MXPA06009833A - Substituted 1,2,3,4-tetrahydroisoquinoline derivatives - Google Patents

Abstract

The invention relates to novel 1,2,3,4-tetrahydroisoquinoline derivatives of formula (I) wherein R1, R2, R3 and X are as defined in the claims, and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and methods of treatment comprising administration of said compounds to a mammal.

Description

DERIVATIVES OF 1,2,3,4-TETRAHIDROISOQUINOLINA SUBSTITUTE Description of the Invention The present invention relates to new substituted 1, 2, 3, 4-tetrahydroisoquinoline derivatives of the general formula (I) and to their use as pharmaceutical substances. The invention also relates to related aspects which include processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of the general formula (I) and especially to their use as antagonists of the orexin receptor. Orexins (orexin A or OX-A and orexin B or OX-B) are novel neuropeptides found in 1998 by two research groups, orexin A is a peptide of 33 amino acids and orexin B is a peptide of 28 amino acids ( Sakurai T. et al., Cell, 1998, 92, 573-585). The orexins are produced in the discrete neurons of the lateral hypothalamus and bind to the receptors bound to the G 'protein (the OXi receptors and OX2). The orexin-1 receptor (OXi) is selective for OX-A, and the orexin-2 receptor (0X) is able to bind to OX-A as well as OX-B. Orexins were found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behavior (Sakurai T. et al., Cell, Ref.175297 1998 , 92, 573-585). On the other hand, it was also observed that orexins regulate sleep and insomnia states by opening potentially novel therapeutic methods to narcolepsy as well as insomnia and other sleep disorders (Chemelli RM et al., Cell, 1999, 98, 437- 451). The orexin receptors are found in the brain of the mammal and may have numerous implications in pathologies such as depression; anxiety; addictions; obsessive-compulsive disorders; affective neurosis; depressive neurosis; anxiety neurosis; dysthymic disorder; mood disorders; sexual dysfunction; psychosexual dysfunction; sexual disorders; schizophrenia; manic depression; delirium; dementia; severe mental retardation and dyskinesias such as Huntington's disease and Tourette's syndrome; eating disorders, - sleep disorders; cardiovascular diseases; diabetes; Appetite / taste disorders; vomiting / nausea; asthma; Parkinson's disease; Cushing syndrome / disease; adenoma caused by basophils; prolactinoma; hyperprolactinemia; hypopituitarism; tumor / adenoma of the pituitary gland; hypothalamic diseases; inflammatory bowel disease; gastric dyskinesia; gastric ulcers; Froehlich syndrome; diseases of the pituitary gland; hypothalamic hypogonadism; Kallman syndrome (anosmia, hyposmia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism, hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth deficiency; dwarfism; giantism; acromegaly; altered biological and circadian rhythms; sleep disturbances associated with diseases such as neurological disorders; neuropathic pain and restless legs syndrome; heart and lung diseases; acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction; ischemic or hemorrhagic attacks; subarachnoid hemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronic renal failure; renal disease; impaired tolerance to glucose; migraine; hyperalgesia; pain; improved or exaggerated sensitivity to pain such as hyperalgesia, causalgia and allodynia; acute pain; pain from burns; atypical facial pain; neuropathic pain; Back pain; syndromes I and II of complex regional pain; arthritic pain; pain from sports injuries; pain related to the infection for example HIV; post-chemotherapy pain; post-attack pain; post-operative pain; neuralgia; conditions associated with visceral pain such as irritable bowel syndrome; migraine and angina; incontinence of the urinary bladder, for example, urge incontinence; tolerance to narcotics or withdrawal from narcotics; Sleep apnea; narcolepsy; insomnia; parasomnia; and neurodegenerative disorders that include nosological entities such as the disinhibition-dementia-parkinsonism-amyotrophy complex; epilepsy due to pallido-ponto-nigral degeneration; Stroke disorders and other diseases related to the dysfunction of the general orexin system. The present invention provides substituted 1, 2,3, 4-tetrahydroisoguinoline derivatives, which are antagonists different from the peptides of human orexin receptors. These compounds are in particular of potential use in the treatment of eating disorders or sleep disorders. So far, some low molecular weight compounds are known to have a potential to antagonize either specifically OXi or 0X, or both receptors at the same time.

In some 'patent applications, for example, SmithKline Beecham reported derivatives of phenylurea, phenylthiourea and cinnamide as selective OXi antagonists (WO 99/09024, WO 00/47576 and WO 00/47580). More recently, in its patent applications, S ithKline Beecham suggests 2-amino-methylpiperidine derivatives (WO 01/96302), 3-aminomethyl-morpholine derivatives (WO 02/44172) and cyclic N-aroyl amines (WO 02/090355, WO 03/002559 and WO 03/002561) as orexin receptor antagonists. In WO 01/85693, Banyu Pharmaceuticals claimed the N-acyltetrahydroisoquinoline derivatives.

Other orexin receptor antagonists such as novel benzazepine derivatives are described in WO 02/051838. Actelion Pharmaceuticals Ltd. claimed the 1, 2, 3, 4-tetrahydroisoquinoline derivatives and their use as active ingredients in the preparation of a pharmaceutical composition (WO 01/68609). In addition, the use of a chemical in a solution phase for the induced optimization of 1, 2,3, -tetrahydroisoquinoline derivatives as antagonists of the potential orexin receptor has already been reported (Chimia, 2003, 57, 1-6 ). It is well known that adequate regulation of plasma concentrations of a drug during the treatment period is one of the crucial aspects in therapy. A very important mechanism for this regulation is the oxidation of a substance of the drug by cytochrome enzymes P450 (CYP). Oxidation of the drug by CYP enzymes should be appropriate with respect to the desired therapeutic indication and a high inhibition of CYP enzymes should be avoided. This is due to the problem of drug-drug interaction, ie the increased plasma concentration of a drug by the inhibition of a CYP enzyme from another drug. The CYP 450s of drug metabolism, predominant, are CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 that represent approximately 30% of the total CYP enzymes. Many drugs are transformed by CYP3A4 and some drugs have no other route of metabolism than this specific cytochrome. As a result, a low inhibition of CYP3A4 is absolutely crucial for a chemical entity to become a candidate for the drug. It has now been found that the compounds of the present invention have low affinities against CYP3A4. In addition, it has been observed that these compounds were active after oral administration. The compounds of the present invention are therefore useful for the treatment of diseases such as, for example, eating disorders or sleep disorders. The following paragraphs provide definitions of the various guiding portions for the compounds according to the invention and are proposed to be applied uniformly from beginning to end of the specification and the claims unless expressly described otherwise provide a broader definition. • The term "alkenyl", alone or in combination with other groups, means a straight chain or branched chain alkyl group with 1 to 6 carbon atoms, preferably a straight or branched chain alkyl group with 1 to 4 carbon atoms. Examples of branched-chain or straight-chain Ci-Cß alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl, isomeric pentyls, isomeric hexyl, preferably methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl or tert-butyl. The term "alkoxy", alone or in combination with other groups, means a group R-0- wherein R is an alkyl group as defined above, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy , sec-butoxy and tert-butoxy, preferably methoxy and ethoxy. The term "pharmaceutically acceptable salts" encompasses either salts with inorganic acids or organic acids similar to hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, fumaric acid, benzoic acid, pamoic acid, stearic acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, succinic acid, trifluoroacetic acid, and the like, which are not toxic to living organisms or in the event that The compound of the formula (I) is of an acid nature, with an inorganic base similar to an alkaline or alkaline-earth base, for example sodium hydroxide, potassium hydroxide, calcium hydroxide and the like. For other examples of the pharmaceutically acceptable salts, reference can be made to "Salt selection for basic drugs", Int. J. Pharmal. (1986), 33, 201-217. Salt-forming groups "are groups or radicals that have basic or acidic properties. Compounds having at least one basic group or at least one basic radical, for example amino, a secondary amino group which does not form a peptide bond or a pyridyl radical, can form acid addition salts, for example with inorganic acids. When several basic groups are present, the mono- or poly-acid addition salts can be formed. Compounds having acidic groups, such as a carboxy group or a phenolic hydroxy group, can form metal or ammonium salts, such as alkali metal or alkaline earth metal salts eg, sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, for example triethylamine or tri- (2-hydroxyethyl) -amine, or heterocyclic bases, for example N-ethyl-piperidine or N, N'-dimethylpiperazine. Mixtures of salts are possible. Compounds having both acidic and basic groups can form internal salts. For the purposes of isolation or purification, as well as in the case of the compounds which are also used as intermediates, it is also possible to use pharmaceutically unacceptable salts, for example the picrates. Only non-toxic, pharmaceutically acceptable salts can be used for therapeutic purposes, however, and therefore these salts are preferred. A first aspect of the invention consists of novel substituted 1, 2,3, 4-tetrahydroisoquinoline derivatives of the following general formula (I): (i) wherein R1 and R2 independently represent hydrogen or alkoxy of C? -C4; R3 represents Ci-Ce alkyl; X represents -CH- or a nitrogen atom. Also encompassed by the present invention are the compounds of the formula (I) and the optically pure enantiomers, and mixtures of enantiomers, racemates, optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereoisomeric racemates, meso forms and salts, complexes of solvents and morphological forms thereof pharmaceutically acceptable. Any reference to a compound of the general formula (I) is to be understood as a reference also to the configurational isomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates and mixtures of diastereomeric racemates, as well as salts, pharmaceutically acceptable salts, solvent complexes, and morphological forms, as appropriate and convenient. As mentioned above, the present invention also encompasses solvation complexes of the compounds of the general formula (I). The solvation can be carried out in the course of the manufacturing process or can be carried out separately, for example, as a consequence of the hygroscopic properties of an initially anhydrous compound of the general formula (I). The invention also encompasses different morphological forms, for example crystalline forms, of compounds of the general formula (I) and their salts and solvation complexes. Particular heteromorphs can exhibit different dissolution properties, stability profiles, and the like, and all are included in the scope of the present invention. Preferred substituted 1,2,3,4-tetrahydroisoquinoline derivatives are those wherein R 1 and R 2 both represent a C 1 -C alkoxy group, particularly a methoxy group. In a preferred embodiment according to the invention, X represents -CH-. In another preferred embodiment, X represents a nitrogen atom. In another preferred embodiment according to the invention, R3 represents a methyl group. In a particularly preferred embodiment according to the invention, R1 and R2 represent a methoxy group, X represents -CH- and R3 represents Ci-Ce alkyl. Examples of the preferred compounds are selected from the group consisting of: 2-. { 6,7-dimethoxy-1- [2- (4-trifluoromethyl-phenyl) -ethyl] -3,4-dihydro-1H-isoquinolin-2-yl} -N-methyl-2-phenyl-acetamide; 2-. { 6,7-dimethoxy-1- [2- (6-trifluoromethyl-pyridin-3-yl) -ethyl] -3,4-dihydro-lH-iso-quinolin-2-yl} -N-methyl-2-phenyl-acetamide. The compounds according to the general formula (I) are useful in the preparation of a medicament for the prevention or treatment of diseases selected from the group consisting of anxiety; dysthymic disorder; mood disorders; sexual dysfunction; psychosexual dysfunction; sexual disorders; schizophrenia; manic depression; delirium; dementia; severe mental retardation and dyskinesias such as Huntington's disease and Tourette's syndrome; eating disorders; sleep disorders; cardiovascular diseases; diabetes; Appetite / taste disorders; vomiting / nausea; asthma; Parkinson's disease; Cushing syndrome / disease; adenoma caused by basophils; prolactinoma; hyperprolactinemia; hypopituitarism; tumor / adenoma of the pituitary gland; hypothalamic diseases; Inflammatory bowel disease Gastric dyskinesia; gastric ulcers; Froehlich syndrome pituitary diseases; Hypothalamic hypogonadism Kallman syndrome (anosmia, hyposmia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism, hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth deficiency; dwarfism; giantism; acromegaly; altered biological and circadian rhythms; sleep disturbances associated with diseases such as neurological disorders; neuropathic pain and restless legs syndrome, -diseases of the heart and lung; acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction; ischemic or hemorrhagic attacks; subarachnoid hemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronic renal failure; renal disease; impaired tolerance to glucose; migraine, -hyperalgesia; pain; improved or exaggerated sensitivity to pain such as hyperalgesia, causalgia and allodynia; acute pain; pain from burns; atypical facial pain; neuropathic pain; Back pain; syndromes I and II of complex regional pain; arthritic pain; pain from sports injuries; pain related to the infection for example HIV; post-chemotherapy pain; post-attack pain; post-operative pain; neuralgia; conditions associated with visceral pain such as irritable bowel syndrome; migraine and angina; incontinence of the urinary bladder, for example, urge incontinence; tolerance to narcotics or withdrawal from narcotics; Sleep apnea; narcolepsy; insomnia; parasomnia; and neurodegenerative disorders that include nosological entities such as the disinhibition-dementia-parkinsonism-amyotrophy complex; epilepsy due to pallido-ponto-nigral degeneration; Stroke disorders and other diseases related to the dysfunction of the general orexin system. The compounds of the general formula (I) are particularly suitable for use in the treatment of diseases or disorders selected from the group consisting of eating disorders or sleep disorders. Eating disorders can be defined as those that comprise metabolic dysfunction; irregular control of appetite; compulsive obesity; emeto-bulimia or anorexia nervosa. This pathologically modified intake of food can result from an altered appetite (attraction or aversion to food); altered balance of energy (consumption versus expense); altered perception of the quality of the food (high fat or carbohydrate content, high taste); altered availability of food (unrestricted diet or deprivation) or altered water balance. Sleep disorders include insomnia, narcolepsy and other disorders of excessive sleep, sleep-related dystonia; Restless Leg Syndrome; sleep apneas; time shift syndrome; syndrome of change of work schedule; advanced or delayed sleep phase syndrome. Insomnia are defined as those that comprise sleep disorders associated with aging; intermittent treatment of chronic insomnia; temporary insomnia due to various situations (new environment, noise) or short-term insomnia due to tension; affliction; pain or illness A further object of the invention is a pharmaceutical composition containing at least one compound according to the general formula (I) and a pharmaceutically acceptable carrier material. Another object of the present invention is a method for the treatment or prophylaxis of diseases that are related to orexin receptors such as eating disorders or sleep disorders., which comprises administering to a patient a therapeutically effective amount of a 1,2,3,4-tetrahydroisoquinoline derivative according to the general formula (I). In a preferred embodiment of the invention, this amount is between 1 mg and 1000 mg per day, particularly from 2 mg to 500 mg per day, more particularly from 5 mg to 200 mg per day. The present invention also relates to a process for the preparation of a pharmaceutical composition comprising a derivative of 1, 2, 3, 4-tetrahydroisoquinoline according to the general formula (I) by mixing one or more active ingredients according to the invention. with the general formula (I) with a carrier material in a manner known per se. The compounds of the general formula (I) and their pharmaceutically acceptable salts can be used as medicaments (for example, in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered enterally, such as orally (for example in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (for example in the form of solutions nasal spray) or rectally (eg in the form of suppositories). However, the administration can also be effected parenterally, such as intramuscularly or intravenously (for example in the form of injection solutions), or topically in the form of ointments, creams or oils. The compounds of the general formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, organic or inorganic adjuvants, for the production of tablets, coated tablets, dragees, and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc., can be used, for example, as adjuvants for tablets, dragees and hard gelatine capsules. Suitable adjuvants for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc. Suitable adjuvants for the production of solutions and syrups are, for example, water, alcohol, polyols, sucrose, invert sugar, glucose, etc. Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils; etc. Suitable adjuvants for suppositories are, for example, natural oils or concentrates, waxes, fats, semi-solid or liquid polyols, etc. The components described above for injectable or orally administered compositions are only representative examples. Additional materials as well as processing techniques and the like are described in Remington's Pharmaceutical Sciences, 20 / a. edition, 2001, Marck Publishing Company, Easton, Pennsylvania, which is incorporated herein for reference. The compounds of this invention can also be administered in sustained release forms using known sustained release drug delivery systems. A further object of the invention is a process for the preparation of 1,2,3,4-tetrahydroisoquinoline derivatives according to the general formula (I). The compounds according to the general formula (1) of the present invention are prepared according to the general sequence of the reactions described in the subsequent schemes wherein X, R1, R2 and R3 are as defined in the general formula (I ). The obtained compounds can also be converted into pharmaceutically acceptable salts thereof, in a manner known per se. As described in reaction scheme 1 below, the key intermediates in the synthesis of the compounds of the general formula (I) are 1-substituted 3,4-dihydroisoquinoline derivatives. These compounds are prepared either by the cyclization of the N-phenethyl-propionamides with P0C13 or by the alkylation of l-methyl-3,4-dihydroisoquinolines with alkyl bromides. The 3,4-dihydroisoquinolines obtained are reduced to 1,2,3,4-tetrahydroisoquinolines with sodium borohydride to give the products as racemic mixtures. The 1,2,3,4-tetrahydroisoquinolines highly enantiomerically enriched, are obtained by a transfer hydrogenation of the respective 3,4-dihydroisoquinoline in the presence of a chiral Ru (II) complex (chiral catalyst), which was described originally by R. Noyori et al. (J. Am. Chem. Soc. 1996, 118, 4916-4917 and WO 97/20789). The chiral catalyst (Ru (II) complex) used is as follows: Reaction Scheme 1 As illustrated in Reaction Hose 2 and Reaction Scheme 3 below, the intermediates "1,2,3-tetrahydroisoquinoline according to the invention can be converted to compounds of the general formula (I ) following one of the three different synthetic routes a), b) or c) In route a), 1,2,3,4-tetrahydroisoquinoline is alkylated with a substituted 2-bromo-acetic acid methyl ester. The ester obtained is hydrolyzed to the corresponding acid and finally converted to the amide by a coupling reaction of the amide with the desired amine in the presence of a coupling reagent.In route b), the side chain is introduced by an alkylation of the respective 1,2,3,4-tetrahydroisoquinoline with a 2-bromoacetamide derivative: Reaction Scheme 2 The 1,2,3,4-tetrahydroisoquinoline derivatives of the general formula (I) can also be prepared in a stereoselective manner starting from the enantiomerically pure (S) - (+) -mandelate by following the route c ) (check reaction thread 3 here later). By treating the ester with an alcohol amine solution, the corresponding amide is obtained, which can be tosylated with p-toluenesulfonyl chloride. In a final stage, the tosylate is coupled with. a 1,2,3,4-tetrahydroisoquinoline derivative to give the respective compound of the general formula (I) Reaction Scheme The 1, 2, 3, 4-tetrahydroisoquinoline derivatives used in this invention can be prepared from readily available raw materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e., reaction temperatures, time, moles of reactants, solvents, etc.) are provided, other experimental conditions may also be used unless establish otherwise. The optimum reaction conditions may vary with the particular reagents or solvents used, but such conditions may be determined by one skilled in the art using routine optimization procedures. Experimental section; Abbreviations: ac. aqueous atmosphere BSA bovine serum albumin CHO Chinese Hamster Ovary d day (s) DCM dichloromethane DIPEA diisopropylethylamine DMAP N, N-dimethyl-4-aminopyridine DMF di-ethylformamide DMSO dimethyl sulfoxide EA ethyl acetate EDC 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide ES electronic spraying FCS fetal bovine serum FLIPR plate reader with fluorescence imaging h hour HBSS Hank's balanced salt solution HEPES 4- (2-hydroxyethyl) -piperazine-1-ethanesulfonic acid HOBt hydroxybenzotriazole CLAR high resolution liquid chromatography Hex hexane HV high vacuum conditions LC liquid chromatography LDA diisopropylamide lithium MeOH methanol min. MS mass spectroscopy po by mouth prep. preparative PyBOP benzotriazole-il-oxy-tris-pyrrolidino-phosphonium-hexafluorophosphate Rf frontal retention RT ambient temperature rt retention time sat. saturated tic thin layer chromatography THF tetrahydrofuran Chemical Preparation The following examples illustrate the preparation of the pharmacologically active compounds of the invention but do not limit the scope thereof. All temperatures are set in ° C. All the analytical and preparative HPLC investigations on the non-chiral phases are carried out using columns based on RP-C18. Analytical HPLC investigations are carried out on two different instruments with cycle times of ~ 2.5 minutes and ~ 3.5 minutes respectively. For CLAR separations on the chiral phases, a Chiralcel OD column from Daicel Chemical Industries is used. The compounds are characterized by XH-NMR (300 MHz) or 13 C-NMR (75 MHz) (Varian Oxford; the chemical changes are given in ppm in relation to the solvent used; multiplicities: s = singlet, d = doublet, t = triplet; c = quartet, m = multiplet, a = broad, coupling constants are given in Hz); by LC-MS, rt is given in minutes; by TLC (Merck TLC plates, silica gel 60 F25); or by the melting point. A. Synthesis of propionic acid derivatives: 1. Synthesis of 3- (6-trifluoromethyl-pyridin-3-yl) -propionic acid: 1.1 Synthesis of 3- (6-trifluoromethyl-pyridin-3-yl) methyl ester ) -acrylic: A solution of 6-trifluoromethyl-pyridine-3-carbaldehyde (570 mg) in DCM (1.0 ml) is added to a solution of the methyl ester of (triphenyl-? 5-fosfanylidene) -acetic acid (990 mg) in DCM (2.5 ml). The mixture is stirred under nitrogen at reflux for 20 hours and concentrated in vacuo. The residue is purified by flash chromatography (EA / heptane 3/7) to give the desired unsaturated ester as a white solid. XH-NMR (300 MHz, CDC13): d = 3.85 (s, 3H), 6.59 (d, J = 16.2 Hz, 1H), 7.70 (d, J = 16.2 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7. 98 (dd, J = 8.1 Hz, J = 2.1 Hz, 1H), 8.84 (s a, ÍH). 1.2 Synthesis of 3- (6-trifluoromethyl-pyridin-3-yl) -propionic acid methyl ester: A solution of the 3- (6-trifluoromethyl-pyridin-3-yl) -acrylic acid methyl ester (720 mg) in methanol (5.0 ml) is treated with Pd / C (10%, 240 mg) and stirred under a hydrogen atmosphere (~ 1 bar) at RT for 20 hours. The suspension is filtered through celite and concentrated in vacuo to give the propionic acid ester as a colorless oil. ^ - MN (300 MHz, CDC13): d = 2.69 (t, J = 7.4 Hz, 2H), 3.05 (t, J = 7.4 Hz, 2H), 3.68 (s, 3H), 7.60 (d, J = 7.8 Hz, 1H), 7.71 (da, J = 8.1 Hz, ÍH), 8.58 (sa, ÍH). 1.3 Synthesis of 3- (6-trifluoromethyl-pyridin-3-yl) -propionic acid: Lithium hydroxide monohydrate (330 mg) is added in one portion to a solution of 3- (6-trifluoromethyl) methyl ester. pyridin-3-yl) -propionic acid (610 mg) in a mixture of THF (15 ml) and water (5 ml). The mixture is stirred for 20 h at RT. DCM and aqueous HCl (1.0 M) are added, the layers are separated and the aqueous layer is extracted twice with DCM. The combined organic extracts are dried over MgSO4 and concentrated in vacuo to give the desired propionic acid as a beige solid. aH-NMR (300 MHz, CDCl 3): d = 2.75 (t, J = 7.4 Hz, 2H), 3.06 (t, J = 7.4, 2H), 7.62 (d, J = 8.1 Hz, HH), 7.73 (da , J = 8.1 Hz, ÍH), 8.62 (sa, ÍH). B. Synthesis of the 2-bromo-acetamide derivatives: 1. Synthesis of 2-bromo-N-methyl-2-phenyl-acetamide: 1.1. Synthesis of N-hydroxy-N-methyl-2-phenyl-acetamide: At 0 ° C phenyl acetyl chloride (11.2 ml) is added dropwise to a solution of N-methylhydroxylamine hydrochloride (7.07 g) and triethylamine (59 ml) in DCM (300 ml). After stirring for 90 minutes, a saturated aqueous NaHC03 solution is added, the layers are separated and the aqueous layer is extracted twice with DCM (2 x 200 ml). The solvents are removed in vacuo and the residue is purified by flash chromatography (EA / heptane 1/1) to give the desired N-hydroxy-acetamide as a colorless liquid. LC-MS: rt = 0.63 min., 166 (M + l, ES +). 1.2 Synthesis of 2-bromo-N-methyl-2-phenyl-acetamide: At 0 ° C triethylamine (5.49 ml) is added to a solution of N-hydroxy-N-methyl-2-phenyl-acetamide (6.5 g) in DCM (200 ml). The mixture is treated dropwise with a solution of methanesulfonyl chloride (3.21 ml) in DCM (60 ml). After 2 hours water (150 ml) is added, the layers are separated and the aqueous layer is extracted twice with EA (2 x 100 ml). The organic extracts are combined and concentrated in vacuo to give the crude mesylate as a pale yellow oil. The mesylate is dissolved in acetonitrile (200 ml). The lithium bromide (15.3 g) is added and the reaction mixture is treated with ultrasound for 5 minutes. After the addition of diisopropyl-ethylamine (6.78 ml) the mixture is again treated with ultrasound for 5 minutes and stirred for an additional 60 minutes at room temperature.

Water (150 ml) and ethyl acetate (200 ml) are added, the layers are separated and the aqueous layer is extracted twice with ethyl acetate (2 x 200 ml). The combined organic extracts are concentrated in vacuo and purified by flash chromatography (ethyl acetate / heptane 2: 3) to give the desired bromide as a white solid. LC-MS: rt = 0.75 min., 228 (M + l, ES +). C. Synthesis of toluene-4-sulfonic acid (S) -methylcarbamoyl-phenyl-methyl ester: 1. Synthesis of (S) -2-hydroxy-N-methyl-2-phenyl-acetamide: The (S) - (+) - methylmandelate (17 g) is dissolved in a solution of methylamine in methanol (230 ml, 2.0 M) and maintained at RT for 1 d. Another portion of methylamine in methanol (10 ml, 2.0 M) is added. A third portion of methylamine in methanol (10 ml, 2.0 M) is added one day later. After an additional 24 hours, the solvents are removed in vacuo to give the desired mandelamide as light yellow crystals, which are used without further purification. LC-MS: rt = 0.52 min., 166 (M + l, ES +). 2. Synthesis of the (S) -methylcarbamoyl-phenyl-methyl ester of toluene-4-sulfonic acid: To RT add DIPEA (2.74 ml) and DMAP (145 mg) to Tina solution of (S) -2-hydroxy-N-methyl-2-phenyl-acetamide (2.4 g) in DCM (50 ml). The mixture is treated in portions with p-toluenesulfonyl chloride (2.75 g) and held for 2 h at RT. The solvent is removed in vacuo and the residue is dissolved in ethyl acetate. The solution is washed twice with a saturated NaHC03 solution and once with brine, the solvents are removed ih vacuo and the residue is recrystallized from ethyl acetate / tert-butyl methyl ether to give the tosylate as white crystals. LC-MS: rt = 0.93 min., 320 (M + l, ES +). D. Synthesis of N- ((IR, 2R) -2-amino-1,2-diphenyl-ethyl) -2,4,6-trimethyl-benzenesulfonamide (precursor of the catalyst): At 0 ° C a solution of mesitylenesulfonyl chloride (3.09 g) in THF (150 ml) is added dropwise to a suspension of (IR, 2R) -1,2-diphenyl-ethane-1,2-diamine (3.00 g). ), diisopropylethylamine (3.87 ml) and potassium carbonate (3.12 g) in a mixture of THF (120 ml) and DMF (30 ml). After 3 hours water (300 ml) and ethyl acetate (300 ml) are added, the layers are separated and the aqueous layer is extracted three times with ethyl acetate (3 x 300 ml). The solvents are removed in vacuo and the residue is purified by preparative HPLC chromatography. To remove the formic acid, the product obtained is extracted with a saturated NaHCO 3 solution / ethyl acetate to give the mono-sulfonamide as a white solid. LC-MS: rt = 0.82 min, 395 (M + l, ES +). E. Synthesis of phenylethylamide (general procedure): A solution of the respective phenylethylamide (110 mmol) in toluene (350 ml) is treated with the respective propionic acid derivative (110 mmol), refluxed for 90 hours in the presence of a Dean-Stark trap and cool slowly to RT. The precipitate is removed by filtration and dried under vacuum to give the desired amide. 1. Synthesis of N- [2- (3,4-dimethoxy-phenyl) -ethyl] -3- (4-trifluoromethyl-phenyl) -propionamide: This compound is prepared by the reaction of 3,4-dimethoxyphenylethylamine and 4- (trifluoromethyl) -hydrocinnamic acid.

LC-MS: rt = 0.97 min, 382 (M + l, ES +). 2. Synthesis of N- [2- (3, 4-dimethoxy-phenyl) -ethyl] -3- (6-trifluoromethyl-pyridin-3-yl) -propionamide: This compound is prepared by the reaction of the 3,4-dimethoxyphenylethylamine and 3- (6-trifluoromethyl-pyridin-3-yl) -propionic acid. LC-MS: rt = 0.88 min, 383 (M + l, ES +). F. Synthesis of 3,4-dihydroisoguinoline derivatives by amide cyclization (general procedure): Phosphorous oxychloride (123 mmol) is added to a suspension. of the respective amide (55.3 mmol) in acetonitrile (300 ml). The mixture is refluxed for 90 minutes and the solvents are removed in vacuo. Methanol (100 ml) is added and evaporated again. The obtained product is recrystallized from dioxane or dioxane / ethanol. After filtration, the obtained hydrochloride salt is converted to the free base by the addition of a saturated aqueous NaHCO3 solution, and extraction with dichloromethane. The solvents are removed in vacuo to give the respective dihydroisoquinoline. 1. Synthesis of 6,7-dimethoxy-1- [2- (4-trifluoromethyl-phenyl) ethyl] -3,4-dihydroisoquinoline: This compound is prepared by the cyclization of N- [2- (3, 4-dimethoxy-phenyl) -ethyl] -3- (4-trifluoromethyl-phenyl) -propionamide. LC-MS: rt = 0.81 min, 364 (M + l, ES +). 2. Synthesis of 6,7-dimethoxy-1- [2- (6-trifluoro-ethyl-pyridin-3-yl) -ethyl] -3,4-dihydroisoquinoline: This compound is prepared by the cyclization of N- [2- (3, 4-dimethoxy-phenyl) -ethyl] -3- (6-trifluoromethyl-pyridin-3-yl) -propionamide. LC-MS: rt = 0.73 min, 365 (M + l, ES +).

G. Synthesis of 1,2,3,4-tetrahydroisoquinolines: 1. Synthesis of 1,2,3,4-tetrahydroisoquinolines by means of the Bischler-Napieralski reaction (general procedure): To a suspension of the respective amide (44.8 mmol) in acetonitrile (500 ml) is added phosphorous oxychloride (224 mmol). The mixture is heated at reflux for 2 hours and the solvent is removed in vacuo. The resulting oil is received either in toluene or MeOH (20 ml), evaporated to dryness, dissolved in MeOH (200 ml) and cooled to 0 ° C. The NaBH 4 (135 mmol) is added in small portions and the reaction mixture is stirred for 2 hours. The solvent is removed in vacuo, EA (400 ml) and water (400 ml) are added, the layers separated and the aqueous layer extracted three times with EA (3 x 200 ml). The combined organic extracts are concentrated in vacuo to give the following 1, 2, 3, -tetrahydroisoquinolines as racemic mixtures, which are purified by crystallization of the hydrochloride salt from isopropanol. 1.1. Synthesis of rac-6, 7-dimethoxy-1- [2- (4-trifluoromethyl-phenyl) -ethyl] -l, 2,3,4-tetrahydroisoquinoline: This compound is prepared by the reaction of N- [2- (3, 4-dimethoxy-phenyl) -ethyl] -3- (4-trifluoromethyl-phenyl) -propionamide. LC-MS: rt = 0.85 min, 366 (M + l, ES +). 1.2. Synthesis of 6,7-dimethoxy-1- [2- (6-trifluoromethyl-pyridin-3-yl) -ethyl] -l, 2,3,4-tetrahydroisoquinoline: This compound is prepared by the reaction of N- [2- (3, 4-dimethoxy-phenyl) -ethyl] -3- (6-trifluoromethyl-pyridin-3-yl) -propionamide. LC-MS: rt = 0.73 min, 367 (M + l, ES +). 2. Synthesis of 1, 2, 3, -tetrahydroisoquinolines by means of transfer hydrogenation (general procedure): The dimer of dichloro- (p-cymene) ruthenium (II) (0.20 mmol) is added to a solution of N- ((IR, 2R) -2-amino-1, 2-diphenyl-ethyl) -2,4,6-tri-ethylbenzenesulfonamide (0.40 mmol) and triethylamine (0.80 mmol) in acetonitrile (3.0 ml). The mixture is stirred for 1 h at 80 ° C and added to a solution of the respective dihydroisoquinoline (28.0 mmol) in dichloromethane (30 ml). An azeotropic mixture of formic acid and triethylamine (5: 2, 14 ml) is added (evolution of gas). After 90 minutes a saturated aqueous NaHOC3 solution (200 ml) is added to the dark red solution. The layers are separated, the aqueous layer is extracted twice with DCM (2 x 200 ml) and the combined organic extracts are concentrated in vacuo. The residue is dissolved in isopropanol (1600 ml) and treated with a solution of HCl in isopropanol (5-6 M, 10 ml). The hydrochloride salt obtained is recrystallized to give the respective 1, 2, 3, 4-tetrahydroisoquinoline with a high enantiomeric excess as determined by chiral HPLC. The hydrochloride salt is converted to the free base by extraction with a saturated NaHC03 / dichloromethane solution. The absolute configuration of the respective product is assigned in analogy with the literature (N. Uematsu, A. Fujii, S. Hashiguchi, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 1996, 118, 4916-4917) . 2.1. Synthesis of (SS) -6,7-dimethoxy-1- [2- (4-trifluoromethyl-phenyl) -ethyl] -l, 2,3,4-tetrahydroisoquinoline: This compound is prepared by transfer hydrogenation of 6,7-dimethoxy-1- [2- (4-trifluoromethyl-phenyl) -ethyl] -3,4-dihydroisoquinoline. LC-MS: rt = 0.80 min, 366 (M + l, ES +). Chiral HPLC: rt = 12.0 min (hexane / ethanol 9/1; enantiomer: rt = 17.1 min) "'. 2.2 Synthesis of the (1S) -6,7-dimethoxy-l- [2- (6-trifluoromethyl-pyridin-3-yl) -ethyl] -l, 2,3,4- tetrahydroisoquinoline: This compound is prepared by the transfer hydrogenation of 6,7-dimethoxy-1- [2- (6-trifluoromethyl-pyridin-3-yl) -ethyl] -3,4-dihydroisoquinoline. LC-MS: rt = 0.73 min, 367 (M + l, ES +). Guiral HPLC: rt = 10.9 min (hexane / ethanol 4/1; enantiomer rt = 24.4 min). 3. Synthesis of 1, 2, 3, 4-tetrahydroisoquinolines by alkylation of l-methyl-3,4-dihydroisoquinolines (general procedure): At 0 ° C a solution of n-BuLi in hexane (1.6 M, 0.63 mmol) is added dropwise to a mixture of 6,7-dimethoxy-l-methyl-3,4-dihydroisoguinoline (0.50 mmol). ) and diisopropylamine (0.63 mmol) in THF (1.0 ml). The reaction mixture is stirred at RT for 1 h and added at 0 ° C to a solution of the respective benzyl bromide (0.50 mmol) in THF (1.0 ml). The solution is stirred for 1 h, warmed to RT and diluted with DCM (3.0 ml). In a second flask the dimer (p-cymene) ruthenium (II) dimer (0.15 mmol) is added to a solution of N- ((IR, 2R) -2-amino-1-, 2-diphenyl-ethyl) - 2,4,6-Trimethylbenzenesulfonamide (0.30 mmol) and triethylamine (0.60 mmol) in acetonitrile (3.3 ml). The mixture is stirred for 1 h at 80 ° C. A portion of this solution (0.10 ml) is added to the solution of the respective dihydroisoquinoline (described above) An azeotropic mixture of formic acid and triethylamine (5: 2, 0.3 ml) is added (evolution of gas). 2 days, the mixture is concentrated in vacuo and purified by preparative HPLC to give the respective 1,2,3,4-tetrahydroisoquinoline.The enantiomeric excess is determined by chiral HPLC.The absolute configuration of the respective product is assigned in analogy with the literature (N. Uematsu, A. Fujii, S. Hashiguchi, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 1996, 118, 4916-4917.) 3.1 Synthesis of (IS) -6, 7- dimethoxy-1- [2- (4-trifluoromethyl-phenyl) -ethyl] -l, 2,3,4-tetrahydroisoquinoline: This compound is prepared by the alkylation of 6,7-dimethoxy-1-methyl-3, 4- dihydroisoquinoline with 1-bromomethyl-4-trifluoromethyl-benzene LC-MS: rt = 0.80 min, 366 (M + 1, ES +). CLAR chiral: rt = 12.0 min (hexane / ethanol 9/1; enantiomer: r t = 17.1 min) H. Synthesis of (3,4-dihydro-lH-isoquinolin-2-yl) -phenyl-acetic acid methyl ester derivatives (general procedure): DIPEA (43.0 mmol) is successively added and a methyl ester of a-bromo-phenyl-acetic acid (21.5 mmol) to a solution of the respective 1, 2, 3, 4-tetrahydroisoquinoline (21.5 mmol) in either THF, dioxane or toluene (150 ml). The mixture is refluxed for 20 h and allowed to reach RT. Water (250 ml) and EA (200 ml) are added, the layers separated and the aqueous layer extracted twice with EA (2 x 100 ml). The combined organic extracts are concentrated in vacuo and either purified by flash chromatography or used with additional purification. The following ester derivatives described hereinafter are obtained. 1. Synthesis of the acid methyl ester. { 6,7-dimethoxy-1- [2- (4-trifluoromethyl-phenyl) -ethyl] -3,4-dihydro-1H-isoquinolin-2-yl} - phenyl-acetic.

This compound is prepared by the reaction of 6,7-dimethoxy-1- [2- (4-trifluoromethyl-phenyl) -ethyl] -l, 2,3,4-tetrahydroisoquinoline with a methyl ester of a-bromo- phenyl-acetic LC-MS: rt = 0.93 min, 514 (M + l, ES +). 2. Synthesis of the acid methyl ester. { 6,7-dimethoxy-1- [2- (6-trifluoromethyl-pyridin-3-yl) -ethyl] -3,4-dihydro-lH-isoquinolin-2-yl} -phenyl-acetic: This compound is prepared by the reaction of 6,7-dimethoxy-1- [2- (6-trifluoromethyl-pyridin-3-yl) -ethyl] -l, 2,3,4-tetrahydroisoquinoline with the methyl ester of - bromo-phenyl-acetic. LC-MS: rt = 1.68 min, 515 (M + l, ES +). 3. Synthesis of the methyl ester of "acid { (1S) -6,7-dimethoxy-l- [2- (4-trifluoromethyl-phenyl) -ethyl] -3,4-dihydro-lH-isoquinoline-2- il.}. -phenyl-acetic: This compound is prepared by the reaction of the (1S) -6,7-Dimethoxy-1- [2- (4-trifluoromethyl-phenyl) -ethyl] -l, 2,3,4-tetrahydroisoquinoline with the methyl ester of a-bromo-phenyl-acetic acid. LC-MS: rt = 0.93 min, 514 (M + l, ES +). I. Synthesis of (3,4-dihydro-1H-isoguinolin-2-yl) -phenyl-acetic acid derivatives (general procedure): A solution of sodium hydroxide in water (2.0 M, 50 ml) is added to a solution of the respective ester (21.5 mmol) in methanol (400 ml). The mixture is heated to 60 ° C and stirred for 20 h. The majority of the methanol is removed in vacuo and the residue is taken up in a solution of sodium hydroxide (2.0 M, 20 ml), water (100 ml) and DCM (100 ml). The layers are separated and the aqueous layer is extracted three times with DCM (3 x 100 ml). The combined organic extracts are concentrated in vacuo to give the respective carboxylic acid, which is used without further purification: 1. Synthesis of the acid. { 6,7-dimethoxy-1- [2- (4-trifluoromethyl-phenyl) -ethyl] -3,4-dihydro-lH-isoquinolin-2-yl} -phenyl-acetic: This compound is prepared by the saponification of the acid methyl ester. { 6,7-dimethoxy-1- [2- (4-trifluoromethyl-phenyl) -ethyl] -3,4-dihydro-1H-isoquinolin-2-yl} -phenyl-acetic.

LC-MS: rt = 0.88 min, 500 (M + l, ES +). 2. Synthesis of the acid. { 6,7-dimethoxy-1- [2- (6-trifluoromethyl-pyridin-3-yl) -ethyl] -3-dihydro-lH-isoquinolin-2-yl} -phenyl-acetic: This compound is prepared by the saponification of the acid methyl ester. { 6,7-dimethoxy-l- [2- (6-trifluoromethyl-pyridin-3-yl) -ethyl] -3,4-dihydro-lH-isoquinolin-2-yl} -phenylacetic LC-MS: rt = 1.18 min, 449 (M-l, ES-), 501 (M + l, ES +). 3. Synthesis of the acid. { (SS) -6,7-dimethoxy-1- [2- (4-trifluoromethyl-phenyl) -ethyl] -3,4-dihydro-1H-isoquinolin-2-yl} - phenyl-acetic: This compound is prepared by the saponification of the acid methyl ester. { (1S) -6,7-Dimethoxy-1- [2- (4-trifluoromethyl-phenyl) -ethyl] -3,4-dihydro-1H-isoquinolin-2-yl} - phenyl-acetic. LC-MS: rt = 0.88 min, 500 (M + l, ES +). Example 1: Synthesis of 2-. { 6,7-dimethoxy-1- [2- (4-trifluoromethyl-phenyl) -ethyl] -3,4-dihydro-1H-isoquinolin-2-yl} -N-methyl-2-phenyl-acetamide The methylamic a hydrochloride at 0 ° C (15.0 mmol) and NaHCO 3 (20.0 mmol) are added to a solution of the acid. { 6,7-Dimethoxy-1- [2- (4-trifluoromethyl-phenyl) -ethyl] -3,4-dihydro-1H-isoquinolin-2-yl} phenyl acetic acid (10.0 mmol) in DMF (200 ml).

After 15 minutes, HOBt (12.0 mmol) and EDC hydrochloride (22.0 mmol) are added. The mixture is stirred for 10 minutes and maintained for an additional 14 h at 0 ° C without stirring. Water (100 ml), EA (300 ml) and cyclohexane (100 ml) are added, the layers separated and the aqueous layer extracted twice with EA / cyclohexane 3: 1 (2 x 150 ml). The combined organic extracts are washed with a saturated aqueous NaHCO3 solution (100 ml) and brine (100 ml) and dried over Na2SO4. The solvents are removed in vacuo and the residue is purified by flash chromatography (gradient: EA / heptane 1/2 to EA / ethanol / heptane 2/1/2) to give the desired amides as a mixture of all 4 stereoisomers possible. LC-MS: rt = 0.89 min, 513 (M + l, ES +). Example 2: Synthesis of (2R) -2-. { (SS) -6,7-dimethoxy-l- [2- (4-trifluoromethyl-phenyl) -ethyl] -3,4-dihydro-lH-isoquinolin-2-ylj- -methyl-2-phenyl-acetamide a) Procedure 1 (by coupling the amide): At 0 ° C methylamine hydrochloride (23.7 mmol) and NaHCO 3 (2.01 g, 23.9 mmol) are added to a solution of the acid. { (SS) -6,7-dimethoxy-1- [2- (4-trifluoromethyl-phenyl) -ethyl] -3,4-dihydro-1H-isoquinolin-2-yl} phenyl acetic acid (21.5 mmol) in DMF (300 ml). After 5 minutes, HOBt (23.8 mmol) and EDC hydrochloride (47.6 mmol) are added. The mixture is stirred for 2 h and is maintained for an additional 14 h at 0 ° C without stirring. Water (300 ml) and EA (300 ml) are added, the layers are separated and the aqueous layer is extracted three times with EA (3 x 150 ml). The combined organic extracts are washed with water (3 x 100 ml) and brine (100 ml). The solvents are removed in vacuo and the residue is purified by flash chromatography (EA / heptane 3/2) to give the desired amides as separate diastereoisomers. b) Procedure II (by means of alkylation with a bromide derivative): DIPEA (119 mmol) is added to a solution of 2-bromo-N-methyl-2-phenyl-acetamide (59.6 mmol) in THF (150 ml) . A solution of (IS) -6,7-dimethoxy-1- [2- (4-trifluoromethyl-phenyl) -ethyl] -l, 2,3,4-tetrahydroisoquinoline is added. (62.7 mmol) in THF (200 ml) and the reaction mixture is stirred at 60 ° C for 7 days. Ethyl acetate (200 ml) and a saturated aqueous solution of NaHCO 3 (200 ml) are added, the layers are separated and the aqueous layer is extracted twice with ethyl acetate (2 x 100 ml). The combined organic extracts are washed with water (3 x 50 ml), dried over MgSO 4 and concentrated in vacuo. The residue is purified by flash chromatography (ethyl acetate / heptane 3/2) to give the desired amides as separate diastereoisomers. c) Process III (by means of alkylation with a tosylate derivative): A solution of the (1S) -6, 7-dimethoxy-1- [2- (4-trifluoromethyl-phenyl) -ethyl] -l, 2,3,4-tetrahydroisoquinoline (100 mg), methyl (S) -methylcarbamoyl-phenyl-methyl ester of toluene-4 -sulfonic (100 mg) and DIPEA (0.065 ml) in butanone (5.0 ml) is heated to reflux for 3 days and cooled to RT. Ethyl acetate is added and the mixture is washed with an aqueous, saturated NaHCO3 solution, and brine. The organic layer is dried over Na2SO4 and the solvents are removed in vacuo. THF (2.0 ml) and a solution of HCl in isopropanol (5-6 M, 0.10 ml) are added to the unrefined product and the solvents are removed in vacuo. The solid obtained is recrystallized from THF (2.0 ml) to give the desired amide as white crystals. Data are provided for the free base of the most active diastereomer (IC50, FLIPR). Rf = 0.21 (EA / heptane 2/1); LC-MS: rt = 0.90 min, 513 (M + l, ES +); Chiral HPLC: rt = 18.9 min (hexane / ethanol 95/5, diastereoisomer: rt = 22.3 min; the other two possible stereoisomers with an opposite configuration in the ring system of 1, 2, 3, 4-tetrahydroisoquinoline are prepared in analogy with the synthesis described above using the N- ((1S), 2S) -2-amino-1, 2-diphenyl-ethyl) -2,4,6-trimethyl-benzenesulfonamide (step G.2) for hydrogenation transfer: these isomers have retention times of: rt = 26.2 min, 33.8 min); X H-NMR (300 MHz, CDCl 3): d = 1.74-1.87 (m, ÍH), 2.04-2.19 (, ÍH), 2.40-2.52 (m, ÍH), 2.59-2.72 (m, 1H), 2.86 (d, J = .8 Hz, 3H), 2.86-3.01 (m, 1H), 3.03-3.18 (m, 2H), 3.30-3.41 (m, 2H), 3. 69 (s, 3H), 3.84 (s, 3H), 4.25 (s, 1H), 6.03 (s, ÍH), 6.57 (s, ÍH), 6.87 (c, J = 4.8 Hz, 1H), 7.10-716 (m, 2H), 7.19-7.28 (m, 5H), 7.50 (d, J = 8.1 Hz, 2H); 13 C-NMR (75 MHz, CDC13): d = 21.9, 26.1, 33.4, 37.8, 40.7, 55.8, 55.9, 57.0, 70.1, 110.0, 111.4, 124.2, (c, JC, F = 271. Hz), 124.9, 125.1 (c, JC, F = 4 Hz), 128.0 (c, JC, F = 32 Hz), 128.1, 128.4, 128.5, 129.0, 137.0, 146.2, 147.1, 147.6, 172.2. Example 3: Synthesis of 2-. { 6,7-dimethoxy-l- [2- (6-trifluoromethyl-pyridin-3-yl) -ethyl] -3,4-dihydro-lH-isoquinolin-2-yl} - -methyl-2-phenyl-acetamide A mixture of acid. { 6,7-dimethoxy-1- [2- (6-trifluoromethyl-pyridin-3-yl) -ethyl] -3,4-dihydro-lH-isoquinolin-2-yl} phenyl acetic acid (0.20 mmol), methylamine hydrochloride (0.20 mmol), PyBOP (0.20 mmol) and DIPEA (0.46 mmol) in DMF (1.0 ml) were stirred at RT for 20 h. Water and EA are added, the layers are separated and the aqueous layer is extracted with EA. The combined organic extracts are dried over MgSO and concentrated in vacuo. The residue is purified by flash chromatography (EA) to give the desired product as a viscous oil. LC-MS: rt = 1.17 min, 514 (M + l, ES +). Example 4: Synthesis of (2R) -2-. { (1S) -6,7-dimethoxy-1- [2- (6-trifluoromethyl-pyridin-3-yl) -ethyl] -3,4-dihydro-1H-isoquinolin-2-yl} -N-methyl-2-phenyl-acetamide The DIPEA (20.8 mmol) is added to a solution of (SS) -6,7-Dimethoxy-1- [2- (6-trifluoromethyl-pyridin-3-yl) -ethyl] -1,2,3,4-tetrahydroisoquinoline (10.0 mmol) in THF (40 mL). The 2-bromo-N-methyl-2-phenyl-acetamide (10.4 mmol) is added and the mixture is stirred at 60 ° C for 5 days. Water (100 ml) and ethyl acetate (200 ml) are added, the layers are separated and the aqueous layer is extracted twice with ethyl acetate (2 x 100 ml). The combined organic extracts are concentrated in vacuo and the residue is purified by flash chromatography (ethyl acetate / heptane 3/1) to give the desired amides as separate diastereoisomers. The data are provided for the most active diastereomer (IC50, FLIPR). Rf = 0.15 (EA / heptane 3/1); LC-MS: rt = 0.81 min, 514 (M + l, ES +). ^ - MN (300 MHz, CDC13): d = 1.73-1.86 (m, ÍH), 2.02-2.16 (m, 1H), 2.41-2.52 (m, 1H), 2.59-2.71 (m, 1H), 2.87 (d, J = 5.1 Hz, 3H), 2.88-3.03 (m, ÍH), 3.04-3.17 (m, 2H), 3.26-3.36 (m, 2H), 3.69 (s, 3H), 3.83 (s, 3H), 4.23 (s, ÍH) , 6.04 (s, 1H), 6.55 (Yes H) ,. 6.74 (c, J = 5.1 Hz, ÍH), 7.10-7.16 (m, 2H), 7.19-7.27 (m, 3H), 7.51-7.61 (m, 2H), 8.52 (s, ÍH). Biological Assays In Vitro Assay The orexin receptor antagonist activity of the compounds of the general formula (I) is determined according to the following experimental method. Experimental method: • Intracellular calcium measurements: Chinese hamster ovary (CHO) cells expressing the human orexin-1 receptor and the human orexin-2 receptor, respectively, are grown in the culture medium (Ham F -12 with L-glutamine) containing 300 μg / ml of G418, 100 U / ml of penicillin, 100 μg / ml of streptomycin and 10% of inactivated fetal bovine serum (FCS). The cells are seeded at 80,000 cells / well in 96-well black, clear, black-bottomed sterile plates (Costar), which have been pre-coated with 1% gelatin in Hank's balanced salt solution (HBSS). All reagents are from Gibco BRL. The sown plates are incubated overnight at 37 ° C in 5% C02. Human orexin-A as an agonist is prepared as a 1 mM storage solution in methanol: water (1: 1), diluted in HBSS containing 0.1% bovine serum albumin (BSA) and 2 mM HEPES for use in the assay at a final concentration of 10 nM. Antagonists are prepared as a 10 mM storage solution in DMSO, then diluted in 96-well plates, first in DMSO, then in HBSS containing 0.1% bovine serum albumin (BSA) and 2 mM HEPES. On the day of the assay, 100 μl of the loading medium (HBSS containing 1% FCS, 2 mM HEPES, 5 mM probenecid) (Sigma) and 3 μM fluorescent calcium indicator fluo-3 AM (a 1 mM storage solution in DMSO with 10% pluronic acid) (Molecular Probes) are added to each well. The 96-well plates are incubated for 60 minutes at 37 ° C in 5% C02. The loading solution is then aspirated and the cells are washed 3 times with 200 μl of HBSS containing 2.5 mM of probenecid, 0.1% BSA, 2 mM HEPES. 100 μl of this same buffer is left in each cavity. Within the plate reader for fluorescent imaging (FLIPR, Molecular Devices), the antagonists are added to the plate in a volume of 50 μl, incubated for 20 minutes and finally 100 μl of the agonist are added. Fluorescence is measured for cavity at intervals of 1 second, and the height of each fluorescence peak is compared to the height of the fluorescence peak induced by 10.nM orexin-A with the buffer in place of the antagonist. For each antagonist, the IC50 value (the concentration of the compound needed to inhibit 50% of the agonist response) is determined. The antagonist activities of the compounds are in the nanomolar range. • Measurements of inhibitory potency against different CYPs: CYP inhibition studies are performed using human liver microsomes (group of 10 individuals), selective substrates of the CYP isoform established in the literature, and quantification by either LC- MS / MS (for CYP3A4 and CYP2C9) or conventional CLAR with a fluorimetric detection (for CYP2D6). Specific probes were hydroxylation with 1 'midazolam for CYP3A4, hydroxylation with dextromethorphan 3 for CYP2D6 and hydroxylation with diclofenac 4' for CYP2C9. The experiments were carried out in duplicate in 96-well plates with the substrate concentrations around the respective Km values (Table 1 shows a summary of the experimental conditions) and the inhibitor concentrations of 7 up to 50 μM. The controls (sulfafenazole for CYP2C9, fluoxetine for CYP2D6, and nicardipine for CYP3A4) were run in parallel on each plate. Table 1 As illustrated in Table 2 hereinafter, the compounds described in Examples 1 to 4 show remarkably low affinities against CYP3A.

Table 2 In vivo test: Spontaneous home cage activity and body temperature measured by radiotelemetry in laboratory rats: The objective of the present test is to record the activity of the circadian behavior of rats after oral administration of a compound according to the general formula (I) of the invention. The reduced activity in a homemade cage, measured by telemetry in male Wistar rats was considered as an indication of a potential sleep inducer of a restricted number of highly optimized 1, 2, 3, 4-tetrahydroisoquinoline derivatives. Psychotropic drugs such as antidepressants, antipsychotics, sleep inducers or psychostimulants are well known to reduce or improve activity in a homemade cage and body temperature after oral administration to laboratory animals. Thermoregulation is a complex process that contributes to homeostasis by the coordination of metabolism, energy balance and behavior. The temperature, body changes with the activity of circadian behavior and increases when locomotion increases. These two parameters were measured by telemetry in Wistar rats that are moving freely, consciously. The anesthetized animals were implanted, under aseptic conditions, a telemetric device of activity / body temperature in the peritoneal cavity. More than two weeks after the implantation of the telemetry system, the data were collected at 5-minute intervals for 96 hours. The averages per hour were calculated for each rat. The first 48 hours were used as an internal control trace and the effects of the drugs were compared with the vehicle placebo. This method is pharmacologically validated by measuring the amplitude and time course of both hypoactivity and hypothermia induced by GABA-A receptor modulators such as zolpidem. As illustrated in table 3 here below, the administration of orexin receptor antagonists of the present invention such as those described in Examples 1 to 4, are orally active. Table 3 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 (14)

1. Having described the invention as above, the content of the following claims is claimed as property. 1. The 1, 2, 3, 4-tetrahydroisoquinoline derivatives of the general formula (I): (i) characterized in that: R1 and R2 independently represent hydrogen or C? -C alkoxy; R3 represents Ci-Ce alkyl; X represents -CH- or a nitrogen atom; and optically pure enantiomers, mixtures of enantiomers, racemates, optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates, a mixture of diastereoisomeric racemates, or pharmaceutically acceptable salts and meso forms, solvent complexes, and morphological forms thereof.
2. 2. The 1, 2, 3, -tetrahydroisoquinoline derivatives according to claim 1, characterized in that R1 and R2 both represent a C? -C4 alkoxy group.
3. 3. The 1,2,3-tetrahydroisoquinoline derivatives according to claim 2, characterized in that R 1 and R 2 both represent a methoxy group.
4. 4. The 1,2,3,4-tetrahydroisoquinoline derivatives according to any of claims 1 to 3, characterized in that X represents a nitrogen atom.
5. 5. The 1, 2, 3, 4-tetrahydroisoquinoline derivatives according to any of claims 1 to 3, characterized in that X represents -CH-.
6. 6. The 1,2,3-tetrahydroisoquinoline derivatives according to any of claims 1 to 5, characterized in that R 3 represents a methyl group.
7. 7. The 1, 2, 3, 4-tetrahydroisoquinoline derivatives according to any of claims 1, 2, 3 or 5, characterized in that R1 and R2 represent a methoxy group, X represents -CH- and R3 represents Ci alkyl -Ce-
8. 8. A 1, 2,3, 4-tetrahydroisoquinoline derivative according to any of claims 1 to 3, characterized in that it is selected from the group consisting of: 2-. { 6,7-dimethoxy-1- [2- (4-trifluoromethyl-phenyl) -ethyl] -3,4-dihydro-lH-iso-quinolin-2-yl} -N-methyl-2-phenyl-acetamide; 2-. { 6,7-dimethoxy-1- [2- (6-trifluoromethyl-pyridin-3-yl) -ethyl] -3,4-dihydro-lH-iso-quinolin-2-yl} -N-methyl-2-phenyl-acetamide.
9. 9. A 1, 2, 3, 4-tetrahydroisoquinoline derivative according to any of the preceding claims, characterized in that it is used as a medicament.
10. 10. A pharmaceutical composition, characterized in that it contains at least one compound according to any of claims 1 to 8 and a pharmaceutically acceptable carrier material.
11. 11. The use of a 1,2,3,4-tetrahydroisoquinoline derivative according to any of claims 1 to 8 in the preparation of a medicament for the prevention or treatment of diseases selected from the group consisting of depression; anxiety; addictions; obsessive-compulsive disorders; affective neurosis; depressive neurosis; anxiety neurosis; dysthymic disorder; mood disorders; sexual dysfunction; psychosexual dysfunction; sexual disorders; schizophrenia; manic depression; delirium; dementia; severe mental retardation and dyskinesias such as Huntington's disease and Tourette's syndrome; diabetes; Appetite / taste disorders; vomiting / nausea; asthma; Parkinson's disease; Cushing syndrome / disease; adenoma caused by basophils; prolactinoma; hyperprolactinemia; hypopituitarism; tumor / adenoma of the pituitary gland; hypothalamic diseases; inflammatory bowel disease; gastric dyskinesia; gastric ulcers; Froehlich syndrome; diseases of the pituitary gland; hypothalamic hypogonadism; Kallman syndrome (anosmia, hyposmia); functional or psychogenic amenorrhea; hypothalamic hypothyroidism, hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth deficiency; dwarfism; giantism; acromegaly; altered biological and circadian rhythms; sleep disturbances associated with diseases such as neurological disorders; neuropathic pain and restless legs syndrome; heart and lung diseases; acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction; ischemic or hemorrhagic attacks; subarachnoid hemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronic renal failure; renal disease; impaired tolerance to glucose; migraine; pain; improved or exaggerated sensitivity to pain such as hyperalgesia, causalgia and allodynia; acute pain; pain from burns; atypical facial pain; neuropathic pain; Back pain; syndromes I and II of complex regional pain; arthritic pain; pain from sports injuries; pain related to the infection for example HIV; post-chemotherapy pain; Post-attack pain; post-operative pain; neuralgia; conditions associated with visceral pain such as irritable bowel syndrome; migraine and angina; incontinence of the urinary bladder, for example, urge incontinence; tolerance to narcotics or withdrawal from narcotics; sleep disorders; eating disorders; cardiovascular disorders; neurodegenerative disorders; Sleep apnea; narcolepsy; insomnia; parasomnia; and neurodegenerative disorders that include nosological entities such as the disinhibition-dementia-parkinsonism-amyotrophy complex; epilepsy due to pallido-ponto-nigral degeneration; Stroke disorders and other diseases related to the dysfunction of the general orexin system.
12. 12. The use according to claim 11, wherein the diseases are selected from the group consisting of eating disorders or sleep disorders.
13. 13. The use according to claim 12, wherein the eating disorders comprise metabolic dysfunction, unregulated control of appetite, compulsive obesity, emeto-bulimia or anorexia nervosa.
14. 14. The use according to claim 12, wherein the sleep disorders comprise insomnia, narcolepsy and other disorders of excessive sleep, sleep-related dystonia, restless legs syndrome, sleep apnea, time-out syndrome, change of work schedule, delayed or advanced sleep syndrome.