WO1994020109A1

WO1994020109A1 - Use of 2h-1,2,4-benzothiadiazine 3(4h)-one 1,1 dioxide derivatives as non-competitive nmda receptor antagonists

Info

Publication number: WO1994020109A1
Application number: PCT/FR1994/000207
Authority: WO
Inventors: François Audiau; Patrick Jimonet; Serge Mignani
Original assignee: Rhone-Poulenc Rorer S.A.
Priority date: 1993-03-03
Filing date: 1994-02-25
Publication date: 1994-09-15
Also published as: PL310439A1; FR2702150B1; EP0687178A1; AU6143694A; FR2702150A1; HU9502572D0; CA2153951A1; NO953387L; IL108784A0; JPH08507303A; NO953387D0

Abstract

The use of compounds of formula (I) or salts thereof for preparing non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists is disclosed.

Description

APPLICATION OF DERIVATIVES OF

2H-1, 2,4-BENZOTHIADIAZINE-3 (4H) -ONE-1, 1 -DIOXIDE AS

NON-COMPETITIVE NMDA RECEPTOR ANTAGONISTS

The present invention relates to a new therapeutic application of the compounds of formula:

or a salt of such a compound.

In formula (I), Rj, R2, R3 and R4, identical or different, represent a hydrogen atom, halogen or an alkyl or alkoxy radical, it being understood that Rj, R2, R3 and Rφ do not represent all four a hydrogen atom.

In the definitions which precede and those which follow, the alkyl and alkoxy radicals contain 1 to 6 carbon atoms in straight or branched chain, and, preferably, from 1 to 4 carbon atoms.

The compounds of formula (I) are described as antihypertensive agents

(patent BE 614008), antimicrobials (Il Farmaco, 29, 915 (1974); Il Farmaco, 28, 777 (1973)), bactericides (Chem. Abst., 98, 179337 (1983)), hyperglycaemic (J. Pharmacol. Exp. Ther., 164, 421 (1968), for their sweet taste (Chem. Abst., 55, 19943 (1960) and as synthesis intermediates (patent EP 161498; Chem. Abst., 85, 63097 (1976); Chem. Abst. 69, 2940 (1968)).

It has now been found that these compounds are non-competitive antagonists of the N-methyl-D-aspartate receptor (NMDA) and, more particularly, are ligands for the glycine modulator sites of the NMDA receptor. The compounds of formula (I) can be prepared by reaction of an aniline of formula:

in which R-j, R2, R3 and R4 have the same meanings as in formula (I) with chlorosulfonyl isocyanate.

This reaction is carried out in an inert solvent such as nitromethane, nitroethane, nitrobenzene, carbon disulfide, tetrachloroethane, in the presence of a FRIEDEL-CRAFTS type catalyst such as aluminum chloride, titanium tetrachloride, zirconium tetrachloride, at a temperature of 40 to 105 ° C.

The compounds of formula (I) can be purified by the usual known methods, for example by crystallization, chromatography or extractions.

The compounds of formula (I) can optionally be converted into metal salts or into addition salts with nitrogenous bases according to methods known per se. These salts can be obtained by the action of a metal base (alkaline or alkaline earth for example), ammonia, a tetraalkylammonium, an amine or a salt of an organic acid on a compound of formula ( I), in a solvent. The salt formed is separated by the usual methods.

Examples of pharmaceutically acceptable salts which may be mentioned are the salts with alkali metals (sodium, potassium, lithium) or with alkaline earth metals (calcium, magnesium), the ammonium salt, the tetraalkylammonium salts (tetrabutylammonium for example), salts of nitrogenous bases (ethanolamine, trimethylamine, methylamine, benzylamine, N-benzyl-β-phenethylamine, choline, arginine, leucine, lysine, N-methyl glucamine). As non-competitive antagonists of the N-methyl-D-aspartate receptor (NMDA) and more particularly as ligands for the glycine modulating sites of the NMDA receptor, these compounds are useful for treating or preventing all ischemias (such as focal or global ischemia) following stroke, cardiac arrest, low blood pressure, cardiac or pulmonary surgery or severe hypoglycemia. They are also useful in the treatment of effects due to anoxia, whether perinatal or consecutive to drowning or cerebro-spinal lesions. These compounds can also be used to treat or prevent the development of neurodegenerative diseases, HUNTINGTON chorea, ALZHEIMER disease, amyotrophic lateral sclerosis, olivopontocerebellar atrophy, PARKINSON disease . These compounds can also be used with respect to epileptogenic and / or convulsive manifestations, for the treatment of cerebral or spinal trauma, of anxiety (KEHNE et al., Eur. J. Pharmacol., 193, 283 (1991 ), depression (TRULLAS et al., Eur. J. Pharmacol., 185, 1 (1990), schizophrenia (REYNOLDS, TIPS, 13, 116 (1992), as analgesics (DICKENSON et al. , Neurosc. Letters, 121, 263 (1991), anti-anorexics (SORRELS et al., Brain Res., 572, 265 (1992), anti-emetics, anti-migraine and to treat poisonings by neurotoxins or other agonist substances of the NMDA receptor , as well as neurological disorders associated with viral diseases such as AIDS (LIPTON et al., Neuron, 7, 111 (1991), rabies, measles and tetanus (BAGETTA et al., Br. J. Pharmacol., 101, 776 (1990). These compounds are also useful for the prevention of symptoms of drug and alcohol abstinence and the inhibition of opiate addiction and dependence.

The affinity of the compounds of formula (I) for the glycine site linked to the NMDA receptor was determined by studying the antagonism of the specific binding of [ ³ H] -DCKA (6,8-dichloro kynurenic acid) on membranes of rat cerebral cortex according to a method derived from that described by BARON et al., Eur. J. Pharm., 206, 149 (1991). [ ³ H] -DCKA (20 nM) is incubated in the presence of 0.1 mg of proteins at 4 ° C. for 10 minutes in HEPES buffer (acid (N- [2-hydroxyethyl] piperazine-N'- [ 2-ethanesulfonic]) 50 mM, pH 7.5. The non-specific binding is determined in the presence of 1 mM glycine. The bound radioactivity is separated by filtration on Whatman GF / B filters. The inhibitory activity of these products is generally less than 100 μM.

The compounds of formula (I) have a low toxicity. Their LD50 is greater than 50 mg / kg by the IP route.

Of particular interest are the following compounds:

- 5-chloro-2H-1, 2,4-benzothiadiazine-3 (4H) -one-1, 1-dioxide,

- 6-iodo-2H-1, 2,4-benzothiadiazine-3 (4H) -one-1, 1-dioxide,

- 6,8-dimethyl-2H-1, 2,4-benzothiadiazine-3 (4H) -one-1, 1-dioxide,

- 6-chloro-2H-1, 2,4-benzothiadiazine-3 (4H) -one-1, 1-dioxide,

- 6,8-dichloro-2H-1, 2,4-benzothiadiazine-3 (4H) -one-1, 1-dioxide.

EXAMPLE 1

To a solution cooled to -5 ° C of 17.7 g of chlorosulfonyl isocyanate in 110 cm3 of nitromethane, a solution of 12.76 g of 2-chloroaniline in 35 cm3 of nitromethane is slowly added, then around 0 ° C 16.67 g of aluminum chloride. It is then heated to reflux and the reaction is stopped as soon as the reflux temperature reaches 101-102 ° C. by cooling in an ice bath. The reaction mixture is poured onto crushed ice and the precipitate obtained is filtered, washed with water and air dried. The colored solid (12.47 g) is crystallized from 160 cm3 of isopropanol and recrystallized from 135 cm3 of isopropanol to give 5.5 g of 5-chloro-2H-1, 2,4-benzothiadiazine-3 (4H) -one-1, 1-dioxide melting at 245 ° C.

EXAMPLE 2

The procedure is as in Example 1 but starting with 17.7 g of chlorosulfonyl isocyanate, 21.9 g of 3-iodoaniline and 16.67 g of aluminum chloride in nitromethane. Part of the crude product (9 g) is chromatographed on a silica column (500 g) with a mixture of ethyl acetate, methanol and triethylamine (80/20/1 by volume) and the product obtained (4 g) is crystallized twice from isopropanol, treated with 20 cm3 of 0.1 N hydrochloric acid, filtered and dried at 50 ° C to give 0.95 g of 6-iodo-2H-1,2 , 4-benzothiadiazine-3 (4H) -one-1, 1-dioxide as an off-white solid melting above 260 ° C (Analysis% calculated C: 25.94, 1-1: 1, 56, N : 8.64, 1: 39.16, 0: 14.81, S: 9.89,% found C: 26.3; H: 1.5; N: 8.8; 1: 39.0; 0 : 14.6; S: 9.6).

EXAMPLE 3

The procedure is as in Example 1, but starting from 17.7 g of chlorosulfonyl isocyanate, 12.12 g of 3,5-dimethylaniline and 16.67 g of aluminum chloride in nitromethane. The crude product (17 g) is treated by beating in 100 cm3 of tert-butyl methyl oxide and provides, after filtration and drying, 11.3 g of 6,8-dimethyl-2H-1, 2,4-benzothiadiazine-3 (4H ) -one- 1, 1-dioxide in the form of a light beige solid melting above 260 ° C (Analysis% calculated C: 47.78, H: 4.45, N: 12.38, 0:21, 21 , S: 14.17,% found C: 47.1; H: 4.5; N: 12.4; 0:21, 1; S: 14.1).

EXAMPLE 4

The procedure is as in Example 1, but using 51 g of chlorosulfonyl isocyanate, 38.1 g of 3-chloroaniline and 49.35 g of aluminum chloride in nitromethane. The crude product (19.2 g) is recrystallized from boiling isopropanol to yield 8.3 g of 6-chloro-2H-1,2,4-benzothiadiazine-3 (4H) -one-1, 1-dioxide as a light beige solid melting above 260 ° C (Analysis% calculated C: 36.14, H: 2.17, Cl: 15.24, N: 12.04, 0: 20.63, S: 13.78,% found C: 36.1; H: 2.4; Cl: 15.0, N: 11.7; 0: 20.8; S: 13.3).

EXAMPLE 5

The procedure is as in Example 1, but using 3.5 g of chlorosulfonyl isocyanate, 3.24 g of 3,5-dichloroaniline and 3.29 g of aluminum chloride in nitromethane. The crude product (3 g) is recrystallized from boiling 2-butanone to yield 0.8 g of hydrate of 6,8-dichloro-2H-1,2,4-benzothiadiazine-3 (4H) -one-1 , 1-dioxide in the form of a white solid melting above 260 ° C (Analysis% calculated C: 31, 48, H: 1.51, CI: 26.55, N: 10.49, 0: 17.97, S: 12.00,% found C: 31.5; H1.5; Cl: 26.5, N: 10.4; 0: 17.3; S: 12.1).

The medicaments consist of a compound of formula (I) in free form or in the form of a salt, in the pure state or in the form of a composition in which it is associated with any other pharmaceutically compatible product, which may be inert. or physiologically active. These drugs can be used orally, parenterally, rectally or topically.

As solid compositions for oral administration, tablets, pills, powders (gelatin capsules, cachets) or granules can be used. In these compositions, the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under a stream of argon. These compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (dragees) or a varnish.

As liquid compositions for oral administration, there may be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or oil paraffin. These compositions can include substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.

The sterile compositions for parenteral administration can preferably be aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other organic solvents can be used. suitable. These compositions can also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example by filtration sanitizer, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use 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 polyethylene glycols.

The compositions for topical administration can 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 the treatment and / or prevention of conditions which require the administration of an NMDA receptor antagonist or an AMPA receptor antagonist. These compounds are in particular useful for treating or preventing all ischemias and in particular cerebral ischemia, the effects due to anoxia, the development of neurodegenerative diseases, HUNTINGTON chorea, ALZHEIMER disease, amyotrophic lateral sclerosis, olivo-pontocerebellar atrophy and PARKINSON's disease, with respect to epileptogenic and / or convulsive manifestations, for the treatment of cerebral or spinal trauma, anxiety, depression, schizophrenia, as analgesics, antianorexics, antiemetics, antimigraine and to treat poisoning by neurotoxins or other substances agonists of the NMDA receptor, as well as the neurological disorders associated with viral diseases such as AIDS, rabies, measles and tetanus. These compounds are also useful for the prevention of symptoms of abstinence from drugs and alcohol and the inhibition of addiction and dependence on opiates.

The doses depend on the desired effect, on the duration of the treatment and on the route of administration used; they are generally between 10 mg and 100 mg per day orally for an adult with unit doses ranging from 5 mg to 50 mg of active substance. In general, the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated.

The following examples illustrate compositions according to the invention:

EXAMPLE A

Using the usual technique, capsules containing 50 mg of active product having the following composition are prepared:

- 5-chloro-2H-1, 2,4-benzothiadiazine-3 (4H) - one-1, 1-dioxide 50 mg - Cellulose 18 mg

- Lactose 55 mg

- Colloidal silica 1 mg

- Carboxymethyl starch sodium 10 mg

- Talc 10 mg - Magnesium stearate 1 mg

EXAMPLE B

Tablets containing 50 mg of active product having the following composition are prepared according to the usual technique:

- 6-iodo-2H-1, 2,4-benzothiadiazine-3 (4H) - one-1, 1-dioxide 50 mg

- Lactose 104 mg

- Cellulose 40 mg

- Polyvidone 10 mg

- Carboxymethyl starch sodium 22 mg - Talc 10 mg

- Magnesium stearate 2 mg

- Colloidal silica 2 mg

- Mixture of hydroxymethylcellulose, glycerin, titanium oxide (72-3,5-24,5) q.s.p. 1 film-coated tablet finished at 245 mg

EXAMPLE C A solution for injection containing 10 mg of active product having the following composition is prepared:

- 6,8-dimethyl-2H-1, 2,4-benzothiadiazine-3 (4H) - one-1, 1-dioxide 10 mg - Benzoic acid 80 mg

- Benzyl alcohol 0.06 cm ³

- Sodium benzoate 80 mg

- 95% ethanol 0.4 cm ³

- Sodium hydroxide 24 mg - Propylene glycol 1.6 cm ³

- Water q.s.p. 4 cm3

Claims

1 - Application of the compounds of formula:

in which Rj, R2, R3 and R4, identical or different, represent a hydrogen or halogen atom or an alkyl or alkoxy radical, it being understood that all R-), R2, R3 and R4 do not represent an atom of hydrogen and that the alkyl and alkoxy radicals contain 1 to 6 carbon atoms in a straight or branched chain or their salts, for the preparation of non-competitive antagonist drugs for the N-methyl-D-aspartate receptor (NMDA).

2 - Application according to claim 1 to the preparation of ligands for the glycine modulating sites of the NMDA receptor.

3 - Application according to one of claims 1 or 2 of the following compounds:

- 5-chloro-2H-1, 2,4-benzothiadiazine-3 (4H) -one-1, 1-dioxide, - 6-iodo-2H-1, 2,4-benzothiadiazine-3 (4H) -one- 1,1-dioxide,

- 6,8-dimethyl-2H-1, 2,4-benzothiadiazine-3 (4H) -one-1, 1-dioxide,

- 6-chloro-2H-1, 2,4-benzothiadiazine-3 (4H) -one-1, 1-dioxide,

- 6, 8-dichloro-2H-1, 2,4-benzothiadiazine-3 (4H) -one-1, 1-dioxide, or their salts.