DIfflDRODEBENZO / B, F / AZEPINAS, METHOD FOR ITS PREPARATION, ITS USE IN THE TREATMENT OF SOME DISORDERS OF THE CENTRAL NERVOUS SYSTEM AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM The present invention refers to dihydrobenzo / b, f / azepines, to the method for its preparation and pharmaceutical compositions containing them. The compounds have valuable pharmaceutical properties for the treatment of some disorders of the central and peripheral nervous system. The compounds with the dibenz / b, f / azepine ring system are well known and some of them have been widely used to treat some pathological conditions in humans. For example, it is known that dibenz / b, f / azepine-5-carboxamide (carbamazepine) is an effective agent for the management of epilepsy, trigeminal neuralgia and emotional disorders. However, its administration to humans is complicated by its potent induction of hepatic oxidative enzymes, its adverse effects on the central nervous system and the frequent and serious idiosyncratic reactions it causes. An analogue of carbamazepine, 10,11-dihydro-10-oxo-5H-dibenz / b, f / azepine-5-carboxamide (oxcarbazepine, see eg German patent 2,011,087) avoids the drawback of induction of hepatic microsomal enzymes due to their different metabolic profile, although other of the disadvantages mentioned above still exist. It has been proven that in mammals oxcarbazepinasemetabolizes to give 10,11-dihydro-10-hydroxy-5H-dibenz / b, f / azepine-5-carboxamide having anti-epileptic activity comparable to that of the related drug. The use of this metabolite as an antiepileptic has been described (see Belgian patent No. 747,086), but it is not used in practice because its preferred oral administration is hampered by its poor bioavailability. The invention aims at obtaining an improvement in some of the
features mentioned above and refers to new compounds of the general formula I, including all possible stereoisomers:
wherein R is hydrogen, alkyl, aminoalkyl, halogenalkyl, aralkyl, cycloalkyl, cycloalkylalkyl, alkoxy, phenyl or a substituted phenyl or pyridyl group; the term "alkyl" means carbon chain, straight or branched, containing from 1 to 18 carbon atoms; the term halogen represents fluoro, chloro, bromo or iodo; the term "cycloalkyl" represents an alicyclic group saturated with 3 to 6 carbon atoms; the term aryl represents an unsubstituted phenyl group or phenyl substituted by an alkoxy, halogen or nitro group. Preferred compounds of Formula I include: 1. 10-acetoxy-10, 1-dihydro-5H-dibenz / b, f / azepine-5-carboxamide; 2. 10-benzoyloxy-10, 1 l-dihydro-5H-dibenz b, f / azepine-5-carboxamide; 3. 10- (4-methoxybenzoyloxy) -10,1-dihydro-5H-dibenz / b, f / azepine-5-carboxamide; 4. 10- (3-methoxybenzoyloxy) -10,1 l-dihydro-5H-dibenz / b, f / azepine-5-carboxamide;
. 10- (2-methoxybenzoyloxy) -10,1-dihydro-5H-dibenz / b, f / azepine-5-carboxamide;
6. 10- (4-nitrobenzoyloxy) -10,1-dihydro-5H-dibenz / b, f / azepine-5-carboxamide; 7. 10- (3-nitrobenzoyloxy) -10,1-dihydro-5H-dibenz / b, f / azepine-5-carboxamide; 8. 10- (2-nitrobenzoyloxy) -10,1-dihydro-5H-dibenz / b, f / azepine-5-carboxamide; 9. 10- (4-chlorobenzoyloxy) -10,1-dihydro-5H-dibenz / b, f / azepine-5-carboxamide; 10. 10- (3-chlorobenzoyloxy) -10,1-dihydro-5H-dibenz / b, f / azepine-5-carboxamide;
11. 10- (2-acetoxybenzooxy) -10,1-dihydro-5H-dibenz / b, f / azepine-5-carboxamide;
12. 10-propionyloxy-10, 1 l-dihydro-5H-dibenz / b, f / azepine-5-carboxamide; 13. 10-butyryloxy-10,1-dihydro-5H-dibenz / b, f / azepin-5-ca * rboxamide; 14. l-pivaloyloxy-10, l-dihydro-5H-dibenz b, f / azepine-5-carboxamide; 15. 10 - [(2-propyl) pentanoyloxy] -10,1-dihydro-5H-dibenz / b, f / azepine-5-carboxamide;
16. 10 - [(2-ethyl) hexanoloyloxy] -10,1-dihydro-5H-dibenz / b, f / azepine-5-carboxamide;
17. 10-stearoyloxy-10, 1-dihydro-5H-dibenz / b, f / azepine-5-carboxamide; 18. 10-cyclopentanoyloxy-10, l-dihydro-5H-dibenz / b, f / azepine-5-carboxamide; 19. 10-cyclohexanedioxy-10, 1-dihydro-5H-dibenz / b, f / azepine-5-carboxamide; 20. 10-phenylacetoxy-10, 1 l-dihydro-5H-dibenz / b, f / azepine-5-carboxamide; 21. 10- (4-methoxyphenyl) acetoxy-10,1-dihydro-5H-dibenz / b, f / azepine-5-carboxamide;
22. 10- (3-methoxyphenyl) acetoxy-10,1-dihydro-5H-dibenz / b, f / azepine-5-carboxamide;
23. 10- (4-nitrophenyl) acetoxy-10,1-dihydro-5H-dibenz / b, f / azepine-5-carboxamide; 24. 10- (3-nitrophenyl) acetoxy-10,1-dihydro-5H-dibenz b, f / azepine-5-carboxamide;
. 10-nicotinoyloxy-10, 1 l-dihydro-5H-dibenz / b, f / azepine-5-carboxamide; 26. 10-isonicotin-yloxy-10, 1-dihydro-5H-dibenz / b, f / azepine-5-carboxamide; 27. 10- (4-aminobutanoyloxy) -10,1-dihydro-5H-dibenz / b, f / azepine-5-carboxamide;
28. 10- (2-amino-3-methylbutanoyloxy) -10, l-dihydro-5H-dibenz / b, f / azepin-5-carboxamide;
29. 10-chloracetoxy-10, 1 l-dihydro-5H-dibenz / b, f / azepine-5-carboxamide; 30. 10-Bromacetoxy-10, 1-dihydro-5H-dibenz / b, f / azepine-5-carboxamide; 31. 10-formyloxy-10, l-dihydro-5H-dibenz / b, f / aze? In-5-carboxamide; 32. 10-ethoxycarbonyloxy-10, 1-dihydro-5H-dibenz / b, f / azepine-5-carboxamide; 33. 10- (2-chloropropionyloxy) -10,1-dihydro-5H-dibenz b, f / azepine-5-carboxamide; Another aspect of the invention comprises the method for preparing compounds of the formula I, wherein R is as defined above, by reacting the compound of the formula II
with a compound of the general formula III A CO R III in which: R is the same as defined for the general formula I; A is hydroxy, halo or a group -O-CO-R or -O-CO-OR ', where R' is lower alkyl (C1-C4), in the presence of condensing agents including dicyclohexylcarbodi ida, carbonyldiimidazole and ethyl- or isobutylchloroformate in the presence of organic or inorganic bases such as pyridine, triethylamine, quinoline, imidazole or alkylcarbonates, in inert solvents such as hydrocarbons (eg hexane,
cyclohexane), ethers (eg diethyl ether, tetrahydrofuran), chlorinated alkanes (eg dichloromethane, 1,2-dichloroethane) or dipolar aprotic solvents (eg acetonitrile, dimethylformamide) or the reaction can be made in a mixture of the solvents mentioned above or in the absence of any solvent. The acylation reaction described above can be carried out at different temperatures and pressures, for example between 0 ° C and boiling temperature of the reaction mixture and at atmospheric or high pressure. The compound of the formula II is known (German patent 2,011,045) and the compounds of the formula III are also known and can be obtained by methods known to those skilled in the art, including, for example, methods described in the book "Comprehensive Organic Transformations "by Richard C. Larock, VCH Publishers, 1989, pp 966-972. In the method described above, it is sometimes necessary to protect some functional groups during the reactions. Conventional protecting groups, such as benzyloxycarbonyl- or tert-butyloxycarbonyl- are operable and can be removed after acylation by standard procedures. Yet another aspect of the invention is a method for preparing pharmaceutical compositions comprising mixing a compound of the formula I with a pharmaceutically acceptable carrier. The compounds of the formula I have valuable pharmaceutical properties for the treatment of some disorders of the central and peripheral nervous system, specifically for the treatment of epilepsy, trigeminal neuralgia, emotional brain disorders and nervous function alterations in post-ischemic diseases. . Epilepsy is one of the most common conditions in man, with a
frequency of approx. 1 %. Since the time of Hughlings Jakson, more than 100 years ago, attacks of epilepsy were considered "occasional, sudden, excessive, rapid and local discharges of nervous tissue". The attacks of epilepsy are divided fundamentally into two groups: partial and generalized. Partial attacks are those in which the discharge begins locally and frequently remains localized. Generalized attacks involve the entire brain, including the reticular system, producing as a result, abnormal electrical activity in both hemispheres and immediate loss of consciousness. Partial attacks are divided into: (a) simple partial attacks, (b) complex partial attacks and (c) partial attacks of secondary generalization. Generalized attacks include: (1) tonic-clonic attacks (grand mal), (2) abortive attacks (petit mal), (3) myoclonic attacks, (4) atonic attacks, (5) clonic attacks, and (6) tonic attacks . Epilepsy is, contrary to attacks, a chronic disorder characterized by recurrent attacks (Gastaut, H .: Dictionary of Epilepsy, World Health Organization, Geneva, 1973). There are two ways for drugs to eliminate or attenuate attacks, (a) through effects on altered neurons or foci of attack, to prevent or reduce their excessive discharge, and (b) through effects that reduce the spread of excitation from the foci of attack and prevent the disruption of the function of normal aggregates of neurons. Most, if not all, of the antiepileptic drugs available, act at least according to the second mechanism, since they all modify the ability of the brain to respond to different stimuli reminiscent of attack. Secondary drugs, such as pentylenetetrazole (metrazol), are frequently used, particularly in the testing of anticonvulsant agents and attacks caused by nerve stimulation of the entire brain. It has been proven
empirically that the inhibitory activity of attacks induced with metrazol and to increase the threshold of production of electrically induced attacks is a good indication of effectiveness against abortive attacks. On the other hand, the effect of reducing the duration and dispersion of electrically induced seizures coincides with the effectiveness of the control of other types of epilepsies, such as tonic-clonic seizures. The anticonvulsant effect of the compounds of the formula I was studied in a model of electrically induced seizures, in the maximum electroshock test (MES) and in a model of chemically induced seizures, the metrazole assay. The MES assay allows evaluating the ability of drugs to prevent the electrically induced tonic extension of the hind legs in the rat, efficacy that seems to indicate anticonvulsant efficacy in generalized tonic-clonic seizures in man (grand mal). The metrazol assay indicates the ability of potential antiepileptic agents to prevent clonic attacks and abortive attacks (petit mal). MATERIALS AND METHODS Male Wistar rats, obtained from Dto. of Animals of the Gulbenkian Institute of Science (Oeiras, Portugal) weighing 180 to 280 g. Two animals were kept per cage under controlled environmental conditions (day / night cycles of 12 hours, room temperature 24 ° C). Food and water were given ad libitum and all the experiments were carried out in daylight. 1. MES trial The MES stimulation was applied for 0.2 seconds using a Ugo Basile 7801 ECT unit, with a frequency of 100 Hz, a pulse amplitude of 0.6 ms and a current of 150 mA through bipolar corneal electrodes . It instilled a
electrolyte drop / oxybuprocaine chloride anesthetic in the eyes of all animals immediately before placing the corneal electrodes. The proposed goal was the elimination of the extensor tonic component of the hind legs. These experimental conditions caused tonic-clonic seizures in 97% of the animals tested and only rats were used that had characteristic tonic-clonic seizures. All rats were subjected to a maximum of 3 sessions of MES. The first was done to select the animals that had a characteristic convulsive behavior. The next day, the test compound or vehicle was administered to the rats and subjected to a second session of MES 2-4 hours after having administered the test drugs. The third session of MES was performed 6,8 or 12 hours after having administered the test drugs. The interval between the sessions of MES was at least 4 hours (the rats tested at 2 hours were retested at 6 hours and the rats tested at 4 hours were retested at 8 hours). The evaluation of the anticonvulsive profile of the test drugs was based on the duration of the tonic phase (in seconds), with each rat having its own control (internal control) according to the result of the first session of MES. An external control group was also studied. In this particular case, the vehicle was administered to the rats and subjected to the three sessions of MES as described above. All drugs used were suspended in 0.5% carboxymethylcellulose (4 ml / kg) and administered by stomach tube. Metrazole assay Compounds were administered 2 h before administering metrazole. The metrazol (75 mg / kg) was administered subcutaneously in the back. It was found that this dose of merazol produced seizures in 95% of the animals. The
observed parameters related to the duration of the attacks in an observation period of 3 minutes after the administration of metrazol. A dose of EDjo (mg / kg) gave a 50% reduction in the duration of the attack. Results 1. MES Test With the highest dose tested (35 mg / kg), the compounds of the formula I produced complete protection against MES 2 hours after their administration. At 4 and 8 hours, the protection conferred by the compounds of the formula I was similar to that produced by the reference carbamazepine compound. At the maximum dose tested (35 mg / kg), carbamazepine produced complete protection against MES 2 hours after administration. At 4 and 8 hours after administration, the protection conferred was still more than 80%. The ED ^ values for carbamazepine at 2, 4 and 8 hours after administration were 7.95, 15.80 and 2.70 mg / kg respectively. Contrary to oxcabazepine compounds and similarly to carbamazepine compounds, compounds of formula I were found to be more potent after 8 hours, with ED * values, substantially lower than those corresponding to oxacarbazepine. The EDg values for the compounds of formula 1 at 2.4 and 8 hours of administration were 17.97, 13.90 and 3.90 mg / kg respectively. Oxcarbazepine was not as potent as carbamazepine and the compounds of formula 1. The EDJO values for oxcarbazepine at 2.4 and 8 hours of administration were 16, 18, 16.28 and 13.24 mg / kg, respectively . 2. Metrazole Assay The compounds of formula 1 were effective in protecting rats against seizures induced by metrazole. The highest effective dose of compounds of the
Formula 1 was 30 mg / kg and reduced the total attack time by 69%. The ED value for the compounds of formula 1 was 14.7 mg / kg. 30 and 60 mg / kg of carbamazepine produced a reduction in attack time of 41 and 44% respectively. Oxcarbazepine was less potent than carbamazepine. With 30 and 60 mg / kg of oxcarbazepine a reduction of 3 and 32%, respectively, was observed in the total attack time. CONCLUSIONS The compounds of formula 1 possess a valuable antiepileptic activity as demonstrated in the MES and metrazole assays and possess greater or similar anticonvulsive potency to the reference carbamazepine and oxcarbazepine compounds. The use of compounds of the formula I can be useful in man, for the treatment of some disorders of the central and peripheral nervous system, eg for trigeminal neuralgia and emotional brain disorders, alterations of nervous function in degenerative diseases and postisqué icas. For the preparation of pharmaceutical compositions from compounds of the formula I, pharmaceutically acceptable carriers are mixed with the active compound. The pharmaceutically acceptable carriers can be solid or liquid. Solid preparations include powders, tablets, dispersible granules and capsules. A solid carrier may comprise one or more substances, which may also act as diluents, flavoring agents, ubiquitous solvents, lubricants, suspending agents, binders and tablet disintegrating agents. It can also be an encapsulating material. Preferably, the pharmaceutical preparation is in unit dosage form, eg a packaged preparation, the package of which contains discrete amounts of
p preparation, in the form of packed tablets, capsules or powders in tubes or ampoules. The doses may vary according to the patient's requirements, the severity of the disease and the particular compound used. Conveniently the daily dose can be divided and administered in portions throughout the day. The doctor will be responsible for determining the appropriate dose for a particular situation. The invention disclosed herein is exemplified by means of the following preparation examples, which should not be considered as limiting the scope of the disclosure. Alternative procedures and analogous structures will be evident to art connoisseurs. EXAMPLES Example 1; 10-formyloxy-10, 1-dihydro-5H-dibenz / b, f / azepine-5-carboxamide A suspension of 2.54 g (10 mmol) of 10-hydroxy-10, l-dihydro-5H-dibenz / b, f / azepine-5-carboxamide in 50 mL of 1,2-dichloroethane was treated with 1.23 g (15 mmol) of a mixture of acetic-formic anhydride acid and 1.36 g (20 mmol) of imidazole The mixture was stirred at 25 ° C for 3 hours and then poured into a stirred mixture of 100 mL 0.1 M aqueous HCl and 50 g of ice. The organic layer was separated and extracted with a saturated solution of NaHCO3, brine and the volatile components were removed by evaporation under reduced pressure. The remaining crude product was purified by silica gel chromatography, eluting first with a mixture of methylene chloride and then with 1% methanol-methylene to give the desired product as white crystals of m.p. 202-203 ° C. Examples 2 v 3 With the application of the techniques mentioned above and known procedures
in the art and using appropriate anhydrides, the following compounds were prepared: 10-propionyloxy-10,1-dihydro-5H-dibenz / b, f / azepine-5-carboxamide and 10-butyryloxy-10,1-dihydroxy 5H-dibenz / b, f / azepine-5-carboxy ida. Example 4 (+) - 10-acetoxy-10, l-dihydro-5H-dibenz / b, f / azepine-5-carboxamide A solution of 9.42 g (0.12 mol) of acetylchloride in 100 mL of dichloromethane was added dropwise to a stirred and cooled suspension (t <10 ° C) of 25.4 g 0.1 mol) of (-) - 10-hydroxy-10, 1 l-dihydro-5H-dibenz / b, f / azepine-5-carboxamide in 500 mL of dichloromethane and, 9 g (0.15 mol) of pyridine. The reaction mixture was stirred and boiled for 2 hours. It was then cooled to 5 ° C and extracted successively with 500 mL of 0.2 M sulfuric acid, saturated aqueous sodium bicarbonate and brine. The organic phase was dried with sodium sulfate, filtered through a short column of silica gel and the volatile components of the filtrate were removed by evaporation under reduced pressure. The residue was crystallized with a mixture of dichloromethane and ethyl acetate to give the desired compound as white crystals of m.p. 186-187 ° C, [alpha ^ 20 = +21.5 (c = 1, pyridine). Examples 5-17 Applying the techniques described above and corresponding procedures known in the art and using appropriate acid halides, the following compounds were prepared: 10-benzyloxy-10, l-dihydro-5H-dibenz / b, f / azepin- 5- carboxam ida, 10- (4-methoxybenzoyloxy) - 10, 11 -dihydro-5H-d ibenz / b, f / azepine-5-carboxamide, 10- (4-nitrobenzoyloxy) -10, l-dihydro- 5H-dibenz / b, f / azepin-5-carboxamide, 10- (4-chlorobenzoyloxy) -10,1-dihydro-5H-dibenz / b, f / azepin-5-carboxamide 0-ethoxycarbonioxy-10, l -dihydro-5H-dibenz / b, f / azepine-5-carboxamide,
-acetoxybenzoyloxy-10, l-dihydro-5H-dibenz / b, f / azepine-5-carboxamide, 10-
pivaloyloxy-10,1-dihydro-5H-dibenz / b, f / azepine-5-carboxamidal 0-stearoyloxy-10,11-dihydro-5H-dibenz / b, f / azepine-5-carboxamide, 10-phenylacetoxy-10 , 1-dihydro-5H-dibenz / b, f / azepine-5-carboxamide, 10-chloroacetoxy-10, 1-dihydro-5H-dibenz / b, f / azepine-5-carboxamide, 10-bromacetoxy-10 , 1 l-dihydro-5H-dibenz / b, f / azepine-5-carboxamide. Example 18 10-nicotinoyloxy-10,1-dihydro-5H-dibenz / b, f / azepine-5-carboxamide To a suspension of 0.254 g (1 mmol) of 10-dihydro-10,1-dihydro-5H- dibenz / b, f / azepine-5-carboxamide and 0.130 g (1 mmol) of nicotinic acid in 5 ml of tetrahydrofuran, 0.230 g (1.1 mmol) of dicyclocarbodiimide and 0.02 g (0.2 mmol) were added. ) of 4-dimethylaminopyridine and the mixture was stirred at 20 ° C for 6 hours. The precipitated urea was removed by filtration and the filtrate was evaporated under reduced pressure. The residue was chromatographed on silica gel with a mixture of 0.5% methanol-dichloromethane. The chromatographically homogeneous fractions were pooled, the solvents were removed by distillation under reduced pressure and the residue was crystallized with acetonitrile to give the desired compound (mp 196 to 198 ° C). Examples 19-23 Applying the techniques described above and corresponding procedures known in the art and using the appropriate acids, the following compounds were prepared: 10 - [(2-propyl) pentanoyloxy] -10,1-dihydro-5H-dibenz / b, f / azepine-5-carboxamide, 10 - [(2-ethyl) hexanoyloxy)] - 10,1-dihydro-5H-dibenz / b, f / azepin-5-carboxamide, 10-cyclohexanedioxy-10, 1 l-dihydro-5H-dibenz / b, f / azepine-5-carboxamide, 10- (4-methoxyphenyl) -10, l-dihydro-5H-dibenz / b, f / azepine-5-carboxamide, 10- (4-nitrophenyl) acetoxy-10, l-dihydro-5H-dibenz / b, f / azepine-5-carboxamide. Example 24: 10- (4-aminobutanoyloxy) -10, l-dihydro-5H-dibenz / b, f / azepin-5-
carboxamide A solution of isobutyl chloroformate (0.144 g, 1.05 mmol) in 2 mL of tetrahydrofuran was added slowly to a solution of 0.204 g (1 mmol) of N-tert-butoxycarbonyl-gamma-aminobutyric acid and 0.106 g. (1.05 mmol) of triethylamine in 3 mL of tetrahydrofuran. The reaction mixture was stirred for 1 hour at -5 ° C, then filtered and the filtrates slowly added to a suspension of 0.254 g (1 mmol) of 10-hydroxy-10,1-dihydro-5H-dibenz / b, f / azepine-5-carboxamide in 5 mL of tetrahydrofuran and 0.09 g (1.1 mmol) of pyridine. The reaction mixture was stirred for 4 hours at 25 ° C, then poured into 50 mL of cold 5% KHSO 4 solution and extracted with dichloromethane. The organic layer was extracted with a saturated aqueous solution of NaHCO3 and brine, dried over sodium sulfate and the volatile components were removed by distillation under reduced pressure. The residue was chromatographed on silica gel with 0.5% methanol in dichloromethane. The homogeneous fractions were combined and the solvent was evaporated in vacuo. The remainder of the protected derivative was dissolved in 10 mL of dichloromethane and 1 mL of trifluoroacetic acid. The reaction mixture was stirred for 1 hour at room temperature and then extracted with saturated solution of cold NaHCO3 and brine. The organic layer was dried over magnesium sulfate, evaporated to a small volume under reduced pressure and then diluted with 5 mL of diethyl ether and 2 mL of 2% HCl solution in diethyl ether was added. The precipitated crystals were collected by filtration and dried to give the hydrochloride of the desired compound. The salt was resuspended in 5 mL of 2% aqueous sodium carbonate solution and extracted with 10 mL of dichloromethane. The organic solvent was dried over sodium sulfate and evaporated under reduced pressure to leave the desired product as an amorphous solid which decomposes without melting at approx. 120 ° C.
EXAMPLE 25 Applying the techniques described above and corresponding procedures known in the art and using the appropriate acids, we prepared: 10- (2-amino-3-methylbutanoyloxy) -10, l-dihydro-5H-dibenz / b, f / azepine-5-carboxamide.