RU2171256C2 - 4-amino-2-(4-methylpiperazine-1-yl)-5-(2,3,5-trichlorophenyl)- -pyrimidine and its salts of acid addition, methods of their synthesis (variants) and pharmaceutical composition - Google Patents

Abstract

FIELD: organic chemistry, chemical technology, pharmacy. SUBSTANCE: invention relates to the novel compound, 4-amino-2-(4-methyl- piperazine-1-yl)-5-(2,3,5-trichlorophenyl)-pyrimidine (compound A) and its salts of acid addition, methods of their synthesis (variants) and pharmaceutical composition. The first method of synthesis of compound (A) or its salts involves interaction of compound of the formula (I)

where L is the group to be removed and Y is cyano-group with compound of the formula (II)

or its salt. Another method of synthesis involves interaction of compound of the formula (IV)

where Y is cyano-group and R₁₀ and R₁₁ are alkyl or in common they form the group -(C(R)₂)_n where R means hydrogen atom or alkyl and n = 2-4 with compound of the formula (II). Indicated compounds are able to inhibit glutamate release and can be used for treatment of patients with disorders of central nervous system, for example, for prophylaxis of cerebral ischemic damages. Pharmaceutical composition shows property of inhibitor of glutamate release and has the compound (A) as an active component or its pharmaceutically acceptable salt of acid addition and pharmaceutically acceptable carrier. Composition is made in the form for oral intake. EFFECT: new compound indicated above, improved method of synthesis, valuable medicinal properties. 18 cl, 1 tbl, 1 ex

Description

 The invention relates to a pyrimidine compound, which is suitable for the treatment of diseases and disorders of the central nervous system (CNS), for example, for the prevention of cerebral ischemic lesions, to pharmaceutical compositions containing it and to methods for its preparation.

 Glutamate is an excitatory amino acid that acts as a neurotransmitter. However, if its extracellular concentration is high enough, glutamate acts as a strong neurotoxin that can kill central nervous system neurons (Rothman and Olney (1986) Prog. Drain. Res., 63, 69). The neurotoxic effects of glutamate contribute to a number of diseases and disorders of the central nervous system, including cerebral ischemic damage, epilepsy and chronic neurodegenerative disorders such as Alzheimer's disease, disorders of the motor system and Huntington’s chorea (Meldrum Clinical Science, (1985), 68, 113-122 ) In addition, glutamate contributes to other neurological disorders, such as manic depression, depression, schizophrenia, high-pressure neurological syndrome, chronic pain, trigeminal neuralgia, and migraine.

 EP-A-21121 discloses a group of 3,5-diamino-6 (substituted phenyl) -1,2,4-triazines that are active in the treatment of CNS diseases, for example in the treatment of epilepsy. One of the compounds described in this application, 3,5-diamino-6 (2,3-dichlorophenyl) -1,2,4-triazine (lamotrigine) has been shown to inhibit the release of excitatory amino acids, glutamate and aspartate (Leach et al., Epilepsia, 27, 490-497, 1986, AA Miller et al., New anticonvulsant drugs. Ed. Meldrum and Porter, 165-177, 1987).

 The present inventors have found that the substituted pyridine compound is a potential inhibitor of glutamate release; this compound is useful in the treatment of the above diseases and disorders of the central nervous system. The pyrimidine compound is also an aspartate release inhibitor.

 Thus, the present invention relates to 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine or its pharmaceutically acceptable acid addition salts.

 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine and its pharmaceutically acceptable acid addition salts are useful in diseases or disorders of the central nervous system in mammals that involve glutamate . Therefore, they can be used in the treatment or prevention of acute and chronic disorders of the central nervous system of mammals. Acute conditions include cerebral ischemia, which can occur for a variety of reasons, including stroke, cardiac arrest, bypass surgery, neonatal hypoxia, and hypoglycemia; and also physical lesions or injuries to the spinal cord or brain.

 Chronic neurodegenerative disorders that can be treated include Alzheimer's disease, Huntington’s chorea, Olivopontocerebral atrophy, and motor system disorders. Other neurological conditions that can be treated with the compound of the present invention include depression, manic depression, schizophrenia, chronic pain, epilepsy, trigeminal neuralgia, and migraines.

 The compound of the present invention can be used in the treatment of diseases or disorders of the central nervous system in mammals in which neurotoxic extracellular glutamate is involved. You can treat mammals with or predisposed to neurotoxic levels of extracellular glutamate in the central nervous system.

 Suitable pharmaceutically acceptable acid addition salts of 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine include those which are formed with both organic and inorganic acids. Typically, such acid addition salts are pharmaceutically acceptable. Thus, preferred salts include those derived from hydrochloric, hydrobromic, sulfuric, citric, tartaric, phosphoric, dairy, pyruvic, acetic, succinic, fumaric, maleic, oxalic, acetic, methanesulfonic, ethanesulfonic, para-toluenesulfonic acid and benzene, . These salts can be obtained by reacting the compounds in the form of free bases with the corresponding acids.

 Although 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine can be administered as a pure chemical compound, it is preferable to include it in pharmaceutical compositions. The pharmaceutical composition of the present invention includes 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine or its pharmaceutically acceptable acid addition salts together with one or more of their acceptable carriers, and optionally with other therapeutic ingredients. The carrier (s) should be "acceptable" in the sense that it must be compatible with the other ingredients of the composition and should not harm anyone who takes it.

 These compositions include those suitable for oral, parenteral (including subcutaneous, intramuscular and intravenous injection), rectal and superficial (including application to the skin, through the nose or under the tongue) administration, although the most appropriate method will depend on the condition and degree of the disease the patient. Compositions can usually be made in unit dosage form, and can be obtained by any means known to pharmacists. All methods include the step of combining 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine or a pharmaceutically acceptable acid addition salt thereof (“active ingredient”) with a carrier that consists of one or more accessory ingredients. Typically, compositions are prepared by thoroughly mixing the active ingredient with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the composition.

 Compositions of the present invention suitable for oral administration may be presented in discrete form, for example in the form of capsules, cachets or tablets, each containing a certain amount of the active ingredient; in the form of a powder or granules, in the form of a solution or suspension in an aqueous diluent or in a non-aqueous liquid; or in the form of an oil in water liquid emulsion, or water in oil. The active ingredient may also be presented as a bolus, a medicinal porridge or paste.

 Tablets can be made by compression or melt, optionally with one or more of the auxiliary ingredients. Compressed tablets may be prepared by compressing, in a suitable device, the active ingredient in a free-flowing form, for example in the form of a powder or granules, optionally in admixture with a binder, lubricating agent, inert diluent, surface active or dispersing agent. Melt tablets can be prepared by melting in a suitable device a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated and may be designed to provide a slow or controlled release of the active ingredient from them.

 Compositions from parenteral administration include aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, buffering agents, bacteriostats and dissolved substances, which render the compositions isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending and thickening agents. Such compositions may exist in unit dose or in multi-dose packages, for example, in sealed ampoules and tubes, and may be stored in freeze-dried lyophilized conditions that require only the addition of a sterile liquid carrier, e.g., water for injection, immediately before use.

 Injectable solutions and suspensions can be prepared for immediate administration from sterile powders, granules and tablets of the types previously described.

 Formulations for rectal administration may be formulated as suppositories with such conventional carriers as cocoa butter or polyethylene glycol.

 Topical compositions, for example, over the cheek or under the tongue, include lozenges containing the active ingredient with flavors such as sucrose and acacia or tragacanth, and lozenges containing the active ingredient in a base such as gelatin and glycerin, or sucrose and acacia .

 Preferred unit dosage formulations comprise an effective dose, as will be described later, or an appropriate portion thereof of the active ingredient.

 It should be borne in mind that, in addition to the ingredients specified above, the compositions of the present invention may include other agents customary for practice and concerning the type of composition under consideration; for example, compositions for oral administration may include flavoring agents or perfumes.

 Tablets or other forms provided in discrete form may contain such amounts of 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine which are effective at such doses or in in multiple doses, for example, single doses can be from 5 to 500 mg, and usually from 10 to 250 mg.

 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine is preferably used to treat disorders and diseases of the central nervous system by oral administration or by injection (intraparenteral or subcutaneous). The exact amounts administered to a patient will depend on the attending physician. However, the dose administered should depend on a number of factors, including the age or gender of the patient, the exact diagnosis and the degree of the disease to be treated. So, for example, in the treatment of a patient with epilepsy, the dose range should apparently be significantly lower than in the treatment of a patient after an impact to relieve cerebral ischemic lesions. Similarly, the route of administration, apparently, should vary depending on the condition and its severity.

 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine can be administered orally or by injection in doses of 0.1 to 30 mg / kg per day. The dosage range for adults is usually from 8 to 2400 mg / day, and preferably from 35 to 1050 mg / day. Since some compounds of formula I are long-acting compounds, it may be convenient to administer an initial dose of 70 to 2400 mg on the first day, and then reduce the dose on subsequent days to 20-1200 mg.

 A long-acting compound is especially important in clinics, as it is easier to work with. In chronic situations, they can be administered without infusion, and thus minimize medical intervention; also in acute conditions, it is possible to reduce inconvenience to the patient by reducing the daily dose.

где L представляет уходящую группу и является циано, с соединением формулы II:

или его солью, и выделение полученного таким образом 4-амино-2-(4-метилпиперазин-1-ил)-5-(2,3,5-трихлорфенил)пиримидина в виде свободного основания или в виде его соли присоединения кислоты.4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine or its pharmaceutically acceptable acid addition salts can be prepared by a process that involves reacting a compound of the formula:

where L represents a leaving group and is cyano, with a compound of formula II:

or a salt thereof, and isolating the 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine thus obtained as the free base or as its acid addition salt.

Examples of suitable leaving groups (L) include C _1-4 alkoxy, halogen, animino, morpholino, C _1-4 alkylamino, benzylamino and alkylthio.

Preferably, the reaction of the compounds of formula I and II is carried out in a non-aqueous solvent, for example in an alkanol such as ethanol, at elevated temperatures (for example, between 50 and 110 ^° C.) in a base, preferably in an alkoxide, preferably under reflux using sodium ethoxide as a basis.

где Y представляет циано (JACS, 1951, 73, 3763-3770), с диазометаном или алкилортоэфирами (JACS, 1952, 74, 1310-1313), или при конденсации с амином.Compounds of formula I can be prepared by methods known in the art, for example, by reacting a compound of formula III:

where Y is cyano (JACS, 1951, 73, 3763-3770), with diazomethane or alkyl orthoesters (JACS, 1952, 74, 1310-1313), or by condensation with an amine.

The compound of formula II can be obtained by standard methods, for example, by reacting the known compound H ₂ NC (NH) -R ₁ , where R ₁ is alkylthio, with N-methylpiperazine. This reaction preferably proceeds at room temperature in water.

где Y представляет циано и R₁₀ и R₁₁ представляют алкил, или вместе образуют группу -(C(R)₂)_n-, где n представляет целое число от 2 до 4, и R представляет H или алкил, с соединением формулы II, которое определено выше. Предпочтительно реакцию вести в неводном растворителе, например этаноле, при кипячении с обратным холодильником, используя этоксид натрия в качестве основания.4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine can alternatively be prepared by a process that involves reacting a compound of formula IV:

where Y represents cyano and R ₁₀ and R ₁₁ represent alkyl, or together form a group - (C (R) ₂ ) _n -, where n represents an integer from 2 to 4, and R represents H or alkyl, with a compound of formula II, which is defined above. Preferably, the reaction is carried out in a non-aqueous solvent, for example ethanol, under reflux, using sodium ethoxide as the base.

 The following example illustrates the invention. 2 reference examples are also provided.

REFERENCE EXAMPLE 1
Obtaining N-methylpiperazinformamidine iodohydrate
10.8 g of thiourea are dissolved in acetone (250 ml) at 50 ^° C. 10 ml of iodomethane are added and the reaction mixture is stirred at 50 ^° C. for 4 hours. After cooling, the solution is diluted with ether (1 l) and the methyl iodide salt is filtered off, washed ether and dried in vacuum, get 29.2 g, so pl. 113-115 ^o C. 5 g of methyl iodide salt is dissolved in water (30 ml) and N-methylpiperazine is added. The resulting solution was stirred, sparging nitrogen through it at room temperature for 24 hours. The solution was concentrated in vacuo. The residue was stirred with ethanol, filtered and dried in vacuo. 4.98 g, mp. 230-242 ^o C.

REFERENCE EXAMPLE 2
1. Obtaining 2,3,5-trichlorobenzyl alcohol
To a solution of 2,3,5-trichlorobenzaldehyde (Aldrich, 50 g) in ethanol (1.0 L) was added NaBH ₄ (7.0 g) at room temperature and the resulting mixture was stirred for 3.5 hours. The reaction was quenched with water, and the solvent was evaporated in vacuo before partitioning the residue between CHCl ₃ and saturated NaHCO ₃ solution. The organic phase was washed with brine, dried over MgSO ₄ , filtered, and the solvent was evaporated in vacuo to a solid. Obtain 43.0 g, so pl. 90-93 ^o C.

2. Obtaining 2,3,5-trichlorobenzyl bromide
PBr ₃ (126.58 g) was added to a solution of alcohol in benzene (400 ml) under a nitrogen atmosphere, and the resulting mixture was stirred at 55-60 ^° C for 3.5 hours. After cooling, the mixture was poured onto crushed ice (2 L) and the benzene layer is isolated. The aqueous phase was washed with benzene (x3), and the combined benzene extracts were washed with saturated NaHCO ₃ solution and water, dried with MgSO ₄ , filtered, and the solvent was evaporated to a brownish liquid, which solidified upon standing; 37.53 g, mp 40-42 ^o C.

3. Obtaining 2,3,5-trichlorophenylacetonitrile
The bromide is suspended in a mixture of dimethylformamide (130 ml) and water (86.67 ml) at 0 ^° C. and KCN (12.99 g) is added in portions. After stirring at 30-35 ^° C. for 3 hours, the suspension was diluted with water and extracted with EtO ₂ . The combined ether extracts were washed with water, dried over MgSO ₄ , filtered, and the solvent was evaporated in vacuo. After chromatographic treatment on silica gel using hexane up to 20% ether-hexane as the eluent, the expected product is obtained in the form of a white solid, 18.52 g, mp 60-62 ^o C.

EXAMPLE
Preparation of 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine mesylate
1. Obtaining the sodium salt of 2- (2,3,5-trichlorophenyl) -3-oxo-propionitrile
To a solution of sodium ethoxide (NaOEt) (from 0.803 g of sodium) in ethanol (55 ml), ice-cooled under nitrogen atmosphere was added 1,3,5-trichlorophenylacetonitrile (Reference Example 2). Ethyl format (5.1 ml) was added and the resulting mixture was stirred at room temperature overnight. After stirring for a further 2.5 hours at 50 ^° C., the resulting mixture was cooled and filtered. The resulting filtrate was evaporated, and the residue was triturated thoroughly with diethyl ether, filtered and dried (6.82 g).

2. Preparation of 2- (2,3,5-trichlorophenyl) -3-methoxy-acrylonitrile
The above solid was dissolved in DMF (36 ml) and 2 ml of methyl iodide was added. The reactor was sealed before its contents were stirred for 3 hours at 40 ^° C. The solvent was then evaporated. The residue was partitioned between water and ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and the solvent is evaporated to obtain the crude product as a red-brown oil, which solidifies upon standing (5.04 g).

3. Preparation of 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine
To a solution of NaOEt (from 0.21 g of sodium) in ethanol (20 ml) was added N-methylpiperazinformamidine hydroiodide (2.06 g) (Reference Example 1). After stirring for another 10 minutes, 2- (2,3,5-trichlorophenyl) -3-methoxyacrylonitrile (1 g) was added, and the resulting mixture was stirred at reflux for 4 hours. The resulting mixture was allowed to stand at room temperature at overnight and then filtered. The resulting filtrate was concentrated, and the residue was purified by chromatography on SiO ₂ , eluting with CHCl ₃ to 4% MeOH / CHCl ₃ to give the title compound as a free base. 0.89 g, mp 162-164 ^o C.

Then 0.805 g of the free base is dissolved in ethanol (35 ml) and cooled in an ice bath. Methanesulfonic acid (0.21 g) was added and the reaction mixture was stirred at room temperature for 2 hours. Then the solvent was evaporated and the residue was triturated with diethyl ether, filtered, dissolved in cold water and freeze dried to give the title salt as solid product, pale green, 0.98 g, so pl. 143-146 ^o C.

¹ H NMR (δ), dimethylformamide (DMSO) -d ₆ : 7.8 (1, 1H), 7.65 (s, 1H), 7.36 (d, 1H), 6.33-6.23 ( broad, 2H), 3.68 (t, 4H), 2.32 (t, 4H), 2.2 (s, 3H).

Accepted abbreviations for designations:
s - singlet, d - doublet, t - triplet, wide - wide singlet.

Examples of pharmaceutical compositions
A: Injection (I)
The 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine salt is dissolved in sterile water for injection.

Pharmacological activities
Inhibition of Glutamate Release and Inhibition of Rat Liver DHFR
4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine was tested for efficacy against veratrin-induced glutamate release from rat brain slices according to the protocol described in Epilepsia 27 ( 5): 490-497, 1986. A protocol for testing inhibition of DHFR activity is a modification of the method described by Biochemical Pharmacology, Vol. 20, pp. 561-574, 1971.

The results are shown in the table, and the IC ₅₀ is the concentration of the compound, causing 50% inhibition of (a) induced by glutamate release veratrin, and (b) DHFR enzyme activity.

 In the following examples of pharmaceutical compositions B to D, 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine or a pharmaceutically acceptable acid addition salt thereof can be used as the active compound .

B: Compositions for capsules
Composition for capsule A, mg / capsule.

 Composition A can be prepared by mixing the ingredients and filling two-piece hard gelatin capsules with the resulting mixture.

(a) Active ingredient - 250
(b) Lactose BP - 143
(c) Sodium starch glycolollate - 25
(d) Magnesium stearate - 2-420
Composition for capsule B, mg / capsule:
(a) Active ingredient - 250
(b) Macrogel 400 BP - 350 - 600
Capsules can be made by melting Macrogel 400 BP, dispersing the active ingredient in the melt and filling them with two-part gelatin capsules.

Compositions for capsules C (capsules with controlled release), mg / capsule:
(a) Active ingredient - 250
(b) Microcrystalline cellulose - 125
(c) Lactose BP - 125
(d) Ethyl cellulose - 13 - 513
Controlled release capsule compositions can be prepared by extruding the mixed ingredients (a) to (c) using an extruder, spherical, and drying the extrudate. The dried tablets are coated with ethyl cellulose (d) as a release control membrane and filled into two-piece hard gelatine capsules.

C. Syrup composition, g:
Active ingredient - 0.2500
Sorbitol solution - 1.5000
Glycerin - 1,0000
Sodium benzoate - 0.0050
Flavoring agent, ml - 0.0125
Purified water, ml - Up to 5.0
Sodium benzoate is dissolved in a portion of purified water and a solution of sorbitol is added. The active ingredient is added and dissolved. The resulting solution is mixed with glycerin, and then adjusted to the desired volume of purified water.

D. Suppository Compositions, mg / suppository:
Active ingredient (63 μm) ^* - 250
Solid Fat, BP (Witepsol H15 - Dynamit Nobel) - 1770 - 2020
^{* The} active ingredient is used in the form of a powder in which at least 90% of the particles have a diameter of 63 microns or less.

One fifth of Witepsol H15 is melted in a vessel with a steam jacket at a maximum of 45 ^° C. The active ingredient is passed through a 200 μm sieve and added to the molten base using Silverson with a cutting head until a uniform dispersion is obtained. Maintaining the temperature of the mixture at 45 ^° C, Witepsol H15 residue is added to the suspension, which is stirred to ensure a homogeneous mixture. Then, the entire suspension is passed through a 250 μm stainless steel sieve, and with continuous stirring, it is allowed to cool to 40 ^° C. At a temperature of 38-40 ^° C, 2.02 g aliquots of the mixture are filled into suitable plastic forms and the suppositories are allowed to cool to room temperature.

Claims (18)

 1. 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine and its acid addition salt.  2. The compound according to claim 1, which is a pharmaceutically acceptable acid addition salt of 4-amino-2- (4-methyl-piperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine.  3. The compound according to claim 2, which is a salt formed by hydrochloric, hydrobromic, sulfuric, citric, tartaric, phosphoric, dairy, pyruvic, acetic, succinic, fumaric, maleic, oxalic-acetic acid, methanesulfonic acid, ethanesulfonic acid, sulfonate, paratol isethionic acid.  4. The compound according to claim 2, which is 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) -pyrimidine mesylate. 5. A method of producing 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine or an acid addition salt thereof, characterized in that it comprises reacting a compound of formula (I)

where L is a leaving group;
Y is cyano
with a compound of formula (II)

or a salt thereof, and isolating the thus obtained 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine as the free base or as its acid addition salt. 6. The method according to claim 5, where L is C _1-4 alkoxy.  7. The method according to claim 5 or 6, where the specified interaction is carried out in a non-aqueous solvent at an elevated temperature in the presence of a base.  8. The method according to claim 7, where the specified interaction is carried out at the boil under reflux.  9. The method according to claim 7 or 8, where the solvent is an alcohol.  10. The method according to claim 9, where the solvent is ethanol. 11. The method of obtaining 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine, characterized in that it involves the interaction of the compounds of formula (IV)

where Y is cyano;
R ₁₀ and R _{11 are} both alkyl or together form a group - (C (R) ₂ ) _n -, where R is hydrogen or alkyl and n = 2, 3, 4,
with a compound of formula (II) as defined in claim 5.  12. The method according to claim 11, where the specified interaction is carried out in a non-aqueous solvent at the boil under reflux in the presence of sodium ethoxide as the base.  13. A pharmaceutical composition having the properties of a glutamate release inhibitor and containing an active principle and a pharmaceutically acceptable carrier thereof, characterized in that the active principle is 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3, 5-trichlorophenyl) pyrimidine or a pharmaceutically acceptable acid addition salt thereof.  14. The pharmaceutical composition according to p. 13, characterized in that it has a form suitable for oral administration.  15. The pharmaceutical composition according to 14, characterized in that it is in the form of tablets or packaged in capsules.  16. The pharmaceutical composition according to p. 13, characterized in that it has a form suitable for parenteral administration.  17. The pharmaceutical composition according to p. 13, characterized in that it is made in the form of a single dose, packaged in a container.  18. The compound according to any one of claims 1 to 4, having inhibitory activity of glutamate activity. Priority on points:
08/18/1989 according to claims 1 - 10, 13 - 18;
12/06/1989 according to claims 11-12.

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