MXPA01001174A - Aminomethylcarboxylic acid derivatives - Google Patents

Abstract

The present invention relates to aminomethylcarboxylic acid derivatives having general formula (I), wherein Z is (CH2)n, O, S, SO, SO2 or N-R5;n is 0, 1 or 2;X represents 1-3 substituents independently selected from hydrogen, halogen,(C1-6)alkyloxy, (C3-6)cycloalkyloxy, (C6-12)aryloxy, (C6-12)aryl, thienyl, SR6, SOR6, SO2R6, NR6R6, NHR6, NH2, NHCOR6, NSO2R6, CN, COOR6 and (C1-4)alkyl, optionally substituted with halogen, (C6-12)aryl, (C1-6)alkyloxy or (C6-12)aryloxy;or 2 substituents at adjacent positions together represent a fused (C5-6)aryl group, a fused (C5-6)cycloalkyl ring or O-(CH2)m-O;m is 1 or 2;Y represents 1-3 substituents independently selected from hydrogen, halogen, (C1-4)alkyloxy, SR6, NR6R6 and (C1-4)alkyl, optionally substituted with halogen;R1 is COOR7 or CONR8R9;R2 and R6 are (C1-4)alkyl;R3, R4 and R5 are independently hydrogen or (C1-4)alkyl;R7, R8 and R9 are independently hydrogen, (C1-4)alkyl, (C6-12)aryl or arylalkyl;or a pharmaceutically acceptable salt thereof. The invention also relates to pharmaceutical compositions comprising said derivatives, as well as to the use of these aminomethylcarboxylic acid derivatives in therapy, more specifically for the treatment of CNS disorders.

Description

DERIVATIVES OF ACID AMINOMETICARBOXÍLICO Field of the Invention The invention relates to aminomethylcarboxylic acid derivatives, to pharmaceutical compositions containing the same, as well as to the use of these aminomethylcarboxylic acid derivatives in therapy.

BACKGROUND OF THE INVENTION The simplest glycine of a-amino acid, or aminomethylcarboxylic acid, has several important roles in the central nervous system of mammals (CNS). Together with α-aminobutyric acid (GABA), it is a major post-synaptic inhibitor in the spinal cord and brain, acting through ion channels linked by ligand. The interaction of glycine with these receptors can be antagonized by the alkaloid strychnine. Accordingly, these receptors are referred to as 'strychnine sensitive' glycine receptors. Glycinemic neurotransmission is important in the processing and control of visual, auditory and motor signaling. Glycine is also a mandatory co-agonist along with glutamate at the N-methyl-D-aspartate (NMDA) receptor. Accordingly, glycine functions in the excitatory transmission by modulating the actions of glutamate, the main excitatory neurotransmitter in the CNS. In addition, the amino acid plays a role in the metabolism of peptides and proteins, including the exchange of units of a carbon. Controlling the availability of glycine for any of the above processes will potentially influence its function and provide means to treat various diseases and conditions. Apart from metabolism, one of the main processes that controls free glycine concentrations in the vicinity of strychnine sensitive and strychnine-insensitive glycine receptors is the functioning of high-affinity glycine transporters. These proteins can actively limit glycine diffusion beyond the immediate environments of the receptors, thus maintaining both spatial and temporal fidelity of receptor activation. The rapid sequence ordering of the transmitter in the neuronal or gual cells through the transporter will also conserve the glycine for its future release. The glycine transporters have been cloned to reveal two main classes, GlyT-1 and GlyT-2. GlyT-1 is expressed throughout the brain, detecting higher levels of mRNA in caudal areas and predominantly glial cellular localization. They have been identified by Kim et al. three isoforms of GlyT-1, a, 1 b and 1 c, arising from the deferential division and the exon use. (Molecular Pharm, 1994, 45, 608-617). The distribution of GlyT-2, as indicated by immunochemistry studies, corresponds exactly to that of the receptors of glycine, 'sensitive to strychnine', inhibitors, particularly in the spinal cord. By regulating glycine synaptic levels, glycine transporters GlyT-1 and GlyT-2 are expected to selectively influence activity at NMDA receptors and strychnine responsive glycine receptors, respectively. Compounds that alter the functional activity of glycine transporters may, therefore, result in changes in tissue glycine levels, which may be useful in the treatment of various disease states. Such disease states include those associated with diminished or exaggerated function of NMDA receptors, i.e., psychosis, depression, dementia and other forms of loss of consciousness, such as attention deficit disorders. NMDA receptors have also been implicated in conditions arising from neuronal cell death and neurodegeneration such as, for example, shock (cranial trauma), Alzheimer's disease, Parkinson's disease and Huntington's disease. Enhanced inhibitory glycinergic transmission resulting from the inhibition of GlyT-2 or Glyt-1 activity may be useful in the treatment of muscle hyperactivity associated with spasticity, myoclonus and epilepsy. The compounds that raise spinal glycine may also have analgesic properties. The aminomethylcarboxylic acid derivatives, wherein the amino group contains an ethyl or propyl group, which is substituted by two or three aryl and / or aryloxy groups, are disclosed in WO97 / 451 (TRPHIX PHARM. INC.) as useful compounds in the treatment of neurological and neuropsychiatric disorders discussed above. The structurally related aminomethylcarboxylic acid derivatives, wherein the amino group is part of a cyclic amine which is substituted in a single position with (a substitute containing) two aryl or cycloalkyl groups, are disclosed in WO 97/45423 (TRPHIX PHARM. INC) as having a similar activity.

DETAILED DESCRIPTION OF THE PREFERRED MODALITY There is a need for additional compounds suitable for the treatment of psychiatric and neurological disorders, especially of compounds having a selective pharmacological profile. For this purpose, the present invention provides, in a first aspect, aminomethylcarboxylic acid derivatives having the general formula I Formula l wherein Z is (CH2) n, O, S, SO, SO2 or N-R5; n is 0, 1 or 2; X represents 1 -3 substitutes independently selected from hydrogen, halogen, (C1-6) alkyloxy, (C3-6) cycloalkyloxy, (C6-) 12) aryloxy, (C6-i2) aryl, thienyl, SRβ > SOR6, SO2Re, NRßR6, NHR6, NH2, NHCORβ, NHSO 2 R 6, CNOROR6 and (C 1-4) alkyl, optionally substituted with halogen, (Cβ-i 2) aryl, (C?-Β) alkyloxy or (Cβ-12) aryloxy; or 2 substitutes in adjacent positions together represent a group (C5.β) fused aryl, a ring (C5.6) fused cycloalkyl or O- (CH2) m-O; m is 1 or 2; Y represents 1 -3 substitutes independently selected from hydrogen, halogen, (C? -) alkyloxy, SR6, NR6Re and (Ci.) Alkyl, optionally substituted with halogen; n is COOR7 or CONR8R9; R2 and Re are (C1-4) alkyl; R3, R and Rs are independently hydrogen or (C? -) alkyl; R7, R8 and Rg are independently hydrogen, (C1-) alkyl, (C6-? 2) aryl or arylalkyl; or a pharmaceutically acceptable salt thereof. The term (C? -4) alkyl, as used in the definition of formula I, means a branched or unbranched alkyl group having 1-4 carbon atoms, such as butyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl and methyl. In the term (C1.6) alkyloxy, (C1.6) alkyl means a branched or unbranched alkyl group having 1-6 carbon atoms, such as hexyl, pentyl, neopentyl (2,2-dimethypropyl) and the meanings given above for (C 4 -4) alkyl. The (C? -6) alkyloxy group can be substituted with halogen, (C-?) Cycloalkyl or (C? -4) alkyloxy. Examples of such substituted (C 1-6) alkyloxy groups are trifluoromethyloxy and cyclopropylmethyloxy. The term (C3-6) cycloalkyl means a cyclic alkyl group having 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The term halogen means F, Cl, Br or I. When the halogen is a substitute in an alkyl group, F. is preferred. A preferred halogen-substituted alkyl group is trifluoromethyl. In the term (C6-i2) aryloxy, as used in the definition of the formula I, (C6-i2) aryl means an aromatic group having 6-12 carbon atoms such as for example phenyl, naphthyl or biphenyl. These aromatic groups can be substituted with halogen or with (C) alkyl or (C? -4) alkyloxy, wherein (C? -) alkyl has the previously given meaning and can be substituted with halogen or (C? -4) alkyloxy. The term "arylalkyl", as used in the definition of formula I, means a (C 4 -4) alkyl group which is substituted with a (C 6-2) aryl group, such as for example the benzyl group. In the definition of formula I, X can represent a fused aryl group (C5-6), which means that X is an aromatic ring composed of 5 or 6 members, fused to the benzene ring to which X is attached to form a aromatic ring system (Cn-12), such as a naphthalene or indene ring. X it can also represent a fused (C5-β) cycloalkyl ring, which means that X is a saturated ring composed of 5 or 6 members, fused to the benzene ring to which X binds to form a tetrahydronaphthalene or indane ring system. X may also represent O- (CH2) mO, where m is 1 or 2, which is fused to the benzene ring to which X binds to form a 1,3-benzodioxole ring system (m = 1) or of 1,4-benzodioxane (m = 2). The meaning of Ri in the formula l is exemplified by the groups COOR7 and CONR8Rg. In addition, R ^ can be any other group from which the free acid (R ^ COOH) can be generated (in vivo). Such acid, alternative, precursors or prodrugs, such as additional ester or amide derivatives, are known in the art and are within the scope of the present invention. The invention includes as specific examples of aminomethylcarboxylic acid derivatives of the formula I the aminomethylcarboxylic acid derivatives of (4-phenyl-3,4-dihydro-2H-1-benzothiopyran-3-ylmethyl), wherein Z = S; and the aminomethylcarboxylic acid derivatives of 84-phenyl-3,4-dihydro-2H-1-benzopyran-3-ylmethyl), wherein Z = 0. The preferred aminomethylcarboxylic acid derivatives of the invention correspond to the compounds of the formula I wherein Z is (CH2) n and n is 1, and wherein R? -R, X and Y have the previously given meanings. These compounds are aminomethylcarboxylic acid derivatives of (1-phenyl-1, 2, 3,4-tetrahydronaphthalene-2- ilmethyl), of which derivatives are preferred in which R2 is methyl and R3 and R4 are hydrogen. Particularly preferred are the derivatives wherein Ri is also COOR7. Most preferred are compounds of formula I wherein Z is (CH2) n, n is 1, Rt is COOH, R2 is methyl, R3 and R are hydrogen, and pharmaceutically acceptable salts thereof. The null substitute (s) (X), when presented, can be found in any and up to three of the available positions. Specific examples of individual X-ring substitutes include 6-methoxy, 6-ethoxy, 6-isopropyloxy, 6-phenoxy, 6-cyclohexyloxy, 6-cyano, 6-carboxylate, 6-trifluoromethyl, 6-trifluoromethoxy, 5-fluoro, -fluoro and 6-methyl. The Y substitute in the phenyl ring, when present, can be found in any and up to three of the available positions. Specific examples of Y individual phenyl substitute include 3-fluoro and 4-fluoro. An example of multiple substitutes includes 3,4-difluoro. The compounds of the formula I and their salts contain at least two centers of chirality, ie, at the two adjacent positions of the saturated ring containing Z where the phenyl group and the group CHR4-NR2-CHR3R are joined? and they exist accordingly as stereoisomers. The present invention includes the aforementioned stereoisomers within its scope and each of the individual cisk and trans isomers, enantiomers and diaesteromers of the compounds of the formula I and their salts, substantially free, i.e. associated with less than 5%, preferably less than 2%, in particular less than 1% of the other enantiomer, and mixtures of such stereoisomers in any ratio including racemic mixtures containing substantially equal amounts of the two enantiomers. Preferred are the aminomethylcarboxylic acid derivatives of the formula I wherein the phenyl group and the group CHR4-NR2-CHR3R1 appear in the cis configuration. The compounds of the invention can be used in the treatment of schizophrenia, depression, dementia and other forms of loss of consciousness, for the treatment or prevention of neurodegeneration following a blow or trauma to the head, for the treatment of neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's diseases, for the treatment of muscular hyperactivity associated with spasticity, myoclonus and epilepsy, for the treatment or prevention of pain, character disorders or learning disorders. The invention provides in a further aspect, pharmaceutical compositions comprising an aminomethylcarboxylic acid derivative having the general formula I, or a pharmaceutically acceptable salt thereof, in admixture with pharmaceutically acceptable auxiliaries.

Formula 11 The compounds of the formula (I) can be prepared by the reaction of a compound of the formula (11) wherein X, Y, Z, R2 and R4 have the previously defined meanings, with a compound of the formula L-CHR1R3 , where R ^ is COOR7 or CONR8R9 > R7-R9 and R3 are as previously defined, and L is a suitable leaving group, such as for example halogen, preferably bromine. The reaction is typically carried out in the presence of a suitable solvent such as N, N-dimethylformamide and an acidic cleaner such as potassium carbonate or cesium carbonate at elevated temperatures, for example at 80 ° C. The compounds of the formula (I) wherein R1 is carboxylate COOR, wherein R7 is hydrogen, can conveniently be prepared by hydrolysis of COOR7 of the corresponding esters, wherein R is (C1-) alkyl, (C6-? 2) aryl or arylalkyl, by using standard conditions for ester hydrolysis, for example, by heating in the aforementioned esters in a mixture of aqueous potassium hydroxide in ethanol at reflux temperature, or by catalytic hydrogenation of, for example, benzyl esters. The compounds of the formula (I), wherein Rn is CONR8R9 of carboxamide, wherein R8 and R9 are (C1-4) alkyl, can also be prepared by reaction of the carboxylic acid with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride ( EDC) in the presence of a tertiary amine in N, N-dimethylformamide. Alternatively, they can be made by, for example, the reaction of the aforementioned carboxylic acids with thionyl chloride or oxalylchloride in methylene chloride containing a catalytic amount of N, N-dimethylformamide followed by the reaction of the resulting acid chlorides with amines HNR8R9 in the presence of an acidic tertiary amine cleaner in methylene chloride at room temperature. The compounds of the formula (II) wherein the phenyl group and the group CHR4-NHR2 appear in the trans configuration, can be prepared from the 1-phenyl-1, 2,3,4-tetrahydro-2-naphthoic acids, appropriately substituted, by methods well known in the art. The aforementioned 1-phenyl-1, 2,3,4-tetrahydro-2-naphthoic acids, prepared by the method described in J. Chem. Soc., 1936, 596-599, can react, for example, to form the corresponding halides or acyl anhydrides by using standard methods. This, in turn, upon reaction with amines of R2NH2 followed by reduction of the resulting amides, provides the desired compounds (II). For the reduction of the amides, sodium borohydride can be used in the presence of certain catalysts, borane or lithium aluminum hydride in a non-protic solvent such as diethyl ether or tetrahydrofuran. The compounds of the formula (II) wherein the phenyl group and the CHR -NHR2 group appear in the cis configuration, are obtained by reacting the compounds of the formula (III) with hydrogen in the presence of a palladium on a carbon catalyst. in ethanol containing aqueous hydrochloric acid. Typically, the reaction occurs in the temperature range of 0-50 ° C and at a pressure ranging from 1 to 4 atmospheres. Alternatively, debenzylation can be achieved by treating the compounds of the formula (III) with (1-chloroethyl) chloroformate in dichloromethane at reflux temperature, followed by heating in the presence of methyl alcohol.

Formula III The compounds of the formula (III) can be conveniently prepared by dehydration of a compound of the formula (IV) by the use of standard conditions, for example, by the use of trifluoroacetic acid at room temperature.

Formula IV The compounds of formula (IV) can be prepared by the reaction of an appropriate aryl organometallic reagent, such as a Grignard or lithium derivative derived from Aryl-L, wherein Aryl represents a phenyl group substituted with Y, which has the previously defined meaning and wherein L is a halogen atom such as bromine or chlorine, with compounds of the formula (V). The reaction is typically carried out in the presence of an apolar aprotic solvent, such as, for example, diethyl ether at a temperature in the range of -10 to + 20 ° C.

Formula V The compounds of the formula (V) are obtained by reacting the compounds of the formula (VI) with the appropriate HCO-R4 aldehyde and a compound of the formula NHR2CH2C6H5 in ethanol containing aqueous hydrochloric acid at reflux.

Formula VI The compounds of the formula (VI) are commercially available or are prepared by methods described in the literature. Such methods are described, for example, in Comprehensive Organic Transformations (by Richard C. Larock, 1989, VCH). For example, the compound of formula VI wherein X is 6-fluoro and Z is methylene, can be prepared by cyclization of 4- (3-fluorophenyl) butyric acid by the use of acid catalyst such as polyphosphoric acid. The latter compound can be conveniently prepared by the reaction of 3-fluorobenzaldehyde with methyl acrylate in the presence of potassium cyanide in N, N-dimethylformamide, at 45 ° C, followed by the reduction of the resulting oxobutanoate by the use of hydrazine hydrate and potassium hydroxide in ethylene glycol at reflux temperature. Similarly, the compound wherein X is 6-thiomethyl and Z is methylene can be prepared from the commercially available 6-methoxy, analogous by the method described in Chem. Pharm. Bull. , 1984, 32, 1 30. Compounds wherein X is (CL-C-J-alkyloxy, wherein (C? -6) alkyloxy has the previously defined meaning, can be prepared from the 6-methoxy analogue by treatment with hydrogen bromide in acid acetic followed by the reaction of resulting phenol with an appropriate alkyl halide, typically an alkyl bromide or alkyl iodide in dimethylformamide in the presence of a suitable acidic cleaner, such as potassium or cesium carbonate, at elevated temperatures. Alternatively, the required ethers can be prepared by reaction of the phenol with an alcohol according to the Mitsunobo conditions that are known to those skilled in the art. Compounds wherein X is (Ce-i2) aryloxy, wherein (Cβ-i2) aryloxy is defined as above, can be prepared from the aforementioned phenol by using the methods described in Chem. Pharm. Bull. 1978, 26, 2475-2482. Said phenol derivatives can be converted in the same manner with triflic anhydride to the corresponding triflate derivative, the triflate group from which it can be converted to an amino group by using methods known to those skilled in the art. The compounds of the formula (VI) wherein Z is oxygen, can be prepared as described in J. Chem. Soc., 1954, 4299-4303; those in which Z is S can be synthesized as indicated in J. Am. Chem. Soc, 1954, 76, 5065-5069. The person skilled in the art will be aware of several general synthetic methods that allow the conversion of a certain group X into a compound according to one of Formula I-VI into another group X according to the definition of X. For example, a Composed according to formula III; where X is a 6-bromo group, it can be converted sequentially into a group of methoxycarbonyl (X = COOR6, wherein R6 is methyl) and a cyano group. The compounds of this invention possess at least two chiral carbon atoms and, therefore, can be obtained as pure stereoisomers or as a mixture of stereoisomers. The methods for the asymmetric synthesis by which the pure stereoisomers are obtained are well known in the art, for example, synthesis with chiral induction, hydrolysis of enantioselective enzymatic ester, crystallization of salts obtained from optically active acids and the mixture racemic, separation of stereoisomers or enantiomers by the use of chromatography on chiral media or on a straight phase or reverse phase chromatography medium. Such methods are described, for example, in Chirality in Industry (edited by A. N. Collins, G. N. Sheldrake and J. Crosby, 1992, John Wiley). The pharmaceutically acceptable salts of the compounds of formula I can be obtained by treating the free base of the compounds according to formula I with a mineral acid such as hydrochloric acid, phosphoric acid, sulfuric acid, preferably hydrochloric acid, or with an organic acid such as for example ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonic acid and the like. The pharmaceutically acceptable salts of the compounds of the formula I wherein Ri is COOR7 and R7 is hydrogen, they can be obtained by treating the acid or the amphoteric ion form of those compounds with an organic base or a mineral base, such as sodium, potassium or lithium hydroxide. These compounds of the invention can be administered to humans in a dose of 0.001 -50 mg per kg of body weight, preferably in a dose of 0.01 -20 mg per kg of body weight. The pharmaceutical compositions for use according to the invention comprise an aminomethicarboxylic acid derivative having the formula I or a pharmaceutically acceptable salt thereof in a mixture with pharmaceutically acceptable auxiliaries, and optionally other therapeutic agents. The term "acceptable" means that it is compatible with the other ingredients of the composition and not harmful to the containers thereof. The compositions can be prepared according to standard techniques such as are described, for example, in the standard reference, Gennaro et al. , Remington's Pharmaceutical Sciences, (1 8th ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture). The compositions include, for example, those suitable for oral, sublingual, intranasal, subcutaneous, intravenous, intramuscular, local or rectal administration and the like, all in unit dosage form for administration. For oral administration, the active ingredient may be presented as discrete units, such as tablets, capsules, powders, granulates, solutions and suspensions. For parenteral administration, the pharmaceutical composition of the invention can be presented in single dose or multi-dose containers, for example, injection liquids in predetermined amounts, for example, in sealed vials and ampoules and can also be stored in a lyophilized condition ( dry by freezing) which requires only the addition of a sterile liquid vehicle, eg, water, before use. The invention further includes a pharmaceutical composition, as described above, in combination with packaging material suitable for said composition, said packaging material including instructions for the use of the composition as described above. The invention is illustrated by the following examples.

General: All mass spectrometry was carried out either on a SCIEX API 1 50EX or PE SCIEX API 365 machine. The melting points are not correct and were determined by using a Leica Galen III instrument. The optical rotations were determined in a Shimadzu Graphicord UV-Visible recording spectrophotometer.

Example 1 (see Scheme for Process 1) C / s -? / - methyl -? / - (6-fluoro-1-phenyl-1, 2,3,4-tetrahydronaphthalen-2-ylmethyl) aminomethylcarboxylate Lithium Step A: Methyl-4- (3-fluorophenyl) - 4-Oxobutanoate To a stirred suspension of potassium cyanide (3.25 g) in N, N-dimethylformamide (30 cm3), maintained at a temperature of 45 ° C, 3-fluorobenzaldehyde (25.0 g) was added. Ethyl acrylate (18.46 cm3) was then added and the resulting mixture was stirred at 40 ° C for 2 h. Water (200 cm3) was added and the aqueous mixture was extracted with diethyl ether (2 x 125 cm3). The organic extracts were rinsed with water (100 cm3) and saturated aqueous sodium chloride solution (100 cm3) before being dried (Na2SO4) and the solvent was removed under reduced pressure to yield the main compound (25.27 g) as a yellow oil. .

Scheme for Process 1 Step B: 4- (3-Fluorophenyl) butanoic acid Methyl-4- (3-fluorophenyl) -4-oxobutanoate (25.27 g), hydrazine hydrate (24.29 cm3) and potassium hydroxide beads (20.50 g) were dissolved in ethylene glycol (150 cm3) and the mixture was refluxed for 1 .25 h. Excess hydrazine hydrate was removed by distillation until the temperature at the top reached 160 ° C. The reaction mixture was then allowed to cool, diluted with water (400 cm 3) and the resulting aqueous mass was rinsed with diethyl ether (2 x 150 cm 3) and then acidified with hydrochloric acid (5 M, 150 cm 3). The acidic mixture was then extracted with diethyl ether (2 x 150 cm 3) and the combined extracts were dried (Na 2 SO 4) and the solvent was removed under reduced pressure to give the main compound (15.51 g) as a dark oil. Step C: 6-Fluoro-3,4-dihydro-2H-naphthalene-1 -one A mixture of 4- (3-fluorophenyl) butanoic acid (10 g) and polyphosphoric acid (100 g) was heated to 70 ° C with agitation for 2 h. The reaction mixture was cooled and water was added carefully (400 cm3). The aqueous mixture was extracted with diethyl ether (3 x 75 cm 3) and the combined extracts were sequentially rinsed with an aqueous solution of potassium hydroxide (1 M, 75 cm 3), water (75 cm 3) and a saturated aqueous solution of chloride of sodium (75 cm3). The combined organic extracts were dried (Na2SO4) and the solvent was distilled off under reduced pressure. The crude product 86.58 g) was purified by column chromatography [silica, levigation with petroleum ether (b.p. 40-60 ° C) -ethyl acetate (20: 1)] to yield the main compound (6.36 g). Stage D: 2 - (? / - benzylmethylamino) methyl-6-fluoro-3,4-dihydro-2-naphthalene-1 -one hydrochloride To an ice-cooled solution of N-benzylmethylamine (5.67 cm3) in ethyl alcohol (60 cm3) was added hydrochloric acid (5 M, 10 cm3). 6-fluoro-3 was then added, 4-dihydro-2H-naphthalene-1 -one (6.00 g) and paraformaldehyde (1.32 g) and the resulting mixture was stirred and heated to reflux for 4 h. After cooling, the alcohol was removed under reduced pressure and water (100 cm3) was added. The remaining tetralone was extracted into diethyl ether (100 cm3) and the aqueous mixture was further extracted with dichloromethane (2 x 100 cm3). The combined extracts were dried (Na2SO4) and concentrated under reduced pressure. Trituration with diethyl ether and filtration gave the main compound (3.18 g) as a white solid. Step Ex 2 - (? / - Benzylmethylamino) methyl-6-fluoro-1-phenyl-1,2,3,4-tetrahydronaphthalene-1 -o! Phenylmagnesium bromide (3 M solution in diethyl ether, 9 cm3) was added to dry diethyl ether (20 cm3) under nitrogen with stirring. This was then cooled to below 0 ° C (salt-ice bath) and 2- (N-benzylmethylamino) methyl-6-fluoro-3,4-dihydro-2H-naphthalene-1-hydrochloride in small portions at such a rate to keep the temperature below 0 ° C (approximately 15 minutes). The reaction mixture was stirred for an additional 1 h at 0 ° C and then emptied on ice. Water (100 cm3) and diethyl ether (100 cm3) were added and the aqueous layer was separated and extracted with additional diethyl ether (100 cm3). The combined ether layers were extracted with hydrochloric acid (5 M, 3 x 50 cm 3). The acidic extracts were basified (K2CO3) and re-extracted with dichloromethane (3 x 75 cm3). The combined extracts were dried (Na2SO) and the solvent was removed under reduced pressure to give the main compound (1.55 g) as a brown oil which solidified by stagnation. Step F: 2 - (? / - Benzylmethylamino) methyl-6-fluoro-1-phenyl-3,4-dihydronaphthalene Trifluoroacetic acid (10 cm.sup.3) was added to 2- (N-benzylmethylamino) methyl-6-fluoro-1- phenyl-1, 2,3,4-tetrahydronaphthalen-1-ol (1.5 g) and the resulting solution was stirred at room temperature for 2 h. Excess trifluoroacetic acid was removed under reduced pressure and the resulting brown oil was taken in petroleum ether (bp 40-60 ° C) and passed through a short column [basic alumina, levigated with petroleum ether ( bp 40-60 ° C) -ethyl acetate (20: 1)]. The fractions containing the product were combined and the solvent was removed under reduced pressure to yield the main compound (0.97 g). Stage G: c's-6-fluoro-2-methylaminomethyl-1-phenyl-1, 2,3,4-tetrahydronaphthalene hydrochloride To a mixture of 2- (N-benzylmethylamino) methyl-6-fluoro-1-phenyl-3 , 4-d-hydronaphthalene (0.95 g) in ethyl alcohol (50 cm3) and acid hydrochloric (5 M, 1 cm3) was added palladium on charcoal (5%, 0.25 g). The resulting mixture was stirred under a hydrogen atmosphere at a pressure of 2 atm at room temperature for 60 h. The catalyst was removed by filtration through a Dicalite® bearing and the solvent was evaporated under reduced pressure to provide the main compound (0.75 g) as a white solid. Step H: c / sN-methyl-N- (6-fluoro-1-phenyl-1, 2,3,4-tetrahydronaphthalen-2-ylmethyanoaminomethylcarboxylate ethyl) To a mixture of c / s-6-fluoro-2 hydrochloride -methylaminomethyl-1-phenyl-1, 2,3,4-tetrahydronaphthalene (0.74 g), cesium carbonate (2.36 g) and N, N-di-methylformamide (15 cm3) was added ethyl bromoacetate (0.29 cm3) and The resulting mixture was stirred and heated at 80 ° C. for 4 h The reaction was allowed to cool to room temperature and water (100 cm 3) was added before the mixture was extracted with diethyl ether (2 x 100 cm 3). Combined organic extracts were rinsed with water (100 cm3), dried (Na2SO4) and the solvent was evaporated under reduced pressure.The crude product (0.95 g) was purified by column chromatography [silica, oil petroleum levigation (bp 40 -60 ° C) -ethyl acetate (5: 1)] to produce the main compound (0.73 g) ESI of positive ion (M + H) + 356.2 Stage I: c / s -? / - methyl-N - (6-fluoro-1-phenyl-1, 2,3,4-tetrahydronaphthale Lithium n-2-ylmethyl-methylcarboxylate To a solution of ethyl c / s -? / - methyl-N- (6-fluoro-1-phenyl-1, 2,3,4-tetrahydro-naphthalene-2-ylmethyl) aminocarboxylate (0.1 g) in ethyl alcohol (0.5 cm3) was added an aqueous solution of lithium hydroxide (2 M, 0.15 cm3). The reaction mixture was heated to 80 ° C with stirring for 3 h. After cooling to room temperature, the solvent was removed under reduced pressure to yield the main compound (90 mg) as a white solid; m.p. 133-.136 ° C; ESI of positive ion (M + H) + 328.4. The following compounds (Examples 2-22) were prepared in a similar manner (using the process steps of the Scheme 1) from the appropriate a-tetralones: Example 2: c / s -? / - methyl -? / - [6-fluoro-1- (4-fluorophenyl) -1, 2,3,4-tetrahydronaphthalene- Lithium 2-ylmethyl] aminomethylcarboxylate; m.p. 141-145 ° C; ESI of positive ion (M + H) + 346.2. Example 3: c s -? / - methyl- / V- [1- (4-fluorophenyl) -1,2,3,4-tetrahydronaphthalen-2-ylmethyl] aminomethylcarboxylate lithium; m.p. 177-183 ° C; ESI of negative ion (MH) "326.4 Example 4: c / 's -? / - methyl -? / - [6-methoxy-1-phenyl-1, 2,3,4-tetrahydronaphthalen-2-ylmethyl] aminomethylcarboxylate lithium; ESI positive ion (MH) + 340. 3. Example 5: c / s -? / - methyl-? - [1 - (4-fluorophenyl) -6-methoxy-1, 2,3,4-tetrahydronaphthalen-2-ylmethyl] aminomethylcarboxylate lithium; m.p. 129- 132 ° C; ESI of positive ion (M-H) + 358.2. Example 6: c / s -? / - methyl -? / - [7-methoxy-1-phenyl-1, 2,3,4-tetrahydronaphthalen-2-ylmethyl)] aminomethylcarboxylate lithium; ESI of positive ion (M + H) + 340. 3. Example 7: c s -? / - methyl -? / - (1-phenyl-6-trifluoromethyl-1, 2,3,4- lithium tetrahydronaphthalen-2-ylmethyl) aminomethylcarboxylate; m.p. 131 - 137 ° C; ESI of positive ion (M + H) + 378.2. Example 8: c / s- / V-methyl- / V- [1- (4-fluorophenyl) -6-trifluoromethyl-1, 2,3,4-tetrahydronaphthalen-2-ylmethyl] aminomethylcarboxylate lithium; m.p. 137-142 ° C; ESI of positive ion (M + H) + 396.2. Example 9: c / 's -? / - methyl -? / - [1 - (2,4-difluorophenyl) -6-methoxy-1, 2,3,4-tetrahydronaphthalen-2-ylmethyl] aminomethy! Carboxylate lithium; ESI of positive ion (M + H) + 376.4. Example 10: c / 's-? Í-methyl-? - [1 - (3,4-difluorophenyl) -6-methoxy-1, 2,3,4-tetrahydronaphthalen-2-ylmethyl] aminomethylcarboxylate lithium; ESI of positive ion (M + H) + 376.4. Example 11_: c s -? / - methyl -? / - [6-ethoxy-1 - (4-fluorophenyl) -1,2,3,4-tetrahydronaphthalen-2-ylmethyl] aminomethylcarboxylate lithium; ESI of positive ion (M + H) + 372.2. Example 12: c / s- / V-methyl -? / - (5-fluoro-1-phenyl-l, 2,3,4-tetrahydronaphthalen-2-methylmethyl] aminomethylcarboxylate, mp 159-161 ° C; ESI of positive ion (M + H) + 328.4 Example 13 .: c / s -? / - methyl -? / - [7-fluoro-1- (4-fluorophenyl) -1, 2,3,4-tetrahydronaphthalene Lithium-2-ylmethyl] aminomethylcarboxylate; ESI of positive ion (M + H) + 346.2.Example 14: c / s -? / - methyl -? / - [7-fluoro-1-phenyl-1, 2,3 , 4-tetrahidronaftalen- 2-ylmethyl] aminometilcarboxilato lithium; mp 137-158 ° C; positive ion ESI (M + H) + 328.2 Eiemplo 1_5: c / s- / V-methyl- - (1 -phenyl.? -6-trifluoromethoxy-1, 2,3,4-tetrahydronaphthalen-2-ylmethyl] aminomethylcarboxylate, lithium mp 127- 129 ° C; ESI of positive ion (M + H) + 394.2. Eiemplo 16: c's - / - methyl - / - (6-ethoxy-1 -phenyl-1, 2,3,4-tetrahydronaphthalen-2-ylmethyl] aminometilcarboxilato lithium; mp 238-249 ° C Eiemplo 17?:. c / s -? / - methyl -? / - (6-phenoxy-1-phenyl-1, 2,3,4-tetrahydronaphthalen-2-ylmethyl] aminomethyl-1-carboxylic acid, mp 191 - 200 ° C. Example 18 c / s - / - methyl - / - (6-isopropyloxy-1-phenyl-1, 2,3,4-tetrahydronaphthalen-2-ylmethyl] aminometilcarboxilato lithium;? ESI positive ion (M + H) + 374.4 Eiemplo. 19 .: c / s- / V-methyl -? / - [6-methoxy-1- (4-methoxyphenyl) -1, 2,3,4-tetrahydronaphthalen-2-ylmethyl] aminomethyl-1-carboxylic acid, mp 148- 150 ° C; ESI of positive ion (M + H) + 370.4 Example 20: acid trifluoroacetic acid salt c / s -? / - methyl-? - [6-methoxy-1- (3-methylphenyl) -1, 2 , Lithium 3,4-tetrahydronaphthalen-2-methylmethylcarboxylic acid mp 96-1 06 ° C, positive ion ESI (M + H) + 354.4 Example 21: c / s -? / - methyl -? / - (4-phenyl-3,4-dihydro-2H-1-benzothiopyran-3-ylmethyl) aminomethylcarboxylate lithium was prepared as a brown foam, according to the gene protocol rich in thiochroman-4-one commercially available; ESI of positive ion (M + H) + 328.0. Example 22: c / s -? / - methyl -? / - (4-phenyl-3,4-dihydro-2H-1-benzopyran-3-ylmethyl) aminomethylcarboxylate lithium; prepared from 4-chromanone; m. p. 207-21 0 ° C; ESI of positive ion (M + H) + 312.4. Example 23: c / s -? / - methyl -? / - (6-methyl-1-phenyl-1, 2,3,4-tetrahydronaphthalen-2-ylmethyl-methylcarboxylate lithium A: 4- (3-methylphenyl) - 4-oxobutanoic N, N-dimethylamidosuccinic acid (14.5 g) was dissolved in anhydrous tetrahydrofuran (400 cm3) and stirred at 0 ° C. To this was added a solution of m-tolyl-magnesium chloride in tetrahydrofuran (1 M, 200 cm3) over a period of about 2.5 h. Once the addition was complete, the reaction mixture was stirred for a further 2 h. Saturated aqueous ammonia chloride (200 cm3) was added and most of the tetrahydrofuran was distilled off under reduced pressure before the residue was treated with ether (100 cm3). After acidification with hydrochloric acid (5 M), the aqueous component was extracted with ethyl acetate (2 x 100 cm3), dried (Na2SO) and the solvent removed under reduced pressure to give the main compound (8.8 g). B: Starting from 4- (3-methylphenyl) -4-oxobutanoic acid and using procedures similar to those described in Scheme 1 for Process 1, the main compound was obtained; m.p. 135-138 ° C; ESI of positive ion (M + H) + 324.2. Example 24: c / s -? / - methyl-? - (1-phenyl-1, 2,3,4,5,6,7,8-octahydrofenantrenemethyl-pyatomethylcarboxylate lithium A: 4- (1-naphthyl) nutenóic acid To a mixture of 3-triphenylphosphorylpropionic acid chloride (12.40 g) and 1-naphthaldehyde in dry tetrahydrofuran (30 cm3) at 0 ° C under a nitrogen atmosphere, a solution of potassium io-butoxide (7.54 g) in tetrahydrofuran (30 cm3) was added over a period of 1 h.

Room temperature and stirred for a further 12 h before being quenched with water (40 cm.sup.3) and extracted with diethyl ether (2 x 40 cm.sup.3). The aqueous portion was acidified with hydrochloric acid (5 M) and extracted into dichloromethane (3 x 40 cm 3). The organic extracts were dried (Na2SO4) and the solvent was removed under reduced pressure to give a brown oil which crystallized by stagnation. The product was recrystallized from aqueous ethyl alcohol to yield the main compound (3.96 g). B: 4- (1-naphthyl) butanoic acid To a solution of 4- (1-naphthyl) butenoic acid (3.96 g) in ethyl alcohol (45 cm3) was added palladium on carbon (10%, 400 mg). The mixture was stirred under hydrogen (approximately 2 atmospheres) for 3 h. The catalyst was then removed by filtration through a Dicalite® bearing and the solvent was removed under reduced pressure to produce the main compound (3.59 g). C: 3,4-Dihydro-2H-phenanthren-1 -one To 4- (1-naphthyl) butanoic acid (3.52 g) polyphosphoric acid (35.0 g) was added and the mixture was stirred at 40 ° C for 20 h. The reaction was then diluted with water (200 cm3) and extracted with dichloromethane (3 x 1000 cm3). The organic extracts were rinsed with water, aqueous sodium hydrogen carbonate solution (0.5 M) and then with saturated aqueous sodium chloride solution. It was then dried (Na2SO) and the solvent was removed under reduced pressure to yield the main compound as an oil that solidifies by stagnation (3.09 g).

D: 2 - (? / - Benzylmethylamino) methyl-3,4-dihydro-2H-phenanthren-1 -one hydrochloride A mixture of 3,4-dihydro-2H-phenanthren-1 -one (3.09 g), benzylmethylamine (2.51 g) ), paraformaldehyde (0.8 g), hydrochloric acid (5 M, 4.76 cm 3) and ethyl alcohol (60 cm 3), was heated to reflux for 48 h. It was then allowed to cool to room temperature and the alcohol was removed under reduced pressure. Water (100 cm 3) was added and the remaining phenanthren-1 -one was extracted into diethyl ether (2 x 100 cm 3). The aqueous layer was subsequently extracted with dichloromethane (2 x 100 cm 3) and the combined dichloromethane extracts were dried (Na 2 SO 4) and concentrated under reduced pressure to yield the main compound as a pink solid (3.5 g). The c / 's -? / - methyl -? / - (1-phenyl-1, 2,3,4,5,6,7,8-octahydrofenantrenemethyl) aminomethylcarboxylic acid (0.20 g) was prepared from of 2- (N-benzylmethylamino) -methyl-3,4-dihydro-2H-phenanthren-1 -one hydrochloride according to procedures similar to those established in the Scheme for Process 1. The only difference being that during the hydrogenation step one of the aromatic rings was saturated, m.p. 164-166 ° C; ESI of positive ion (M + H) + 364.4. Example 25: cis-N-methyl-N- (1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl) aminomethylcarboxylic acid hydrochloride A solution of c / sN-methyl-N- (1-phenyl) Ethyl -1, 2,3,4-tetrahydronaphthalen-2-ylmethyl) aminomethylcarboxylate (0.1 g, prepared by using the methods described in Process 1 from Example 1) in ethyl alcohol (2 cm3) was added potassium hydroxide (10 M, 0.1 cm3). The reaction mixture was heated and stirred at 80 ° C for 3 h. After cooling, the alcohol was removed under reduced pressure and water (10 cm3) was added. The aqueous mixture was rinsed with ethyl acetate (2 x 10 cm3), acidified with aqueous hydrochloric acid (5 M) and concentrated under reduced pressure. Crystallization of the methyl alcohol-diethyl ether provided the main compound as a white solid (0.012 g); m.p. 205-21 1 ° C (decomp.); ESI of positive ón (M + H) + 310.2. The following was obtained in a similar manner: Example 26: cis-N-methyl-Nr (1- (3-fluorophenyl) -I ^ .S ^ -tetrahydronaphthalen-S-illmethiparninomethylcarboxylic acid hydrochloride; mp 212-218 ° C; positive ion (M + H) + 328.2 Example 27: c / 'sN-methyl-Nr hydrochloride (1- (4-trif luoromethylphenyl) -1.2.3.4-tetrahydronaphthalen-2-ylmethylaminomethylcarboxylic acid A: 2- (N -Benzylmethylamino) methyl-1 - (4-trif luoromethylphenyl) -3, 4-dihydro-2H-naphthalene-1-ol To a stirred, cooled (-78 ° C) mixture of n-butyllithium in hexane (1.6 M, 34.7 cm3) and diethyl ether (25 cm3) was added 4-dihydro-2H-naphthalene-1-ol. -bromobenzotrifluoride (7.8 g). After 15 min. Further, 2- (N-benzylmethylamino) methyl-3,4-dihydro-2H-naphthalen-1 -one hydrochloride was added portion by portion (prepared by using the methods described in Process 1). The reaction mixture was then stirred for 1 h before being allowed to warm to room temperature and then water (50 cm3) was added. The organic layer was separated and rinsed with water (50 cm3). It was then extracted with hydrochloric acid (2 M, 50 cm3) and the aqueous acidic portion was basified with solid sodium carbonate and extracted with dichloromethane (100 cm3). The combined organic extracts were dried (Na2SO) and the solvent was removed under reduced pressure to yield the main compound as a colorless oil. B: The main compound was prepared from 2- (N-benzylmethylamino) methyl-1- (4-trifluoromethylphenyl) -3,4-dihydro-2H-naphthalen-1 -ol according to the procedures described in Examples 1_ and 25. Separated as a white solid; m.p. 163-166 ° C; ESI of positive ion (M + H) + 378.0. Example 28: acid hydrochloride c / s-? -methyl-? - (1, 6-diphenyl-1,2,3,4-tetrahydro-phalen-2-ylmethyl) aminomethylcarboxylic acid A: c / s-2- (N-Benzylmethylamino) methyl-6-trifluoromethanesulfonyl-1-phenyl-1, 2,3, 4-tetrahydronaphthalene A solution of c / s-2- (N-benzylmethylamino) methyl-6-hydroxy-1-phenyl-1, 2,3,4-tetrahydronaphthalene (prepared as described in Example 1 and Example 32A; 3.23 g) in pyridine (15 cm3) was cooled in an ice bath. Trifluoromethanesulfonic anhydride (1.68 cm3) was added dropwise to this solution and the resulting mixture was stirred at 0 ° C for 5 min before allowing it to warm to room temperature. The mixture was then stirred at this temperature for 18 h, before being poured into water (90 cm3). The resulting mixture was extracted with diethyl ether (2 x 1 00 cm 3) and the Combined extracts were dried (Na2SO4). The solvent was removed under reduced pressure to yield a gum (4.83 g) which was purified by column chromatography [silica, levigation with toluene-ethyl acetate (19: 1)] to yield the main compound as a gum (4.10 g); ESI of positive ion (M + H) + 490.4. B c / s-2- (N-benzylmethylamino) methyl-1,6-diphenyl-1, 2.3.4-tertrahydronaphthalene Benzene boronic acid (301 mg), tetrakis (triphenylphosphine) palladium (0) (65 mg) , lithium chloride (238 mg) and aqueous sodium carbonate solution (2 M, 2.25 cm3) to a stirred solution of c / s-2- (N-benzylmethylamino) methyl-6-trifluoromethanesulfonyl-1-phenyl-1, 2,3,4-tetrahydronaphthalene (1.1 g) in 1,2-dimethoxyethane (60 cm3) under a nitrogen atmosphere. The stirred mixture was heated at 90 ° C for 46 h before being allowed to cool to room temperature. Water (100 cm3) and ethyl acetate (100 cm3) were added and the organic layer was rinsed with water (3 x 100 cm3), dried (Na2SO4) and the solvent was removed under reduced pressure. The crude product (908 mg) was purified by column chromatography [silica, levigation with toluene-ethyl acetate (19: 1)] to give the title compound as a gum (452 mg); ESI of positive ion (M + H) + 417.9. C: the main compound (Example 28) was prepared from c / s-2- (N-benzylmethylamino) methyl-l, 6-diphenyl-1, 2,3,4-tetrahydronaphthalene according to the procedure described in the Examples 1 and 25. However, in this case, once the reaction of Hydrolysis, hydrochloric acid (2M, 5 cm) was added and the mixture was then extracted with dichloromethane (50 cm3) and then with a mixture of dichloromethane-ethyl alcohol (1: 1, 75 cm3). This second extract was dried (Na2SO4) and the solvent was removed under reduced pressure to produce a solid. Crystallization of the ethyl alcohol-diethyl ether produced the main compound as a white solid; m.p. 210-221 ° C; ESI of positive ion (M + H) + 386.2. Example 29: c / s-N-methyl-N-ri-phenyl-6- (thien-2-yl) -1,2,3,4-tetrahydronaphthalen-2-ylmethyl] aminomethylcarboxylate hydrochloride. A c / s-2- (N-Benzyl-N-methylamino) methyl-1-phenyl-6- (thien-2-yl) -1 .2.3.4-tetrahydronaphthalene A mixture of trifluoromethanesulfonate of c / s-5- (N-benzyl-N-methylaminomethyl) -4-phenyl-4,5,6,7-tetrahydronaphthalene (prepared according to Example 28A; 960 mg), tetrakis (triphenylphosphine) palladium (0) (59 mg), Lithium (213 mg), aqueous sodium carbonate solution (2 M), 2.0 cm3) and thiophene-2-boronic acid (276 mg) in 1,2-dimethoxyethane (57 cm3) was heated to reflux under nitrogen for 24 h. The reaction was allowed to cool, diluted with water (150 cm3) and extracted with ethyl acetate (4 x 50 cm3), which was rinsed with water (2 x 50 cm3), dried (Na2SO4) and the solvent was added. evaporated The crude product was purified by column chromatography [silica, levigation with heptane-ethyl acetate (gradient 4: 1 to 1: 1)] to afford the main compound as pale yellow crystals (762 mg); ESI of positive ion (M + H) + 424.2.

B: Cs-2- (N-methylamino) methy! -1-phenyl-6- (thien-2-yl) 1, 2,3,4-tetrahydronaphthalene hydrochloride To a solution of c / s-2- (N- benzyl-N-methylamino) methyl-1-phenyl-1, 2,3,4-tetrahydro-6- (2-thienyl) -maphthalene (727 mg) in dichloromethane (75 cm 3), which was maintained at 0 ° C under nitrogen, 1-chloroethylchloroformate (0.208 cm3) was added dropwise. The mixture then heated to room temperature, before being heated to reflux. After about 2 h, the analysis of the reaction mixture indicated a complete consumption of the starting material. The dichloromethane was evaporated and the residue was then taken up in methyl alcohol and heated to reflux for 1 h. The solvent was evaporated to produce the main compound which was used in the next reaction without further purification; ESI of positive ion (M + H) + 334.2. Ci To a solution of c / s -? / - methyl -? / - [6- (thien-2-yl) -1-phenyl-1, 2,3,4-tetrahydronaphthalen-2-ylmethyl] aminomethylcarboxylate ethyl ester ( prepared from the compound under B_ by using procedures as described in Process 1) in ethyl alcohol, an aqueous solution of sodium hydroxide (2 M, 0.55 cm 3) was added and the reaction allowed to stir at room temperature . After 2 h, the reaction was incomplete so an additional portion of aqueous sodium hydroxide solution (as above) was then added and the mixture was heated to reflux overnight. After cooling, it was partitioned between hydrochloric acid (5 M) and a mixture of dichloromethane and chloroform (4: 1). The insoluble material that remained isolated by filtration to yield the main compound (Example 29; 346 mg). ESI of positive ion (M + H) + 392.0. Example 30: c / s -? / - Methyl -? / - (6-cyano-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl) aminomethylcarboxylic acid hydrochloride A: Methyl ester of 1-phenyl acid -2-methylmethyl (phenylmethyl) aminomethyl-1,3-dihydronaphthalene-6-carboxylic acid A mixture of 2- (N-benzylmethylamino) methyl-6-bromo-1-phenyl-3,4-dihydronaphthalene (1 1 .44 g; prepared according to Process 1), 1,3-bis (diphenylphosphino) -propane (229 mg), palladium acetate (ll) (185 mg), triethylamine (5.55 g), methyl alcohol (45 cm3) and Dimethyl sulfoxide (100 cm3) was stirred vigorously until all the particles dissolved. A stream of carbon monoxide gas (Caution! Highly toxic!) Was passed through the solution for 2-3 min. The mixture was left placed under a positive pressure of carbon monoxide and heated to 100 ° C in a sealed reaction pump. After stirring for 4 h the mixture was cooled and water (400 cm3) was added. The aqueous component was extracted with diethyl ether (3 x 150 cm3) and the combined extracts were dried (Na2SO) and filtered. The solvent was evaporated under reduced pressure to give a mixture of the main compound and the starting bromine compound. This mixture was resolved by column chromatography [silica, levigation with petroleum ether (bp 40-60 ° C) -ethyl acetate (9: 1)] to yield the main compound (4.20 g) and the starting bromine compound ( 3.0 g). Bj 1 -Fenyl-2- (methylaminomethyl) -1, 2,3,4-tetrahydronaphthalene-6- methyl carboxylate To a mixture of methyl ester of 1-phenyl-2- [methyl (phenylmethyl) aminomethyl] -3,4-dihydronaphthalene-6-carboxylic acid (4.20 g), methyl alcohol (120 cm3) and hydrochloric acid (5 M, 2.4 cm 3) palladium on charcoal (5%, 500 mg) was added. The resulting suspension was stirred at 50 ° C under an atmosphere of hydrogen (5 atm) for 18 h. After cooling, the mixture was filtered through a Dicalite® bearing and the solvent was evaporated under reduced pressure to produce the main compound (3.49 g, 95%) as a white powder. C: 1-phenyl-2-rmethyl (methyl phenylmethylmethylmethipyl-1,2,3,4-tetrahydronaphthalene carboxylate) To a mixture of cesium carbonate (7.04 g), 1-phenyl-2- (methylaminomethyl) -l, 2,3, 4-Tetrahydronaphthalene-6-carboxylic acid methyl ester (3.41 g) and N, N-dimethylformamide (30 cm3), benzyl bromide (1.28 cm3) was added. The mixture was heated to 80 ° C and stirred for 2 h. After cooling to room temperature, water (200 cm3) was added and the aqueous component was extracted with diethyl ether (2 x 100 cm3). The combined extracts were rinsed with water (75 cm3), dried (Na2SO), filtered and the solvent was evaporated under reduced pressure to give a brown oil. The crude product was purified by column chromatography [silica, levigation with dichloromethane-methyl alcohol (19: 1)] to yield the main compound (3.46 g) as a yellow oil which solidifies upon settling.

D: 1-phenyl-2-methyl (phenylmethyl) aminomethyl-1, 2,3,4-tetrahydronaphthalene carboxamide To a stirred mixture of 1-phenyl-2- [methyl (phenylmethyl) aminomethyl] 1 carboxylic acid methyl ester, 2,3,4. (1 .53 mg) of tetrahydronaphthalene, formamide (577 mg) and N, N-dimethylformamide (5 cm3), kept at 100 ° C under a nitrogen atmosphere, by syringe, for a period of 20 min, a solution of sodium methoxide in methyl alcohol (0.5 M, 5 cm3). After 2.5 h, the reaction had not come to an end so additional portions of formamide (577 mg) and sodium methoxide in methyl alcohol (0.5 M, 5 cm3) were added and the mixture was stirred at 100 ° C under a nitrogen atmosphere for 2 more hours. The mixture was then allowed to cool to room temperature and water (50 cm3) was added. The reaction was then carried out in diethyl ether (3 x 50 cm 3) and the combined extracts were dried (Na 2 SO 4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography [silica, levigation with dichloromethane-methyl alcohol (24: 1)] to yield the main compound (927 mg) as a white foam. E 2- (N-Benzylmethylammon) methyl-6-cyano-1-phenyl-1, 2,3,4-tetrahydronaphthalene To a solution of 1-phenyl-2- [methyl (phenylmethyl) aminomethyl] -1, 2 , 3,4-tetrahydronaphthalene carboxamide (588 mg, 1.53 mmol) in N, N-dimethylformamide (5 cm3) under an argon atmosphere was added phosphorus oxychloride (0.429 cm3, 4.6 mmol). The mixture heated to 80 ° C and stirred for 3 h. After cooling, water (20 cm3) was added and the mixture basified with aqueous sodium carbonate solution (20 cm3). The aqueous component was extracted with diethyl ether (3 x 50 cm 3) and the coiled extracts were dried (Na 2 SO 4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography [silica, levigation with petroleum ether b.p. 40-60 ° C-ethyl acetate (2: 1)] to yield the main compound (450 mg) as a white solid. F: cs-N-methyl-N- (6-cyano-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethylmethylcarboxylic acid hydrochloride Prepared from 2- (N-benzylmethyl) amino) methyl-6 -cyano-1-phenyl-3,4-dihydronaphthalene by using the process steps described in Scheme 1; mp 197 ° C (decomp.); ESI positive (M + H) + 335.2. Example 31: Salt of acid hydrochloride c / s- / V-methyl -? / - r6- (methoxycarboniP-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethaminomethylcarboxylic acid A: c / 'sN-methyl-N-F6- (methoxycarboniP Benzyl-1-phenyl-1, 2,3,4-tetrahydronaphthalen-2-ylmethylpaminomethylcarboxylate To a mixture of c / s-6- (methoxycarbonyl) -2-methylaminomethyl-1-phenyl-1, 2,3-hydrochloride, 4-tetrahydronaphthalene (0.23 g, prepared as described in Example 30), cesium carbonate (0.48 g) and N, N-dimethylformamide (3 cm 3) was added benzyl bromoacetate (0.1 1 cm 3) and the resulting mixture was stirred with heating at 85 ° C for 4 h. The reaction was allowed to cool to room temperature and water (20 cm3) was added. The resulting aqueous mixture was extracted with diethyl ether (2 x 20 cm3), and the combined extracts were rinsed with water (2 x 20 cm3), dried (Na2SO), filtered and the solvent was evaporated under reduced pressure. The crude product (0.29 g) was purified by column chromatography [silica, levigation with petroleum ether (b.p. 40-60 ° C) -ethyl acetate (9: 1)] to yield the main compound (0.20 g). B: To a mixture of c / s-N-methyl-N- [6- (methoxycarbonyl) -1-phenyl-1, 2,3,4-tetrahydronaphthalen-2-ylmethyl] aminomethylcarboxylate benzyl (0.2 g), methyl alcohol (5 cm3) and hydrochloric acid (5 M, 0.1 cm3) was added palladium on charcoal (10%, 0.02 g). The reaction was stirred under a hydrogen atmosphere (ca. 1.0 atm) at room temperature for 6 h. The catalyst was then removed by filtration through a Dicalite® bearing and the solvent was removed under reduced pressure. The products were crystallized from methyl alcohol-diethyl ether to produce the main compound (0.12 g) as a white solid; m.p. 166-171 ° C, ESI of positive ion (M + H) + 368.0. Example 32: C / 's N-methyl-N-r6-cyclohexyloxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-methylmethanolaminecarboxylic acid hydrochloride A: 2- (N-Benzylmethylamino) methyl-6-hydroxy-1-phenyl-3,4-dihydronaphthalene To a solution of 2- (N-benzylmethylamino) methyl-6-methoxy-1-phenyI-3,4-dihydronaphthalene (0.375 g, prepared according to the Process 1) in dichloromethane (15 cm3) which was stirred at 0 ° C under nitrogen added a solution of boron tribromide in dichloromethane (1 M, 2.2 cm3). The resulting solution was stirred at 0 ° C for 30 min and then at room temperature for 1.5 h. Methyl alcohol (5 cm3) was added and the solvents were drained under reduced pressure. The residue was treated with hydrochloric acid (6 M, 2 cm3) and dichloromethane (4 cm3) and stirred at room temperature for 30 min. The mixture was basified with potassium carbonate, diluted with water (50 cm3) and extracted with dichloromethane (3 x 25 cm3). The combined organic extracts were rinsed with saline (25 cm3), dried (MgSO) and the solvent removed under reduced pressure. The crude product was purified by column chromatography [silica, levigation with ethyl acetate-heptane (1: 1)] to yield the main compound (0.202 g) as a brown oil. B: 2- (N-benzylmethylamino) methyl-6-cyclohexyloxy-1-phenyl-3,4-dihydronaphthalene To a mixture of 2- (N-benzylmethylamino) methyl-6-hydroxy-1-phenyl-3,4-dihydronaphthalene (0.53 g), cyclohexanol (0.26 cm3), triphenylphosphine (0.579 g) and tetrahydrofuran (20 cm3), diethyl azodicarboxylate (0.35 cm3) was added at room temperature. After stirring for 5 h, the solvent was removed under reduced pressure. The crude product was purified by column chromatography [silica, levigation with ethyl acetate-heptane (1: 4)] to yield the main compound (0.442 g) as a yellow oil. C: The main compound was prepared from 2- (N-benzyl methylamino) methyl-6-cyclohexylloxy-1-phenyl-3, 4-d i h id naphtha wood according to Process 1; m.p. > 210 ° C (decomp.); ESI of positive ion (M + H) + 408.2. Example 33: c / sN-Methyl-N- (6-benzyloxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl-aminophenylcarboxylic acid hydrochloride A c / s-2- (N-benzylmethylamino) methyl- 6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalene To a mixture of cis-6-methoxy-2-methylamino-1-phenyl-1, 2,3,4-tetrahydronaphthalene (3.55 g, prepared according to Process 1), triethylamine (3.12 cm3) and N, N-dimethylformamide (40 cm3), benzyl bromide (1.60 cm3) was added. The mixture was heated to 80 ° C and stirred for 2 h. After cooling, the solvent was evaporated under reduced pressure to produce a brown oil. This was purified by column chromatography [silica, levigation with petroleum ether (bp 40-60 ° C) -ethyl acetate (4: 1)] to yield the main compound (3.52 g) as a light brown oil which solidified by stagnation. B: c / s-2- (N-benzylmethylamino) methyl-6-hydroxy-1-phenyl-1, 2,3,4-tetrahydronaphthalene This compound was prepared according to the procedure outlined in Example 32A, using the c / s-2- (N-benzylmethylamino) methyl-6-methoxy-1-phenyl-1, 2,3,4-tetrahydronaphthalene as the starting material. C: c / s-2- (N-benzylmethylamino) methyl-6-benzyloxy-1-phenyl-1, 2,3,4-tetrahydronaphthalene To a mixture of cesium carbonate (1 .09 g), c / s- 2- (N- benzylmethylamino) methyl-6-hydroxy-1-phenyl-1, 2,3,4-tetrahydronaphthalene (600 mg) and N, N-dimethylformamide (10 cm3), benzyl bromide (0.236 cm3) was added. The resulting mixture was heated to 80 ° C and stirred for 2 h. After cooling, water (50 cm3) was added and the aqueous mass was extracted with ether (2 x 50 cm3). The combined ether extracts were rinsed with water (30 cm3), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure to produce a yellow oil. This was purified by column chromatography [silica, levigation with petroleum ether (bp 40-60 ° C) -ethyl acetate (15: 1)] to afford the main compound (538 mg, 72%) as a light yellow oil . D: c / s-6-benzyloxy-2-methyl-amino-1-phenyl-1 .2.3.4-tetrahydronaphthalene hydrochloride To a cooled (0 ° C), stirred solution of c / s-2- (N- benzylmethylamino) rnethyl-6-benzyloxy-1-phenyl-1, 2,3,4-tetrahydronaphthalene (264 mg) in dichloromethane (15 cm 3), 1-chloroethyl chloroformate (0.085 cm 3) was added. After stirring at that temperature for 30 min, the mixture was allowed to warm to room temperature and stirred for 1.5 h more. The dichloromethane was evaporated under reduced pressure and methyl alcohol (20 cm3) was added. The mixture was heated to reflux for 1.5 h before being allowed to cool to room temperature and evaporated to dryness. The resulting gum was triturated with ether to yield the main compound as a white solid (210 mg). Ex c / s -? / - methyl -? / - (6-benzyloxy-1-phenyl-1,2, 3,4-tetrahydronaphthalene-2 Ethyl ilmethylmethyl carboxylate Prepared from c / s-6-benzyloxy-2-methylamino-1-phenyl-1, 2,3,4-tetrahydronaphthalene hydrochloride using the method described in Process 1 F: Example 33_ was prepared from ethyl c-sN-methyl-N- (6-benzyloxy-1-phenyl-1, 2,3,4-tetrahydronaphthalen-2-ylmethyl) aminomethyl carboxylate by using the method described in Example 25; m.p. 200-210 ° C; ESI positive (M + H) + 416.2. Methods similar to those of Example 33 were used to obtain: Example 34: c-N-methyl-N-r6- (2,2-dimethylpropyloxP-1-phenyl-1, 2,3,4-tetrahydronaphthalene-2-hydrochloride methylmethaminomethylcarboxylic, mp 151-155 ° C; ESI positive (M + H) + 396.4; and Example 35: c-N-methyl-N- (6-cyclopropylmethoxy-1-phenyl-1,2,3,4-tetrahydronaphthalene) acid hydrochloride 2-ylmethylmethylcarboxylic acid mp 173-177 ° C; positive ion ESI (M + H) + 380.4 Example 36: acidic hydrochloride c / sN-methyl-N-. {5-phenyl-5,6,7} 8-tetrahydronaphthalic acid 2,3-d1-f1, 3] dioxolmethyl}. Aminomethylcarboxylic acid A: 6.7-Dihydroxy-3,4-dihydro-2H-naphthalene-1 -one A mixture of 6,7-dimethoxy-3,4- dihydro-2H-naphthalene-1 -one (15.0 g) and 48% aqueous hydrobromic acid (60 cm3), heated under reflux for 1 h After cooling to room temperature, water (100 cm3) was added and the resulting aqueous mass extracted with ethyl acetate (3 x 100 cm). The combined extracts were dried (Na2SO), filtered and evaporated to dryness to leave a brown powder. This was recrystallized from acetonitrile to yield the main compound (9.4 g) as a red powder. B: 7,8-Dihydro-6H-naftor2,3-dlM, 31-dioxol-5-one A mixture of 6,7-dihydroxytetralone (1 g), cesium carbonate (2.75 g), bromochloromethane (0.549 cm3) and acetonitrile ( 20 cm3), was heated to reflux with continuous stirring for 4 h. After cooling, the resulting suspension was filtered through a Dicalite® bearing, which was further rinsed with ethyl acetate (50 cm3). The crude product was then purified by column chromatography (silica, levigation with dichloromethane) to produce the main compound. C: Example 36. was prepared from 7,8-dihydro-6H-naphtho [2,3-d] [1, 3] dioxol-5-one by using the method described in Examples 1_ and 25; m.p. 210 ° C (decomp.); ESI of positive ion (M + H) + 354.5. Example 37; c / sN-methyl-N-r6- (2-phenoxyethoxp-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethylaminomethylcarboxylate sodium A: 6- (2-phenoxyethoxy) -3,4-dihydro-2H- naphthalene-1 -one A mixture of 6-hydroxy-3,4-dihydro-2H-naphthalen-1 -one (2.5 g), 2-phenoxyethyl bromide (3.4 g) and cesium carbonate (5.5 g) The mixture was stirred in N, N-dimethylformamide (1.5 cm.sup.3) and heated at 100.degree. C. for 2.5 h. The reaction mixture was allowed to cool to room temperature. environment and then diluted with water (150 cm3). The aqueous mixture was extracted with ethyl acetate (2 x 50 cm 3) and the organic extracts were rinsed with aqueous sodium hydroxide (1 M, 50 cm 3), water (50 cm 3) and then hydrochloric acid (2 M, 50 cm 3) . The organic extracts were dried (Na2SO) and the solvent was removed under reduced pressure to yield the crude product which was suspended in diethyl ether and filtered to yield the main compound (3.2 g). B: The main compound (Example 37) was prepared from 6- (2-phenoxyethoxy) -3,4-dihydro-2H-naphthalene-1 -one according to the procedures described in Process 1; m.p. 109-1 13 ° C; ESI of positive ion (M + H) + 446.4. Obtained in a similar way were: Example 38: c / sN-methyl-N-r6- (2-methoxyethoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethylnaminomethylcarboxylic acid hydrochloride; positive ion ESI ( M + H) + 384.4 Example 39: r2-c / s-N-methyl-N- (6-methoxy-1-phenyl-1,2-, 3,4-tetrahydronaphthalen-1-methylmethyl) propionic acid hydrochloride A: Methyl-2 -cyc / s-N-methyl-N- (6-methoxy-1-phenyl-1, 2,3,4-tetrahydronaphthalen-2-ylmethylPamino] propionate To a mixture of c / s-6-methoxy-2-methylaminomethyl hydrochloride -1-phenyl-1, 2,3,4-tetrahydronaphthalene (1 .00 g, prepared according to the procedures in Process 1), cesium carbonate (5.13 g) and N, N-dimethylformamide (20 cm3) ) methyl-2-bromopropionate (0.35 cm3) was added and the resulting mixture was stirred at 75 ° C for 5 h. The reaction was then allowed to cool to room temperature and water (100 cm3) was added. The resulting mixture was extracted with diethyl ether (2 x 100 cm3) and the combined organic extracts were rinsed with water (100 cm3), dried (Na2SO) and the solvent removed under reduced pressure. The crude product (1.1 g) was purified by column chromatography [basic alumina, levigation with toluene-hexane (1: 1)] to yield the main compound as a gum (284 mg); ESI of positive ion (M + H) + 368.4. B: Example 39 was prepared from methyl-2- [c / sN-methyl-N- (6-methoxy-1-phenyl-1, 2,3,4-tetrahydronaphthalen-1-ylmethyl) amino] propionate by the use of the methods described in Example 25. The product was reprecipitated from dichloromethane-diethyl ether; m.p. 124-129 ° C; ESI of positive ion (M + H) + 354.4. Example 40: C / sN-Methyl-N- (6-methoxy-1-phenyl-1, 2,3,4-tetrahydronaphth-1-methylmethyl benzoacetate benzyl hydrochloride c / 'sN-methyl-N - [( Lithium 6-methoxy-1-phenyl-1, 2,3,4-tetrahydronaphth-2-yl) methi) -aminoacetate (prepared as described in Process 1; 249.8 mg), PyBrOP® (374.2 mg) , 4-dimethylaminopyridine (67.5 mg), diisopropylethylamine (0.1 51 cm3) and benzyl alcohol (0.079 cm3) in N. N-dimethylformamide (1.0 cm3) and stirred overnight under nitrogen, the solvent was evaporated and the residue it was taken up in water (25 cm3) and extracted into dichloromethane (3 x 25 cm3), which was dried (Na2SO4) and the solvent was evaporated.The crude product was purified by column chromatography [silica, levigation with petroleum ether (b.p. 40-60 ° C) -diethyl ether (1: 1)] to produce the desired compound as its free base. This was taken in dichloromethane and converted to the hydrochloride salt; ESI of positive ion (M + H) + 430.3. Example 41: cSN- (6-methoxy-1-phenyl-1, 2,3,4-tetrahydronaphth-2-ylmethylPaminocarboxylic acid hydrochloride: c / sN- (6-methoxy-1-phenyl-1 hydrochloride, Benzyl 2,3,4-tetrahydronaphth-2-ylmethylpharmacarboxylate Benzyl c-'N-methyl-N- (6-methoxy-1-phenyl-1, 2,3,4-tetrahydronaphth-2-ylmethyl) aminocarboxyiazole was dissolved. (prepared as described in Process 15; 96.9 mg) in dichloromethane (25 cm3) under a nitrogen atmosphere, 1-chloro-ethyl chloroformate (0.254 cm3) was added and the mixture was heated to reflux for 72 h. The solvent was evaporated before an additional portion of 1-chloroethyl chloroformate (0.254 cm 3) was added and the mixture was heated to 100 ° C for about 7 days, after cooling, methyl alcohol (25 cm 3) was added and the mixture was heated overnight, the solvent was then evaporated and the residue was purified by high performance liquid chromatography [using a Supelco ABZ + column; tooth with water-acetonitrile (95: 5) through clean acetonitrile, treated all with 0.05% aqueous formic acid]. The fractions containing the product were treated with hydrochloric acid (5 M) and the volatiles were removed in vacuo to provide the main compound (37.4 mg); ESI of positive ion (M + H) + 416.2.

B: Palladium on carbon (10%, 17.3 mg) was added to a solution of c / sN- (6-methoxy-1-phenyl-1, 2,3,4-tetrahydronaphth-2-ylmethyl) benzyl aminocarboxylate hydrochloride. (37.8 mg) in ethyl alcohol (10 cm3) and hydrochloric acid (5 M, 1 cm3) and the mixture was stirred under hydrogen gas (1.5 bar) overnight. The mixture was filtered and the solvent was evaporated. The residue was purified by high performance liquid chromatography (conditions as above) and treated with hydrochloric acid (5 M) to give the main compound (10 mg); ESI of positive ion (M + H) + 326.0. Example 42: Resolution of Racemic Ethyl-N-methyl-N- (6-methoxy-1-phenyl-1, 2,3,4-tetrahydronaphthalen-2-ylmethydiomethylcarboxylate The racemate of Example 4, c / sN-methyl- N- (6-methoxy-1-phenyl-1, 2,3,4-tetrahydro-naphthalen-2-ylmethyl) aminocarboxylic acid ethyl ester was prepared according to the procedures in Example 1. It was then resolved (2.87 g) by chiral HPLC using a Chiracel OJ 250 x 4.6 mm column (JT Baker), levigating with hexane- (2-propanol) (97: 3) at a flow rate of 8 mL / min at room temperature. The fractions containing the two enantiomers (4.86 and 5.83 min) were combined and the volatiles were removed to provide the desired products: Example (-) - 4: c / sN-methyl-N- (6-methoxy-1-phenyl- 1, 2, 3,4-tetrahydronaphthalen-2-ylmethylmethylcarboxylate (-) - Lithium hydrolyzed c / sN-methyl-N- (6-methoxy-1-phenyl-1, 2,3,4-tetrahydronaphthalene-2- ilmethyl) aminomethicarboxylate of (-) - Ethyl (0.58 g), as described in Process 1, to produce the main compound (0.51 g) as a white solid; m.p. 173.-184 ° C (foam); ESI of positive ion (M + H) + 346.2, [a] D (MeOH, c = 9.26) -241 ° C; and Example (+> -4: c / s -? / - methyl -? / - (6-methoxy-1-phenyl-1 .2.3.4-tetrahydronaphthalen-2-ylmethylmethylcarboxylate of (+) - Lithium Hydrolysed / - S-methyl-N- (6-methoxy-1-phenyl-1, 2,3,4-tetrahydronaphthalen-2-ylmethyl) aminomethicarboxylate of (-) - Ethyl (0.58 g), as described in Process 1, to produce the main compound (0.54 g) as a white solid, mp 146.-154 ° C (foam), positive ion ESI (M + H) + 346.2, [a] D (MeOH, c = 8.53) +220.4 C. NOTE: Unless otherwise established, all other racemic esters were resolved using the chiral HPLC technique, as exemplified in Example 42. The subsequent hydrosylation of the resulting esters, levogy and dextrogyrators, was performed using the procedure described in Step 9 of Example 1. The following enantiomers were obtained: Example (-1-23: c / s -? / - methyl-? / - (6-methyl-1-phenyl-1 .2.3.4-tetrahydronaphthalene Sodium-2-ylmethylmethylcarboxylate-prepared from the enantio ester purely pure (retention time = 4.27 min); [α] D (MeOH, c = 1.51) -228 ° C. Example (+) - 23: c s- / V-methyl -? / - (6-methyl-1-phenyl-1, 2,3,4-tetrahydronaphthalen-2-ylmethylmethylcarboxylate of (+) - Sodium: prepared from of the enantiomerically pure ester (retention time = 5.23 min); [] D (MeOH, c = 1.59) + 226 ° C.

Example M-17: c / s -? / - methyl -? / - (6-phenoxy-1-phenyl-1, 2,3,4-tetrahydronaphthalen-2-ylmethylmethylcarboxylate of (-) - Sodium: prepared from enantiomerically pure ester (retention time = 14.40 min); [a] D (MeOH, c = 1.29) = - 188 ° C Example (+) - 17: c / s -? / - methyl -? / - (6-phenoxy-1-phenyl-1 .2.3.4-tetrahydronaphthalen-2-ylmethylmethylcarboxylate (+) - Sodium) prepared from the enantiomerically pure ester (retention time = 18.70 min); [a] D (MeOH, c = 1 .67) = + 192 ° C. Example 43: Resolution of? / - methyl-? - [1 - (4-fluorophenyl) -6-trifluoromethyl-1, 2,3,4, -tetrahydronaphthalene-2- Ethyl ilmethyl] aminomethylcarboxylate The racemic ester was separated by chiral HPLC on a Chiracel OJ250 x 4.6 mm column (JT Baker), eluting with hexane-ethyl alcohol-diisopropylethylamine (98: 2: 0.1); [(-) - enantiomer retention time = 9.02 mins; (+) - enantiomer retention time = 10.75 mins]: hydrolysis of the esters produced: Example (-) - 8:? / - methyl -? / - M - (4-fluoropheni-6-) trifluoromethyl-1,2,3,4-tetrahydronaphthalen-2-ylmethanamine methylcarboxylate (-) - Lithium. m. p. 1 61-164 ° C; ESI positive (M + H) + 396.2, [a] D (MeOH, c = 4.17) = -208.2 ° C; and Example (+) - 8:? / -methyl-? / - ri - (4-fluorophenyl) -6-trifluoromethyl-1, 2,3,4-tetrahydronaphthalen-2-ylmethylaminomethylcarboxylate of (+) - c / 's -Lithium. m. p. 167-169 ° C; ESI positive (M + H) + 396.2, [a] D (MeOH, c = 4.33) = + 222.4 ° C.

Example 44: Resolution of c / s -? / - methyl -? / - [1-phenyl-6- (2,2-dimethylpropyloxy) -1, 2,3,4-tetrahydronaphthalen-2-ylmethyl] aminomethylcarboxylate Lithium . The racemic ester was separated by chiral HPLC on a Daicel Chemical Industries Chiralpak AD column (25 X 2 cm) eluting with 2-propanol; (-) - enantiomer retention time = 7.0 mins; (+) - enantiomer retention time = 8.0 mins; hydrolysis of produced esters: Example -34: c / s -? / - methyl -? / - ri -phenyl-6- (2,2-dimethylpropyloxy) -1 .2.3.4.-tetrahydronaphthalen-2-ylmethylaminomethylcarboxylate (-) -Lithium. m. p. 168-170 ° C; ESI positive (M + H) + 396.2, [a] D (MeOH, c = 1.50) = -176.0 ° C; and Example (+) - 34: c s-? -methyl-? - [1-phenyl-6- (2,2-dimethylpropyloxy) -1 .2.3.4.-tetrahydronaphthalen-2-ylmetinaminomethylcarboxylate of (+) - Lithium. m. p. 169-171 ° C; ESI positive (M + H) + 396.1, [a] D (MeOH, c = 1 .49) = + 176.5 ° C; and Example 45 Method for the determination of glycine uptake in cells of CHO that heterologously express the human transporter GlyT- 1 b. TO; Cloning: cDNA was generated by PCR according to the method described by Kim, K.-M. et al. Mol. Pharmacol. 1 994, 45, 608-61 7. The sequence was verified by ordering in dideoxy sequence using the DNA sequencer ALF (Pharmacia) and cloned into the expression construct pcDNA3 (Invitrogen). B: Transfection: The transfection of hGlyT-1 b in CHO cells was carried out using a standard calcium phosphate technique as described by Sambrook, J. et al. (1989) in Molecular Clonin: A Laboratory Manual, Cold Spring Harbor Laboratory, Col Spring Harbor, NY. C: Selection: The stably transfected cells were selected to 1 week in the development medium containing 1 mg.cm 3 of Geneticin, individual clones were collected for further analysis and the positive ones went through routinely as described below D: Crop Conditions: Cells stably expressing the gene hGlyT-1 b were cultured at 37 ° C in a 5% CO2 atmosphere in DMEM-NUT.MIX.F12 with Glutamax-1 (Gibco) containing Geneticin (0.5 mg.cm "3, Gibco) and supplemented with 10% Clonafetal ll (Hyclone). The maintenance of the culture was carried out in standard 80 cm2 ventilated flasks (2 m "6 filter, Nunc) and the cells were subcultured by trypsinization (Sigma) when they were confluent E: Assay Procedure The cells for the studies of collection were placed in plates on plates of 96 perforations (1 7,000 cells per perforation) in the absence of Geneticin and were cultured for 48 h before use. To measure the glycine transport, the cells were rinsed twice with Hanks Balanced Salt Solution (HBSS) reheated at 37 ° C and the excess fluid was removed before the addition of the test compounds dissolved in 0.200 cm3 of Hbss . Plates were incubated at 37 ° C for 5 minutes before the addition of [3H] glycine (0.050 cm3, 150 M-6, 248 Bq.nmol "1, NEN) and incubation continued for 10 more minutes. finished by rinsing the cells with frozen Hbss before removing the excess fluid and adding 0.200 cm3 of scintillation cocktail in each perforation.The plates were sealed with adhesive film, shaken to ensure that the samples were homogeneous before counting. scintillation in a plate counter F: Data Analysis: Data were analyzed by using standard curve fitting procedures to produce a plC5o value for active compounds (where plC5o is the negative logarithm of the concentration of the test compound which causes 50% inhibition of the harvest.) G: Results: The compounds of the invention selectively inhibit the transport of glycine by the human transporter GlyT-1 b compared to the transporter. GlyT-2 human sporter (molecular cloning and functional expression of the human GlyT-2 transporter is described by Morrow, J.A. i went to FEBS letters 1 998, 439, 334-340.

The plC50 values of the racemic materials and the levogyrative enantiomers of the compounds described in Examples 4, 8, 17, 23 and 34 (the chiral separation of which is described in Examples 42-44) are given in Table 1 . COMPOUND EXAMPLE plC50 (+/-) - 4 c / sN-methyl-N- (6-methoxy-1-phenyl-1, 2,3,4-6,3-tetrahydronaphthalen-2-ylmethyl) aminomethylcarboxylate of (+/-) - Lithium (- ) -4 c / 's-N-methyl-N- (6-methoxy-1-phenyl-1, 2,3,4-6,8-tetrahydronaphthalen-2-ylmethyl) aminomethylcarboxylate of (-) - Lithium (+/-) - 8 N-methyl-N- [1- (4-fluorophenyl) -6-trifluoromethyl-6.9-l, 2,3,4-tetrahydronaphthalen-2-ylmethyl] aminomethylcarboxylate of (+/-) - Lithium (-) - 8 N- methyl-N- [1- (4-fluorophenyl) -6-trifluoromethyl-7.3.1, 2,3,4-tetrahydronaphthalen-2-ylmethyl] aminomethylcarboxylate of (-) - Lithium (+/-) - 17 c sN-methyl -N- (6-phenoxy-1-phenyl-1, 2,3,4-6,8-tetrahydronaphthalen-2-ylmethyl) aminomethylcarboxylate of (+/-) - Sodium (-) - lX c / sN-methyl-N- ( 6-phenoxy-1-phenyl-1, 2,3,4-7,0-tetrahydro afat-2-ylmethyl) aminomethylcarboxylate (-) - Sodium (+/-) - 23 c / s-N-methyl-N- (6-methyI-1-phenyl-1, 2,3,4-6,6 tetrahydronaphthalen-2-ylmethyl) aminomethylcarboxylate of (+/-) - Sodium (-) - 23 c / s-N-methyl-N- (6-methyl-1-phenyl-1, 2,3,4-6,9 tetrahydronaphthalen-2-ylmethyl) aminomethylcarboxylate (-) - Sodium (+/-) - 34 c sN-Methyl-N- [1-phenyl-6- (2,2-6,6-dimethylpropyloxy) -1,2,3,4-tetrahydronaphthalen-2-ylmethyl] aminomethylcarboxylate (+/- ) - Lithium (-) - 34 c sN-Methyl-N- [1-phenyl-6- (2,2-6,6 dimethylpropyloxy) -1,2,3,4-tetrahydronaphthalen-2-ylmethyl] aminomethylcarboxylate (-) -Lithium

Claims (10)

1. CLAIMS 1. A derivative of aminomethylcarboxylic acid having the general formula I.
2. Formula I wherein Z is (CH2) n, O, S, SO, SO2 or N-R5; + n is 0, 1 or 2; X represents 1 -3 substitutes independently selected from hydrogen, halogen, (C? -6) alkyloxy, (C3-6) cycloalkyloxy, (C6-12) aryloxy, (C6-y2) aryl, thienyl, SR6, SOR6, SO2R6, NR6R6, NHR6, NH2, NHCOR6, NHSO2R6, CN COOR6 and (C1-4) alkyl, optionally substituted with halogen, (C6-? 2) aryl, (C? -6) alkyloxy or (C6-? 2) aryloxy; or 2 substitutes in adjacent positions together represent a group (C5-6) fused aryl, a ring (C5-6) fused cycloalkyl or O- (CH2) m-O; m is 1 or 2; Y represents 1 -3 substitutes independently selected from hydrogen, halogen, (C1-) alkyloxy, SR6, R6R6 and (C? _) Alkyl, optionally substituted with halogen; R, is COOR7 or CONR8R9;
3. R2 and R8 are (C1-) alkyl; R3, R and R5 are independently hydrogen or (C? -4) alkyl; R7I R8 and R9 are independently hydrogen, (C1-4) alkyl, (C6-1) aryl or arylalkyl; or a pharmaceutically acceptable salt thereof. 2. The aminomethylcarboxylic acid derivative according to claim 1, characterized in that Z is (CH2) n and n is 1. 3. The aminomethylcarboxylic acid derivative according to claim 2, characterized in that R is methyl and R3 and R are each hydrogen.
4. 4. The aminomethylcarboxylic acid derivative according to claim 3, characterized in that R-i is COOR7.
5. 5. The aminomethylcarboxylic acid derivative according to any of claims 1-4, characterized in that it has the cis configuration.
6. 6. A derivative of aminomethylcarboxylic acid according to claim 1, characterized in that it is selected from the following levogyratory enantiomers: c / sN-methyl-N- (6-methoxy-1-phenyl-1, 2,3,4-tetrahydronaphthalene -2-ylmethyl) aminomethylcarboxylate of (-) - Lithium; c / s-N-methyl-N- (6-methyl-1-phenyl-1, 2,3,4-tetrahydronaphthalen-2-ylmethyl) aminomethylcarboxylate of (-) - Sodium; c) S-N-methyl-N- (6-phenoxy-1-phenyl-1, 2,3,4-tetrahydronaphthalen-2-ylmethyl) aminomethylcarboxylate of (-) - Sodium; N-methyl-N- [1- (4-fluorophenyl) -6-trifluoromethyl-1, 2,3,4-tetrahydronaphthalen-2-ylmethyl) aminomethylcarboxylate of (-) - Lithium; c s-N-methyl-N- [1-phenyI-6- (2,2-dimethylpropyloxy) -1, 2,3,4-tetrahydronaphthalene-2- ilmethyl) aminomethylcarboxylate of (-) - Lithium.
7. 7. The aminomethylcarboxylic acid derivatives according to any of claims 1-6 for use in therapy.
8. 8. A pharmaceutical composition comprising an acidiccarboxylic derivative having the general formula I or a pharmaceutically acceptable salt thereof, and mixing with pharmaceutically acceptable auxiliaries.
9. 9. The use of an aminomethylcarboxylic acid derivative having the general formula I or a pharmaceutically acceptable sai thereof, for the manufacture of a medicament having CNS activity.
10. 10. The use of an aminomethylcarboxylic acid derivative having the general formula I or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of schizophrenia, depression, dementia, and other forms of loss of consciousness or of neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's disease, or muscular hyperactivity associated with spasticity, myoclonus and epilepsy.