MXPA97009311A - Semicarbazonas that have activity in the central sistemanervioso and pharmaceutical preparations that contain them - Google Patents

Abstract

A compound characterized by the general formula (I) useful as an anticonvulsant for disorders of the central nervous system characterized in that: R1, R2, R3 and R4 can be the same or different and each represents a hydrogen atom or a halogen atom, or a C1-9 alkyl, C5-9 cycloaliphatic, cyano, C1-9 alkoxy or C6-10 aryloxy group, R5 represents a hydrogen atom or a C1-9 alkyl group, C5-9 cycloalkyl or C6-10 aryl, and X is oxygen or sulfur, or a pharmaceutically acceptable salt thereof. The compounds can be administered orally to treat seizures in humans and animals

Description

SEMICARBAZONAS THAT HAVE ACTIVITY IN THE CENTRAL NERVOUS SYSTEM AND PHARMACEUTICAL PREPARATIONS THAT CONTAIN THEM TECHNICAL FIELD This invention describes the semicarbazone compounds having activity on the central nervous system (CNS) and for pharmaceutical preparations containing such compounds. More particularly, the invention describes semicarbazones having anticonvulsant properties and the use of such semicarbazones for the treatment or prevention of seizures and seizures in humans and animals.

ANTECEDENTS OF ART It has been a business of great interest for many years in the identification of drugs that exhibit activity on the central nervous system in humans and animals and these are, in particular, the anticonvulsants used for the treatment and prevention of epileptic seizures and other disorders. of the central nervous system.

A previous study carried out by one of the inventors of the present invention (Dimmock et al., J. Med. Chem., 1993, 36, pp.2243-2252) revealed that a REF: 26165 number of aryl semicarbazones of the general formula A possess anticonvulsant activity in the maximal electroshock screen (MES) and the subcutaneous pentylenetetrazole reticula (scPTZ, subcutaneous penylenetetrazole screen) when administered intraperitoneally to mice. The reticles are test systems developed to detect compounds which will provide protection against tonic-clonic seizures and generalized seizures of absence, respectively. The MES reticule and the scPTZ reticule have been discussed by Krall, et al. in "Antiepileptic drug development: II Anticonvulsant drug screening", Epilepsia, 1978, 19, pp. 409-428; the discovery of which is incorporated herein by reference.

However, the compounds of formula A exhibit neurotoxicity when administered by this route and the protection indices (Pl, called the TD50 / ED50 ratio) of ten representative compounds were low.

There is an agreed need for compounds showing much improvement in anticonvulsant effects with reduced toxicity.

DISCOVERY OF THE INVENTION An object of the invention is to provide compounds having activity on the central nervous system.

Another objective of the invention is to provide pharmaceutical compositions having good anticonvulsant activity and acceptable neurotoxicity.

Still another objective is to provide seizure treatment methods in human and animal patients without the production of unacceptable side effects.

According to one aspect of the invention, a compound of the general formula I is provided where: R1, R2, R3 and R4 can be the same or different and each represents a hydrogen atom or a halogen atom, or a C9-9 alkyl, C5-9 cycloaliphatic group, cyano, C 1-9 alkoxy or C 6 -? 0 aryloxy; R5 represents a hydrogen atom or a C1-9 alkyl group, C5-9 cycloalkyl or C6-? O aryl; and X is oxygen or sulfur. In the compounds of the invention the alkyl substituents, when present, may be straight or branched chain.

It should be noted, however, that the compound of Formula I above in which R1, R2, R3, R4 and R5 are all hydrogens is known from Tomita et al., "Synthesis of Aldehyde Derivatives Containing a Diphenyl Ether Nucleus", J. Pharm. Soc. Japan, 1955, 75, 1021-1023, but this reference does not describe the anticonvulsant property of the compound.

According to another aspect of the invention, there is presented a composition comprising a compound of general formula I and a pharmaceutically acceptable diluent, excipient or carrier.

In accordance with yet another aspect of the invention, a method of treating diseases of the central nervous system of a human or animal patient is presented, which comprises the administration for said patient in an effective amount of a compound with general formula I.

The compounds of this invention can be administered orally and may present very high activities against CNS seizures, p. ex. , they may have ED50 values (for maximum electroshock grating in rats) in the range of 1-5 mg / kg (more generally the range of 2-3 mg / kg) while exhibiting an absence of neurotoxicity at a maximum dose used (eg, 500 mg / kg), thus leads to extremely favorable protection index (Pl) values.

The compounds of the invention appear to act by one or more mechanisms which are different from those of conventional anticonvulsant drugs. On the other hand, the compounds of the invention may be free of some of the disadvantages of conventional anticonvulsant drugs from the procolvulsant properties and effects on the activities of certain liver enzymes that are absent in at least some of the compounds of the invention. invention.

BRIEF DESCRIPTION OF THE DRAWINGS Figure I is a simplified representation of the site of the postulated receptor showing different binding regions for the compounds according to the present invention; Figure 2 shows the basic structures of the skeleton to indicate the compounds listed in Tables 1 to 3; Figure 3 shows the basic chemical structures to indicate the compounds listed in Tables 4 to 6.

THE BEST WAYS TO CARRY OUT THE METHODS OF SYNTHESIS OF THE INVENTION The compounds of the present invention and the compounds having related structures can be synthesized by various chemical routes, e.g. ex. , by a modification of the method presented by Yeager et al. ("A Convenient Method for the Preparation of 4-Aryloxyphenols", Synthesis, 1991, pp. 63-68, the discovery of which is presented here as a reference). Yeager et al. describes a process for the production of aryloxybenzaldehyde or aryloxyaryl ketones. These intermediates can be reacted with semicarbazides. This route is illustrated by the scheme of the following reaction: The reaction scheme shown above requires the formation of an aryloxy- or arylthiobenzaldehyde or ketone intermediate by appropriate reaction of phenols or thiophenols with fluorobenzaldehyde or fluoroaryl ketones in a suitable solvent (eg, dimethylacetamide) in the presence of anhydrous potassium carbonate. at temperatures in the range of 100 to 200 ° C under atmospheric pressure of a non-oxidizing gas (e.g., nitrogen) with reflux for a period of about 5-10 hours. After cooling and adding water, the intermediate compound can be extracted with an organic solvent (eg, chloroform) and dried. The intermediates aryloxy (thiol) benzaldehydes and aryloxy (thio) aryl ketones are then converted to the desired semicarbazones by reaction with semicarbazide in an ethanolic solution water for a period of one or several hours at room temperature, and the precipitate resulting from the final product is then collected and recrystallized. The initiator materials, which are generally reacted in approximately stoichiometric amounts, are themselves commercially available products and can, in particular, be obtained from Aldrich Chemical Company, Milwaukee, USA.

STRUCTURES Without waiting for the invention to be limited to a particular theory, it is believed that the compounds of the present invention exert their anticonvulsant activity by aligning their molecules to a postulated receptor site in the human and animal brain, and it is theorized that such interactions take place in three areas of the receptor, called an aryl bond site, a hydrogen bond area and a distal link site as illustrated in FIG. 1.

These sites are believed to react with the proximal aryl ring (the ring following the semicarbazone group), the semicarbazone group (H2NC0NHN =) by itself and the distal aryl ring of the compounds, respectively. The presence of the distal aryl ring and certain groups substituents on the distal and, to a lesser degree, the proximal aryl ring in the compounds of the invention appear to strengthen the coupling of the molecule to the receptor and thereby increase the potency of the compounds.

A synthesis and systemic evaluation of the compounds of Formula I and the compounds with very closely related structures have revealed the following general principles (i) The substitution of methine hydrogen coupled to the carbimino carbon atom by large groups does not significantly affect the anticonvulsive activity of the compounds; (ii) the positioning of the aryloxy or arylthio groups in the ortho or meta positions of the proximal ring leads to a decrease or abolition of the anticonvulsant activity; (iii) replacement of oxygen ether by sulfide or sulfonyloxy groups leads to compounds with similar anticonvulsant activities, while other spacers lower anticonvulsant potency; (iv) a decrease in the size of the substituents of the distal aryl ring, increases the anticonvulsant activity; (v) the anticonvulsive activity of the distal aryl group is the para position.

Hence, the compounds of the present invention which are particularly preferred those in which R and R 2 are hydrogen or halogen (more preferably fluoride), R 3, R 4 are each hydrogen and R 5 is hydrogen or alkyl d-3 and X is O or S (most preferred O).

Particularly preferred compounds according to the present invention are 4- (4'-fluorophenoxy) benzaldehyde semicarbazone and 4- (thiophenoxy) benzaldehyde carbazone. The compounds show high activity in the MES lattice, low toxicity and provide protection in the rat excited cornea lattice without negative characteristics, such as proconvulsive properties.

Incidentally, excited rat reticles are described by R.J. Racine in "Modification or Seizure Activity by Electrical Stimulation II Motor Seizure", Electroencephalogr. Clin. Neurophysiol. , 1972, 32, 281-294, and by G. Skeen et al. in "Development of Kindled Seizures Following Electrical Stimulation via the Cornea", Soc. Neurosci., 1990, 16 (1), 307; the discoveries of which are included here as a reference.

PHYSIOLOGICAL ACTIVITY The compounds of the present invention may in some cases have very high neurotoxicity when injected intraperitoneally into mice. For example, neurotoxicity was found to be present in approximately 65% of the compounds tested and quantification of the bioactivities of the compounds of the invention has revealed PI's in the range of 2-14 in the MES and 1-3 in the lattice. scPTZ. However, it has been found that such neurotoxicity disappears or is reduced to an acceptable level when the compounds are orally administered to the rats. In addition, while the compounds exhibit high activity in both the MES lattice and scPTZ lattice when administered intraperitoneally, the activity in the MES lattice remains high when the compounds are administered orally, but the activity in the scPTZ lattice may decay. For example, the compounds of semicarbazone 4- (4'-fluorophenoxy) benzaldehyde, in oral doses produce an ED50 amount in the rat oral grid of 1.59 mg / kg and a Pl greater than 315. However, the compound did not provide ScPTZ reticle protection at a dose of 250 mg / kg. An absence of neurotoxicity at the maximum dose used (500 mg / kg) leads to exceptionally high protection rates.

ADMINISTRATION The compounds of the invention can be administered orally to humans, preferably at dosages of 50-75 mg / kg, generally in the form of compositions with inert pharmaceutically acceptable compounds, for example diluents (e.g., phosphate dihydrate). calcium, calcium sulfate dihydrate, cellulose, dextrose, lactose, mannitol, starch, sorbitol sucrose, and sucrose-based materials), binders and adhesives (eg, acacia, cellulose derivatives, gelatin, glucose, polyvinylpyrrolidone (PVP), alginates, sorbitol, pregelatinized starches or starch and tragacanth paste), dispersants (eg, alginates, cellulose and cellulose derivatives, clays, PVP with cross-links, starch and starch derivatives), lubricants (eg, polyethylene glycols, stearic acids, salts and derivatives, surfactants, talc and waxes), fluidizers (corn starch, derivatives of silica and talc), and colors, flavors and edulcorentes (eg, colors and lacquers of FD & amp;; C D &C, essential oils and flavors spray dried, artificial sweeteners and natural sweeteners).

The compositions can be prepared in any of the conventional forms for oral administration, e.g. ex. , powders, capsules, tablets, capsules, dragees, solutions, syrups, etc.

The invention is described in more detail in the following Examples, which, however, do not attempt to limit the scope of the invention.

EXAMPLE 1 The compounds 2a to 5v shown in Table 1 below were synthesized by the previously mentioned method. The structures of the listed compounds correspond to those shown in Fig. 2 identified by the same number (2, 3, 4 or 5), with only the substituents being identified in Table 1.

Table 1 . Aryl substituents, data on physical and anti-iconvulsant evaluation after intraperitoneal injection in mice and oral administration in rats of compounds in series 2 - 5 Intraperitoneal injection in mice Oral oral administration in retina Reticle MES Reticle Reticle Oo O ? MES scPTZ or co-opted toxicity Substituents p. F. Yield of aryl (° C)% O.Sh 4h 0.5 4h 0.5h 4h Dose 0.25h O.Sh lh 2h 4h (mg / kg) 2a H 198-199 40 50 2 1 1 2b 4-F 210-212 48 30 1 2 4 3 H 224-225 70 - 300 50 4a H 224-225 60 100 300 50 3 4 4 4 4b 4-F 233-234 65 30 100 50 2 4 4 4 4 4c A-CL 225-226 40 30 30 30 300 30 50 4 4 4 4 4 4 4 4-Br 225-226 60 30 30 300 30 50 1 4 4 4 4 4e 4-1 221-222 71 30 30 100 300 300 100 50 3 4 4 4 4 ÍA 4-CH3 219-221 50 30 100 50 3 4 4 4 4 Í3. 4-C6H5 280 72 300 300 300 12.5 3 1 Intraperitoneal injection in mice 3 Administer ration ora 1 in rats 0b OR CO Reticula MES Reticula Reticula reticula MES co scPTZ toxicity 0 0 N > Substitute p. F. Rendi CD aryl (° C) tion% 0.5h 4h 0.5h 4h 0.5h 4h Dose 0 .25h 0. Sh lh 2h 4h (mg / kg) li4-0CH3 218-220 60 100 100 300 50 4 4 4 4 li 4-OC6H3 209-210 55 - 300 - - - - 50 1 1 Cl li 4-CN 218-220 40 30 30 30 30 300 100 12.5 2 4 4 4 4 5a 2-F 228-230 42 100 300 300 - - - 50 2 4 4 4 4 5b 3-F 209 42 30 300 100 - 300 300 50 4 4 4 4 4 5c 2,3-F2 225 50 100 100 300 - - - 12.5 - 3 4 4 4 5d 2,4-F2 229-230 42 30 30 100 - - - 50 3 4 4 4 4 5e 2,5-F2 230 65 100 300 100 - 300 300 12.5 - 1 1 4 1 5f 2,6-F2 232 30 30 30 300 300 300 300 12.5 0 2 4 4 4 52 3.4-F2 212-213 86 100 30 30 300 - - 50 2 4 4 4 4 5h 2-CL 207-208 42 30 30 100 300 300 50 3 4 4 4 4 Intraperitoneal injection in mice4 Oral administration in groups' Reticle MES Reticle Reticle Reticle MES scPTZ toxicity c c ompuesto Substituents p. F. I gave aplo (° C) c ction 0 0.5h 4h O.Sh 4h 0.5h 4h Dose 0., 25h 0 .5h lh 2h h (mg / kg) 5? 3-CL 185-186 35 30 100 30 300 300 100 50 - 4 4 4 3 51 3,4-CL2 216-217 45 300 30 - - 300 50 - 2 4 4 4 5k 2-F, -CL 225-226 60 30 30 - 100 30 12.5 2 4 4 4 4 51 2-CL, 4-F 209-210 59 30 30 - 100 300 50 4 4 4 4 4 5m 2, Br, 4-F 203-205 40 100 100 300 300 300 50 4 4 4 4 4 5n 2-CH3 205 25 30 100 100 100 300 300 12.5 - 4 3 4 4 CO 5th 3-CH3 205-206 35 30 100 - 100 300 12.5 - 4 4 3 2 £ 4-C2H3 210 40 30 30 300 300 100 12.5 - 2 4 4 4 Sg 4-nC3H3 215 53 100 100 300 - 300 12.5 - 1 2 4 2 5r 4-s-C4H9 192-193 38 100 30 100 300 100 12.5 - 2 2 3 4 5s 4-tC, H9 200-202 48 100 30 100 100 100 12.5 4 4 4 Intraperitoneal injection in mice3 Reticula MES Reticula Reticula Reticula MES scPTZ C toxicity Substitute Compound p. F. Rendered aril CC) t t O.Sh 4h 0.5h 4h 0.5h 4h Dose 0.25h 0.5h lh 2h 4h (mg / kg) St 4-t-CeH17 190 30 300 5u 4-0-n-C4H9 203 35 300 100 300 300 300 300 12.5 5v 4-0-N-C7-H15 204-206 20 - - - 300 Phenytoin 30 30 - 100 100 Carbamazepine 30 100 100 300 100 300 Valproic acid - - 300 Doses of 30, 100, 300 mg / kg were administered. The values in the table indicate the minimum dose at which bioactivity was demonstrated in half or more of the mice. The animals were examined at 0.5 and 4 h after the injections were made. The lines - indicate an absence of anticonvulsant activity and neurotoxicity. J O The values in the grid indicate the number of rats of 4 which were protected. H O The lines mean that no activity was shown and the designation - indicates that the compound was not reticulated. o o c oo o The details of the synthesis of the various compounds are indicated below.

SYNTHESIS OF INTERMEDIARIES The 3-phenoxybenzaldehyde used as a starter material required in the synthesis of compound 3 FUE obtained from Aldrich Chemical Company, Miwaukee, WI. the aryloxyaryl and arylioaryl intermediates required in the synthesis of other compounds were prepared as follows.

Anhydrous potassium carbonate (0.12 M) was added to an appropriate solution of phenol or thiophenol (0.15 M) and 4-fluorobenzaldehyde, 4-fluoroacetophenone or 4-fluoropropiophenone (0.14 M) in dimethylacetamide (100 ml). The mixture was heated under reflux at 155 ° C under nitrogen and the advance was monitored by thin layer chromatography (TLC) using a benzene solvent system rmetanol (9: 1 by volume). After about 5-10 hours, the mixture was cooled and water (100 ml) was added. The reaction mixture was extracted with chloroform (2x100 ml) and the combined organic extracts were washed with aqueous sodium hydroxide solution (4% w / v) and water. After drying over anhydrous magnesium sulfate, the solvent was / CA96 / 00380 19 stirring in vacuo and the resulting oil was distilled under reduced pressure to give the appropriate aryloxyaryl aldehyde, arylthioaryl or ketone. The purity of the distillates was verified by thin layer chromatography (TLC) using benzene: methanol (9: 1 by volume) as solvent. The 1H NMR spectrum of the representative intermediate, called 4-phenoxybenzaldehyde, was as follows: d (CDCL3) .- 9.94 (s, ÍH, CHO), 7.82-7.88 (2t, 2H, ortho H of the proximal aryl ring), 7.38- 7.46 (3t, 2H, meta H of the proximal aryl ring), 7.20-7.27 (3t, ÍH, for H of the distal aryl ring), 7.03-7.12 (3t, 4H, ortho and meta H of the distal aryl ring).

SYNTHESIS OF THE FINAL COMPOUNDS A mixture of semicarbazide hydrochloride (0.10 M), sodium acetate (0.10 M) and water (10 ml) was added gently to a stirring solution of aryloxyaryl or arylthioaryl aldehyde (0.01 M) in ethanol (95%, 30 ml) . The reaction mixture was stirred at room temperature for 1-2 hours, the precipitate was collected, washed with ether, dried and recrystallized from 95% ethanol (compounds 3, 4b, 4e, 4h, 5b-3, 5k-e, 5v), in absolute ethanol (compounds 4a, 4c, 4d, g_, 4_i, 5a, 5f-j, 5u) or methanol ( compound 4_f). The melting point (° C) of the literature for compound 4a was 219-220 ° C.

The melting points indicated for the various compounds are not corrected. An elemental analysis (C, H, N) were within 0.4% of the calculated values except for compound 5n (calculated for C? 5H? 5H302: N, 15.60 Found: N, 14.80). Chromatography XH NMR was carried out using BRUKER AM 300 FT (registered trademark) NMR instrument. Thin layer chromatography (TLC) was performed using silica gel films with a fluorescent indicator.

SYNTHESIS OF THE COMPOUNDS OF TYPE 15 OF FIGURE 3 The 3-benzyloxybenzaldehyde required in the synthesis of an unsubstituted compound was obtained from Aldrich Chemical Company, Milwaukee, WI. The other intermediate aldehydes were prepared as follows.

Benzoyl chloride or 4-chlorobenzoyl chloride (0.05 M) was added to a solution of 4-hydroxybenzaldehyde (0.04 M) in pyridine (100 ml). After leaving overnight at room temperature, the reaction mixture was poured onto acetic acid (2 N, 100 ml). The precipitate was collected, washed with water and recrystallized from water-methanol to give 4-benzoyloxybenzaldehyde and 4- (4- chlorobenzoyloxy) benzaldehyde required in the synthesis of 68 and 69 respectively. The 4-phenylsulfonylbenzaldehyde used in the synthesis of 70 was prepared as follows. A mixture of sodium benzensulfinate (0.11 M) and 4-fluorobenzaldehyde (0.1 M) in dry dimethylsulfoxide (75 ml) was stirred at 100 ° C for 18 h under nitrogen and then poured onto ice (-200 g). The precipitate was collected, washed with water and recrystallized from ethanol (95% v / v). Finally, the benzenesulfonyl chloride or 4-methylbenzenesulfonyl chloride (0.20 M) was added dropwise to a stirred solution of 4-hydroxybenzaldehyde (0.16 M) in dichloromethane) (90 ml) and triethylamine (3-5 ml) at 0 at 10 ° C over a period of 10 min. After an additional 15 min, the reaction mixture was diluted with dichloromethane and successively extracted with water, hydrochloric acid (10% w / v), saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying the organic extract, the solvent was removed producing the intermediate products required for further synthesis. The compounds were homogeneous by TLC using a benzene solvent system: methanol (7: 3) and the melting points were in agreement with the values of the literature.

These intermediate aldehydes were reacted with semicarbazide as previously described.

SYNTHESIS OF THE COMPOUNDS OF TYPES 17 AND 18 OF FIGURE 3 These compounds were prepared from the aryloxyaryl and arylioaryl aldehydes using literature methodologies (Dimmock, JR, McColl, JM, Onko, SL, Thayer, RS, Hancock, DS Evaluation of the thiosemicarbazones for anticonvulsant activities, Eur. J. Med. Chem. 1991, 26, 529-534; and Dimmock, JR; Puthucode, RN; Lo, MS; Quail, J.;; Yang, J.; Stables, JP Structural modifications of the primary amino group of anticonvulsant aryl semicarbazones. 1996, 51, 83-88.). The heating time of the reactants under reflux was six hours, while the stirring times of the reactants at room temperature were eight, ten and fourteen hours. In one case, the reaction mixture was heated at 60 ° C for 0.5 hours. All compounds of this type were recrystallized from ethanol (95% v / v).

DETERMINATION OF LOG P VALUES The log values of P were determined by previously reported procedures (Dimmock, J.R .; Phillips, O.A; Onko, S.L .; Hickie, R.A .; Tuer, R.G .; Ambrose, S.J .; Reid, r. s.; Mutus, B.; Talpas, C.J. Evaluation of some Mannich bases od conjugated styryl ketones and related compounds versus the iDr colon cancer in vitro. Eur. J. Med. Chem. 1989, 2_4, 217-226) except that the solutions were made using 1-octanol to which the buffer was added. The γ max and e values of the compounds were obtained in 1-octanol and not in phosphate buffered saline solution, pH 7.4 due to the low aqueous solubilities of the compounds.

EXAMPLE 2 An initial anticonvulsant evaluation of the compounds prepared according to Example 1 was carried out by administering the compounds by intraperitoneal route to mice. The protection and / or neurotoxicity was manifested after 0.5 and 4 hours of administration of the doses of 30, 100 and 300 mg / kg of each semicarbazone to the animals.

All compounds were active in the MES grid except for compounds 2a, b, 5t, v and protection was produced by 60% of the compounds in the scPTZ test.

Neurotoxicity was shown by approximately 70% of the semicarbazones. The bioactivity was quantified by selected compounds and these data are given in Table 2 shown below: Table 2. Evaluation of selected compounds in MES reticles, scPTZ and neurotoxicity c after intraperitoneal injection in mice Reticula MES Reticular scptZ Reticula Pl Neurotoxicity Compound t ED50 (mg / kg) Slope t ED50 (mg / kg) Slope t TD50 (mg / kg) Slope TD5p Tm (h) (95% Cl) (SE) (h) (95 % Cl) (SE) (h) (95% Cl) (SE) ED50 MES ED50 scPTZ 4b 1 1 122..8866 8 8..2288 1 > > 5544 - 108.03 3. .69 8.40 (10.54-17.09) (3.00) (71.52-157.52) (0, .96) 4f 1 144..6655 5 5..5599 1 8 888..5555 1 1..8877 203.73 4. .29 13.91 2.30 (10.44-19.23) (1.91) (45.52-173.94) (0.57) (132.44-271.13) (1. .31) 5a 0.5 2 200..6699 1 188..5599 0 0..55 > > 222200 - 170.01 12 .36 8.22 cn (18.68-22.14) (5.63) (146.81-191.65) (3..80) 5c 1 45.78 15.53 1 > 350 292.55 5. .78 6.39 (41.39-52.15) (5.71) (209.59-379.29 (1.77) 5d 0.25 11.25 2.78 0.25 57.85 1.70 1 96.81 11.50 8.61 1.67 (6.68-19.16) (0.86) (30.13-93.95) (0.54) (77.60-113.81) (4.08) 5a 1 14.48 4.62 0.5 72.78 4.27 2 94.80 3.17 6.55 1.30 (9.53-18.91) (1.35) (49.01-99.12) (1.34) (59.86-156.29) (1.09) TJ 5i 0.5 27.69 6.01 0.5 41.16 3.53 2 64.48 4.54 2.33 4.57 O (20.39-36.12) (2.08) (26.98-56.74) (0.91) (42.03-84.72) (1.36) O O o oo o Reticula MES Reticular scptZ Reticula Pl Neurotoxicity Compound t ED50 (mg / kg) Slope t ED50 (mg / kg) Slope t TD50 (mg / kg) Slope TD ^ TD. ,,, (h) (95% Cl) (SE) (h) (95% Cl) (SE) (h) (95% Cl) (SE) EDS0 MES EDbu scPTZ 51 13.12 13.12 > 68 62.46 15.48 4.76 (8.70-20.12) (1.03) (55.56-67.86) (.84) Sn Programmed Scheduled Sp. 5r 13.36 6.945 86.93 11.442 4 131.27 6.467 9.825 1.510 (10.393- (2.045) (71.514-108.966) (4.493) (110,848-158,464) (1,703) c 16,258) 5s 8.87 13,063 > 150.00 - 4 105.92 6.3131 11.934 < 0.706 (7.7047-4.957) (3.833) (85.053-142.591) (1.976) 5t 2 11.27 10,881 > 200 2 124.53 3,924 11 .048 < 0.623 (8.313-12.872) (4.272) (81.064-175.187) (1.095) Phenytoin 1 6.32 11.24 > 50 - 0.5 41.23 14.39 6, .52 (5.44-7.23) (3.52) (36.90-46.14) (4.82) Carbamazepine 0.25 9.85 20.8 0.25 > 50 - 0.2 47.8 7.98 4. .85 (8.77-10.7) (7.15) 5 (39.2-59.2) (2.37) Valproate 0.25 287 7.31 0.25 209 8.51 0.2 483 12.3 1. 68 2.31 (237-359) (2.48) (176 -249) 2.69) 5 (412-571) (4.01) The majority of the compounds were examined by oral activity in rats. Initially 50 mg / kg doses of semicarbazones were administered. However, as the data in Table 1 reveal, with the exception of compound 3, all compounds examined at this dose showed activity in the MES lattice. In an attempt to discern that these compounds possess marked oral activity, the dose was reduced four times to 12.5 mg / kg, revealing that the protection in the MES reticle was retained in all cases. Using the doses indicated in Table 1, neurotoxicity was absent for a period of time between 0.25 - 4 hours with the exception of compound 51 in which case 1/4 of the rats were caused neurological deficit at 1, 2, and 4 hours after oral administration. Compounds 4e, 5b, d gi, g, r were evaluated in the scPTZ lattice at the doses indicated in Table 1 because they were either inactive (compounds 5b, d, g, I q) or showed only marginal activity, details of which are given below. The quantification of the selected compounds was carried out and the values obtained are presented in Table 3.

Table 3. Evaluation of selected compounds in the MES and Neurotoxicity tests after oral administration in rats Reticula MES Reticula neurotoxicidad Pendien Slope Pl3 te Compound t (h) ED5o (mg / kg) (SE) 't () TD50 (mg / kg) (SE) (95% Cl) (95% Cl) 4b 2 1.59 3.17 4--24 ° > 500 > 315 (1.01-2.25) (0.84) 4f 2 3.43 4.121 2 > 500 > 145.57 (2.282-4.726) (1.324) 5c 4 6.15 2.55 _ (3.69-9.71) (0.69) 5e 2 11.44 4.12 .. (7.61-15.75) (1.32) ~ 12 4 2.37 3.18 4--24 ° > 500 > 210 (1.54-3.62) (0.81) 5k 4 1.13 2.661 > 90 > 79,179 (0.713-2.005) (0.949) 5n 2 5.65 3.65 4--24 ° > 500 > 88 (3.79-7.81) (0.98) 5o 1 3.07 7.114 > 500 > 162.47 (2.579-3.944) (2.092) 5 £ 6 6.48 1.98 (2.970-15.536) (0.753) ~ 53 2 2.63 3.213 > 500 > 190.02 (1689-3.926) (0.819) 5r 4 3.21 3.575 > 3.22 > 100.16 (2,252-4,636) (1,022) 5s 4 1.68 4,437 > 500 > 297.24 (1,146-2,438) (1,281) 5u 4 45.81 1,327 (19,481-315,522) (0.524) Continuation Reticula MES Reticulum neurotoxicity Slope Slope Pl3 Compound t (h) ED5o (mg / kg) (SE) t (h) TD50 (mg / kg) (SE) (95% CI) (95% Cl) Phenytoin 2 23.2 15.1 4-24 ° > 500 > 21.6 (21.4-25.4) (4.28) Carbamazepine 1 3.57 3.84 1 361 11.4 101 (2.41-4.72) (1.15) (319-402) (2.96) Valproate 0.5 395 8.13 0.5 859 6.57 2.17 (332-441) (2.76) ( 719-1148) '(2.17) Pl Indicates the protection index i.e. TD50 / ED50 b The compound was examined 0.25, 0.5, 1, 3, 4, 6, 8 and 24 hours after administration.

Subsequent bioevaluations of compound 4b were carried out. After intraperitoneal injection in the rats, the ED50 and TD50 values in the MES reticles and the neurotoxicity for 4b were 2.37 and 80.09 mg / kg respectively revealed a Pl of 33.8. Using an excited rat lattice, the ED50 value of this compound was 3.93 mg / kg. A daily dose of 100 mg / kg of b was administered orally for three days to the rats. Afterwards, the livers were removed and comparisons were made between the liver tissue of the treated and control animals., said liver weights and yields of microsomal proteins in addition to the activities of cytochrome P450 enzymes, p-nitoanisole o-demethylase, UDP-glucuronosyl transfease, sulfotransferase, ethoxylosorphine O-deethylase, pentoxiresorfin O-dealkylase, glutathione S-transferase and quinone reductase. No differences were detected in the properties between treated and control livers (p >; 0.05).

Both compounds 4b and 5g_ were examined for anticonvulsant properties in the pentylenetetrazole tests in mice; the doses administered were the values of MES ED50 and of TD50 of 4b and 5g indicated in Table 2. None of the compounds possessed this undesirable characteristic and using a dose of 108 mg / kg, 4b increased the time to clonus (one T / CA96 / 00380 31 series of alterations and partial relaxations that in certain nervous diseases occur in the form of convulsive spasms involving complex groups of muscles). Compounds 4b and 5_ were evaluated for their ability to prevent seizures induced by the subcutaneous administration of bicuculline and picrotoxin in mice. Semicarbazone 4b showed no protection in the subcutaneous strychnine test in mice.

Full details of these tests are provided below INTRAPERITONEAL INJECTION IN MICE In addition to the information summarized in Table 1, intraperitoneal injection of a number of compounds in mice had the following side effects at various doses (mg / kg) and time intervals. First, in the scPTZ reticle, myoclonic jerks were noticed with the following compounds namely _4c: 30, 100; 0.5 h and 5f: 100, 300; 0.5 h. A second continuous attack activity was observed in the scPTZ lattice as follows: 4c: 300; 0.5 h; 100, 300; 4 h; 4d: 100, 300; 0.5 h and 4 h; 4: 100, 300; 0.5 and 4 h: 5i: 300; 0.5 h; 51: 300; 0.5 h and 4 h; 5th: 100, 300; 0.5h and 5s: 300; 4 h. At the end of 4 hours, the continuous attack activity followed by death resulted in the scptz reticle when the mice received 300 mg / kg of 5o.

ORAL ADMINISTRATION IN RATS Using the doses indicated in Table 1, some compounds showed marginal activity in the scPTZ lattice. These compounds as well as the number of rats protected at different periods of time are as follows: 4e: 1/4 after 0.5, 1, 4 h; 5h: 1/4 after 4 h; 5n: 1/4 after 0.5, 1, 2 h; 5_r: 1/4 after 1, 4 h and 2/4 after 2 hours.

INTRAPERITONEAL REACTION OF COMPOUND 4b in rats.

The values of ED50, 95% of the Cl values and the slope (SE) for 4_b in the MES grid obtained after 4 hours of the intraperitoneal injection in rats were as follows: 2.37, 1.39-3.57 and 2.65 (0.76) while the corresponding TD5o were 80.09, 66.14-87.27 and 17.02 (6.41). The protection afforded after intraperitoneal administration of 125 and 250 mg / kg of 4JD in the scPTZ lattice was shown in 0/2 and 1/10 rats.

TESTING IN EXCITED RATS USING COMPOUND 4b The test of excited rats was performed by the reported procedures (as indicated above). Compound 4b was administered orally and animals subjected to an electrical stimulus after 2 h. The ED50 is the dose required to reduce attacks from states 5 to 3 or less and those states are described as follows ie state 1 is clonus in the mouth and facial, state 2 is a state 1 plus alternative movements in the head, state 3 is state 2 plus clonus of the upper extremity, state 4 is state 3 plus hind limb and state 5 is state 4 more repeated in the hind legs and fall. The ED50 (mg / kg), 95% Cl and slope (SE) values for 4b were as follows 3.93, 2.40-6.09 and 3.62 (1-10). The data (mg / kg, 95% Cl in parentheses) and the times of the tests for three different reference drugs were as follows: phenytoin: > 100, valproate: 117.41 (67.98-189.02), 0.25 h.

EFFECTS OF CHRONIC ORAL ADMINISTRATION OF 4B IN RAT LIVES The rats were administered with 100 mg / kg of 4b daily for 3 days. The livers were removed, heavy and the effect of 4b on the microsomal system of the liver was compared to that of the control animals which received the vehicle (sonicated 0.5% methylcellulose). 21"23 (VI) EVALUATION OF 4b and 5g_ IN THE INTRAVENOUS PENTILTETRAZOL TIME TEST Compounds 4b and 5g_ in a solution of methylcellulose (0.5%) were injected intraperitoneally into mice. The two doses used were approximately the ED50 values in the MES test and the TD50 values. After 1 h, a solution of pentyletetrazole (0.5%), sodium chloride, sodium heparin (10 USP units / ml) in water was infused into the tail veins of the mice at a rate of 0.37 ml / min ( b) and 0.34 ml / min (5g). The times from the start of the infusion to the appearance of the first shake and also the beginning of the clonus were recorded for the test and the control animals. From those data, the amounts of pentyletrazole infused were obtained. Ten animals were used as control and for each dose administered except for the dose 13 mg / kg of 4b in which case 9 animals were used. The values for the times of the first shake in seconds, the amount of pentyletrazol administered in mg / kg (SE) and the p values were as follows: 4b (dose of 13 mg / kg): 32.2, 32.3 (1.4), > 0.05; 4b (dose of 108 mg / kg): 32. 2, 32.6 (0.8), > 0.05; 5_ £ (dose of 15 mg / kg): 32.8, 32.9 (1.4), > 0.05; 5g_ (dose of 95 mg / kg): 34.6, 34. 6 (1.5), > 0.05. The relevant data for clonus times in seconds, the amount of pentyl tetrazol administered in mg / kg (SE) and the p values were as follows: 4b (dose of 13 mg / kg): 37.6, 37.6 (1.5), > 0.05; 4b (dose of 108 mg / kg): 41.5, 42.1 (1.4), < 0.01; 5g (dose of 15 mg / kg): 41.2, 41.2 (2.6), 0.05. 5g_ (dose of 95 mg / kg): 44.4, 44.4 (2.5), > 0.05.

(VII) EVALUATION OF 4b AND 5g_ USING OTHER MODELS OF ATTACK CHEMICALLY INDUCED Several doses of 4b and 5g_ were administered to mice 1 h (4_b) or 0.5 h (5g_) before the doses of bicucullin and picrotoxin were given subcutaneously to the mice. Compound 4b_ was also examined for protective effects after subcutaneous administration of strychnine. In the case of 4b_, the number of animals protected in the subcutaneous bicuculline test at different doses (mg / kg) were the following: 0/8 (54), 3/8 (108) and 3/8 (216). In the subcutaneous test of picrotoxin, protection at different doses (mg / kg) were as follows: 1/8 (27), 5/16 (108) and 2/8 (216). The compound 5_g_ showed no effect in the dose range 12-96 mg / kg in the two tests. Semicarbazone 4b did not present protection in the subcutaneous strychnine test using a dose in the range of 13.5 - 108 mg / kg. Two animals per dose were used except in the bicuculline and picrotoxin tests for 4b in which cases, 8 or 16 animals per dose were used.

EXAMPLE 3 The compounds having the structures shown in Table 4 were prepared. The structures of the listed compounds correspond to those shown in Fig. 3 identified by the same number (12, 13, 14, 15, 16, 17, or 18), with only the substituents identified in Table 4.

Table 4. Aryl substituents, physical data and anticonvulsant evaluation after intraperitoneal injection in mice and oral administration in rats of the series of compounds 12-18 r - g Intraperitoneal injection in mice Oral administration in rats c Reticle Reticle Reticle Reticle MES MES scPTZ toxicity Compound R1 p.f. Yield (° C)% 0.5h 4h 0.5h 4h 0.5h 4h Dose 0.25h O.Sh lh 2h 4h (mg / kg) 12a H F 240 ° 65 30 100 - - 50 4 4 or -4 12b HH 224-255 60 100 300 - - 50 3 4 12c H Cl 225-226 40 30 30 30 300 30 50 4 4 12d H Br 225-226 60 30 30 300 30 50 4 4 12e H CH3 219-221 50 30 100 - - 50 4 4 13a CH3 H 169-171 60 30 100 100 100 30 4 4 13b CH3 F 182-184 74 30 30 100 300 100 12.5 4 4 13c CH3 Cl 192-194 60 30 30 30 30 100 30 4 4 13d CH3 Br 195-197 30 30 30 300 300 100 12.5 3 4 TJ OR H O o o o 0o0 Intraperitoneal injection in mice Oral administration in rats r Reticle Reticle Reticle Grid MES MES scPTZ Toxicity Compound R1 R2 p.f. Yield (° C)% 0.5h 4h 0.5h 4h 0. Sh 4h Dose 0.25h 0.5h lh 2h 4h (mg / kg) 13e C2H5 H 154-156 58 30 100 - 100 100 30 3 3 13f C2H3 F 170- 172 72 30 30 100 300 100 12.5 4 4 O 135 C2Hb Cl 186-188 38 30 - 300 300 100 30 4 4 oo 13h C, H5 Br 184-186 38 30 30 100 300 100 12.5 4 4 14a CH3 H 136-138 14 300 - 300 300 __ _ 14b CH3 F 154-157 27 30 14c CH3 CL 167-169 32 300 300 300 300 300 300 14d CH3 Br 183-186 28 300 14e C2H5 F 156-158 55 300 12.5 14f C2H5 CL 136-138 15 300 300 - 14g C2H5 Br 155-157 5 300 - 15a SH 226-227 40 30 30 - 300 50 TJ 15b oco H 237-238 70 - 300 - - 12.5 __ __ __ __ O; H 15c oco CL 245-246 80 - 300 - - 12.5 1 - 1 - 2 O 15d 0CH2 H 212-213 52 300 300 - 100 - - 1122..55 - - 1 1 - - o co oo o Intraperitoneal injection in mice Oral administration in rats c Reticle Reticle Reticle Grid MES MES scPTZ Toxicity Compound R1 R2 p.f. Performance < ° C)% 0.5h 4h 0.5h 4h 0.5h 4h Dose 0.25h 0.5h lh 2h 4h (mg / kg) 15e S02 H 254 40 - 300 - - - - - 15f 0S02 H 146 40 30 30 30 - 300 300 12.5 15g bear2 CH3 205-207 70 CO O 16a HF 230-231 52 3 300 3 300 3 300 - - 3 30000 1 10000 1 122..55 3 4 4 4 16b H Cl 216 40 1 10000 3 300 3 30000 - - ---- 1 100 5 500 4 4 4 4 16c H Br 212-213 30 1 10000 3 300 - - 3 30000 - - 3 30000 1 122..55 1 3 4 4 16d H CH3 225-227 32 3 300 3 300 1 10000 1 10000 3 30000 1 10000 1 122..55 0 4 4 4 16e CH3 H 208-210 60 1 10000 1 10000 3 30000 - - - - - - 3 300 4 4 4 4 16f CH3 F 204-207 91 1 10000 3 300 - - 3 30000 3 30000 3 30000 3 300 4 4 4 4 16g C2H5 H 131-133 16 3 300 3 300 1 10000 1 10000 1 10000 1 10000 3 300 3 4 3 4 16h C2H5 F 150-157 18 3 300 1 10000 - - - - 1 10000 1 10000 3 300 0 2 3 3 or TJ 17a s 167 56 3 300 3 300 3 300 3 300 1 10000 3 300 1 122..55 2 2 3 1 O 17b NH or 181-183 50 3 30000 3 300 3 300 --- 1 10000 H 1 10000 1 122..55 1 2 O 17c s s 171-172 62 110000 110000 110000 110000 - 110000 1122..55 - 1 2 1 1 (or * CO 17 NH s 172-173 40 330000 ---- 3300 3300 110000 110000 1122..55 - - - 1 - 3 O co 00 o Intraperitoneal injection in mice Oral administration in rats Reticle Reticle Reticle Reticle MES O CD CO MONTH scptz toxicity or Compound R p.f. Yield CC)% oo 0.5h 4h 0.5h 4h 0.5h 4h Dose 0.25h O.Sh lh 2h 4h (mg / kg) 18a H 0 176-178 60 300 300 300 - 300 - 18b CH3 O 160 83 30 30 100 100 100 100 12.5 18c NHNH2 O 220 80 300 100 300 - 300 30 18d CONH, O 253 75 300 300 - 18e HS 146-148 80 100 100 300 - 300 30 O Phenytoin 30 30 100 100 - Carbazepi 30 100 100 300 100 300 - Valproate 300 Doses of 30, 100 and 300 mg / kg were administered. The values in the table indicate the minimum dose J in which the bioactivity was demonstrated in half or more of the mice. The O animals were examined at 0.5 h and 4 h after the injection was made. O The lines - indicate an absence of anticonvulsant activity and neurotoxicity. or The values in the table indicate the number of rats out of 4 which were protected. o ooo These compounds were synthesized as follows, in spite of the attempts to isolate the 2-phenoxypropiophenone, required in the synthesis of the compound 4_ (R1 = C2H5; R2 = H), were not successful; the reactions invariably led to the formation of a number of compounds. The aldehydes and intemediate ketones were reacted with semicarbazide (13-16), thiosemicarbazide (17a, c), aminoguanidine (17b, d), formic acid hydrazide (18a, e), acetic hydrazide (18b), carbohydrazide (18c) and oxidized hydrazide (18d).

The initial anticonvulsant evaluation of compounds 13-18 was carried out as follows. Doses 30, 100 and 300 mg / kg were injected by the intraperitoneal route in mice and evaluated in the MES, scPTZ and neurotoxicity reticles at mid and four hours after administration. The results were presented in Table 4 above in addition to the data for 12a-e which were included for comparative purposes.

The quantification of the activity of the selected compounds was carried out and their results are shown in Table 5.

Table 5. The quantification of the activity of certain compounds in the MES reticles, scPTZ and neurotoxicity after intraperitoneal injection in mice. Reticle MES Reticle scPTZ Reticle Pl neurotoxicity Compound t ED50 (mg / kg) Slope t ED50 (mg / kg) Slope t TD50 (mg / kg) Slope D ^ or TDy) () (95% Cl) (SE) (h) (95% Cl) (SE) < h) (95% Cl) (SE) ED50 MONTH ED..o scPTZ 12a 1 12.86 8.28 1 > 54 - 1 108.03 3.69 8.40 - (10.54-17.09) (3.00) - - (71.52-157.52) (0.96) l3a 0.25 9.08 6.21 0.25 43.31 1.54 1 73.48 10.51 8.09 1.70 (6.45-11.31) (1.91) (18.36-) 112.07) (0.57) (64.32-86.40) (3.08) 13b 1 11.63 22.69 0.25 > 80 - 2 60.74 45.21 5.22. (10.96-12.48) (9.34) - - (58.92-63.84) (14.45) 13f 1 5.46 11.64 2 12.84 3.34 2 35.26 6.78 6.45 2.75 (4.57-6.46) (3.74) (8.25-18.55) (1.16) (25.02-43.44) ) (2.05) the 4 11.09 20.278 < 100 < 9,017 (10,367-12,583) (6,827) 15a 1 15.62 4.50 1 > 46 - 2 181.00 4.59 11.59 - (10.45-20.56) (1.36) (122.53-250.73) (1.27) 15f 0.5 25.27 9.52 0.5 > 100 - 1 113.00 17.38 4.47 - (21.50-29.87) (3.00) (103.02-122.68) (5.73) Reticle MES Reticle scPTZ Reticle Pl neurotoxicity Compound t ED50 (mg / kg) Slope t ED50 (mg / kg) Slope t TD50 (mg / kg) Slope TD50 TD ^ (h) (95% Cl) (SE) (h) (h) 95% Cl) (SE) (h) (95% Cl) (SE) EDbu MES ED5U scPT 16th 12.37 6.372 > 120 2 88.00 24,001 7.112 < 0.733 (9.247-16.128) (1.915) (83.311-94.847) (6.853) 16b 16.22 23.21 > 120 2 53.18 5.90 3.28 - (14.63-17.59) (8.59) (41.42-72.54) (1.89) 16c 24.34 5.92 > 200 2 122.57 6.92 5.03 - (18.45-30.93) (1.72) (101.63-149.51) (2.10) 16d 9.46 3.676 > 300 4 196.52 12,821 20,776 < 0.655 (6.353-13.026) (0.986) (174.429-226.447) (3.957) Phenytoin 6.48 12.4 > 50 0.5 42.8 10.2 6.60 - (5.66-7.24) (3.60) (36.4-47.5) (3.13) Carbamasepipa 0.25 9.85 20.8 0.25 > 50 0.25 47.8 7.98 4.85 - (8.77-10.7) (7.15) (39.2-59.2) (2.37) Valproate 0.25 287 7.31 0.25 209 8.51 0.25 483 12.3 1.68 2.31 The evaluation of most of the semicarbazones and their analogs in the MES and neurotoxicity tests after oral administration in rats was carried out. At the doses indicated in Table 4, the neurotoxicity was absent and some of the compounds examined in the scPTZ lattice were both inactive or exhibited only minimal protection. Hence, only the MES data are presented in Table 4. The ED50 values of some compounds in the oral MES grid in rat are given in Table 6.

Table 6. Quantification of the activity of the selected compounds in the MES reticles and neurotoxicity after oral administration in rats. Reticle MES Reticle neurotoxicity Slope Slope Pl3 Compound t ED5o (mg / kg) (SE) T (h) TD50 (mg / kg) (SE) (h) (95% Cl) (95% Cl) 12ab 2 1.59 3.17 -24c > 500 - > 315 (1.01-2.25) (0.84) - "13a 4 9.73 3.844 -" "- ~ (6.440-14.141) (1.300) 13b 2 3.37 5.74 2 108.77 4.82 32.3 (2.37-4.72) (1.80) (80.26-177.74) ( 1.82) 13c 4 2.92 5.774 4 < 500"~ < 170.73 (2,203-3,464) (1,595) 13d 4 1.52 3,600 - > 500 > 328.28 (0.989-2.300) (1.024) "13e 0.5 23.08 3.14 - - - - (14.33-36.64) (0.92) - - 13f 2 4.25 3.67 4> 72 (<240) -> 16.9 (< 56,436) (2.89-5.97) (1.04) - - 13a 2 2.89 2.035 0> 500> 172.81 (1,568-5,294) (0.594) "13h 4 4.39 4.206 (2.67-5.833) (1.279) 14b 2 43.37 2.287 (25.078-66.343) ) (0.569) 15a 4 4.29 6.02 -Z > 496 - > 115.6 (3.20-5.24) (2.00) - - Reticle MES Reticle neurotoxicity Slope Slope Pl3 Compound t EDso (mg / kg) (SE) t TD50 (mg / kg) (SE) () (95% Cl) (h) (95% Cl) 16a 2 4.98 3.92 4 183.05 2.49 36.8 (3.24-7.01) (1.10) (100.59-338 .: 35) (0.86) 16f 2 9.11 5,285 - - - - (6,185-11,658) (1,496) 16g 2 18.58 5,238 - - - - (14,195-25,038) (1,674) 18b 0.5 18,66 3,993 2 > 125 - > 6.70 (12.40-27.60) (1.11) - - - Phenytoin 2 23.2 15.1 - > 500 - > 21.6 (21.4-25.4) (4.28) 243 - - Carbamazepine 1 3.57 3.84 1 361 11.4 101 (2.41-4.72) (1.15) (319-402) (2.96) Valproate 0.5 395 8.13 0.5 859 6.57 2.17 (332-441) (2.76) (719-1148) (2.17) a The letters of Pl refer to the protection index viz TD50 / ED50 b The data for this compound were taken from reference 1. c The compound was examined 0.25, 0.5, 1, 2, 4, 6, and 24 hours after the administration.

The final pharmacological evaluation of the representative compounds was carried out using an epileptic chicken model.6 In this case, seizures which were induced by intermittent photic stimulation have been shown to be prevented by a number of anticonvulsants at blood levels similar to those used in humans. Two series of compounds were examined with the objective of observing whether oxygen or sulfur is a preferred spacer atom between the two aryl rings and also to compare the values of ED50 with those obtained in rat oral and intraperitoneal reticles in mice. The ED50 values of the ethers of 12a-d were 1.5, 2.5, 1.0, and 2.0 mg / kg respectively and for the behavior of the thioethers the same pattern of the aryl substitution is 16a, 15a, 16b, c, values were 1.5, 2.5, 1.0, and 1.5 mg / kg respectively. Hence, its potencies are not affected by oxygen or by sulfur when used as a spacer group. The ED50 values of 12a, 15a, 16a, in the rat oral grid are in the range between 1-5 mg / kg while for 12a, 15a, 16b, c the values in the intraperitoneal test in the mouse are approximately 15-25 mg / kg. Therefore, the results of the model in epileptic chicken are comparable with the data provided in the rat oral grid.

Having described the invention as above, the content of the following is claimed as property

Claims (15)

1. A compound characterized by general formula I, characterized in that: R1, R2, R3 and R4 may be the same or different and each represents a hydrogen atom or a halogen atom, or a C1-9 alkyl, cycloaliphatic Cs-9 / cyano, C1-9 alkoxy or aryloxy group Cß-io; R5 represents a hydrogen atom or a C1-9 alkyl group, C5-9 cycloalkyl or C ar-io aryl and X is oxygen or sulfur; except that R1, R2, R3, R4 and R5 may not all be hydrogen; or a pharmaceutically acceptable salt thereof.
2. 2. A compound according to claim 1 characterized in that R1 and R2 can be the same or deferent and each represents a hydrogen or a halide, R3 and R4 are each hydrogen, R5 is hydrogen or alkyl C1-3, and X is 0 or S.
3. 3. A compound according to claim 1 characterized in that R1 and R2 represent hydrogen or fluoride, R5 is hydrogen and X represents oxygen.
4. 4. A semicarbazone 4- (4'-fluorophenoxy) benzaldehyde or a pharmaceutically acceptable salt thereof.
5. 5. A semicarbazone 4- (thiophenoxy) benzaldehyde or a pharmaceutically acceptable salt thereof.
6. 6. A compound for the treatment of diseases of the central nervous system, characterized in that said composition contains a compound of general formula I: characterized in that: R1, R2, R3 and R4 can be the same or different and each represents a hydrogen atom or a halogen atom, or a C1-9 alkyl, C5-9 cycloaliphatic, cyano, C1-9 alkoxy or aryloxy group Cß-io; R5 represents a hydrogen atom or a C? _ 9 alkyl, C5-9 cycloalkyl or Cß-io aryl group; and X is oxygen or sulfur; or a salt of themselves accepts bJ.es pharmaceutically; and a pharmaceutically acceptable excipient.
7. 7. A compound according to claim 6 characterized in that R1 and R2 can be the same or deferent and each represents a hydrogen or a hydrogen, RR33 and RR44 ssoonn ccaaddaa one hydrogen, R5 is hydrogen or alkyl C? _3, and X is 0 or S
8. 8. A compound according to claim 6 characterized in that R1 and R2 represent hydrogen or fluoride, R5 is hydrogen and X represents oxygen.
9. 9. A compound according to claim 6 characterized in that said compound is a semicarbazone 4- (4'-fluorophenoxy) benzaldehyde or a salt thereof or a pharmaceutically acceptable salt thereof.
10. 10. A compound according to claim 6 characterized in that said compound is a semicarbazone 4- (thiophenoxy) benzaldehyde or a pharmaceutically acceptable salt thereof.
11. 11. A method of preparing a compound of general formula I: 80 52 characterized in that: R1, R2, R3 and R4 can be the same or different and each represents a hydrogen atom or a halogen atom, or a C? _9 alkyl, C5-9 cycloaliphatic, cyano, C1-9 alkoxy or aryloxy group? C6-? O; R5 represents a hydrogen atom or a C1-9 alkyl group, C5-9 cycloalkyl or Ce-1 aryl; and X is oxygen or sulfur, except that R1, R2, R3, R4 and R5 may not all be hydrogen; whose method is characterized in that the formation of an aryloxy- or arylthiobenzaldehyde or ketone intermediate by reaction of the corresponding (thio) phenol with a fluorobenzaldehyde or fluoroaryl ketone in a solvent in the presence of anhydrous potassium carbonate at temperatures in the range of 100 to 200 ° C under a non-gas oxidant, extracting the intermediate and then reacting the intermediate with semicarbazide and collecting the resulting precipitate of the desired compound.
12. 12. A method of preparing a compound of general formula I: characterized in that: R1, R2, R3 and R4 can be the same or different and each represents a hydrogen atom or a halogen atom, or a C1-9 alkyl, C5-9 cycloaliphatic, cyano, C9-9 alkoxy or aryloxy group C6-? O; R5 represents a hydrogen atom or a C1-9 alkyl group, C5-9 cycloalkyl or Cß-io aryl; and X is oxygen or sulfur; except that R1, R2, R3, R4 and R5 may not all be hydrogen; whose method is characterized in that the intermediate aldehydes were prepared by the addition of benzoyl chloride or 4-chlorobenzoyl chloride to a solution of 4-hydroxybenzaldehyde in pyridine, pouring the reaction mixture over acetic acid, collecting the precipitate and recrystallizing said precipitate to give 4-benzoyloxybenzaldehyde or 4- (4-chlorobenzoyloxy) benzaldehyde.
13. 13. A method for the treatment of a human or animal patient for a disorder of the central nervous system, characterized in that by administering to said patient an effective amount of a compound having the general formula I: characterized in that: R1, R2, R3 and R4 can be the same or different and each represents a hydrogen atom or a halogen atom, or a C1-9 alkyl, C5-9 cycloaliphatic, cyano, C1-9 alkoxy or aryloxy group C6-? O; R5 represents a hydrogen atom or a C1-9 alkyl group, C5-9 cycloalkyl or C6-? O aryl; and X is oxygen or sulfur; or a pharmaceutically acceptable salt thereof.
14. 14. A method according to claim 12 characterized in that said disorder exhibits convulsions or attacks.
15. 15. A method according to claim 12 characterized in that said disorder in a material epileptic seizure test.