JPH08507303A - Use of 2H-1,2,4-benzothiadiazin3 (4H) -one 1,1 dioxide derivatives as non-competitive NMDA receptor antagonists - Google Patents

Abstract

(57) Summary Disclosed is the use of a compound of formula (I) or salt thereof for the preparation of a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist.

Description

Detailed Description of the Invention 2H-1,2,4-benzothia as a non-competitive NMDA receptor antagonist Use of diazin 3 (4H) -one 1,1 dioxide derivative   The present invention has the formula: To a novel therapeutic use of the compounds of or of salts of such compounds.   In formula (I), R₁, R₂, R₃And R_FourAre the same or different and hydrogen Or a halogen atom or an alkyl or alkoxy group, R₁, R₂, R₃ And R_FourIt is understood that not all four of the above represent hydrogen atoms.   In the above definitions and below, alkyl or alkoxy groups are straight-chain or Contains 1 to 6 and preferably 1 to 4 carbon atoms in the branched chain.   Compounds of formula (I) are antihypertensive agents (Belgian Patent No. 614,008), antibacterial agents. (I1 Farmaco, 29, 915 (1974); I1 Farmaco, 28,777 (1973)), bactericide (Chem. Abst., 98, 1793). 37 (1983)), because of their sweetness, hyperglycemic agents (J. Pharmaco l. Exp. Ther. , 164, 421 (1968)) and during synthesis Interstitial (European Patent 161,4 No. 98; Chem. Abst. , 85, 63097 (1976); Chem. A bst. , 69, 2940 (1968)).   These compounds are non-competitive for N-methyl-D-aspartate (NMDA) receptors. An antagonist, more particularly a glycine modulator of the NMDA receptor It has now been found to be a ligand for position.   The compound of formula (I) has the formula   Where R₁, R₂, R₃And R_FourIs synonymous with formula (I), It can be prepared by the reaction of aniline with chlorosulfonyl isocyanate.   This reaction can be performed, for example, with nitromethane, nitroethane, nitrobenzene, carbon disulfide. In an inert solvent such as elemental or tetrachloroethane, for example aluminum chloride, Friedel Crafts type catalysts such as titanium tetrachloride or zirconium tetrachloride At a temperature of 40-105 ° C.   The compounds of formula (I) may be prepared by known methods, eg crystallization, chromatography or It can be purified by extraction.   The compounds of formula (I) are optionally provided with metal salts or nitrites according to methods known per se. It can be converted into an addition salt with a base. These salts are prepared by reacting a compound of formula (I) in a solvent. A metal (eg, alkali metal or alkaline earth metal) base, ammonia , Tetraalkylammonium, amine or It can be obtained by acting a machine salt. The salt formed is separated in the usual way.   Examples of pharmaceutically acceptable salts include alkali metals (sodium, potassium). , Lithium) or salts with alkaline earth metals (calcium, magnesium) , Ammonium salts, tetraalkylammonium (eg tetrabutylammonium Um) salts and nitrogenous bases (ethanolamine, trimethylamine, methyl Amine, benzylamine, N-benzyl-β-phenethylamine, choline, al Ginine, leucine, lysine, and N-methylglucamine).   Non-competitive antagonis of N-methyl-D-aspartate (NMDA) receptor And more specifically a ligand for the glycine regulatory site of the NMDA receptor Thus, these compounds may cause seizures, cardiac arrest, hypotension, surgical heart or lung surgery. Intervention or treatment or treatment of global ischemia with severe hypoglycemia (eg focal or global ischemia) Is effective in prevention. They also have the effects of anoxia (they are perinatal Or associated with either drowning injury or cerebrospinal injury) It is also useful for the treatment of These compounds are also used in the neurodegenerative disease Hunting Chorea, Alzheimer's disease, amyotrophic lateral sclerosis, olive pontine cerebellar atrophy and It can be used to treat or prevent the progression of Parkinson's disease. These compounds are even more epileptic Brain or spinal cord injury, anxiety (Kehne et al., E. ur. J. Pharmacol. , 193, 283 (1991)), depression (Tr ullas et al., Eur. J. Pharmacol. , 185, 1 (1990)) , Schizophrenia (Reynolds, TIpS, 13, 116 (1992)) For treatment, analgesics (Dicken Son et al., Neurosc. Letters, 121, 263 (1991)), Anti-anorexic (Sorrels et al., Brain Res., 572, 265 (1 992)), as an antiemetic agent, a migraine agent, and as a neurotoxin or NMDA receptor agonist Poisoning with other substances that are nysts, as well as AIDS (Lipton et al., N euron, 7, 111 (1991),), rabies, measles and tetanus (Bag). etta et al., Br. J. Pharmacol. , 101, 776 (1990)) It can be used to treat neurological problems associated with viral diseases such as. A combination of these Things further prevent drug and alcohol withdrawal symptoms, and against opiates It is useful for suppressing addiction and dependence.   The affinity of compounds of formula (I) for the glycine site bound to the NMDA receptor is Baron et al., Eur. J. Pharm. , 206, 149 (1991). According to the method derived from the above method, the rat cortical membrane [³H]- Investigate the specific binding antagonism of DCKA (6,8-dichlorokynurenic acid) Be measured. [³H] -DCKA (20 nM), 0.1 mg of protein Quality of 50 mM HEPES (N- [2-hydroxyethyl] piperazi -N '-[2-ethanesulfonic acid]) buffer, pH 7.5 at 4 ° C for 10 minutes. Incubate for Non-competitive binding is measured in the presence of 1 mM glycine . Bound radioactivity is separated by filtration through Whatman GF / B filter paper. Inhibition of these products The activity is generally less than 100 μM.   The toxicity of the compounds of formula (I) is low. These LD₅₀50 mg / in the intraperitoneal route Greater than kg.   The following compounds are of particular interest: -5-chloro-2H-1,2,4-benzothiadiazin-3 (4H) -one 1 , 1-dioxide, -6-Iodo-1,2,4-benzothiadiazin-3 (4H) -one 1,1- Dioxide, -6,8-Dimethyl-2H-1,2,4-benzothiadiazine-3 (4H)- On 1,1-dioxide, -6-Chloro-2H-1,2,4-benzothiadiazin-3 (4H) -one 1 , 1-dioxide, -6,8-Dichloro-2H-1,2,4-benzothiazin-3 (4H) -one 1,1-dioxide.Example 1   110 cm³17.7 g of chlorosulfonyl isocyanate in nitromethane 35 cm to the solution cooled to −5 ° C.³12.76g of 2 in nitromethane A solution of chloroaniline is added slowly; then 16.67 g in the region of 0 ° C. Aluminum chloride is added. The mixture is then heated to reflux and the reflux temperature As soon as the temperature reaches 101 to 102 ° C, the reaction is stopped by cooling in an ice bath. Reaction mixture The mixture was poured onto crushed ice and the resulting precipitate was filtered, washed with water and blown. Dried 160 cm³A colored solid (12.47 g) was crystallized from isopropanol. And then 135 cm³Recrystallized from isopropanol, mp 245 ° C 5.5 g of 5-chloro-2H-1,2,4-benzothiadiazine-3 (4)- An on 1,1 dioxide is obtained.Example 2   17.7 g of chlorosulfonyl isocyanate, 21.9 g of 3-yo Starting from doaniline and 16.67 g of aluminum chloride and nitrometa The same operation as in Example 1 is carried out except that the treatment is carried out in the room. Part of crude product (9 g ) Is a mixture of ethyl acetate, methanol and triethylamine (80/2 by volume). Chromatograph on a column of silica (500 g) with 0/1) and obtain The product obtained (4 g) was crystallized twice from isopropanol, 20 cm³0. Treated with 1N hydrochloric acid, filtered and dried at 50 ° C, melting point above 260 ° C 0.95 g of 6-iodo-1,2,4-benzothiadiazin-3 (4) -one 1 , 1 dioxide is obtained in the form of an off-white solid (Analysis: calculated% C: 25.94, H: 1.56, N: 8.64, I: 39.16, O: 14.81, S: 9.89, measured% C: 26.3, H: 1.5, N: 8.8, I: 39.0 , O: 14.6, S: 9.6).Example 3   17.7 g chlorosulfonyl isocyanate, 12.12 g 3,5-dime Starting from tilaniline and 16.67 g of aluminum chloride and nitrometa The same operation as in Example 1 is carried out except that the treatment is carried out in the room. The crude product (17 g) 100 cm³In tert-butyl methyl ether, filtered and dried Then, 11.3 g of 6,8-dimethyl-2H-1,2,4 having a melting point higher than 260 ° C. -Benzothiadiazin-3 (4) -one 1,1 dioxide as a light beige solid Obtained in body form (analysis:% calculated C: 47.78, H: 4.45, N: 12. 38, O: 21.21, S: 14.17, measured% C: 47.1, H: 4.5, N: 12.4, O: 21.1, S: 14.1).Example 4   51 g of chlorosulfonyl isocyanate, 38.1 g of 3-chloroaniline Starting from 49.35 g of aluminum chloride and treating in nitromethane Except for the above, the same operation as in Example 1 is performed. The crude product (19.2 g) was boiled Recrystallized from propanol to give 8.3 g of 6-chloro-m.p. 2H-1,2,4-benzothiadiazin-3 (4) -one 1,1 dioxide Obtained in the form of a light beige solid (analysis:% calculated C: 36.14, H: 2. 17, Cl: 15.24, N: 12.04, O: 20.63, S: 13.78, Found% C: 36.1, H: 2.4, Cl: 15.0, N: 11.7, O: 20 ． 8, S: 13.3).Example 5   3.5 g chlorosulfonyl isocyanate, 3.24 g 3,5-dichloro Starting from aniline and 3.29 g of aluminum chloride and in nitromethane The same operation as in Example 1 is performed except that the treatment is performed. Boiling crude product (3 g) 2- Recrystallized from butanone to give 0.8 g of 6,8-dichloro having a melting point higher than 260 ° C. -2H-1,2,4-benzothiadiazin-3 (4) -one 1,1 dioxide The hydrate is obtained in the form of a white solid (analysis: calculated% C: 31.48, H: 1.5). 1, Cl: 26.55, N: 10.49, O: 17.97, S: 12.00, fruit % C: 31. 5, H: 1.5, Cl: 26.5, N: 10.4, O: 17 ． 3, S: 12.1).   The drug is either pure, inactive or physiologically active. Release in the form of a composition in combination with any other pharmaceutically compatible substance A compound of formula (I) in the form or in the form of a salt Become These drugs are used by the oral, parenteral, rectal or topical routes. Can be used.   Solid compositions for oral administration include tablets, pills, powders (gelatin capsules if A bag or granules can be used. In these compositions, the active ingredient according to the invention is Is one or more inert diluents such as starch, cellulose, sucrose, lactose Alternatively, it is mixed with silica under an argon stream. These compositions are also diluents One or more substances other than, eg magnesium stearate or talc Lubricants, colorants, coatings or glazes can be included.   Liquid compositions for oral administration include, for example, water, ethanol, glycerol, plant Pharmaceutically acceptable, containing an inert diluent such as a substance oil or paraffin oil Solutions, suspensions, emulsions, syrups and elixirs can be used. these The composition may include substances other than diluents, such as wetting agents, sweetening agents, thickening agents, flavoring agents, or stabilizing agents. A fixed agent can be included.   As a sterile composition for parenteral administration, preferably an aqueous or non-aqueous solution, It can be a suspension or an emulsion. Solvents or excipients include water, Ropylene glycol, polyethylene glycol, vegetable oil, especially olive oil, injection Possible organic esters such as ethyl oleate or other suitable organic solvent are used it can. These compositions further include adjuvants, especially wetting agents, isotonic agents, emulsifying agents, Dispersants and stabilizers can be included. Sterilization can be accomplished in many ways, for example by sterile filtration. It can be achieved by the incorporation of sterile agents into the composition, by irradiation or by heating. They are Furthermore, it can be prepared in the form of a sterile solid composition, which is either sterile water or It can be dissolved in any other sterile injectable medium.   Compositions for rectal administration include, for example, cocoa butter and semi-synthetic glycerides in addition to the active ingredients. Suppository or rectal capsule containing an excipient such as polyethylene glycol. It   Compositions for topical administration include, for example, creams, lotions, eye drops, mouthwashes, nasal drops. It is an agent or an aerosol.     In the treatment of humans, the compounds according to the invention are suitable for antagonizing the NMDA receptor. Treatment of diseases requiring administration of nyst or AMPA receptor antagonists and And / or is particularly useful for prevention. These compounds cause global ischemia, and especially cerebral ischemia , Effects of anoxia, neurodegenerative diseases, Huntington's chorea, Alzheimer's disease Disease, amyotrophic lateral sclerosis, olive pontine cerebellar atrophy and Parkinson's disease progression For treatment or prevention, brain or spinal cord injury, anxiety, with regard to epilepsy and / or convulsive symptoms For the treatment of depression and schizophrenia, as an analgesic, antidepressant, antiemetic, migraine, And poisoning by neurotoxins and other substances that are agonists of NMDA receptors, Gods associated with viral diseases such as AIDS, rabies, measles and tetanus It is especially useful in treating medical problems. These compounds are also available as drugs and alcohols. Useful for the prevention of withdrawal symptoms of opiates and for controlling addiction and dependence on opiates. is there.   The dose depends on the desired effect, the duration of treatment and the route of administration used, but These are generally 10 mg to 100 mg per day orally for adults, single dose The amount ranges from 5 mg to 50 mg of active substance.   In general, doctors will be admitted according to age, weight and other factors specific to the subject being treated. Will determine the appropriate dose.   The following examples illustrate compositions according to the present invention.Example A   A gelatin capsule containing 50 mg of active ingredient and having the following composition was prepared in a conventional manner. Prepare according to.   -5-chloro-2H-1,2,4-benzothia-50 mg       Diazin-3 (4H) -one 1,1-dioxide   -Cellulose 18 mg   -Lactose 55 mg   − Colloidal silica 1 mg   -Carboxymethyl sodium starch 10 mg   − Talc 10 mg   -Magnesium stearate 1 mgExample B   A tablet containing 50 mg of active ingredient and having the following composition is prepared in a conventional manner It   -6-iodo-1,2,4-benzothiadiazine-50 mg       3 (4H) -one 1,1-dioxide   -Lactose 104 mg   -Cellulose 40 mg   -Polyvidone 10mg   -Carboxymethyl sodium starch 22 mg   − Talc 10 mg   -Magnesium stearate 2 mg   − Colloidal silica 2 mg   -Hydroxymethyl cellulose, glycerin,       Of titanium oxide (72 / 3.5 / 24.5)       Mixture, one finish film coating weighing 245 mg total       Enough to make a tabletExample C   Prepare an injectable solution containing 10 mg of active ingredient and having the following composition .   -6,8-Dimethyl-2H-1,2,4-benzo-10 mg       Thiadiazin-3 (4H) -one 1,1-       Dioxide   -Benzoic acid 80mg   -Benzyl alcohol 0.06       cm³   -Sodium benzoate 80mg   -95% ethanol 0.4       cm³   -Sodium hydroxide 24mg   -Propylene glycol 1.6       cm³   -Total water 4 cm³Enough to say

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Claims (1)

[Claims] 1. formula In the formula, R ₁ , R ₂ , R ₃ and R ₄ are the same or different and each represents a hydrogen atom, a halogen atom or an alkyl or alkoxy group (wherein R ₁ , R ₂ , R ₃ and R ₄ are 4 Not all represent hydrogen atoms, and the alkyl or alkoxy groups are understood to contain 1 to 6 carbon atoms in a straight-chain or branched chain), or salts thereof, Use for the preparation of non-competitive antagonists of the N-methyl-D-aspartate (NMDA) receptor. 2. Use according to claim 1 for the preparation of a ligand for the glycine regulatory site of the NMDA receptor. 3. The following compounds: -5-chloro-2H-1,2,4-benzothiadiazin-3 (4H) -one 1,1-dioxide, -6-iodo-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-benzothiadiazin-3 (4H) -one 1,1-dioxide, -6,8-dichloro-2H-1,2,4-benzothiazin-3 (4H) -one 1,1 -The use of a dioxide, or a salt thereof, according to any of claims 1 and 2.