MXPA99011993A - 1-amino-alkylcyclohexane nmda receptor antagonists - Google Patents

Abstract

Certain 1-amino-alkylcyclohexanes are systemically-active uncompetitive NMDA receptor antagonists having rapid blocking/unblocking kinetics and strong voltage-dependency and are therefore useful in the alleviation of conditions resulting from disturbances of glutamatergic transmission giving them a wide range of utility in the treatment of CNS disorders involving the same, as well as in non-NMDA indications, due to their immunomodulatory, antimalarial, anti-Borna virus, and anti-Hepatitis C activities and utilities. Pharmaceutical compositions thereof and a method of treating conditions which are alleviated by the employment of an NMDA receptor antagonist, as well as the aforementioned non-NMDA indications, and a method for the preparation of the active 1-amino-alkylcyclohexane compounds involved.

Description

ANTAGONISTS OF THE RECEPTOR OF N-METHYL D-ASPARTATE OF 1- AMINO-ALKYLCYCLOHEXANE 1. Field of the Invention The 1-amino-alkylcyclohexane compounds which are systemically active as NMDA receptor antagonists, the pharmaceutical compositions comprising the same, a method for the preparation thereof, and a method for treating CNS disorders that they involve disturbances of glutamatergic transmission with these. 2. Background Art Antagonism of glutamate receptors of the N-methyl-D-aspartate (NMDA) type have a potentially wide range of therapeutic applications [19]. Functional inhibition of NMDA receptors can be achieved through actions at different recognition sites, such as the site of the primary transmitter, the strychnine-insensitive glycine site (glycineB), the polyamine site, and the site of the pheniciclidine located within the cation channel. NMDA receptor channel blockers act in a "non-competitive", "use dependent" manner, which means that they usually only block REF: 32243 the channel in the open state. This has been interpreted by many that this dependence on use means a stronger activation of the receptor will lead to a greater degree of antagonism. It has further been interpreted that such a mode of action implies that this class of antagonist may be particularly useful when overactivation of NMDA receptors can be expected, such as in epilepsy, ischemia and trauma. However, the initial clinical experience with the NMDA receptor antagonist, non-competitive, strongly dependent on the use, high affinity, selective, maleate of (+) - 5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5 , 10-imine ((+) -MK-801) has been contradictory. Namely, the therapeutic efficacy in poor epilepsy because some psychotropic side effects were evident at therapeutic doses. These observations, together with the fact that they abuse Phencyclidine, experience similar psychotropic symptoms, leading to the conclusion that non-competitive antagonism of NMDA receptors may not be a promising therapeutic method. However, the use of more elaborate electrophysiological methods indicates that there is no equality between the different non-competitive antagonists since factors such as the receptor blocking rate (on-off kinetics) and the voltage dependence of this effect can determine the pharmacodynamic characteristics in vivo, that is, therapeutic safety as well. Paradoxically, agents with low to moderate affinity, instead of high, may be desirable. Such discoveries led to a reconsideration of the concept of non-competitive antagonism of NMDA receptors in drug development [19,22]. Until now, many agents are in different stages of development, for example, carvedilol, ADCI, ES 242S, remacemide, felbamate, and budipine. On the other hand, non-competitive NMDA receptor antagonists, such as amantimidine and nemantine - which satisfy the above criteria - have been used clinically for several years in the treatment of Parkinson's disease and dementia, respectively, and in In reality, they rarely produce side effects at the therapeutic doses used in their respective indications. In view of the evidence mentioned above, we have developed a series of non-competitive NMDA receptor antagonists based on the structure of 1-aminoalkylcyclohexane. The present study was devoted to comparing the NMDA receptor antagonist properties of these 1-aminoalkylcyclohexane derivatives in receptor binding assays, patch succession experiments, in vitro excitotoxicity, three seizure models, and two models of engine damage. Substitutions of these 1-aminoalkylcyclohexanes are detailed in Table 6.

THE PRESENT INVENTION It has now been found that certain 1-aminoalkylcyclohexanes have pronounced and unpredictable NMDA receptor antagonistic activity. Due to the aforementioned property, the substances are suitable for the treatment of a wide range of CNS (Central Nervous System) disorders which involve disturbances of the glutamatergic transmission, preferably in the form of a pharmaceutical composition thereof, where they are present together with one or more diluents as pharmaceutically acceptable carriers or excipients.

OBJECTS OF THE INVENTION It is an object of the present invention to provide novel pharmaceutical compounds which are antagonists of the NMDA receptor of 1-aminoalkylcyclohexane and pharmaceutical compositions thereof. A further object of the invention is to provide a novel method for treating, eliminating, alleviating, alleviating, or decreasing undesirable CNS disorders which involve disturbances of glutamatergic transmission by use of the compound of the invention or a pharmaceutical composition containing the same . A further object of the invention is to provide a process for producing the active principles of 1-aminoalkylcyclohexane. Additional objects will be apparent here later, and additional objects will be apparent to those skilled in the art.

BRIEF DESCRIPTION OF THE INVENTION We therefore believe that what is understood by our invention can be summarized inter alia in the following words: A 1-aminoalkylcyclohexane compound selected from those of the formula wherein R * is - (CH2) n- (CR6R7) m-NR8R9 where n + m = 0, 1 or 2 where R1 to R9 are independently selected from hydrogen and lower alkyl (1-6C), at least R1, R 4 and R 5 are lower alkyl; as well as a compound wherein R1 to R5 are methyl; as well as a compound wherein R1 is ethyl; as well as a compound wherein R2 is ethyl; as well as a compound wherein R3 is ethyl; as well as a compound wherein R4 is ethyl; as well as a compound wherein R5 is ethyl; as well as a compound wherein R5 is propyl; as well as a compound wherein R6 or R7 is methyl; as well as a compound wherein R6 or R7 is ethyl; and as well as a compound wherein the compound is selected from the group consisting of 1-amino-1,3,3,5,5-pentamethylcyclohexane, 1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane, -amino-l, 5, 5-trimethyl-3, 3-diethylcyclohexane, 1-amino-1,5,5-trimethyl-cis-3-ethylcyclohexane, 1-amino-1,5,5-trimethyl-trans-3 -ethylcyclohexane, l-amino-l-ethyl-3, 3,5, 5-tetramethylcyclohexane, l-amino-l-propyl-3, 3, 5, 5-tetramethylcyclohexane, N-methyl-l-amino-1, 3 , 3, 5, 5-pentamethylcyclohexane, and N-ethyl-1-amino-1, 3,3,5,5-pentamethylcyclohexane, and the pharmaceutically acceptable salts of any of the foregoing. In addition, a method of treating a living animal to alleviate a condition which is alleviated by an NMDA receptor antagonist comprising the step of administering to the living animal an amount of 1-aminoalkylcyclohexane compound selected from those of the formula wherein R * is - (CH2) n- (CR6R7) m-NR8R9 where n + m = 0, 1 or 2 where R1 to R9 are independently selected from hydrogen and lower alkyl (1-6C), which is effective to alleviate such a condition; as well as a method where R1 to R5 are methyl; as well as a method where R1 is ethyl; as well as a method where R2 is ethyl; as well as a method where R3 is ethyl; as well as a method where R4 is ethyl; as well as a method where R5 is ethyl; as well as a method where R5 is propyl; as well as a method where R6 or R7 is methyl; as well as a method where R6 or R7 is ethyl; and as well as a method wherein the compound is selected from 1 group consisting of 1-amino-1, 3,3,5, 5-pentamethylcyclohexane, 1-amino-1,3, -, 5, 5-tetramethyl-3. ethylcyclohexane, 1-amino-1,5,5-trimethyl-3, 3-diethylcyclohexane, 1-amino-1,5,5-trimethyl-cis-3-ethylcyclohexane, 1-amino-1,5,5-trimethyl- trans-3-ethylcyclohexane, l-amino-l-ethyl-3,3,5,5-tetramethylcyclohexane, l-amino-l-propyl-3,3,5,5-tetramethylcyclohexane, N-methyl-l-amino- 1, 3, 3, 5, 5-pentamethylcyclohexane, and N-ethyl-l-amino-1, 3,3,5, 5-pentamethylcyclohexane, and the pharmaceutically acceptable salts of any of the foregoing; and as well as a method wherein the compound is administered in the form of a pharmaceutical composition thereof comprising the compound in combination with one or more pharmaceutically acceptable diluents, excipients or carriers. In addition, a pharmaceutical composition comprising an NMDA receptor antagonist, an effective NMDA receptor antagonist amount, or an antimalarial, anti-hepatitis C immunomodulatory or effective anti-hepatitis C amount of a 1-aminoalkylcyclohexane compound selected from those of the formula wherein R * is - (CH2) n- (CR6R7) m-NR8R9 where n + m = 0, 1 or 2 where R1 to R9 are independently selected from hydrogen and lower alkyl (1-6C), at least R1, R 4 and R 5 are lower alkyl, in combination or more diluents, excipients or pharmaceutically acceptable carriers; as well as a pharmaceutical composition wherein R1 to R5 are methyl; as well as a pharmaceutical composition wherein R1 is ethyl; as well as a pharmaceutical composition wherein R2 is ethyl; as well as a pharmaceutical composition wherein R3 is ethyl; as well as a pharmaceutical composition wherein R4 is ethyl; as well as a pharmaceutical composition wherein R5 is ethyl; as well as a pharmaceutical composition wherein R5 is propyl; as well as a pharmaceutical composition wherein R6 or R7 is methyl; as well as a pharmaceutical composition wherein R6 or R7 is ethyl; . as well as a pharmaceutical composition wherein the compound is selected from the group consisting of 1-amino-1, 3,3,5,5-pentamethylcyclohexane, 1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane, 1 -amino-l, 5,5-trimethyl-3, 3-diethylcyclohexane, 1-amino-1,5,5-trimethyl-cis-3-ethylcyclohexane, 1-amino-1,5,5-trimethyl-trans-3 -ethylcyclohexane, l-amino-l-ethyl-3, 3,5, 5-tetramethylcyclohexane, l-amino-l-propyl-3, 3,5, 5-tetramethylcyclohexane, N-methyl-l-amino-1, 3 , 3,5, 5-pentamethylcyclohexane, and N-ethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane, and the pharmaceutically acceptable salts of any of the foregoing.

DETAILED DESCRIPTION OF THE INVENTION The following details and detailed examples are given by way of illustration only and should not be construed as limiting.

Methods Chemistry Preparation of 3-propyl-5, 5-dimethyl-2-cyclohexen-l-one (1- 21) A solution of 3-ethoxy-5, 5-dimethyl-2-cyclohexen-l-one [1] (5.04 g 30 mmol) in ether was added dropwise to a stirring solution of propylmagnesium iodide prepared from 90 mg of magnesium and 90 mmol of 1-iodopropane in 60 ml of ether.After being stirred for 1 h at room temperature, the reaction mixture was treated with a 5% H2SO4 solution, the organic phase was separated, washed with saline, and dried over MgSO4 and evaporated to give a crude oil which was separated on a gel column. silica, eluting with a mixture of hexane-ethyl acetate, cyclohexenone (1.-7) was obtained as a colorless oil. (2.0 g, 70%). 1R NMR (CDC13, TMS) 6: 0.92, (3H, t, J = 7 Hz); 1.03. (6H, s); 1.3 - 1.75 (2H, m); 2.16 (2H, t, J = 7, Hz); 2.1 ^ 7 2H, d, J = 1.5 Hz); 2.21 (2H, s) and 5.87 ppm (1H, t, J = 1.5 Hz). Such known cyclohexenones were used to prepare the compounds 2: 1-1 (R1 = R2 = R3 = H) [commercially available], JL-2 (R3 = Me) * [commercially available], 1-3 (R = R3 = Me) [commercially available], 1-4 (Rx = R2 = Me) [2], 1.-5 (R1 = R2 = R3 = Me) [commercially available], 1-6 (Rx = R = Me , R3 = Et) [3], * Rn = H, if omitted The other starting materials 1 were prepared the same or similarly.

General procedure for the preparation of cyclohexanones 2. Anhydrous copper chloride (1) (7.5 mmol) was added to a cold solution of alkylmagnesium iodide (15-18 mmol) in ether. The mixture was stirred under an inert atmosphere for 5 minutes and a solution of 2-cyclohexen-1-one (10 mmol) in ether was added dropwise, keeping the temperature below -5 ° C. After the addition of the ketone was complete, the reaction mixture was stirred for 1 hour and carefully neutralized with saturated aqueous NH 4 Cl solution. The traditional work for the Grignard reactions gave the crude material which was separated on a column of silica gel, eluting with a mixture of petroleum ether-ethyl acetate. The cyclohexanones 2 were obtained as oils. The 1H NMR spectral data and yields of the compounds 2 are given in Table 1. Such known cyclohexanones 2 were used to prepare the compounds 3 ^. 2-1 (R4 = Me) * [commercially available], 2-2 (R4 = Et) [4], 2-3 (R4 = Pr) [5], 2-4 (R3 = R4 = Me) [6 ], 2-5 (R3 = Me, R = Et) [7], 2-6 (R3 = Me, R = Pr) [8], 2-7 (Rx = R4 = Me) [9], 2- 8 (R2 = R3 = R4 = Me) [10], 2-9 (R2 = R3 = Me, R4 = Et) [11], 2-13 (R1 = R2 = R3 = R4 = Me) [commercially available] , 2-14 (R1 = R2 = R3 = Me, R4 = Et) [10], 2-15 (R1 = R2 = R3 = Me, R4 = Pr) [10], * Rn = H, if it was omitted other cyclohexanones 2 intermediates thereof or a similar manner were prepared. Cyclohexanones 2 were used to prepare compounds 3: General procedure for the preparation of alkylcyclohexanones 3. An ethereal solution of alkylmagnesium iodide (3-4 equivalents) was added dropwise to a cold solution of cyclohexanone 2 in ether. The mixture was stirred for 1 hour at room temperature and carefully destroyed with saturated aqueous ammonium chloride. The traditional work for the Grignard reactions gave mixtures of diastereomeric alcohols 3, which were separated on a column of silica gel eluting with petroleum ether-ethyl acetate. The yields and spectral data of the 1H NMR of the compounds 3_ are given in Table 2. Such known cyclohexanols 3_ were used to prepare the compounds _4: 3-1 ((R3) (R4) = R4 = Me) * [9 ], that is, R3 or R4 and R5 are Me . 3-4 (R3 = R4 = Me, R5 = Me) [12], 3-5 (R3 = R5 = Me, R4 = Et) [13], 3-7 (R1 = R4 = R5 = Me) [14 ], 3-8 (R1 = R3 = R4 = R5 = Me) [10], 3-13 (R1 = R2 = R3 = R4 = R5 = Me) [10], 3-14 (R1 = R2 = R3 = R4 = Me, R5 = Et) [15], * Rn = H, if omitted. Other cyclohexanals _3 intermediates of the same or a similar manner were prepared.

General procedure for the preparation of 1-alkyl? -l-azidocyclohexanes. The alcohol .3 was mixed with a 1.7-2 N hydrazoic acid solution (10-13 equivalents) in chloroform, and cooled in an ice bath. A solution of TiCl4 (1.2 equivalents) in chloroform was added dropwise while the temperature was kept below 5 ° C. The mixture was stirred at room temperature for 24 hours and passed down an alumina column, eluting with chloroform. Evaporation of the solvent afforded the diastereomeric azides 4. which were purified by flash chromatography on silica gel, eluting with light petroleum ether. The 1H NMR spectral data and yields of the compounds are given in Table 3. Other intermediate 1-alkyl-1-azidocyclohexanes 4 were prepared therefrom or similarly.

Preparation of l-nitromethyl-3, 3,5,5-tetramethylcyclohexene (ß). A solution of 3, 3, 3, 5, 5-tetramethylcyclohexanone (2-13) (1.54 g, 10 mmol) and ethylenediamine (60 mg) in nitromethane (45 ml) was refluxed under an argon atmosphere for 25 h. The excess nitromethane was then removed in vacuo and the residue was purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate (6: 1). 1.2 g (61%) of 6 were obtained as an oil. H NMR (CDC13, TMS) d 0.96 and 1.03 (total 12H, s both, cyclohexane 3.5-CH3); 1.34 (2H, s, 4-CH2); 1.82 (2H, broad s, β-CH2); 4.80 (2H, s, CH2N02) and 5.64 ppm (1H, broad s, C = C-H).

Preparation of ethyl 3, 3,5,5-tetramethylcyclohexyl ester (7). To a stirred solution of triethyl phosphonoacetate (49.32 g, 0.22 mol) in dry THF (180 mL) under argon was added NaH (8.8 g, 0.22 mol, 60% suspended in mineral oil) in small portions while cooling with ice water. Stirring was continued for 1 h at room temperature, then a solution of 3,3,5,5-tetramethylcyclohexanone (2-13) (30.85 g, 0.2 mol) was added over 10 minutes and the resulting mixture was refluxed for 20 minutes. h. This was then poured onto ice (400 g), the product extracted with ether (4 * 150 ml) and the solution dried MgSO4. After concentrating in vacuo, an oily residue was distilled at 145 ° C (11 mm) to give 36.8 g (86%) of 6 as an oil. XH NMR (CDC13, TMS) d 0.96 and 0.98 (total 12H, s both, cyclohexane 3.5-CH3); 1.27 (3H, t, CH 3 -ethyl); 1.33 (2H, m, cyclohexane 4-CH2); 1.95 and 2.65 (total 4H, s both, cyclohexane 2,6-CH2); 4.14 (2H, c, CH2-ethyl) and 5.69 ppm (1H, s, = C-H).

Preparation of ethyl 3, 3, 5,5-tefcramethylcyclohexylacetophat (8). 3, 3, 3, 5, 5-tetramethylcyclohexylidene-ethyl acetate (7_) (4.48 g, 20 mmol) was hydrogenated in ethanol (100 ml) over 10% Pd / C (0.22 g, 5% by weight) at 10 atm for 18 h. Filtration through Celite ™ and evaporation gave 4.28 g (95%) of 8% as an oil. XH NMR (CDC13, TMS) d 0.89 and 1.02 (total 12H, s both, cyclohexane 3.5-CH3); 1.26 (3H, t, J = 7Hz, CH3-ethyl); 0.6-1.55 (7H, m, ring protons); 2.13 (2H, m, 2-CH2); and 4.12 ppm (2H, c, J = 7Hz, CH2-ethyl).

Preparation of 2-methyl- (3,3,5,5-tetramethylcyclohexyl) -propan-2-ol (9) • A solution of ethyl 3, 3, 3, 5-tetramethylcyclohexylacetate (_8) (2.26 g, 10 mmol) ) in ether (20 ml) was added dropwise to a solution of 2 M methyl magnesium iodide in ether (20 ml) for 15 minutes, while cooling with ice water. The mixture was refluxed for 2 h, cooled and warmed saturated aqueous NH 4 Cl. After working additionally the product was purified on a column of silica gel, eluting with a mixture of hexane-ethyl acetate (20: 1) to give 1.7 g (80%) of 9 as an oil.

H NMR (CDC13, TMS) d 0.86 and 1.00 (total 12H, s both, cyclohexane 3.5-CH3); 1.23 (6H, s, -CH3); 1.36 (2H, d, J = 5Hz, -CH2-); 0.6-2.04 ppm (8H, m, ring protons and OH).

Preparation of 2-methyl- (3,3,5,5-tetramethylcyclohexyl) -propyl-2-azide (10). Boron trifluoride etherate (0.77 g, 0.69 mL, 5.44 mmol) was added dropwise to a stirred solution of 2-methyl- (3, 3, 3, 5, 5-tetramethylcyclohexyl) -propan-2-ol (_9) ( 0.95 g, 4.53 mmol) and trimethylsilyl azide (0.63 g, 0.72 mL, 5.44 mmol) in benzene (10 mL). After stirring for 24 h at room temperature the mixture was poured into water (20 ml). The organic phase was separated and washed with saturated aqueous NaHCO3 (10 mL) and saline (10 mL). The solution was dried over MgSO4, filtered and concentrated. The crude product was purified on a column of silica gel, eluting with hexane to give 0.56 g (52%) of 1_0 as an oil. 1H NMR (CDC13, TMS) d: 0.87 and 1.01 (total 12H, s both, cyclohexane 3.5-CH3); 1.27 (6H, s, a-CH3); 1.36 (2H, d, J = 5Hz, -CH2-); 0.6-1.85 ppm (7H, m, ring protons).

Preparation of 2- (3,3,5,5-tetramethylcyclohexyl) -ethanol (11). A solution of ethyl 3, 3, 5, 5-tetramethylcyclohexylacetate _8 (1.8 g, 8.0 mmol) in ether (30 mL) was added dropwise to a stirred suspension of lithium aluminum hydride (0.9 g, 24.0 mmol). in ether (30 ml), which was cooled in an ice bath. The reaction mixture was refluxed for 3 h, cooled and the residual lithium aluminum hydride was destroyed with water. The aqueous layer was separated and extracted twice with ether. The combined ether phases were washed with saline, dried over MgSO, filtered and evaporated. The crude product was purified by flash chromatography on silica gel, eluting with a mixture of hexane-ethyl acetate (4: 1) to give 1.2 g (79%) of 11 as an oil. 1 H NMR (CDC13, TMS) d: 0.89 and 1.00 (total 12H, s both, cyclohexario 3,5-CH3); 1.44 (2H, c, J = 7Hz, 2-CH2); 0.55-1.95 (8H, m, ring protons and OH) and 3.70 ppm (2H, t "J = 7Hz, CH20).

Preparation of 2- (3,3,5,5-tetramethylcyclohexyl) -ethyl ester (12). A solution of methanesulfonyl chloride (1.03 g, 0.7 ml, 9.0 mmol) in dry benzene (20 ml) was added to a stirred solution of 2- (3,3,5,5-tetramethylcyclohexyl) -ethanol (JL_1) ( 1.1 g, 6.0 mmol) and triethylamine (1.2 g, 1.7 ml, 12 mmol) in benzene (40 ml), while cooling in an ice bath. The reaction mixture was stirred at room temperature for 3 h, then filtered through a column of short silica gel, eluting with benzene. Evaporation of the solvent gave 1.48 g (94%) of 12 as an oil. XH NMR (CDC13, TMS) d: 0.88 and 0.98 (total 12H, s both, cyclohexane 3.5-CH3); 1.62 (2H, c, J = 7Hz, 2-CH2); 0.65- 2.0 (7H, m, ring protons) 3.0 (3H, s, CH3-S02) and 4.29 ppm (2H, t, J = 7Hz, CH20).

Preparation of 2- (3, 3,5, 5-tetramethylcyclohexyl) -ethylazide (13). The mixture of sodium azide (2.27 g, 34.2 mmol), 2- (3, 3, 5, 5-tetramethylcyclohexyl) -ethylmethanesulfonate- (12) (1.46 g, 5.57 mmol) and dimethyl sulfoxide (20 mL) was stirred at room temperature for 48 h, diluted with water (50 mL) and extracted with ether (3 * 30 mL). The organic phase was washed with saline (30 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by flash chromatography on silica gel, eluting with hexane to give 0.93 g (80%) of (13) as an oil. XH NMR (CDC13, TMS) d: 0.87 and 0.99 (total 12H, s both, cyclohexane 3.5-CH3); 1.47 (2H, c, J = 7Hz, 2-CH2); 0.55-1.9 (7H, m, ring protons) and 3.31 ppm (2H, t, J = 7Hz, CH2N3).

Preparation of N-formyl-1,3,3,5,5-tetramethylcyclohexaneptine (14-1). To a solution with vigorous stirring of 1,3,3,5,5-pentamethylcyclohexanol (3-13) (2.7 g, 15.6 mmol) and trimethylsilyl cyanide (2.36 g, 23.8 mmol) in acetic acid (2.5 ml) under argon 98% sulfuric acid (4.66 g, 47.6 mmol) was added, keeping the temperature below -5 ° C. The mixture was stirred at room temperature for 22 h, then poured onto ice (100 g), neutralized with 50% NaOH solution to pH ~ 7 and extracted with ether (3 * 30 ml). The combined ether phases were washed with saline (50 ml), then dried over MgSO 4 and evaporated. A slightly yellow crystalline residue was treated with a small amount of acetonitrile and filtered to give 2.5 g (80%) of 14-1 as white crystals, m.p. 104-106 ° C. 1 H NMR (CDCl 3, TMS) d: 0.91 and 0.93 (total 6H, s both, 3.5-CH3eq, 1.08 (2H, m, 2.6-CHeq), 1.13 and 1.15 (total 6H, s both, 3, 5-CH3ax), 1.25 (2H, m, 4-CH2), 1.32 and 1.38 (total 3H, s both, 1-CH3), 1.70 and 2.12 (total 2H, d both, 14.7 Hz, 2.6-CHax); 5.30 and 5.60 (total 1H, both broad, NH), 8.05 and 8.30 ppm (total 1H, d both, 2.0 and 12.7 Hz, resp., HCO).

Preparation of N-acetyl-1,3,3,5,5-pentamethylcyclohexanamine (14-2). A solution with vigorous stirring of 1,3,3,5,5-pentamethylcyclohexanol (3-13) (3.0 g, 17.65 mmol) in acetonitrile (20 mL) was added by dripping HN03 fuming (6 mL), maintaining the temperature by below 45 ° C. The resulting mixture was stirred at 45-50 ° C for 6 h, then cooled, poured into water (30 mL) and neutralized with aqueous NH3. The aqueous phase was extracted with ether (3 * 30 ml). The combined ether phases were washed with saline (30 ml), then dried over MgSO 4, filtered and evaporated. The crude product was crystallized from cold acetonitrile to give 2.23 g (60%) of 14-2 as white crystals, m.p. 110 ° C. XH NMR (CDC13, TMS) d: 0.90 and 1.12 (total 12H, s both, 3.5-CH3); 1.33 (3H, s, 1-CH3); 1.88 (3H, s, CH3C = 0); 0.75-2.25 (6H, M. protons of the ring) and 5.3 ppm (1H, broad s, NH).

Preparation of N-methoxycarbonyl-N, 1,3,3,5,5-hexamethyl-cyclohexanamine (15) Methyl chloroformate (0.97 g, 0.8 ml, 10.3 mmol) in one portion was added to a suspension of N-hydrochloride, 1, 3, 3, 5, 5-hexamethylcyclohexanamine (5-20) (1.13g, 5.13 mmol) and Na 2 CO 3 (1.63g, 15.4 mmol) in THF (30 mL). The resulting mixture was stirred at room temperature for 6 h, and then diluted with water (50 ml) and extracted with ether (3 * 30 ml). The combined organic phases were washed with 10% K2SO, saline, dried over MgSO4, filtered and evaporated. The crude product was purified by flash chromatography, eluting with a mixture of hexane-ethyl acetate (6: 1) to give 0.90 g (78%) of (5) as an oil. 1 H NMR (CDC13, TMS) d: 0.93 and 1.07 (total 12H, s both, 3.5-CH3); 1.23 (3H, s, 1-CH3); 1.0-1.4 (4H, m, 4-CH2 and 2,6-CHeq); 2.56 (2H, d, J = 14 Hz, 2.6-CHax); 2.87 (3H, s, CH3N) and 3.64 ppm (3H, s, CH30).

Preparation of ethyl (3, 3, 5, 5-tetramethylcyclohexylidene) cyanoacetate (16). The mixture of 3, 3, 5, 5-tetramethylcyclohexanone (2-13) (2.64g, 17 mmol), ethyl cyanoacetate (1.93, 17 mmol), acetic acid (0.2 mL) and ammonium acetate, (0.2, g) in benzene (6.4 ml) was refluxed with a Dean-Stark apparatus for 10 h. To this was added benzene (30 ml) and saline (30 ml), the organic layers were separated, dried over a 2 SO, filtered and evaporated. The crude product was purified by flash chromatography, eluting with hexane to give 2.0 g (50%) of (1_6) as an oil. 1 H NMR (CDC13, TMS) d ": 1.01 (6H, s, 3.5-CH3eq, 1.05 (6H, s, 3, 5-CH3ax); 1.34 (3H, t, J = 7Hz, ethyl-CH3); 1.42 (2H, s, 4-CH2), 2.46 and 2.79 (total 4H, s both, 2.6-CH2), and 4.29 ppm (2H, c, J = 7Hz, CH20).

Preparation of ethyl (1,3,3,5,5-pentamethylcyclohexyl) cyanoacetate (17) Anhydrous copper (I) chloride (0.8 g, 8 mol) was added to a cold solution of alkylmagnesium iodide (prepared from magnesium (0.46 g, 19.2 mmol) and iodomethane (2.84 g, 20 mmol) in ether (12 mL) The mixture was stirred in an inert atmosphere for 5 minutes and a solution of (3, Ethyl 3,5,5-tetramethylcyclohexylidene) cyanoacetate (.16.) (2 g, 8 mmol) in ether (10 ml), dropwise, keeping the temperature below -15 ° C. After completing the addition of the ketone, the reaction mixture was stirred for 3 h and carefully neutralized with saturated aqueous solution of NH4C1 The traditional work for the Grignard reactions gave the crude material which was separated on a column of silica gel, eluting with a mixture of petroleum ether-ethyl acetate (20: 1) to give 1.0 g (47%) of _17_ as an oil XH NMR (CDC13, TMS) d: 0.98 (9H, s, 3.5-CH3eq and 1- CH3), 1.06 (6H, s, 3.5-CH3ax), 1.31 (3H, t, J = 7Hz, ethyl-CH3), 1.2 -1.5 (6H, m, ring protons), 3.41 (1H, s, a-CH) and 4.25 ppm (2H, q, J = 7Hz, CH20).

Preparation of l-cyanomethyl-l, 3,3,5,5-pentamethylcyclohexane (18). The mixture of ethyl (1, 3, 3, 5, 5-pentamethylcyclohexyl) cyanoacetate. { 11) (Ig, 3.7 mmol), LiCl (0.05 g) and water (0.15 mL) in DMSO (2.5 mL) was heated at 150-160 ° C for 4 h. The solution was poured into water (70 ml) and extracted with ether (4 * 20 ml). The ether was washed with saline (2 * 50 ml), dried over Na 2 SO 4, filtered and evaporated. The crude product was purified on a column of silica gel, eluting with a mixture of petroleum ether-ethyl acetate (20: 1) to give 0.66 g (94%) of 18_ as an oil. * H NMR (CDC13, TMS) d: 0.98 (9H, s, 3.5-CH3eq and 1-CH3); 1.02 (6H, s, 3.5-CH3ax); 1.21 (3H, s, ring protons); 1.31 (3H, s, ring protons) and 2.31 ppm (2H, s, CH2CN). IR (net) vCN = 2242 cm "1.

General procedure for the preparation of alkylacyclohexanamine hydrochlorides 5-1-5-25. A solution of j_ _10 or 13. -15.18 in ether was added dropwise to a stirred suspension of lithium aluminum hydride (4 equivalents) in ether, which was cooled in an ice bath. The reaction mixture was stirred at room temperature • in the case of 4, 10, 13 or refluxed in the case of 14 15, 18 until complete conversion of the material started (control by TLC (Thin Layer Chromatography) ). The residual lithium aluminum hydride was destroyed with water, the aqueous layer was separated and extracted twice with ether. The combined ether phases were washed with saline, dried over NaOH, filtered and evaporated. The amine obtained was treated with HCl without characterization, the amine hydrochloride was prepared either by passing gaseous HCl through the amine solution in hexane or by adding a solution of 1 N HCl in ether to the amine solution. In both cases the solvent was removed after the addition of HCl, the residue treated with hexane or acetonitrile and the crystalline product filtered to give 5-l-5-25 with excellent purity. The physical properties and performance of the compounds 5-1 - 5-25. are given in Table 4. The 1H NMR spectral data of the compounds 5-JL-5-25 are given in Table 5. 1-Aminoalkylcyclohexanes and their additional hydrochlorides were prepared in the same or similar manner. The hydrochlorides can be converted to the free base or other acid addition salts as described under "ACID ADDICTION SALTS".

Preparation of 3, 3, 3, 5, 5-tetramethylcyclohexyl-methylamine hydrochloride (5-26) A solution of l-nitromethyl-3,3,5,5-tetramethylcyclohexene (6) (1.1 g, 5.63 mmol) in a mixture of Ethanol (140 mL) and chloroform (2.8 mL) was hydrogenated over 10% Pd / C (280 mg) at 5 atm for 20 h, filtered and evaporated. The crude product was treated with ether, filtered and washed with ether to give 0.57 g (50%) of the amine 5-26. The physical properties and yield of compounds 5-26 are given in Table 4. The 1H NMR spectral data of compound 5-26 are given in Table 5. Amine 5-27 was prepared according to the known procedure [16] . The amine 5-28 [17] was prepared according to the general procedure from the corresponding azide [18]. All the physical properties agreed well with the data described [17]. k k k k The purity of all the prepared compounds was verified by Gas Chromatography (MN-OV-1, 25m * 0.53m, df = l.Oμm, 50-270 ° C (10 ° C / min)). * * * * * ACID ADDICTION SALTS As suitable acids for the formation of acid addition salts according to the conventional procedure, the following acids of the mineral series can be mentioned: hydrochloric, hydrobromic, methanesulfonic, isothionic, sulfuric, phosphoric acids and sulfamic, and, of the organic series: acetic, propionic, maleic, fumaric, tartaric, citric, oxalic and benzoic acids, to name a few. The preferred acids are hydrochloric, citric and maleic acids. Other pharmaceutically acceptable acid addition salts can be prepared, if desired, and an acid addition salt can be converted into another by neutralizing a salt, for example, the hydrochloride, resulting in the free base, and then reacting with an acid selected organic or mineral, to prepare another pharmaceutically acceptable acid addition salt, as is conventional in the art.

Table 1, Cyclohexanones 2 or Table 2. 1-Alkylcyclohexanol 3? Table 3. 1-Alkalyl-l-azidocyclohexanes 4 Table 4. Amino-S ± Clohexane 5 Derivatives 639 5-21 C, 7H, 7N * HC1 233.82 66.8 12.1 6.0 66.6 12.3 5.9 257-259 82 642 5-22 C ,, H, 7N * HCrH, 0 251.82 62.0 12.0 5.6 62.0 12.0 5.5 > 210 98 645 5-23 C-HJONTHCI 247.85 67.8 12.2 5.7 67.6 12: 3 5.6 205-207 89 644 5-24 CHM -HCI 219.84 65.6 11.9 6.4 65.4 11.9 6.2 > 250 83 662 5-25 C, -, H, 7N-HCI-0.5H, O 242.84 64.3 12.0 5.8 64.9 11.9 5.7 > 250 64 580 5-26 CHTÍN-HC! 205.81 64.2 11.3 6.8 64.1 11.4 6.9 > 230 50 557 5-27 C, nH7, N * HCI 191.75 62.6 11.6 7.3 62.3 11.6 7.2 > 250fdec.) 70 641 5-28 C7H15N-HCI 149.7 I 56.2 10.8 9.4 55.9 11.0 9.2 283-285 69 Table 5. Spectral data of Amino-cyclohexane derivatives 5 Table 5 (continued) -10b 0.7 - 1.0 (m) and 0.90 (total 9H): 1.54 (3H.s): 1.05 - 2.1 (11H. Mi: 8.2 (3H.s broad) g-11a 0.8 - 1.0 (m). And 0.91 (total 6): 1.22 (3H.) 1.44 (3H.sl: 1.0 -2.3 (9H.m): 8.2 (3H.s broad) S-1 Ib 0.88 (m) and 0.98 (3 total 9H): 1.50 (3H, s), 1.0 - 2.15 (9H.m), 8.2 (3H.s broad) 5-12a 0.91 (6H.m., 1.22 (3H.s), 1.45 (3H.s); 1.0 - 2.3 (11H.m); 8.2 (3H.s broad) S-12b 0.89 (m): 0.97 (total 9H): 1.54 (3H, s); 1.0- 22 (11H.m); 8.2 (3H.s broad) 5-13 1.02 and 1.07 (total 12H.s): 1.26 (2H.m), 1.62 (3H, s): 1.71 (4H.m) 5-14 1.03 and 1.07 (total 12H. : 1-09 (3H, t.7Hz): 1.29 (2H, yes: 1.59 and 1-63 (total 3H.s both), 1.70 (4H, m), 8.25 (3H.s broad) 5-15 0.93 (3H.t.7Hz): 1.01 Y. 1.04 (total 12H.s), 1.29 (2H.s), 1.35 -2.0 (4H, m), 1.70 (4H.m): 8.2 broad PH.) 5- 16 0.83 (3H. Mi: 1.00, 1.02. 1.07 (to (OH) s), 1.2 - 1.5 (4H.tn): 1.59 and 1-63 (total 3H. S both), 1.70 (4H, m); 8.25 (3H, broad s) 6-17 0.87 (3H.m): 1.0 - 1.1 (9H. Mi: 1.1 - 1.4 (6H.m); 1.6 0 and 1! 64 (total 3H, s both); 1.70 (4H.m); 8.25 (3H, broad s) t_p -18 0.78 (6H.I.7Hz): 1.04 (6H.Si.:1.7 (2H, m); 1.40 (4H.tn): 1.59 (3H.s): 1.6 - 1.8 (4H.m); 8.25 (3H wide) 5-19 0.87 (6H.m); 1.04 (6H.s): 1.1 - 1.5 (10H.m): 1.60 (3H.s); 1.5 - 1.95 (4H.m): 8.2 ( 3H wide) 5-20 1.00 and 1.11 (12H total), 1.29 (2H.m): 1.57 (3H.Si, 1.72 (4H.D. 14Hz): 2.56 (3H., 6Hz); 9.2 ppm (2H, broad s) 5-21 0.9B and 1.11 (total 12H. if: 129 (2H.m), 1.58 (3H.t. 7Hz), 1.61 (3H.Si: 1.B2 (4H.m) : 3.0 (2H.m), 9.1 ppm (2H, broad s) 5-22 1.03, and 1.12 (total 12H.s); 132 (2H.m); 1.45 (3H. al; 1.64.97.97 (total 4H. d. 14Hz); 2.69 (6H.D. SHz) 5-23 0.85 (6H, s); 1.02 (6H. s): 0.6-1.95 (7H.m): 1.46 (6H.s): 1.60 (2H. d.5Hz): 8.35 (3H.i * wide) 5-24.87 (6H.Si.; 0-98 (6 s): 0.6-185 (9H.m): 3.02 (2H.m); 8.30 (3H. s broad) 5-25 0.96 (6Hs), 102 (6rj SV 1.07 (3Hs), 118 (6Hs), 1.73 (2Hs): 3.03 (2Hs): 8.28 (3Hs); > s broad) 6-26 0.97 (12H. br s); 10-2 (7H.tn); 2.80 (2H.); 8.35ppm (3H.s wide) 5-27.97 (6H.b); 104 (6H. s); 1.12 (1H, 13.7 Hz): 1.2 - 1.4 (5H, pfl, 1.92 (2H, 12.3 Hz, 3.47 (1H), 8.30 (3H, broad) 5-28, 1.47 (3H, s) 1.2 - 22 (10H, m); 8.3 (3H, broad) Table 6. Basic structure of ammonia and ammonium-cyclohexanes R'-Rβ = lower alkyl PHARMACEUTICAL COMPOSITIONS The active ingredients of the invention, together with one or more members, carriers, or diluents, can be placed in the form of pharmaceutical compositions and unit dosages thereof, and in such form can be employed as solids, such as coated or uncoated tablets, or filled capsules, with liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same , all used for oral use; in the form of suppositories or capsules for rectal administration or in the form of sterile injectable solutions for parenteral use (including intravenous or subcutaneous). Such pharmaceutical compositions and unit dosage forms thereof can be conventional or novel ingredients compressed in conventional or special proportions, with or without additional active ingredient compounds, and such unitary dosage forms can contain any suitable effective amount of the active ingredient measured. with the range of daily doses you intend to use Tablets containing twenty (20) to one hundred (100) milligrams of active ingredient or, more broadly, ten (10) to two hundred fifty (250) milligrams per tablet, are result suitable representative unit dosage forms.

METHOD OF TREATMENT Due to the high degree of activity and its low toxicity, together with the presentation of a more favorable therapeutic Index, the active principles of the invention can be administered to a subject, for example, body of living animal (including a human) , that it needs them, for the treatment, relief, or reduction, palliation, or elimination of an indication or condition that is susceptible to them, or in a manner representative of an indication or condition exposed to any other place in this application, of preferably concurrently, simultaneously, or together with one or more pharmaceutically acceptable excipients, carriers, or diluents and preferably in the form of a pharmaceutical composition thereof, either orally, rectally or parenterally (including intravenously and subcutaneously) or in some cases a topical route in an effective amount The dosing intervals are 1-1000 milligrams per day preferably, 10-500 milligrams daily, and especially 50-500 milligrams daily, depending on the exact mode of administration, the manner in which they are administered, the indication to which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the doctor or veterinarian in charge.

EXAMPLES OF REPRESENTATIVE PHARMACEUTICAL COMPOSITIONS With the aid of commonly used solvents, auxiliary agents and carriers, the reaction products can be processed into tablets, coated tablets, capsules, droplet solutions, suppositories, injection and infusion preparations, and the like and can be applied therapeutically by the oral, rectal, parenteral, and additional routes. The representative pharmaceutical compositions are the following: (a) Tablets suitable for oral administration which contain the active ingredient which can be prepared by the techniques for producing conventional tablets. (b) For suppositories, any suppository base may be employed to be incorporated therein by the usual procedures, the active ingredient, such as a polyethylene glycol which is a solid at normal room temperature but which melts at or about body temperature. (c) For sterile parenteral solutions (including intravenous and subcutaneous), the active ingredient is used together with conventional ingredients in the usual amounts, such as for example sodium chloride and double distilled water, according to the conventional procedure, such as filtration, aseptic filling with ampoules or bottles for IV drops, and sterilizing in an autoclave. Other suitable pharmaceutical compositions will be immediately apparent to those skilled in the art. The following examples are given again by way of illustration only and should not be construed as limiting.

EXAMPLE 1 Tablet Formulation A suitable formulation for a tablet containing 10 milligrams of active ingredient as follows: Active ingredient 10 Lactose 63 Microcrystalline cellulose 21 Talcum 4 Magnesium stearate 1 Colloidal silicon dioxide 1 EXAMPLE 2 Tablet Formulation Another suitable formulation for a tablet containing 100 mg is as follows: Mg. Active Ingredient 100 Potato starch 20 Polyvinylpyrrolidone 10 Coated and colored film. The film coating material consists of: Lactose 100 Microcrystalline Cellulose 80 Gelatin 10 Polyvinylpyrrolidone, 10 cross-linked Talcum 10 Magnesium stearate 2 Colloidal silicon dioxide 3 Color pigments 5 EXAMPLE 3 Capsule Formulation A suitable formulation for a capsule containing 50 milligrams of active ingredient as follows: Mg. Active Ingredient Corn Starch 20 Calcium phosphate dibasic 50 Talcum 2 Colloidal silicon dioxide 2 filled in a gelatin capsule.

EXAMPLE 4 Solution for injection A suitable formulation for an injectable solution containing one percent active ingredient as follows: Active ingredient 12 mg Sodium chloride 8 mg Sterile water up to 1 ml EXAMPLE 5 Oral formulation Liquid A formulation suitable for 1 liter of a liquid mixture containing 2 milligrams of active ingredient in one milliliter of mixtures as follows: G. Active ingredient 2 Sucrose 250 Glucose 300 Sorbitol 150 Taste orange 10 Yellow sunset. Purified water to make a total of 1000 ml.

EXAMPLE 6 Liquid oral formulation Another suitable formulation for 1 liter of a liquid sample containing 20 milligrams of active ingredient in one milliliter of the mixture is as follows: Active Ingredient 20 Tragacanth 7 • Glycerol 50 Sucrose 400 Methylparaben 0.5 Propiparaben 0.05 Black currant flavor 10 Soluble red color 0.02 Purified water to make a total of 1000 ml.

EXAMPLE 7 Liquid oral formulation Another formulation suitable for 1 liter of a liquid mixture containing 2 milligrams of active ingredient in one milliliter of the mixture is as follows: Active ingredient 2 Sucrose 400 Tincture of bitter orange peel 20 Tincture of sweet orange peel 15 Purified water to make a total of 1000 ml.

EXAMPLE 8 Aerosol formulation 180 g of aerosol solution contains: G. Active ingredient 10 Oleic acid 5 Ethanol 81 Purified water 9 Tetrafluoroethane 75 15 ml of the solution is filled in aluminum cans for aerosol, equipped with a metering valve, purged with 3.0 bar.

EXAMPLE 9 TDS Formulation 100 g of solution containing: Active ingredient 10 - 0 Ethanol 57. 5 Propylene glycol 7. 5 Dimethylsulfoxide 50. Hydroxyethylcellulose 0 4 Purified water 19. 6 1. 8 ml of solution is placed on a plate covered by an adhesive backing sheet. The system is closed, by means of a protective coating in which it will be removed before use.

EXAMPLE 10 Formulation of Nanoparticles 10 g of polybutyl cyanoacrylate nanoparticles contains: Active ingredient 1.0 - Poloxamer 0.1 Butylcyanoacrylate 8.75 Mannitol 0.1 Sodium chloride 0.05 Plibutylcyanoacrylate nanoparticles are prepared by emulsion polymerization in a water / 0.1 N hCl / ethanol mixture as the polymerization medium. The nanoparticles in the suspension are finally lyophilized under vacuum.

PHARMACOLOGY-SUMMARY The active principles of the present invention, and the pharmaceutical compositions thereof and method of treatment therewith, are characterized by unique unpredictable advantageous properties, making the "subject matter as a whole", claimed herein, more obvious. The compounds and pharmaceutical compositions thereof have exhibited, the procedure of reliable tests, accepted in standard, the following properties and valuable characteristics: They are non-competitive NMDA receptor antagonists, systemically active with rapid block / block kinetics and a strong dependence of the voltage and are consequently useful in the treatment, elimination, palliation, alleviation, and reduction of simple conditions, by application or administration to the living animal host for the treatment of a wide range of central nervous system disorders, which involve a disorder of glutamatergic transmission.

PHARMACOLOGY In Vi tro Receptor Binding Studies Sprague-Dawley male rats (200-250) were decapitated and their brains were removed quickly. The bark was dissected and homogenized in 20 volumes of 0.32 M sucrose cooled with ice using a Teflon-glass homogenizer. The homogenate was centrifuged at lOOOxg for 10 minutes. The pellet was discarded and the supernatant centrifuged at 20,000xg for 20 minutes. The resulting pellet was resuspended in 20 volumes of distilled water and centrifuged for 20 minutes at 8,000xg. The supernatant and the unperceived coating were then centrifuged three times (48,000 xg for 20 minutes) in the presence of 50 mM Tris-HCl, pH 8.0. All centrifugation steps were carried out at 4 ° C. After resuspension in 5 volumes of 50 mM Tris-HCl, the membrane suspension at pH 8.0 is rapidly cooled to -80 ° C. On the day of the test the membranes were frozen and washed four times by resuspension in 50 mM Tris-HCl, pH 8.0 and centrifugation at 48,000 xg for 20 minutes. The final pellet was suspended in a test buffer. The amount of protein in the final membrane preparation was determined according to the Lowry method with modifications. The final protein concentration used for our studies was between 200-250 μq / ml. The membranes were resuspended and incubated in 50 mM Tris-HCl, pH 8.0. Incubations began by adding [3H] - (+) - MK-801 (23.9 Ci / mmol, 5nM) to bottles with glycine (10μg), glutamate (10μg), and 0.1-0.25 mg protein (total volume 0.5ml) and several concentrations of agents were tested (10 concentrations in duplicate). The incubations were continued at room temperature for 120 minutes, "equilibrium was reached under the conditions used.Nonspecific binding was defined by the addition of unlabeled MK-801 (lOMM) .Incubations were terminated using a Millipore filtration system. The samples were rinsed three times with 2.5 ml of ice-cooled assay buffer on glass fiber filters obtained from Scleicher &Schuell under a constant vacuum.The filtration was carried out as quickly as possible after separation and rinsing , the filters were placed in a flashing liquid (5 ml; Ultima Gold) and the radioactivity retained on the filters was determined with a conventional liquid flare counter (Hewlett Packard Liquid Flare Analyzer).

Patch Clip The hippocampi of rat embryos (E20 to E21) were obtained and then transferred to Hank's buffered saline calcium and magnesium salts (Gibco) on ice. The cells were mechanically dissociated in 0.05% DNase / 0.3% ovomucoid (Sigma) after preincubation with 0.66% trypsin / 0.1% DNase (Sigma). The dissociated cells were then centrifuged at 18xg for 10 minutes, resuspended in minimal essential medium (Gibco) and cultured at a density of 150,000 cells cm-2 on plastic petri dishes precoated with poly-L-lysine (Sigma) (Falcon) . The cells were nourished with media buffered with NaHCO3 / HEPES supplemented with 5% fetal sheep serum and 5% horse serum (Gibco) and incubated at 37 ° C with 5% C02 and a humidity of 95%. The medium was completely exchanged after inhibition of additional glial mitosis with cynotoxins ina -? - D-arabinofurano si do (20μq Sigma) after approximately 7 days in vitro. Later the medium was partially exchanged twice a week. The patch clamp records were made from those neurons with polished glass electrodes (4-6 mO) in full cell mode at room temperature (20-22 ° C) with the help of an EPC-7 amplifier (Ready). Substances were applied by changing the channels of a custom made fast superfusion system with a common output flow (exchange times of 10-20 ms). The content of the intracellular solution was as follows (mM): CsCl (120), TEACI (20), EGTA (10), MgCl 2 (1), CaCl 2 (0.2), glucose (10), ATP (2), cAMP ( 0.25); the pH was adjusted to 7.3 with CsOH or HCl. The extracellular solutions had the following basic composition, (mM): NaCl (140), KC1 (3), CaCl (0.2), glucose (10), HEPES (10), sucrose (4.5), tetrodotoxin (TTX 3 * 10"" ") Glycine (lM) was present in all solutions: sufficient concentration to cause activation of around 80-85% of glycine B receptors, only stable cell results were accepted to be included in the final analysis, that is, after the recovery of responses to NMDA by at least 75% of their depression by the antagonists tested.

Exito oxicidad Cortical neurons were obtained from the cerebral cortex of fetal rats of 17/18 days of age (istar), following in general the dissociation procedure described by [23]. After a brief trypsinization and a gentle crushing with fire-blasted Pasteur pipettes, the cell suspension was washed by centrifugation. Cells were suspended in serum-free Neurobasal medium with supplemented B27 (GIBCO) before culturing on 96-well plates coated with poly-L-lysine (Sigma, 0.2mg / ml, 20h, 4 ° C) and lamella (Sigma, 2μg / ml, lh, 37 ° C) (Falcon, Primary) at a density of 5xl04 cells / well. The cortical neurons were maintained at 37 ° C in 10% C02 / 90% humidified air.

One day after the culture, 5μM of cytosine-β-D-arabinofuranoside (Sigma) was added to each well for the inhibition of glial cell proliferation. The medium was changed for the first time 4 days later in vi tro and then every 4 days replacing 2/3 the medium with conditioned medium with astrocyte. The cortical neurons between day 12 and 14 were used for the experiments. Astrocytes from neonatal rats were isolated in non-enzymatic form according to the method of [24]. Briefly, both hemispheres were dissected from 2-day-old rats, passed through a gauze of 80μm, and crushed with Pasteur pipettes. The cell suspension was made in Dulbecco's modified essential medium (DMEM, Gibco) supplemented with 10% fetal sheep serum (FCS, Hye), 2mM glutamine (Gibco) and 50μg / ml gentamicin and transferred to plastic flasks for culture, not treated (Corning; 75 cm2). Two days after the culture, the bottles were shaken for 10 minutes on a rotating platform (150 U / min) to remove microglial cells. The cultures were allowed to grow to confluence within 14 days, and the culture medium was changed twice a week. Subsequently, the monolayers were thoroughly washed with serum-free Neurobasal medium (Gibco) to remove the serum. The flasks or flasks were shaken several times to remove oligodendrocytes and neurons. To obtain the conditioned medium of primary astrocytes, the cultures were incubated with fresh Neurobasal medium supplemented with B27 and glutamine. Every 2t-3 days the conditioned medium was collected and replaced by fresh medium up to 4 times. Exposure to EAA was carried out in serum-free Neurobasal medium containing 100 μm of glutamate and the drug to be tested. After 20h of incubation, the cytotoxic effect was examined morphologically under a phase contrast microscope and quantified biochemically by measuring cell viability with the MTT test (Promega). This colorimetric assay measures the reduction of a tetrazolium component (MTT) in an insoluble formazan product by the mitochondria of living cells. After incubation of the cortical neurons with the dye solution for approximately 1-4 hours, a solution of solubilization was added to lyse the cells and solubilize the colored product (incubation overnight at 37 ° C, 10% C02, 90% RH). These samples were then read using an Elisa plate reader (Thermomax, MWG Biotech) at a wavelength of 570 nm. The amount of color produced was directly proportional to the number of viable cells.

In vivo Antoconvulsive activity Female NMR mice (18-28 g) housed 5 per cage were used for maximum electric shock (MES) and motor damage tests. Everybody the animals were maintained with water and food ad libitum under a 12-hour light-dark cycle (turning on the light at 6 a.m.) and at a controlled temperature (20 ± 0.5 ° C). All the experiments were carried out between 10 a.m. and the 5 p.m. The tested agents were injected 30 minutes by i.p. before induction of convulsions if not that it was started in another way (see below). All the compounds were dissolved in 0.9% saline. The MES test was carried out together with tests for myorelaxing action (traction reflex) and motor coordination (rotavarilla). For the tensile reflex test the mice were placed with their front legs on a horizontal rod and where required the four legs were placed on the wire within 10 seconds. To test for ataxia (motor coordination) the mice were placed on a rotary rod (5 rpm) and were required to remain on the rod for 1 minute. It was considered that only mice that did not reach all three criteria in the three replicates of each test exhibited miorrelaxation and ataxia respectively. These tests were followed by MES (100 Hz, duration of the shock of 0.5 seconds, intensity of the shock of 50 mA, duration of the pulse 0.9 ms, Ugo Basile) applied through corneal electrodes. The presence of tonic seizures was recorded (tonic extension of the hind legs with a minimum angle towards the body of 90 °). The objective was to obtain the ED50 for all the registered parameters (autoconvulsive activity and lateral motor effects) with the use of the Litchfield ilcoxon test to quantify the dose responses. The division of the ED50 by lateral effects (ataxia or myorelaxation) by the ED50 for the antagonism of electroshock seizures was used as a therapeutic index (IT).

Statistical analysis The IC50 in the patch clamp, excitotoxicity, and binding studies were calculated according to the four parametric logistic equations using the Grafit computer program (Erith acus Software, England). The Ki values for the binding studies were then determined according to Cheng and Prusoff. The union values presented are the means ± SEM of 3-5 determinations (each carried out in duplicate). 4-7 doses of antagonists were tested in each of the i_n vivo tests (5-8 animals per dose) to allow the calculation of the ED50 graduated according to the probit analysis (Litchfield and Wilcoxon) with a correction for 0% effects. to 100%. The ED50s were presented with 95% confidence limits (LC). The moment correlation analysis of the Pearson product (Sigma-Stat, Jandel Scientific) was used to compare in vivo potency and anticonvulsant activity in vivo.

RESULTS Union All cyclohexanes displaced the [3H] - (+) - MK-801 binding to rat cortical membranes with IC50 of between 4 and 150 μm from the Ki values evaluated with the Chen-Prusoff equation were twice lower ( see Table 7).

Patch Clip The responses of steady-state inward currents of hippocampal neurons cultured to NMDA (200μM with 1μM of glycine at -70mV) were antagonized by cyclohexanes tested with IC50 of 1.3-99 μM (Table 7). Peak and steady-state currents were affected to a similar degree making it unlikely that their effects would be maintained at the glycineB site. The strong support 'for the non-competitive nature of this antagonism was provided by the clear dependence of the use and the voltage of its blockade. The weaker antagonists showed faster kinetics and a stronger voltage dependence.

Exito oxicidad The low μM concentrations of most cyclohexanes were effective neuroprotective in vi tro, with Mtz 2/579 being observed as the most potent in this respect (see Table 7). With the majority of the compounds a complete protection with 20μM was obtained.

In vivo Anticonvulsive activity All cyclohexane derivatives inhibited seizures inhibited by MES in mice with ED50 fluctuating from 3.6 to 50 mg / kg i.p. (Table 7). The selected compounds were also tested against conditions induced by PTZ and NMDA (see [20, 21] for the methods) and showed a power comparable to the MES test (for example, Mrz 2/579 had DE50 in the tests with PTZ and NMDA of 5.5 and 3.7 mg / kg, respectively). Its anticolnvulsive potency increased after i.v. (for example Mrz / 579 DE50 = 2.5 mg / kg). The Mrz 2/579 was also active after s.c. and somewhat less potent after administration p.o. (ED50 of 4.6 and 13.7 mg / kg respectively). At doses within the anticonvulsant interval, myorelaxation (tensile test) and ataxia (rotavarilla test) were observed with some cyclohexanes. For most of them, acute lethality up to 50 mg / kg was not observed.

Correlation Analysis There was a good cross-correlation between the three in vi tro trials (all correlation coefficients> 0.70, p <0.001). There was also a good correlation between NMDA-induced inward currents potencies and protection against NMDA-induced toxicity in vivo with anticonvulsant activity in vivo (correlation coefficient> 0.56, p <0.01).

Table 7 The effects of standard noncompetitive NMDA receptor cytohexane derivatives and antagonists, on the binding of [3H] - (+) -MK-801, NMDA induced currents in patch clamp experiments, glutamate toxicity in cultured cortical neurons and MES seizures in vivo. The values of the Ki are the means of the means ± SEM of 3-5 experiments. IC5os (± SEM) in patch clamp and glutamate toxicity experiments were determined from data from at least 3 concentrations that produced between 15 and 85% inhibition and at least 5 cells per concentration. For MES-induced cells, the values are ED50s are in mg / kg (the 95% confidence limits are shown in parentheses). In addition, due at least in part to its substituent, the compounds of the present invention are also effective in non-NMDA indications, exhibiting immunomodulatory activities, antimalarial potency, Borna anti-virus activity and anti-Hepatitis C activity. • k -k " k -k -k In conclusion, from the above, it is evident that the present invention provides the novel, valuable and unpredictable applications and uses of the compounds of the present invention, compounds which comprise the active principle according to the present invention, as well as the compositions pharmaceuticals thereof and novel methods for the preparation thereof and for the treatment thereof, which possess the characteristics and advantages enumerated more specifically above. The greater order of activity of the active agent of the present invention and compositions thereof, as evidenced by the reported tests, is indicative of utility based on its valuable activity in humans as well as in lower animals. The clinical evaluation in humans has not been concluded, however. It should be clearly understood that the distribution and commercialization of any compound or composition that falls within the scope of the present invention for use in humans should be practiced after the first approval by government agencies, such as the Federal Food and Drug Administration. United States, which are responsible for and authorized for judgments on such issues.

CONCLUSIONS The 1-amino-alkylocyclohexanes presented represent a novel class of non-competitive, systemically active NMDA receptor antagonists with fast blocking / unblocking kinetics and strong voltage dependence. In view of their relatively low potency and their associated rapid kinetics, they will be useful therapeutic agents in a wide range of Central Nervous System disorders, which involve disorders of glutamatergic transmission. These compounds consequently find application in the treatment of the following disturbances of a living animal body, especially a human. 1. Acute excitotoxicity such as ischemia during stroke, trauma, hypoxia, hypoglycaemia and hepatic encephalopathy. 2. Chronic neurodegenerative diseases such as Alzheimer's disease, vascular dementia, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, AIDS neurodegeneration, olivopontocerebellar atrophy, Tourette's syndrome, neuro-motor disease, mitochondrial dysfunction, Korsakoff's syndrome , Creutzfeldt-Jakob disease. 3. Other disorders related to long-term plastic changes in the Central Nervous System, such as chronic pain, tolerance, dependence and drug addiction (for example, opioids, cocaine, benzodiazepines, and alcohol). 4. Epilepsy, tardive dyskinesia / schizophrenia, anxiety, depression, acute pain, spasticity, and tinnitus. 5. Further, as already established, due at least in part to its amine substituent, the compounds of the present invention are also effective in non-NMDA indications, exhibiting immunomodulatory activity, antimalarial potency, Borna's antiviral activity, and anti-Hepatitis activity. C. It should be understood that the invention is not limited to the exact details of operation, or to the compositions, methods, procedures, or exact modalities shown and described, since modifications and obvious equivalents will be apparent to those skilled in the art, and invention is therefore only limited by the full scope that can be legally agreed upon for the appended claims.

References 1. R.L. Frank, H.K. Hall (1950) J. Am. Chem. Soc. 72: 1645-1648. 2. G.A. Hiegel, P. Burk. (1973) J. Org. Chem '. 38. : 3637-3639. 3. N.F. FirreJ.1, p.W. Hickmott. (1970) J. Chem. Soc. C.716-719. 4. G.H. Posner, L.L. Frye (1984) Isr. J. Chem. 24: 88-92. 5. G.L. Lemiere, T.A. van Osselaer, F.C. Anderweireldt. (1978) Bull. Soc. Chim. Belg. 87: 771-782. 6. H.O. House, J.M. Wilkins. (1976) J. Org. Chem. 41: (25) 4031-4033.

I. A.R. Greenaway, W.B. Whalley. (1976) J. Chem. Soc. P.T. 1.: 1385-1389. 8. S. Matsuzawa, Y. Horiguchi, E. Nakamura, I. Kuwajima. (1989) Tetrahedron 45_: (2) 349-362. 9. H.O. House, W.F. Fischer. (1968) J. Org. Chem. 33: (3) 949-956. 10. Chiurdoglu, G., Maquestiau, A. (1954) Bull. Soc. Chim. Belg. 63: 357-378. _ - II. Zaidlewicz, M., Uzarewicz A., Zacharewicz, W. (1964) Roczniki Chem. 38: 591-597. 12. Crossley, A.W., Gilling, C. (1910) J. Chem. Soc. 2218. 13. Zaidlewicz, M., Uzarewicz, A. (1971) Roczniki Chem. 45: 1187-1194. 14. Lutz, E.T., van der Maas, J.H. (1982 ') Spectrochim. Acta, A. 38A.-283. 15. Lutz, E.T., van der Maas, J.H. (1981) Spectrochim. Acta, A. 37A: 129-134. 16. Ramalingam K., Balasubramanian, M., Baliah, V. (1972) Indian J. Chem. 10: 366-369. 17. Hamlin, K.E., Freifelder, M. (1953) J. Am. Chem. Soc. 75: 369-373. 18. Hassner, A., Fibinger, R., Andisik, D. (1984) J. Org. Chem. 49: 4237-4244. 19. W. Danysz, C.G. Parsons, I. Bresink, G. Quack (1995) Drug News Perspect. 8.261-277. 20. J.D. Leander, R.R. Lawson, PL. , Ornstein, D.M. Zimmerman (1988) Brain Res. 448: 115-120. 21. C.G. Parsons, G. Quack, I. Bresink, L. Baran, E. Przegalinski, w. Kostowski, P. Krzascik, S. Hartmann, W. Danysz (1995). Neuropharmacology 34: 1239-1258. 22. M.A. Rogawski (1993) Trends Pharmacol. Sci. 14: 325-331. 23. Booher J. and Sensenbrenner M. (1972). Neurobiology 2: 97-105. 24. Dichter, M. (1987) Brain Research 149: 279.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (34)

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

1. A 1-aminoalkylcyclohexane compound selected from those of the formula wherein R * is - (CH2) n- (CR6R7) m-NR8R9 where n + m = 0, 1 or 2 where R1 to R9 are independently selected from hydrogen and C6_6 alkyl, at least R1, • R4 and R5 are C6_6alkyl, and pharmaceutically acceptable salts thereof, with the proviso that the 1-aminoalkylcyclohexane compound is not 1-methylamino-1,3,3,5-tetramethylcyclohexane.

2. The compound according to claim 1, characterized in that R1 to R5 are methyl.

3. The compound according to claim 1, characterized in that R1 is ethyl. .

The compound according to claim 1, characterized in that R2 is ethyl.

5. The compound according to claim 1, characterized in that R3 is ethyl.

6. The compound according to claim 1, characterized in that R4 is ethyl.

7. The compound according to claim 1, characterized in that R5 is ethyl.

8. The compound according to claim 1, characterized in that R5 is propyl.

9. The compound according to claim 1, characterized in that R6 or R7 are methyl.

10. The compound according to claim 1, characterized in that R6 or R7 is ethyl.

11. The compound according to claim 1, characterized in that the compound is selected from the group consisting of 1-amino-1, 3,3,5, 5-pentamethylcyclohexane, 1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane, 1-amino-1,5,5-trimethyl-3, 3- diethylcyclohexane, 1-amino-1,5,5-trimethyl-cis-3-ethylcyclohexane, 1-amino-1,5,5-trimethyl-trans-3-ethylcyclohexane, 1-amino-1-ethyl-3, 3 5, 5-tetramethylcyclohexane, l-amino-l-propyl-3, 3,5,5,5-tetramethylcyclohexane, N-methyl-l-amino-1, 3,3,5,5-pentamethylcyclohexane, and N-ethyl-l amino-1, 3, 3, 5, 5-pentamethylcyclohexane, and the pharmaceutically acceptable salts of any of the foregoing.

12. A use of a compound selected from those of the formula mentioned below for the manufacture of a medicament for treating a living animal for the relief of a condition which is alleviated by an NMDA receptor antagonist, or by its immunomodularity, antimalaria effect, Borna virus, or hepatitis C, wherein R * is - (CH2) n- (CR6R7) m-NR8R9 where n + m = 0, 1 or 2 where R1 to R9 are independently selected from hydrogen and C6_6 alkyl, which compound is effective for such a purpose, and pharmaceutically acceptable salts thereof.

13. The use according to claim 12, wherein R1 to R5 are methyl.

14. The use according to claim 12, wherein R1 is ethyl.

15. The use according to claim 12, wherein R2 is ethyl.

16. The use according to claim 12, wherein R3 is ethyl.

17. The use according to claim 12, wherein R4 is ethyl.

18. The use according to claim 12, wherein R5 is ethyl.

19. The use according to claim 12, wherein R5 is propyl.

20. The use according to claim 12, wherein R6 or R7 is methyl.

21. The use according to claim 12, wherein R6 or R7 is ethyl.

22. The use according to claim 12, wherein the compound is selected from the group consisting of .1-amino-1,3,3,5,5-pentamethylcyclohexane, 1-amino-1, 3, 5, 5 tetramethyl-3-ethylcyclohexane, 1-amino-1,5,5-trimethyl-3, 3-diethylcyclohexane, 1-amino-1,5,5-trimethyl-cis-3-ethylcyclohexane, 1-amino-1, 5, 5-trimethyl-trans-3-ethylcyclohexane, l-amino-l-ethyl-3,3,5,5-tetramethylcyclohexane, l-amino-l-propyl-3, 3,5,5,5-tetramethylcyclohexane, N-methyl- L-amino-1, 3,3,5,5-pentamethylcyclohexane, N-ethyl-l-amino-1,3,3,5,5-pentamethylcyclohexane, and pharmaceutically acceptable salts of any of the foregoing.

23. Use in accordance with the claim 12, wherein the compound is administered in the form of a pharmaceutical composition thereof comprising the compound in combination with one or more pharmaceutically acceptable diluents, excipients or carriers.

24. A pharmaceutical composition comprising an effective amount of the NMDA receptor antagonist, or an effective amount of immunomodularity, antimalarial, Borna anti-hepatitis C or anti-hepatitis C, of a 1-aminoalkylcyclohexane compound selected from those of the formula wherein R * is - (CH2) n- (CR6R7) m-NR8R9 where n + m = 0, 1 or 2 wherein R1 to R9 are independently selected from hydrogen and C6-alkyl, at least R1, R4 and R5 are C? -e alkyl, and pharmaceutically acceptable salts thereof, in combination with one or more pharmaceutically acceptable diluents, excipients or carriers.

25. The pharmaceutical composition according to claim 24, characterized in that R1 to R3 are methyl.

26. The pharmaceutical composition according to claim 24, characterized in that R1 is ethyl.

27. The pharmaceutical composition according to claim 24, characterized in that R2 is ethyl.

28. The pharmaceutical composition according to claim 24, characterized in that R is ethyl.

29. The pharmaceutical composition according to claim 24, characterized in that R4 is ethyl.

30. The pharmaceutical composition according to claim 24, characterized in that R5 is ethyl.

31. The pharmaceutical composition according to claim 24, characterized in that R5 is propyl.

32. The pharmaceutical composition according to claim 24, characterized in that R6 or R7 is methyl.

33. The pharmaceutical composition according to claim 24, characterized in that R6 or R7 is ethyl.

34. The pharmaceutical composition according to claim 24, characterized in that the compound is selected from the group consisting of 1-amino-1, 3,3,5, 5-pentamethylcyclohexane, 1-amino-1,3, "5, 5-tetramethyl-3-ethylcyclohexane, 1-amino-1,5,5-trimethyl-3, 3-diethylcyclohexane, 1-amino-1,5,5-trimethyl-cis-3-ethylcyclohexane, 1-amino-1, 5, 5-trimethyl-trans-3-ethylcyclohexane, l-amino-l-ethyl-3,3,5,5-tetramethylcyclohexane, l-amino-l-propyl-3, 3,5, 5-tetramethylcyclohexane, N- methyl-l-amino-1,3,3,5,5-pentamethylcyclohexane, and N-ethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane, and the pharmaceutically acceptable salts of any of the foregoing.