CO-NH-alk; either R3 represents: a ~ chlorine or bromine atom, R2 and R4 represent a atom ~ of hydrogen ~ and R; 1 represents a carboxy radical, alkoxyc ~ rbonyl, : ~ ~ 25 -CO-NH2 or -CO-NH ^ alk. ::

drugs containing at least one new compound of ormule (lj, a s01 of a compound tet ~ or a pre ~ urseur dlun such compound 70nt also part of: the invention.
The new compounds of formula (i) for which ~ 1 represents 30 a: radica! carboxy can be ~ prepared by hydrolysis of compos0s d ~
. ~,.

WO 93/21171 PCI / FR93 ~ 00361 2 ~ `4 forrnute (I) correspondents for which R1 represents a radical alkoxycarbonyl.
This hydrolysis is generally carried out by means of a base such than an alkali metal hydroxide (soda, potash, lithium hydroxide by 5 example), in an inert solvanf such as an alcohol or a mixture of water-alcohol, water-tetrahydrofuran, e ~ u-dioxane, at a temperature included between 20 and 10QC or by means of potassium trimethylsilanolate, within of an inert sotvant ~ el that tetrahydrofuran, dioxane, dichloromethane, ~ a temperature close to 20C.
The new compounds of tormule (I) for which R ~ r ~ presents an alkoxycarbonyl radical can be prepared by cyclization ~ 'a derivative ~
from ~ ormule::
R
: ~ 12 ~ 3 ~ r S2NH2 (II) R4 ~ NH - CO-COORlo in which R2, R3 and R4 have the same meanings as in the formula (1) and ~ 10 represents an alkyl radical.

~: This cycllsation is preferably carried out by means of a base such : ~ that an alkali mbtai alcoholate, within the corresponding alcohol, to a t ~ mperature cc) mprise en ~ re 15 et 70C ~
:: ~ The derivatives of formula (113 can be prepared by the action of a 20 derivative of formuie ~
~ C (~ OOR1o (111 in which R10 has the same meaning as in formula (II) s ~ r ~. ~
derivative of formula ~
~, ~: ', ',' ;
:
';.;~'",', , ~., WO 93 ~ 21171 ~ 1 3 0 ~ ~ ~ PCr / FRg3 / ~ 0361:

R2 `` "~
i` ~
R3 ~ ~ S2NH2 (IV) R4 ~ H2; `
in which R2, R3 and R ~ have the same meanings as in the ~ ormule (1). ....
This reaction is carried out in an inert solvent such as ~:
té ~ rahydrofuranne, in the presence of a base such as a tertiary amine: ~:
(triethyarnine for example), at a temperature around 20C. ~ `
,::
The derivatives of ~ ormule (IV) are marketed or may be ~
: obtained by application or adaptation of the methods described by JH ~ ;.
SHO ~ T et al., J. Amer. Chem. Soc., 82, 1135 ~ 1960) ~ Y. GIRA ~ D et ooll., J. .:
Chem. Soc. P ~ rkin Trans 1, 1, 1043 (1979 ~, JG TC) PLISS et al., J. M ~ d.
Chem., 6, 122 (1963), in US patent 3251837 and in the examples. In in particular, these derivatives can be prepared by the action of ammonia on a ~ -derivative of formula:;

R3 ~ So2cl (V) R4 ~ H2 ,.,., ~:
15 ~: in which R2, R3 ~ t ~ R4 have the same meanings as in the formula This reaction is generally carried out at ~ a temperature close to : ~: `2Q ~
~ s ~ derived from: formula (V) can be ~ prepared by the action of 20 ~ CISO3H on a form . .

R3 ~ L (Vl) ::,. ~.

,.

WO 93/21171 PCI` / FR93 / 00361 2 ~ -c3a ~ 3gr ~ i 6 in which R2, R3 and R4 have the same meanings as in the formula This reaction is carried out at a temperature in the region of 1 00C. ~;
The new compounds of ~ orrnule (I) for which R1 represents an alkoxycarbonyl radical can also be prepared by the action of a derived from ~ orrnule (IV) on a dialkyl oxalate. : ~
This ~ te reaction is preferably carried out by means of a base such that an alkali metal alcoholate, in an inert solvent such as an alcohol, to a temperature close to 20 ~ C. - ~
The compounds of formula (I) for which R1 represents a radical tetrazolyl can be prepared by reaction of sodium azide on a derived from ~ ormule ~

R3 ~ `NH (Vll) R4 ~ C - N
in which R2, R3 and R4 have the same signi ~ iations ~ ue in ~ a formula.

,. . ~.
:. ".-:
~:: This reaction is preferably carried out in an inert solvent such as that I ~ dimethyiformamide, ~ dim ~ thoxyethane, at a temperature included I erl ~ re ~ 20 ~: and! Atemperature: boiling: reaction medium ~
The derivatives of ~ formula (VII) can be obtained by the action of ~: 2 0 phosphorus pentachloride or phosphoryl chloride on an amide of;
formula ~
:,.
not . ., F / 3 ~ 5 ~ H (Vlll) R ~ ~ LCONH2 ~. -. , ~ ...

~.
,::

WO9Y21171 21 ~ ~ O: j PCI / FIR93 / 01) 361 in which R2, R3 and R4 have the same meanings as in the formula ~; ~
(1). ..:
. ,.
This reaction is generally carried out at a temperature included: ~
between 2Q and 1 60C.
.
The amides of formula (VIII) can be prepared from:
compounds of formula (I) for which R1 represents a carboxy radical or alkoxycarbonyl by any known method for passing from an acid or from an ester to a primary or secondary amide and in particular ~ by adaptation of the methods described by QE KENT et al., Organic:
Syntheses, lil, 490; WS BISHOP, Organic Synthesis, 111, 613.:
The compounds of formula (I) for which R1 represented a radical 1 -CO-NH ~, -CO-NH-alk, -CO-N (alk) 2, -CO-NHOH, -CO-N ~ alk) OH,. ; ~
-CO-NH-O-Rs, -CO-N ~ a! K) -ORs can be prepared by ~ action of a ; corpose of formula (l ~ ~ corresponding ~ for which R1 represents ~ nte a radical carboxy or alkoxycarbonyl on a derivative of ~ ormule:
,.
i-iN (R1 1 ~ -R12:: ~ IX) in which R11 represents ~ a hydrogen atom ~ or an alkyl radical and R12 ~ represents a: hydrogen atom or an alkyl, hydroxy, -O-alk 1 radical or: -ORs in which Rs represents an alkyl or phenylalkyl radical.

When the acid is used, it is carried out in the presence of an agent : of condensation: peptide such as ~ ~ that u ~ carbo ~ iimide (for example the dicyclohexylcarbodiimide) or N, diimidazolecarbonyl, in a solvent i:: inert ~ such as an ether ~ tetrahydrofuran, dioxane for examplej, an amide (dir ~ ethylformamide ~; for example ~): ~ or a ~: ~ chlorinated solvent ~ (chloride of ~
~: 25 m ~ ethyl ~ e:, ~ chloroform, for example ~, àunetempératurecinprise ~ ntre0C:
e ~ the re ~ lux temperature of the medium: reaction. ``
When: we: implement a: ester ,; we operate either in the middle or9anique optionally in ~; presence of an acid acceptor such as `;
butyllithlum, the lithian of ~ diisopropylamine or an organic nitrogen base ~ e (trialkylaminet pyridine, diaza-1,8 bicyclo ~ 5.4. ~] undécene-7 or diaza-1,5;.
; bicycio [4.3.0] n ~ nbne for example), in a soil ~ nt such as qUB cited above or i ~
. ., -:.
, ~

WO 93/21171 PClr / FR93 / 00361 0 ~

a mixture of these solvents, at a temperature of between 0C and reflux temperature of the reaction medium, ie in a hydroorganic medium biphasic in the presence of an alkaline or alkaline earth base (soda, potassium for example) or a carbonate or bicarbonate of an alkali metal or 5 alkaline earth, at a temperature between 0 and 40C.
The new compounds of formula (I) for which R1 represents a radical -CO-R6 in which R6 represents a radical -O-alk-R7, -O-alk-V-CO-alk, -O-alk-O-COOalk, -O-alk-O-CO-R7, -O-alk-OH, -O-alk-O-alk, -O-alk-S-alk, -O-alk-O-R7, -O-alk-S-R7, -O-alk-COOH, 10 -O-alk-COOalk, -O-alk-NRgRg, -NH-alk-O-CO-alk, -NH-alk-C) -COOalk, -NH-alk-O-CO-R7 ~ -NH-alk-OH, -NH-alk-O-alk, -NH-alk ~ S-alk, -NH-alk-O-R7, -NH-alk-S-R7, -NH-alk-COOH, -NH-alk-COOalk, -NH-alk-NRgRg, can be prepared by reaction of a compound of formula ~ I) corresponding to which R1 represents a carboxy or alkoxycarbonyl radical on a derivative ds 15 ~ ormule : ~: R6-H () ~
in which R6 has the same meanings as above.

: This r ~ a ~ tion is carried out under the conditions described above.
for the reaction of acids or esters with derivatives of ~ ormule (IX).
Z0 ~ ~ The compounds of ~ formula (I) ~: can be purified by the methods known usually ~ lles, for example :: by crystallization, chromatography or extraction ~
The compounds of formula (I) ~: 'can optionally be trans ~ or ~ més in metal salts or ~ in addition salts with nitrogenous bases : 25 according to methods ~ nnues in ~ itself. These salts can be obtained by action of a ~ metal base (alkaline ~ or alkaline earth, eg ~ mple), Ammonia, tetraikylammonium, amine or salt of an acid organic on a compound ~ of ~ ormule (I), in a solvent. The salt ~ ormé is separated by the usual methods.
1: ~ 30 These salts ~ also form part of the invention.
::. :;,.
:::

; ',:

::: "
,, ~

wo g3 / 2, l71 2. ~ PCI` / FR93 / 00361 9 ~:

As examples of pharmaceutically acceptable salts, salts with alkali metals (sodium, potassium, lithium) or with alkaline earth metals (calcium, magnesium), salt ammonium, tetraalkylammonium salts (tetrabutylammonium by 5 example), nitrogen base salts (ethanolamine, trimethylamine, methylamine, benzyiamine, N-benzyl- ~ phenethylamine, choline, ar ~ inine, ~ ~
leucine, Iysine, N-methyl glucamine ~. ;
The compounds of ~ ormule (I) have properties interesting pharmacologicals. These compounds are antagonists not of the N-methyl-D-aspar ~ ate (NMDA) receptor and, more in particular, they are ligands for modulating sites ~ e glycine of the NMDA receptor.
, Furthermore, certain compounds of formula (I) are antagonistic of the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA), also known as the quisquaiate receptor.
These compounds are therefore useful for treating or preventing all consecutive ischemias (such as focal or global ischemia) of accidents cerebrovascular disease, cardiac arrest, low blood pressure, ~ cardiac or pulmonary surgery or hypoglytheria; 20 severe. They are also useful in the treatment of effects due to anoxiej whether perinatal or following drowning or lesions cerebro-spinal. ~ These compounds can also be used for trait ~ r or prevent the evolution of neurodegenerative diseases, chorea of HVNTlNGTQN, ALZHElMER's disease, diseases of the m ~ toneurone, amyotrophic lateral sclerosis, olivo- atrophy pontoGérébelleuse, from the May of PARKINSON. These compounds can also be used vis-à-vis the manifesta ~ ion ~ epileptogens eVou convulsive, for the treatment of brain and spinal trauma, I '~ anxiety (KEHNE et c ~ ll., Eur. J. ~ ~ Pharma ~ olO, 193, 283 ~ 1991 ~, de la depression ~ TRULLAS et al., Eur. ~ J. Pharmacol., 185, 1 (1990), de la ~ schizophrenia (RE ~ NOLDS, TIPS, 13, 116 ~ 1992), e ~ as pain relievers (DICKENSON et c ~ il., Neurosc. Letters, 121, 263 (1991), antianorexics ~ SORRELS et al., Brain Res., 572, 265 (1992), antiemetics, ,.
.,:

-. ~
~ ~.

WO 93/21171 PCr / FR93 / 00361 antimigraine and to treat poisoning with neurotoxins or other ~ IMDA receptor agonist substances, as well as disorders neurology associated with viral diseases such as AIDS (LiPTON and coll., Neuron, 7, 111 (1991), rabies, measles and tetanus (BAGETTA and 5 ooll., Br. J. Pharmacol., 101, 776 (1990). These compounds are also useful for the prevention of symptoms of abstinence from drugs and alcohol and inhibition of addiction and dependence on opioids.
The affinity of the compounds of formula (I) for the glycine site linked to NMDA receptor was determined by studying the antagonism of ixation Specific for [3H] -DCKA (6,8-dichloro kynurbnic acid) on membranes of rat cerebral cortex according to a method derived from that described by ~ ARON et al., Eur. J. Pharm., 206, 149 (1991). The [3H] -DCKA
(20nM) is incubated in the presence of 0, ~ mg of protein at 4C p ~ ndant 10 minutes in HEPES (acid (N- [2-hydroxyethyl] piperazine-N'-) buffer 15 [2-ethanesulfonic]) 50 mM, pH 7.5. Non-specific fixation is determined in the presence of lmM glycine. Bound radioactivity is separated by ~ iltration on Whatman GF / B filters. The inhibitory activity of these products ~ st generally less than 100 IlM.
The affinity of the compounds of formula ~ I) with respect to the AMPA receptor has 20 been determined by studying the antagonism of the specific fixation of the [3H] -AMPA on membranes of rat cerebral cortex (HONC) RE et al., ; NeuroscienGe ietters, 54, 27 (1985)). The [3H] -AMPA is incubated in ~: presence of 0j2 mg of proteins at 4C for 30 minutes in buffer KH2POq 10mM, KSGN 100mM, pH7.5. Nonspecific flxation is 2s determined in ~ presence of ~ L-glutamate 1mM. Linked radioactivity is - separated by ~ ilteration on ~ PHARI \ AGIA (Printed Filtermate A) ilterers Activity ~
i nhibltrice of these products is generally in ~ erieure to 100 ~ M.
~ The compos ~ sd ~ formula ~ I) have a low toxicity. Their LD50 is greater than 50 ~ mg / kg by IP route. ~ ~
:
30: are particularly interesting as ~ ntagonists of the receiver NMDA the compounds of ~ formula (i) for which R1 represents a radical carboxy or alkoxycarbonyl and R2t R3 and R4 are hydrogen atoms or well R2 and R3 represent hydrogen atoms and R4 represents a : ~, WO 93/21171; ~; i '''1 ~ 0 9''~ PCr / FR93 / 00361 1] ~:

halogen atom or else R3 represents a hydrogen atom and R2 and R4 represent halogen atoms or alkyl radicals.
Are particularly interesting as receptor antagonists AMPA the compounds of ~ ormule (I) for which R1 represents a radical 5 carboxy, R2 and P ~ 4 represent a halogen atom or an alkyl radical and R3 represents a hydrogen atom.
~. ~
Of particular interest are the following compounds ~
- 2H-1,2,4-ben20thiadiazine-1,1-dioxide-3-carboxylate of ~ thyle, ~:
- 2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylic acid, - 6,8-dichloro-2H-1,2,4benzothiadiazine-1,1-3-dioxide-carboxylate methyl, ' - 6,8-dichloro-2H-1,2,4-benzothladiazine-1,1-dioxide-3-carboxylic acid, - 6-iodo-2H-1,2,4-benzothiadiazine ~ m-hyle dioxide-3-carboxylate, 6-iodo-2H-1,2,4-benzvthiadiazine-1,1-dioxide-3-carboxylic acid, I ~ 15 - 6,8-di ~ luoro-2H-1, ~ j4-benzothi ~ diazine-1,1-dioxide-3-carboxylate methyl, ~ ~ i 6,8-difluoro-2H-1,2,4-benzothidia ~ ine-1,1-dioxide-3-carboxylic acid, 6,8-dimethyl-2H-t, 2,4-benzothiadia ~ ine-1,1-dioxide-3-carboxylate m ~ thyle, 20 -: 6,8-dimethyl-2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylic acid, ~ 8-iodo-2H-1,2,4-benzothidla ~ lne-1,1-dioxide-3-carb ~ xylic acid, - 6,8-dib-omo-2H-1,2,4-benzothiadiæine-1,1-dioxide-3-carboxylic acid, acid ~ 6-chioro 2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylic acid The following examples illustrate the invention without limiting it.

25 ~ m ~
! ~
At 100 cm3 of a lN solution of ~ sodium methylate in methanol acts ~ e under nitrogen at a temperature close to 20 ~ C, it flows slowly WO 93/21171 ~ 3 3 PCr / FR93 / 00361`

':
a solution of 17.2 g of 2-aminobenzenesulfonamide and 14.6 9 of oxalate of diethyl in 40 cm3 of methanol. After 24 hours of agitation at this;
temperature, the reaction medium is poured into 2 liters of distilled water and acidified with 1N hydrochloric acid. The precipitate formed is filtered and washed with 5 water to neutral pH, then dissolved in 50 cm3 of dimethylforrnamide heated to 100 (::. The solution obtained is cooled and diluted with 150 cm3 methanol. The crystals formed are filtered and washed with methanol. 5.3 9 of product thus obtained are dissolved in 70 cm3 of dimethyl ~ ormarnide then added to 40 cm3 of a solution of 1.4 g of potassium hydroxide in ethanol 10 absohJ. The reaction medium is stirred at a temperature close to 20C.
for 15 hours then concentrated to dryness under reduced pressure. After addition of ethyl ether and ~ iltration of the insoluble material, 6.4 g of salt are obtained potassium 2H-1, 2,4-benzothiadiazine-1,1 dioxide-3-carboxylate- ~ 'ethyl s ~ us powder form londant at 235 ~ C.
c, ~ f ~ ealp, e ~
5.4 g - ~ potassium salt of 2H-1,2,4-benzothiadiazine ethyl dioxide-3-carboxylate are dissolved in a mixture of 20 ~ cm3 of ~ ethanol and 50 cm3 of distilled water heated to ~ 0 ~ C. We add then t, 1 9 of potassium hydroxide and the reaction is allowed to continue for 1 hour.
20 The pr ~ precipitate formed is filtered, washed with ethanol and then dried to yield , 7 9 of potassiurn disel of 1,2,4-ben acid othiadiazine 1,1-dioxide-3- ~ arboxyliq ~ eu in the form of a powder with a melting point is greater than 27aC ~ Analysis% calculated C: 31.78; H: 1.33; N: 9.26; S: 10.60;
% found ~ C: 32.4; H: 1.2; N: 9.3; S: 10.8).
.,.
25 x ~ m ~ 1 ~ 3 To a methanolic solution ~ of ~ sodium methylate, prepared by additive) 0.75 9 sodium in 5Q cm3 ~ methanol ~, we add sou ~ nitrogen 11 g

4,6-dichloro ~ 2 ^ ethyloxalylarnino-benzenesul ~ onamide in sotution in ie methanol at 4û ~ C. The reaction is continued for 2 hours at this temperature, 30 then 1 ~ mili ~ u reaction ~ ~ st concentrated to se ~ under reduced pressure. The solid thus obtained is taken up in 1 liter of distilled water and then acidified with acid 1N hydrochloric acid to yield a white precipitate. After ~ iltration, washing ~ `
and drying, 8.6 g of 6,8-dichloro-2H-1,2,4 ^ benzothiadiazine are obtained ::: ~ ,,. ',, ,, ~.,.

WO 93/21171 PCI` / FR93 / û03bl 2 L ~ iJoi ~

1.1 methyl dioxide-3-carboxylate melting towards 270C (% analysis calculated C: 34.97; H: 1.96; Cl: 22.94; N: 9.06; S: 10.37; % found C: 34.8; H: 1.8; Cl: 22.8;
N: 9.2; S: 10 ~ 4).
4,6-dichloro-2- ~ thyloxalylamino-benzenesulfonamide can be prepared from

5 the following manner: to a solution of t 2 9 of 2-amino-4,6-dichloro benz ~ nesuHonamide and 7.1 cm3 of triethylamine in 40 cm3 of anhydrous tetrahydrofuran re ~ stiffness at 5C, added dropwise, about 30 minutes, a solution of 5.8 cm3 of ethyloxalyl chloride in 5 cm3 of tetrahydro ~ uranium. After a night of stirring at a temperature 10 close to 20C the reaction medium is concentrated to dryness under pressure `reduced. The solid residue is washed with water and then dissolved hot in 120 ml of aqueous ethanol at 10% water. After cooling, filtration and secha ~ e of the crystals formed, 11 g of 4,6-dichloro-2-ethyl are obtained oxalylamino-benzenesulfonamide ~ waving at 200 ~ C.
15 2-amino-4,6-dichlorobenzenesulfonamide can be prepared according to the method described by JH SHORT and U. BlERMACtlER, .J. Arn. t: h ~ rn. Soc.
82, 1135-1 137 (1960).
,,.

3.1 9 of 6,8-dichloro-2H-1,2,4-benzothiadiazine-t, 1-dioxide-3-carboxylate ~
20 ~ d0 methyl ~ n solution in 400 cm3 of absolute ethanol are treated at 50 ~ C
with 120 crn3 of an aqueous 1% potassium solution. After 1 hour of reaction at this temperature ~, the precipitate formed is filtered, l ~ vee with ethanol then with water and dried to yield 3.2 g of potassium disel hydrate d ~
6,8-di ~ chloro-2H-1,2,4-benzothiadiazin ~ -1,1-dioxide-3-carboxylic acid 25 in the form of ~ powder ~ fondant ~ at ~ a temperature s ~ greater than 300C
(Analysis% calculated G: 24.68; H: 1.04; Cl: 18.21 ~; N: 7.20; S: 8.24;% found C: 25.5; H: 1.1; Cl: 17.9; N: 6.9; S: 719).

, ~

':.
~,, ~. .

WO 93/21171 PCr / Fl; t ~ 3/00361 1 ~ 14 Example 5 To a solution of sodium methylate, prepared from 10 cm 3 of methanol and 0.06 9 sodium, a suspension of 1.03 g of 2-ethyloxalylamino-4-iodobenzenesulfonarnide in 125 crn3 of methanol.
5 The reaction mixture is heated to ~ 40C for 4 hours, then concentrated under vacuum (16 mm of mercury). The white solid obtained is taken up by 150 cm3 of water, filtered and the filtrate is brought to pH 1 with acid normal hydrochloric. The precipitate ~ ormed is filtered, air dried, then at 50C
under vacuum (2 mm of mercury) to give 0.68 9 of 6-iodo-2H-1,2,4 10 benzothiadiazin ~ -1,1-dioxide-3-carboxylate of rnétyie melting above 260 ~ C. (Analysis% calculated C: 29.53; H: 1.93; N: 7.65; 0: 17.48; S: 8.76, % found C 29.9; H: 2, Q; N: 8.0; 0: 17.4; S: 8.6).
2-Ethylox ~ lylarnino-4-iodobenzenesulfonamide can be prepared from as follows: to a solution of 1.35 g of 2-amino-4iodo 15 ben ~ ènesulfonamide in 10 cm3 of tetrahydro ~ uranne and 0.65 crn3 of ~ riethylamine is added ~ 5C a solution of 0.62 ~ chloride ethyloxalyl in 5 cm3 of tetrahydrofuran. The reaction mixture is stirred for 2 hours at room temperature, then concentrated in vacuo (16 mm of mercury). The solid obtained is triturated with 15 cm3 of ~ thanol 20 ~ aqueous (50% by volume), ~ filtered and air-dried to ~ provide 1.039 2-ethyloxaly! Amino-4-iodoben ~ enesulfonamide used as is in subsequent syntheses. ~
2-amino-4-iodobenzenesuNonamide can be prepared in the last following: to a solution cooled to -5C of 17.7 g of isocyanate Chlorosulfonyl in 110; cm3 of nitromethane we slowly add a solution ~ of 21.9 ~ g of 3-iodoaniline in 35 cm3 of nitromethane, then towards 0C, 16.67 g of ~ alurninium chloride i Then heat ~ reflux and stops the reaction ~ when the r ~ flow temperature reaches 1Q1-102C by ~ cooled in an ice bath. The reaction mixture is poured onto 30 crushed ice and the precipitate ~ formed is ~ re, washed with water and air dried. The crude product is purified by chromatography as follows 9 9 of mixture are dissolved in 200 cm3 of methanol and 50 cm3 of triethylamine, fixed on 20 g of silica by concentra ~ ion to the rotary evaporator ~, deposited on ;: .i ,.
, ~

.,.; ~

WO 93/21171 PCI / FR93 ~ 00361 ~: 1 3 ~

a column of 500 9 of silica and eluted with a mixture of ethyl acetate, methanol and tri ~ thylamine (80/20/1 by volume). We thus isolate a ~ reaction which, after evaporation, is recrystallized twice from isopropanol, treated with 20cm3 of decinormal hydrochloric acid, filtered and dried at 5 50C to give 0.95 g of 6-iodo-1t2,4-benzothiadiazine-3 (4H) -one-1,1-fondan dioxide ~ above 260C. This product is then hydrolyzed by heating at 140C for 3 hours with 50 cm3 of 50% sulfuric acid (by volume) ~ The reaction mixture is cooled and made alkaline at Ammonia, ie precipitate formed, is extracted with 100 cm3 of tert-butyl 10 methyl oxide and the organic solution is evaporated under vacuum (16 mm mercury) to give 0.8 g of 2-amino-4-iodobenzenesulfonamide mowed ~ nt ~
1 60Co ExemP! ~
A suspension of 0.4 9 of 6-iodo-2H-1,2,4 ^ benzothiadiazine ~ dioxide-3 15 methyl carboxyiate in 150 cm3 of ethanol containing 0.18 9 of potassium hydroxide in pellet is heated for 2 hours to 50 (:, then cooled in a bath of ice. The solid formed is filtered, rinsed with ethanol and air dried. We obtains 0.44 g of potassium disel from 6-iodo-2H- acid 1, 2, ~ -benzothiadiazine ~ 3-carboxylic dioxide ~ waving above 260 (: ~
20 (Analysis% calculated C: 22.44; H: 0.71; N: 6.54; S: 7.49,% found ~ C: 22.0; H: 0.9;
N: 6.5; S: 7.4).
Example 7 We operate as in Example 5 but from 1.8 g g of 2-ethyioxalylamino-4,6-difluorobenzenesulfonamicle. We get 1.4 9 of 2j 6,8-ddluoro-ZH-1,2,4-benzoth ~ methyl iadiazine-1,1-dioxide-3-carboxylate fondant ~ above ~ 260G ~ (Analysis% calculated ~: 39.14; H: 2.1g; F: t3.76;
N ~: 10.14; S: 11161,% found C: 39.2; H: 2.2; F: 13.5; N: 10.1; S: 11, ~) .i 2-ethyloxalylamino-4,6-difluorobenzenesutfonamide can be prepared Gum in the example ~ for the preparation of 2-ethyloxalylamino-4-30 iodobenzen ~ sulfonamide ~ but from ~ 3 g of 2-amino-4,6-difluorobenz ~ nesulfonamide and 1.97 9 of chloride of hyloxalyl ~. We ~ 3 rCI '/ FR93 / 00361 ,, ''' obtains 1.89 g of 2-ethyloxalylaminv-4t6-difluorobenzenesul ~ onamide used as is in subsequent syntheses.
2-amino-4,6-di ~ luorobenzènesul ~ onarnide can be prepared as in Example 5 for the preparation of 2-amino-4-iodobenzenesulfonamide but 5 from 10 g of 3,5-difluoroaniiine. The gross product resulting from the cyclization is ~ xtr, ~ it with 600 cm3 of ethyl acetate in total and the organic solution is evaporated under vacuum (16 mm of mercury). The residue evaporation is purified by beating in tert-butyl methyl oxide, filtered ~
and dried. We obtain 11.72 g of 6,8-difluoro-1,2,4-benzothiadiiazine-3 ~ 4H) ~
10 one-1,1-dioxide which is then hydrolyzed with 220 cm3 of sulfuric acid 5û% ~ in volun ~ es) for 5 hours at 130C. The reaction mixture is cooled, alcalini.sé ~ pH 8 and extracted ~ with 900 cm3 of ~ ethyl acetate ~ otal.
The organic salutation is evaporated ~ under vacuum (16 mm of mercury ~ and the evaporation residue is purHied by color chromatography) of silica 15 (500 g) with a mixture of cyclohexane and ethyl acetate ~ 70-30 ~ n vohJrnes) to give 4.86 9 of 2-amino-4,6-di ~ luorobenzenesulfonamide as a ~ pale ~ solid ~ pink ~ used as is in syntheses later.
,, .. ",., 2 0 On ~ op ~ re as in ~ example 6 but from 1 g of 678-difluoro-2H ~
n ~ 1,2,4-benzothiad ~ ne ~ dioxide-3- ~ methyl carboxylate ~. We obtain 1.13 ~ 9 of ~ potassium disel; acid 6,8-difluoro-2H-1,2,4-benzothidiazine-dioxy ~ e-3-carboxy ~ 7ue melting above 260C (Analysis% calculated;
C: 28.40; ~ ~ H: 0.60; ~ F: 1 ~ 1.23; ~ N: 8.28, S: 9.48, ~% t found C: 29.3; H: 0.4; F: 1 1, û; ~ "
25 ~ ~ N: 8.5; S: 9d7).
Ex ~ nple 2 ~
`We oppress ~ as in Example 5 but from d ~ 5.24 9 d ~ ~, ',,"! ~'"
2-ethyloxalyiamino-4,6-dimethylbenzbn ~ su.fonamide. 3.88 g of ~ are obtained;

6, ~ -dimethyl-2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate of I`
30 ~ methyl ~ undulating ~ 260C, :: ~
~ .., ~ ': ~:'' `~

WO 93121171 2 1 3 ~ D g - ~ Pcr / FR93 / oo36l ~

2-ethyloxalylamino-4,6-dimethylbenzenesulfonamide can be prepared as in Example 5 for the preparation of 2-ethyloxalylamino-4-iodobenzenesuHonamide but from 4.15 9 of 2-amino-4,6-dimethylbenzenesulfonamide and 2.73 9 of ethyloxalyl chloride. We 5 obtains 5.24 g of the 2-ethyloxalylamino-4,6-dimethylbenzenesulfonamide used as is in subsequent syntheses.
2-amino-4,6-dimethylbenzenesulfonamide can be prepared as in Example 5 for the preparation of 2-amino-4,6-difluorobenzbnesulfonamide but from 12.12 g of 3,5-dimethylaniline. 11.31 g of 6.8 are obtained.
10 dirnethyl-1,2,4-benzothidiazine-3 (4H) -one-1,1-dioxide which is subjected Acid hydrolysis under the same conditions, which leads, after chromatography on ~ column of silica with a mixture of cyclohe ~ donkey and ethyl acetate (70-30 by volume), 6.15 9 2-amino-4,6-dimethylben ~ ènesul ~ onamide in the form of a pale ros0 solid used as is 15 in subsequent syntheses.
Ex ~ rn ~ le lO-(:) n op ~ re comm ~ in example 6 but from 2.88 9 of 6.8-dimethyl-Methyl H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate. We obtain 1 ~; 3.6 9 of the pot disel ~ 6,8-dimethyl-2H-1,2,4 acid ssium ~
20 benzothiadiazine-1! T-dioxide-3-carboxylic melting above 260C
Analysis% calculated C: 36.35; ~ H: 2.44; N: 8.48,% found C: 36.5; H: 2.0; N: 8.4).
Exerr ple 11 On: operates as in example 6 but starting from 2.9 9 of 7-m ~ thyl-2H-1,2,4-ben ~ othiadiazine-1l1-dioxide-3-methyl carboxylate. We obtain 25 3.4 g of potassium acid of 7-methyl-2H-1,2,4-benzothidiazine acid 1,1-dioxide-3-carboxylic melting above 260C (Analysis% calculations C: 34 ~ 16; H: 1.91; N: 8.85, S: 10.13,% found C: 34.2; H: 1.6; N: 8.7; S: 10.4).
Methyl 7-methyl-2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate can ~ very ~ prepare ~ as in example 5 for the preparation of 30 2-ethyloxalylamino-4-iodob ~ nz ~ nesuHonarnide but from 5.6 ~ 9 of ; ~ 2-ethyloxalylamino-5-methylbenzenesulfonamide. This gives 3.94 9 of :: ~;:

. ,, '; ~ ~'"

WO93 / 21171 PCr / FR93 / 00361 ?, ~ 3 ~ g ~ 3 18

7-methyl-2H-1,2,4-benzothiadiazine-1; methyl 1-dioxide-3-carboxylate melting above 260 ~ C ~ Analysis% calculated C: 47.24; H: 3.96; N: 11.02; ~ -S: 12.61,% found C: 47.2; H: 4.0; N: 11.1; S: 12.5).
2-ethyloxalylamino-5-methylbenzenesulfonamide can be prepared as in Example 5 for the preparation of 2-amino-4,6- ~ -di ~ luorobenzeneisulfonamide but from 4.8i5 9 of 2-amino-5-;
m ~ thylb0nzènesul ~ 0namide and 3.55 g of ethyloxalyl chloride. We obtains 5.65 g of 2-ethyloxalylamino-5-methylbenzenesul ~ onamide fondant 208C.
2-amino-5-methylbenzenesulfonamide can be prepared according to the procedure ~
described by Y. GIRARD et al., J ~ Chem. Soe., Perkin Trans.l, 1, 1043 (1979).
Example 12 ~, C) n operates as in Example 6 from 2.35 g of 7-methoxy-2H-1,214-methyl bsnzcthiadiazine-1,1-dioxide-3-carboxylate. We get 2.52 9 of 7-methoxy-2H-1,2,4-benzothidiazine-1 acid potassium disel 3-carboxylic dioxide ~ wavering above 260C (% analysis calculates C: 32.52; H: 1.87; N: 8.43; S: 9 ~ 65,% found C33.2; H: 1.7; N: 8.5; S: 9.5). ;
:: LQ 7-methoxy-2H-1 ~ 2,4-benzothiadiazine-1, t-dioxide-3-carboxylate;
methyl can be prepared as in Example 5 for the preparation of 6-iodo-2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate ~ of methyl but from 5.15 9 of 2-ethyloxalylamino-5-methoxybenzenesulfonamide. We obtains 2 gd ~ 7 methoxy-2H-1,7,4-benzothidiazine-1,1-dioxide-3 methyl carbvxylate melting at 257C.
. ~
The ~ 2-ethyloxa! Ylamino-5-methoxybenzènesul ~ onamide can be prepar ~
as in Example 5 for the preparation of 2 ~ ethyloxalylarnino-4-iodob ~ enzènesulfonamide but from 4,13 ~ del 2-amino 5-methoxybenzenesul ~ onamide and 2.8 g of thyloxalyl chloride. We get ~ 5,1i5 9 from 2-ethy! oxalylamino-5-methoxybenzbnesu! fonamid0 ~ ondant at 178C. ~ ~
2-amino-5-methoxybenzbnesul ~ onamide can be prepared according to the patent -VS 325 ~ 837. `; ~

'':
~ "

~ 3 ~ 0 ~ 3 Fxem ~ l ~ 1 3 The procedure is as in Example 6 but starting with 0.39 g of 8-iodo-2H-Methyl 1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate. We obtain 0.36 9 of potassium disel of acid 8-iodo-2H-1,2,4-benzothidiazine-1,1-5-3-carboxylic dioxide melting above 260C ~ Analysis% calculation ~
C: 21.53; H: 1.13; 1: 28.43; N: 6.28; S: 7.18,% found C: 21.5; H: 1.1; 1: 28.6;
N: 6, ~; S: 6.8).
Methyl 8-iodo-2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate p ~ ut be prepared as in Example 5 for the preparation of 6-iodo-2H-Methyl methyl 2,4,4-benzothiadiazine-1, 1-dioxide-3-carboxylate but from 0.54 g of 2-ethyloxalylamino-6-methylbenzenesulfonamide. We thus obtain 0.39 g 8-iodo-2H-1,2,4-iodobenzothiadiazine 1, ~ -dioxide-3-carboxylate methyl used as such in subsequent syntheses.
2-ethyloxalylamino-6-iodobenzbnesul ~ onamide ~ can be prepared ~ as 15 in Example 5 for the preparation of 2-ethyloxalylamino-4-iodobenzbnesul ~ onamide but from 0.65 g of 2-amino-6-iodo ~ enzènesulfonamide and 0,30 9 of ethyloxalyl chloride ~. We obtain 0.54 g of 2-ethyloxaiylamino-6-iodobenzenesulfonamide used as is in I es ~ subsequent syntheses.
; ~ 20 The 2-amino-6-iodobenzenesulfonamide can be prepared as in ; . . . ~
I'ex ~ rnple 5 ~ for the ~ preparation of 2-amino-4-iodoberlzbnesulfonamide but from 3-iodoaniline and by continuing to elute the column chromatographic with a mixture of ethyl acetate, methanol and d ~
trlethylamine ~ 70/30/1 by volume). After acid treatment, we obtain 0.6 9 2 ~ dei 8-iQdo-1,2,4benzothiadlazine-3 (4H) -one-191-dioxide. This prodult n ~ suiteihydrolysed ~ in ~ ies m ~ my conditions to give 2-amino-6 iodobenzènesul ~ onarni ~ e ~ in the form of ~ n solid `` yellow '' ~ p ~ the used tel what in the ~ subsequent syntheses. ~ ~ ~

We opbre as in Example 6 ~ but from 1.6 ~ g of 6,8-dibromo-~ 2H-1,2,4-benzothiadiazine-1,1-dioxide-3-methyl carboxylate. We obtain .
~ ~;

:

~, i3 ~ ~ 9 PCI / FR93J00361 1.72 g of potassium disel of 6,8-dibromo-2H-1,2,4- acid benzothiadiazine-1,1-dioxide-3-carboxylic london above 260C
(1H NMR: 7.52 ppm (d, J = 1 ffz, 1H Ar), 7.70 (d, J = 1 Hz, 1H Ar); IR: 1400 cm-1 ~ COO-), 1325 cm-1 (S (: ~ 2), 1150 cm-1 (S02)).
6,8-dibromo-2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate m ~ thyle can be prepared t, omme in J'example 5 for the preparation of 6-iodo-2H-1,2,4-benzothiatliazine ~ methyl dioxide-3-carboxylate but ~ from 2.6 g of 2- ~ thyloxalylamino-4,6-dibromobenzbnesuHonamide. We obtains 1.68 g of 6,8-dibromo-2H-1l2,4-benzothiadiazine-1,1-dioxide 3-m ~ ethyl carboxylate used as is in subsequent syntheses.
2-ethyloxalylamino-4,6-dibromobenzenesulfonarnide can be prepared ~
as in Example 5 for the preparation of 2-ethyloxalylamino-4-iodobenzenesulfonamide rnais from 2.86 9 of ~ 2-amino-4,6 dibromobenzenesulfonamide and 1.18 g of ~ thyloxalyl chloride. We obtains 256 9 of 2-ethyloxalylamino-4,6-dibromobenzenesulfonamid ~ used such as qUBI in subsequent summaries.
..
2- ~ rnino-4,6-dibromoben ~ ènesulfonamide can be prepared as Example 5 for the preparation of 2-amino-4,6-di ~ luorobenzènesul ~ onamide but from 21.9 g of 3,5-dibromoaniline. We get, after ~ s chromatography on silica, 15.5 9 of 6,8-dibrorno-1,2,4-benzothiadiazine- `~
3 (4H) -one-1,1-dioxide which is subjected to acid hydrolysis in the same c ~ nditions, what ~ ournit, after purifioation on a siliGe column ~ 5.1 g of 2-amino-4, B-dibromobenzene sulfonamide as a light beige solid use t ~ l as in ~ subsequent syntheses. ``
25 ~ ~ 3,5-dibromoan ~ iline can be prepared according to IQ process described by F ~. G
SHEPHERD, J. Org. Chem. 12, 275 ~ 47 ~. ;

The operation is carried out in Example 6 but using 0.9 g of 6-chloro-211 ~
1,2,4-benzothiadiazine ~ methyl dioxide-3-carboxylate da ~ We obtain ~ nt 0.74 ~ 9 6-chloro-2H-1,2,4-benzothiadiazine acid potassium disel 1,1-dioxide-3-carboxylic ~ waving at a temperature above 260C ~; ~
..
!

WO 93/21171 PCI / FR93 / 0 (3361 2 l 1 ~

(Analysis / O calculated C: 28.52; H: 0.90; Cl: 10.53; N: 8.32; S: 9.52,% found C: 28.5; H: 0.78; Cl: 10.6; N: 8.1; S: 9.1).
Methyl 6-chloro-2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate can be prepared ~ as in Example 5 for the preparation of 6-iodo-2H-1,2,4-benzothiadiazine-1,1-3-dioxide-methyl carboxylate but ~ from 5.8 g of 2-ethyloxalylamino-4-chlorobenzenesulfonamide. C) n gets 2.3 g of methyl 6-chloro-2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate used as is in subsequent syntheses.
.
2-ethyloxalylamino-4-chlorobenzenesulfonamide can be prepared as in Example 5 for the preparation of 2 ^ ethyloxalylamino-4- - ;;
iodobenz ~ nesuHonamide but from 4.6 g of 2-arnino-4-chloroben ~ ene sulfonamide and 3 g of ethyloxalyl chloride. We obtain 3.8 9 from 2-ethylox ~ lylamino-4-chlorobenzenesulfonamide used as is in subsequent syntheses.
1 ~ 2-amino-4-chlorobenzenesulforlamide can be prepared according to the method ~ i described ~ by JG TOPLISS et al., J. Med. Chem., 6, 122 (1963). ~ `

,.
The medicaments according to the in ~ / srltion are constituted by a horn of formul ~ (I) in free form or in ~ form of a salt, ~ the pure state or in form of a composition ~ in which it is associated ~ any other pro ~ glow pharmaceutically compatible, which may be inert or physiologically active. Medication; according to the invention can be used by way oral, ~ parenteral, rectal ~ outopic.
As solid compositions for oral administration, may be used tablets ~ s, piluîes. ~ powders (capsule9 of g ~ Latin ~ i 25 tablets ~ or granules. In these compositions, the principle acti ~ according to The invention is m ~ changed to one or more inert diluents, such as starch, cellulose, saccharose, lactcse or ~ silica, under dlargon current. These compositions may also include: d substances other than diluents, for example one ~ or more lubricants teis que stéarat ~ de magnesium or talct a dye, a; ~ coating (dragees ~ or a vBrnis.

~;

:

WO93 / Z1171 ~, P ~ / FR93 / 00361 `

As liquid compositions for oral administration, it is possible to i use solutions, suspensions, emulsions, syrups and pharmaceutically acceptable elixirs containing inert diluents such than water, ethanol, glycerol, vegetable oils or paraffin oil. These compositions may include substances other than -thinners, for example wetting, sweetening, thickening products, flavorings or stabilizers.
. .
Sterile compositions for parenteral administration can be pre ~ erence aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, use water, propylene glycol, polyethylene glycol, oils vegetable, in particular olive oil from injectable organic esters, for example example ~ oleate of ethyl or other suitable organic solvents. These compositions may ~ also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. The ~ sterilization can be ~ alre several ~ açons, for example by ~ iitration - ~ sanitizer, by incorporating sterilizing agents into the composition, by irra-diation seen by heating. Elies ~ can also be prepared in ~ elm sterile solid compositions which can be dissolved at the time of 20 ~ employment in sterile water or any other sterile injectable medium.
The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polybthylènegtycols.
; 2 $ ~ ~ The compositions for ~ topical administration may be for example creams, lotions, ~ eye drops, mouthwashes, nasal drops or aerosols.
"
In human therapy, the compounds according to the invention are particularly useful for traling and / or preventing concluding 30 which requires the administration of an NMDA receptor antagonist or a AMPA receptor antagonist. These compounds are particularly useful for treat or prevent all ischemia and in particular ischery ~ brain ~
effects due to anoxia, the course of neurodeg ~ native diseases, . -.
~, ~
....

~.:

W ~ 93/21171 213 i ~ ~ 9 ~ PCr / FR93 / 00361 ':

HUNTlNGTON's chorea, ALZHElMER's disease, diseases of the rnotoneurone, amyotrophic lateral sclerosis, olivo- atrophy pontocerebellar and PARKlNSONt's disease vis-à-vis manifests ~ convulsive epileptogenic eVou, for the treatment of 5 brain or spinal trauma d ~ anxiety, depression, schizophrenia, as analgesics, antiemetic antiemetic, antimigraine and to treat poisoning by neurotoxins or other NMDA receptor agonist substances, as well as disorders neurology associated with viral diseases such as AIDS, rabies, 10 measles and tetanus. These compounds are also useful for prevention symptoms of drug and alcohol abstinence and inhibition of addiction and opioid dependence The doses depend on the desired effect, the dwee of the treatment and the route of administration used; they are generally understood 15 between 10 mg and 100 mg per day orally for an adult with doses units ranging from 5 mg to 50 mg of active substance.
Generally, the doctor will determine the dosage appropriate based on age, weight and all other factors specific to the subject to be treated.
The following examples illustrate compositions according to the invention:

FREE! EA
~.
1 is prepared according to the usual technique, capsules dosed at 50 mg of active product having the following composition: ~ -- Acid 6, ~ -dichloro-2H-1,2,4-benzothiadiazine ~
.
`25-3-carboxylic dioxide .......................... 50mg - Cellulose ...................................... 18 mg - Lactose ........... u .................................... 55 mg - Silioeoolloidal ............. ~ ................... 1 m ~
- Carboxymethylamidon sodium .. O .................. 10 m ~
3G - Talc .............................. .............. 10 mg - Magnesium stearate ............. .............. 1 rng -...

~ ,.

WO 93/21171 P ~ / FR93 / 00361 a ~ 1 24 EXAMPLE B
Tablets dosed with are prepared according to the usual technique;
50 mg of active product having the following composition: ~:
:
- 6,8-dichloro-2H-1,2,4-benzothiadiazine-1,1 ~ `
-methyl dioxide-3-carboxylate ................ 50 rng ~ ::
- Lac ~ ose ......................................... 104 mg - Cellulose ....................................... 40 mg -Polyvidone ........................................ 10mg:;
- Carboxymethyl starch sodium ..................... 22 mg - Talo ............................................ 10 mg - Magnesium stearate ............................ 2 mg ~.
- Colloidal silica ................................ 2 mg - Mixture of hydroxymethylcellulose, glycerin, oxide of, ~
titanium (72-3,5-24,5) qs 1 film-coated tablet ~ ermin ~ ~ 245 mg -.

An inJectabl ~ solution containing 10 mg of active product is prepared.
havinglacom, ~ next position: -, ,, i;
- 2H-1,2,4-Benzothiadiazine-1,1 acid; .
3-carboxy-dioxide ........................ 10 mg - A ~ ideb ~ n ~ oïque .... O .................................. 80 mg Benzyl alcohol ................................. .... Q, 06 cm3 ~ -sodium nzoa ~ e ............................. 80 mg ; ~ Ethanol at ~ 95 ~% ............................... 0.4 cm3 ~.
- Hydroxide of: sodium .... ~ ..................... 24 mg ~:
23 ~ - Propylene gly ~ ol .. ~ ........ ~ ........................ 1.6 cm3 - ^ Water ................ qs 4 cm3 ~ -. .
.

. ;, '~.

': ~' ,,.
: ' ~; ', .-: ~ ..
-:; ...

Claims (11)

1 - Application of 2H-1,2,4 benzothiadiazine-1,1-dioxide-3- acid derivatives carboxylic acid of formula:

(I) in which - R1 represents a carboxy, alkoxycarbonyl, tetrazolyl, -CO-NH2 radical, -CO-NH-alk, -CO-N(alk)2, -CO-NHOH, -CO-N(alk)VH, -CO-NH-O-R5, -CO-N(alk)-OR5 or a group convertible into a carboxy radical in vivo, - R2, R3 and R4, identical or different, represent a hydrogen atom or halogen or an alkyl radical, - R5 represents an alkyl or phenylalkyl radical and - alk represents an alkylene or alkyl radical, it being understood that the alkyl, alkoxy and alkylene radicals and the portions alkyl, alkoxy and alkylene have 1 to 6 carbon atoms in a chain straight or branched, their tautomer, their salts, in the preparation of NMDA receptor and/or AMPA receptor antagonist drugs. 2 - Application according to claim 1 with compounds of formula (I) for which R1 represents a group convertible into a carboxy radical in vivo chosen from the radicals -CO-R6 in which R6 represents a radical -O-alk-R7, -O-alk-O-CO-alk, -O-alk-O-COOalk, -O-alk-O-CO-R7, -O-alk-OH, -O-alk-O-alk, -O-alk-S-alk, -O-alk-O-R7, -O-alk-S-R7 -O-alk-COOH, -O-alk-COOalk, -O-alk-NR8R9, -NH-alk-O-CO-alk, -NH-alk-O-COOalk, -NH-alk-O-CO-R7, -NH-alk-OH, -NH-alk-O-alk, -NH-alk-S-alk, -NH-alk-O-R7, -NH-alk-S-R7, -NH-alk-COOH, -NH-alk-COOalk, -NH-alk-NR8R9, alk represents an alkylene or alkyl radical, R7 is a phenyl radical, R8 and R9, identical or different, represent a hydrogen atom or a radical alkyl, phenyl or phenylalkyl or together with the nitrogen atom to which they are attached to a piperidino, morpholino or pyrrolidino ring being understood that the alkyl, alkoxy and alkylene radicals and the alkyl, alkoxy and alkylene contain 1 to 6 carbon atoms in a straight or branched chain, their tautomer, their salts, in the preparation of drugs antagonists of NMDA receptor and/or AMPA receptor. 3 - Compounds of formula:
(I) in which - R1 represents a carboxy, alkoxycarbonyl, tetrazolyl, -CO-NH2 radical, -CO-NH-alk, -CO-N(alk)2, -CO-NHOH, -CO-N(alk)OH, -CO-NH-O-R5, -CO-N(alk)-OR5 or -CO-R6 in which R6 represents a radical -O-alk-R7, -O-alk-O-CO-alk, -O-alk-O-COOalk, -O-alk-O-CO-R7, -O-alk-OH, -O-alk-O-alk, -O-alk-S-alk, -O-alk-O-R7, -O-alk-S-R7, -O-alk-COOH, -O-alk-COOalk, -O-alk-NR8R9, -NH-alk-O-CO-alk, -NH-alk-O-COOalk, -NH-alk-O-CO-R7, -NH-alk-OH, -NH-alk-O-alk, -NH-alk-S-alk, -NH-alk-O-R7, -NH-alk-S-R7, -NH-alk-COOH, -NH-alk-COOalk, -NH-alk-NR8R9, - R2, R3 and R4, identical or different, each represent an atom hydrogen or halogen or an alkyl radical, - R5 represents an alkyl or phenylalkyl radical, - R7 represents a phenyl radical, - R8 and R9, identical or different, each represent an atom of hydrogen or an alkyl, phenyl or phenylalkyl radical or form with the nitrogen atom to which they are attached a ring piperidino, morpholino or pyrrolidino, - alk represents an alkylene or alkyl radical, with the exception of compounds for which either R2, R3 and R4 represent a hydrogen atom and R1 represents a carboxyl, alkoxycarbonyl, -CO-NH2 or -CO-NH-alk; either R4 represents a chlorine or bromine, R2 and R3 represent a hydrogen atom and R1 represents a carboxy, alkoxycarbonyl, -CO-NH2 or -CO-NH-alk radical; either R3 represents a chlorine or bromine atom, R2 and R4 represent a hydrogen atom and R1 represents a carboxyl, alkoxycarbonyl, -CO-NH2 or -CO-NH-alk, it being understood that the alkyl, alkoxy and alkylene radicals and the portions alkyl, alkoxy and alkylene have 1 to 6 carbon atoms in a chain straight or branched, their tautomer, their salts. 4 - Process for preparing the compounds of formula (I) according to claim 3 for which R1 represents a carboxy radical characterized in that a corresponding derivative of formula (I) is hydrolyzed for which R1 represents an alkoxycarbonyl radical, isolates the product and transforms it possibly salt. 5 - Process for preparing the compounds of formula (1) according to claim 3 in which R1 represents an alkoxycarbonyl radical characterized in that a derivative of formula is cyclized:

(II) in which R2, R3 and R4 have the same meanings as in the claim 3 and R10 represents an alkyl radical, isolates the product and the eventually turns into salt. 6 - Process for preparing the compounds of formula (1) according to claim 3 in which R1 represents an alkoxycarbonyl radical characterized in that a derivative of formula is reacted:

(IV) in which R2, R3 and R4 have the same meanings as in the claim 3, on a dialkyl oxalate, isolates the product and transforms it possibly salt. 7 - Process for preparing the compounds of formula (I) according to claim 3 for which R1 represents a tetrazolyl radical characterized in that the sodium azide is reacted with a derivative of formula:

(VII) in which R2, R3 and R4 have the same meanings as in the claim 3, isolates the product and optionally transforms it into a salt. 8 - Process for preparing the compounds of formula (I) according to claim 3 for which R1 represents a -CO-NH2 radical, -CO-NH-alk, -CO-N(alk)2, -CO-NHOH, -CO-N(alk)OH, -CO-NH-O-R5, -CO-N(alk)-R5 characterized in that a compound of formula (I) corresponding for which R1 represents a carboxy radical or alkoxycarbonyl on a derivative of formula:
HN(R11)-R12 (IX) in which R11 represents a hydrogen atom or an alkyl radical and R12 represents a hydrogen atom or an alkyl, hydroxy, -O-alk radical or -OR5 in which R5 represents an alkyl or phenylalkyl radical isolates the product and eventually transforms it into salt. 9 - Process for preparing the compounds of formula (I) according to claim 3 for which R1 represents a radical -CO-R6 in which R6 represents a radical -O-alk-R7, -O-alk-O-CO-alk, -O-alk-O-COOalk, -O-alk-O-CO-R7, -O-alk-OH, -O-alk-O-alk, -O-alk-S-alk, -O-alk-O-R7, -O-alk-S-R7, -O-alk-COOH, -O-alk-COOalk, -O-alk-NRgRg, -NH-alk-O-CO-alk, -NH-alk-O-COOalk, -NH-alk-O-CO-R7, -NH-alk-OH, -NH-alk-O-alk, -NH-alk-S-alk, -NH-alk-O-R7, -NH-alk-S-R7, -NH-alk-COOH, -NH-alk-COOalk, -NH-alk-NR8R9, characterized in that a corresponding compound of formula (I) for which R1 represents a radical carboxy or alkoxycarbonyl on a derivative of formula:
R6-H(X) in which R6 has the same meanings as above, isolates the product and eventually turns it into salt. 10 - Medicines comprising as active ingredient at least one compound of formula (I) according to claim 3 or their salts. 11 - Medicaments according to claim 10 useful as antagonists of NMDA receptor and/or AMPA receptor.