More particularly the present invention provides a compound of formula I wherein R1 and R2, independently, are hydrogen, (C1-4)alkyl, (C1-4)alkoxy, (C, 4) alkylthio, halogen, trifluoromethyl, trifluoromethoxy, cyano, (C2-5)alkanoyl , (C1-4)alkylsulfonyl or sulfamoyl, at least one of R1 and R2 being other than hydrogen, R3 is hydrogen, hydroxy, (C1-4)alkyl, (C-14)alkoxy, (C3-6)cycloalkyloxy, halogen, cyano, (C2 5)alkanoyl, carbamoyl, (1-4)alkylsulfonyloxy or trifluoro- methylsulfonyloxy, and R4 and R5, independently, are hydrogen, (C1-4)alkyl, hydroxy(C2-4)alkyl or phenyl(C1-4)alkyl, or form together with the nitrogen atom to which they are attached a pyrrolidinyl, piperidino, piperazinyl or morpholino group, in free base or acid addition salt form.

Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

Any alkyl, alkoxy and alIIylthio radicals preferably are straight chain radicals. They preferably have 1 to 3 carbon atoms, more preferably they are methyl, methoxy and methylthio groups.

The following significances and their combinations are preferred: R1 and R2, independently, are hydrogen, (C14)aJkyl, (C14)alkoxy, halogen or trifluoromethyl, at least one of R1 and R2 being other than hydrogen, R3 is hydrogen, hydroxy, (C1-4)alkoxy, (C34) cycloalkyloxy, cyano or carbamoyl, R4 and Rs, independently, are hydrogen or (C1-4)alkyl, or form together with the nitrogen to which they are attached a piperidino or morpholino group.

The compounds of the invention possess an asymmetrical carbon atom in position 3. They may therefore appear in optically active form or in form of mixtures of optical isomers, e.g. in form of racemic mixtures.

Individual optical isomers and their mixtures including the racemic mixtures are part of the present invention.

In a further aspect, the invention provides a process for the production of the compounds of the invention, whereby a compound of formula II wherein Rk R4 and R5 are as defined above and Hal is halogen, is reacted with a compound of formula m wherein R, and R2 are as defined above, and the resulting compound is recovered in free base form or in acid addition salt form.

The reaction may be effected in known manner, preferably by transition metal-catalysed. aryl-aryl coupling, e.g. as described in Example 1. Hal is preferably bromine or iodine, particularly iodine.

Working up of the reaction mixtures obtained according to the above process and purification of the compounds thus obtained may be carried out in accordance to known procedures.

Acid addition salts may be produced in known manner from the free base forms and vice-versa. Suitable pharmaceutically acceptable acid addition salts for use in accordance with the present invention include for example the hydrochloride, the hydrogen maleate, the hydrogen fumarate and the hydrogen malonate.

Racemic compounds of the invention may be obtained from racemic starting materials. Optically active isomers may be obtained form optically active starting materials or from the racemate. The enantiomers may be obtained from the racemate by known methods, for example by fractional crystallization of diastereoisomeric salts, e.g. their salts with (+di-O,O'-ptoluoyl-D-tartartc acid or (-)-di-O, O'-p-toluoyl-Lr tartaric acid.

The starting materials of formula II may be produced by halogenating compounds of formula W wherein R3, R4 and Rg are as defined above, in accordance to known procedures, e.g. as described in Example 1.

The starting materials of formulae III and IV are known or may be produced in analogous manner to known procedures. The compound of formula IV wherein R3 is methoxy and Rx and Rg are both hydrogen, for example, which is used as starting material in Example 1, is known from, and can be prepared according to, M. Al Neirabeyeh et al., Eur. J. Med. Chem. 26, 497 (1991).

The compounds of formula I and their pharmaceutically acceptable acid addition salts, hereinafter referred to as agents of the invention, exhibit pharmacological activity and are, therefore, useful as pharmaceuticals.

The agents of the invention provide long-lasting protection against maximal electroshock-induced convulsions in mice at doses of about 1 to 100 mg/kg p.o. and about 0.32 to 32 mg/kg i.p. [cf. E.A. Swinyard, J.

Am.Pharm. Assoc. Scient. Ed. 38,201(1949) and J.Pharmacol. Exptl. Therap. 106, 319(1952)].

The agents of the invention are therefore useful in the treatment of epilepsy and other convulsive states such as high pressure neurological syndrome.

Furthermore, the agents of the invention reduce ischaemia-induced neuronal damage and ensuing symptoms in the middle cerebral artery (MCA) occlusion model in rats at a dosage of 1-50 mg/kg i.p, i.v. and p.o. [cf. A.

Tamura et al., J. Cereb. Blood Flow Metabol. 1 53-60 (1981), A. Sauter, M. Rudin, Stroke 17, 1228-1234 (1986)].

The agents of the invention are therefore useful in the treatment of any clinical condition involving a component of cerebral anoxia, hypoxia and/or ischaemia, e.g. ischemic damage to grey and white matter, stroke, reperfusion injury, subarachnoid haemorrhage, brain and spinal cord injury/trauma, high intracranial pressure, multi-infarct dementia or vascular dementia, and any surgical procedure potentially associated with cerebral anoxia, hypoxia and/or ischemia (e.g. cardiac bypass, operations on extracerebral vessels).

The agents of the invention display binding to the veratridine-sensitive sodium channel with IC50s of from about 0.1 to about 100 RM. For the binding procedure see for example J.B Brown, Journal of Neuroscience 6 2064-2070 (1986). They block veratridine-induced glutamate release in rat hippocampal slice preparations at concentrations of about 0.1-1 uM. The experiment is performed according to a modification of M. J. Leach et al. in Epilepsia 27 490497(1986) and Stroke 24 1063-1067 (1993), using exogenous glutamate.

As a result the agents of the invention are indicated for the treatment of any pathology, disorder or clinical condition involving glutamate release in their etiology, including psychiatric disorders (such as schizophrenia, depression, anxiety, panic attacks, attention deficit and cognitive disorders, social withdrawal), hormonal conditions (excess GH [e.g. in the treatment of diabetes mellitus, angiopathy and acromegaly] or LH [prostate hypertrophy, menopausal syndrome] secretion, corticosterone secretion in stress), metabolic induced brain damage (hypogiycaemia, non-ketotic hypergiycinaemia [glycine encephalopathy], sulphite oxidase deficiency, hepatic encephalopathy associated with liver failure), emesis, spasticity, tinnitus, pain (e.g. cancer pain, arthritis) and drug (ethanol, opiates [including synthetics with opiate-like effects, e.g. pethidine, methadone etc.], cocaine, amphetamine, barbiturates and other sedatives, benzodiazepines) abuse and withdrawal.

Moreover the agents of the invention are indicated in the treatment of any pathology involving neuronal damage, for example neurodegenerative disorders such as Alzheimer's, Huntington's or Parkinson's diseases, virus (including HIV)-induced neurodegeneration, Amyotrophic lateral sclerosis (AILS), supra-nuclear palsy, olivoponto-cerebellar atrophy (OPCA), and the actions of environmental, exogenous neurotoxins.

For the above-mentioned indications, the appropriate dosage will of course vary depending upon, for example, the compound employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at a daily dosage of from about 0.1 to about 100, preferably from about 0.5 to about 100 mg/kg animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range from about 1 to about 500, preferably from about 1 to about 300 mg of an agent of the invention, conveniently administered, for example, in divided doses up to four times a day or in sustained release form.

For all these indications the preferred compounds are 3,4-dihydro-3-dimethylamino-5-methoxy-8-[4- (trifluoromethyl)phenyl] -2H-l-benzopyran, which is the compound of example 1 and the corresponding antipodes of examples 2 and 3.

The (-)-antipode of example 2 is particularly preferred. It has for example been determined that in the above mentioned electroshock model, this compound provides protection against maximal electroshock-induced convulsions with a threshold dose of 10 mg/kg p.o. and 100% protection at 32 mg/kg p.o. In the MCA occ'usion model, the compound given i. v. 5 minutes after occlusion has been found to reduce infarct size by 25% at about 4.5 mg/kg.

The preferred indications are epilepsy, stroke and brain and spinal trauma The agent of the invention may be administered by any conventional route, in particular enterally, preferably orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions.

In accordance with the foregoing, the present invention also provides an agent of the invention, for use as a pharmaceutical, e.g. for the treatment of epilepsy, stroke and brain or spinal trauma The present invention furthermore provides a pharmaceutical composition comprising an agent of the invention in association with at least one pharmaceutical carrier or diluent. Such compositions may be manufactured in conventional manner. Unit dosage forms contain, for example, from about 0.25 to about 150, preferably from 0.25 to about 25 mg of a compound according to the invention.

Moreover the present invention provides the use of an agent of the invention, for the manufacture of a medicament for the treatment of any condition mentioned above, e.g. epilepsy, stroke and brain or spinal trauma.

In still a further aspect the present invention provides a method for the treatment of any condition mentioned above, e.g. epilepsy, stroke and brain or spinal trauma, in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of an agent of the invention The following examples illustrate the invention. The temperatures are given in degrees Celsius and are uncorrected.

Example 1: (+/-SS (4-trifluoromethvlphenvl !-5-methoxv-3-dimethvlamino-3. 1 - berzopyran 0.67 g (2rmnol) of (+/-)-8-iodo-5-methoxy-3-dimethylamino-3,4-dihydro-2H-1-benz opyran are dissolved in 11 ml toluene. 0.67 g (3.53 mmol) of 4-trifluoromethylphenylboronic acid, 74mg (0.24 mmol) of tri(ortho-tolyl)phosphine, 3 ml of 2N aqueous sodium carbonate and 0.7 ml of methanol are added. After degassing and filling the system with argon, 31 mg (0.14 mmol) of palladium(II)acetate are added and the mixture is stirred over night at 80°. After concentrating on the rotary evaporator, the mixture is extracted with ethyl acetate. After drying the combined organic phases with sodium sulfate, filtering and evaporating the organic phase, the resulting oily residue is taken up in methyl-tert.butyl- ether and a solution of malonic acid in methyl-tert.butyl-ether is added. After evaporation to dryness and taking up in a small amount of isopropanol the hydrogenmalonate salt starts to crystallize. The precipitate is filtered and recrystallized from isopropanol, yielding white crystals of the hydrogenmalonate salt of the title compound, m.p. 127-128°. The starting material may be produced as follows: a) (+/-)-5-methoxv-3-dimethvlamino-3A-dihv 1-benzopyran 1.68 g (9.38 mmol) of (+/-)-3-amino-5-methoxy-3, 4-dihydro-2H-1-benzopyran are dissolved in 20 ml methanol and 6 ml of an aqueous solution of formaldehyde (37%) are added. 3.6 g (47.82 mmol) of sodium cyanoborohydride are added in portions within 15 minutes under ice cooling. The mixture is stirred over night at room temperature, concentrated on a rotary evaporator, and distributed between water and methyl-tert.butyl-ether. The organic phase is dried with sodium sulfate, filtered and evaporated. The resulting colourless liquid is distilled at 175° bath temperature under 0.01 mbar, yielding a colourless, slightly viscous liquid. b) (+/-)-8-iodo-5-methoxy-3-dimethylamino-3,4-dihydro-2H-1-benz opyran 2.34 (11.3 mmol) of (+/-)-5-methoxy-3-dimethylamino-3,4-dihydro-2H-1- benzopyran obtained under a) are dissolved in 120 ml dichloromethane, then 3.52 g (11.3 mmol) silver sulfate are added. At 0-5° a solution of 4.3 g (16.9 mmol) iodine in 120 ml of dichloromethane is added dropwise within 30 minutes. After further 30 minutes at this temperature, the cooling bath is removed and the mixture stirred over night at room temperature. The mixture is filtered and concentrated at the rotary evaporator. Aqueous ammonia is added to the residue and the mixture is extracted with ethyl acetate. The organic phases are washed first with aqueous sodium bisulfite, then with water. Drying the organic phase with sodium sulfate, filtering and evaporating yields a brown viscous oil. After flash chromatography over silica gel with hexane/ethanoVammonia 85/15/1, the title compound is obtained as a bright orange viscous oil. <BR> <BR> <BR> <BR> <BR> <P>Example 2: (-S8-(4-trifluoromethylphenvl)-5-methoxv-3-dimethvlamino-3. -benzopvaan A mixture of (+/-)-8-(4-trifluoromethylphenyl)-5-methoxy-3-dimethylamino- 3,4-dihydro-2H-1- benzopyran (3.98g) and (+)-Di-O,O'-p-toluyl-D-tartaric acid (4.37g) in aqueous EtOH (85%, 200 ml), is heated to reflux, and the resulting solution is allowed to crystallize overnight. The precipitate [4.39g; free base: [α]D20= A2 (c= 0.001, MeOH), enantiomeric purity (capillary electrophoresis):75%] is recrystallized from boiling aqueous EtOH (85%, 165 ml), to give a precipitate (3.39g) which is dissolved in water (20 ml) and ammonia (conc., 20 ml) and extracted with methyl-tert-butyl ether (3 x 50 ml). The organic phases are washed with brine, dried (MgSO4) and evaporated to give a white powder [1.58 g;[α]D20 =43.9 (c= 0.01, MeOH); enantiomeric purity (capillary electrophoresis) 84%].

A portion of this free base (1.2 g) is treated with (+)-Di-O,O'-ptoiuyl-D-tartaric acid ( 1.32g) and crystallized from boiling EtOH (85%, 150ml) to give a precipitate [1.93 g; [a]D20 = -44.9 (c= 0.01, MeOH); enantiomeric purity (cap. electrophoresis) 95.46%] which is recrystallized from boiling EtOH (85%, 100 ml). The free base of the resulting 1.67 g is obtained as above by partitioning between aqueous ammonia and methyl-tert-butyl ether, as a waxy white solid [0.78 g; [α]D20 =-52.5 (c= 0.01, MeOH); enantiomeric purity (cap. electrophoresis) >99%].

Example 3. (+/-)-8-(4-trifluoromethylphenyl)-5-methoxy-3-dimethylamino- 3,4-dihydro-2H-1-benzopyran This enantiomer is obtained in analogous manner to Example 2, by fractional crystallization of the salt with (-)-Di-O,O'-p-tolyyl-L-tartaric acid. As free base, [α]D20 = +52 (c= 0.001, MeOH).