MXPA01006840A - Triazole compounds with dopamine-d3-receptor affinity - Google Patents

Abstract

The invention relates to triazole compounds of formula (I) in which R1, R2, A and B have the meanings given in the description. The compounds provided for in the invention have a high affinity for the dopamine-D3-receptor and are therefore suitable for the treatment of diseases which respond to the influence of dopamine-D3-receptor ligands.

Description

TRIAZOL COMPOUNDS WITH AFFINITY FOR THE DOPAMINE D3 RECEPTOR. Description The invention relates to triazole compounds and to the use of these compounds. They possess valuable therapeutic properties and can be used for the treatment of diseases that respond to the influence of the ligands of the dopamine D3 receptors. Compounds of the type mentioned herein with physiological activity are already known. Thus WO 94/25013; 96/02520; 97/43262; 97/47602; 98/06699; 98/49145; 98/50363; 98/50364 and 98/51671 describe compounds that act on dopamine receptors. Other compounds with activity as ligands of the dopamine D3 receptors are known from DE 44 25 144 A, WO 96 // 30333 and from WO 97/25324, WO 97/40015, WO 97/47602, WO 97/17326 , EP 887 350, EP 779 284 A and from Bioorg. & Med. Chem. Letters 9 (1999) 2059-2064. Triazole compounds with antiallergic or antipsychotic activity are known from US Patents 4,338,453; 4,408,049 and 4,577,020. WO 93/08799 and WO 94/25013 describe compounds of the type mentioned herein which represent endothelin receptor antagonists. In Pharmazie (1991), 109-112, other triazole compounds are described which inhibit platelet aggregation and act by lowering blood pressure. Other triazole compounds with physiological activity are known from EP 691,342, EP 556,119,, WO. Neurons obtain their information, among others, through receptors coupled with G proteins. There are numerous substances that act on these receptors. One of them is dopamine. There is certain knowledge about the presence of dopamine and its physiological function as a neurotransmitter. Disorders in the dopaminergic transmitter system result in diseases, such as eg. , schizophrenia, depression and Parkinson's disease. The treatment of these and other diseases is done with drugs that interact with dopamine receptors. Until 1990 there were two pharmacologically defined, well-defined subtypes of dopamine receptors, namely, the D? and D2. Recently a third subtype was found, namely the D3 receptor, which seems to act as an intermediary of some effects of the antipsychotic and anti-Parkinson's drugs (JC Schwartz et al., "The Dopamine D3 Receptor as a Target for Antipsychotics", in Novel Antipsychotic Drugs, HY Meltzer, Ed. Raven Press, New York 1992, pp. 135-144; M. Dooley et al., Drugs and Aging 1998, 12, 495-514). As the D3 receptors are expressed mainly in the limbic system, it is assumed that a D3-selective ligand could have the properties of the known antipsychotics but not their neurological side effects transmitted by the D2 receptors of dopamine (P. Sokoloff et al., "Localization and Function of the D3 Dopamine Receptor", Arzneim, Forsch./Drug Res. 42. (1), 224 (1992), P. Sokoloff et al., "Molecular Cloning and Characterization of a Novel Dopamine Receptor (D3) as a Target for Neuroleptics ", Nature 3A1, 146 (1990)). Surprisingly it was now found that certain triazole compounds have a high affinity for the D3 receptor of dopamine and a reduced affinity for the D2 receptor. It is therefore selective ligand with respect to D3. Object of the present invention are therefore the compounds of the general Formula I: wherein: R 1 represents H, C, - ^ alkyl, optionally substituted by OH, C 0 alkyl- C 6, halogen or phenyl, cycloalkyl C3-C6 or phenyl; R2 represents H, Ci-Cg alkyl, optionally substituted by OH, OCi-Cg alkyl, halogen or phenyl, alkoxy alkylthio Ci-Ce, Cz-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, halogen, CN, COOR3, CONR3R \ NR3R \ S02R3, S02NR3R4, or an aromatic moiety, selected from phenyl, naphthyl and a 5- or 6-membered heterocyclic moiety with 1, 2, 3 or 4 heteroatoms, independently selected from O, N and S, being able to the aromatic moiety having one or two substituents, selected independently from each other from C 1 -C 6 alkyl, optionally substituted by OH, 0C] -C 6 alkyl, halogen or phenyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl , C3-C6 cycloalkyl, halogen, CN, COR3, NR3R4, N02, S02R3, S02NR3R4 and phenyl, optionally substituted by one or two residues independently selected from Ci-Cg alkyl, Ci-Cg alkoxy, NR3R4, CN, CF3 , CHF2 or halogen; R3 and R4 independently represent each other H, Cj-C6 alkyl optionally substituted by OH, 0C-C6 alkyl, halogen or phenyl, or phenyl; A represents C4-C10 alkylene or C3-C10 alkylene, comprising at least one Z group, selected from O, S, CONR3, COO, CO, C3-C6 cycloalkyl and a double or triple bond; B means a remainder of the following formula: wherein: X represents CH2 or CH2CH2; Rb R7 and R8 independently selected from H, d-Cg alkyl optionally substituted by OH, 0C? -C6 alkyl optionally substituted by amino, mono- or di-alkylamino CÍ-CJ, alkylthio Ci-C, halogen or phenyl; OH, Ci-Cg alkoxy, 0CF3, 0S02CF3, SH, C?-C6 alkylthio, C2-C6 alkenyl, C2-C6 alkynyl, halogen, CN, N02, C02R3, S02R3, S02NR3R4, wherein R3 and R4 have the The aforementioned meaning and together with the N atom, to which they are bound, can also form a saturated or unsaturated heterocycle with 5 to 7 ring atoms and 1 or 2 N heteroatoms; C0NR3R4, NHS02R3, NR3R4, a 5- or 6-membered carbocyclic aromatic or non-aromatic ring and a 5- or 6-membered heterocyclic aromatic or non-aromatic ring with 1 or 2 heteroatoms, independently selected from 0, N and S, being able to present the carbocyclic or heterocyclic ring one or two substituents, selected independently from each other between alkyl d-Cg, phenyl, phenoxy, halogen, Cx-C alkoxy, OH, N02, CF3 and CHF2, and two of the substituents R6, R7 can be present and R8 together with the carbon atom of the phenyl ring, to which they are attached, form a phenyl, cyclopentyl or cyclohexyl ring fused to the phenyl ring, wherein one or two of the CH or CH2 groups can be replaced by a nitrogen atom, an NH group or an N- (alkyl) group Cx-Cg); as well as their salts with physiologically compatible acids. The compounds according to the invention are selective ligands of the D3 receptors of dopamine, which regioselectively attack the limbic system and due to their reduced affinity with respect to the D2 receptor have fewer side effects than the classical neuroleptics, which are antagonists of the D2 receivers. The compounds can therefore be used for the treatment of diseases which respond to the dopamine D3 ligands, that is, they are useful for the treatment of diseases in which an influence (modulation) on the dopamine D3 receptors leads to an improvement of the disease picture or the cure of the disease. Such diseases are, for example. , diseases of the cardiocirculatory system, as well as the kidneys, diseases of the central nervous system, especially schizophrenia, affective disorders, neurotic stress and somatoform disorders, psychosis, Parkinson's disease, attention disorders ("attention deficit disorders"), hyperactivity in children, epilepsy, amnestic and cognitive disorders, such as impaired cognitive function, fear states, dementia, delirium, personality disorders, sleep disorders (eg, "restless legs") syndrome "), disorders of sexual life (impotence in man), eating disorders and addiction diseases. They also come into consideration for the treatment of stroke.

Addiction diseases also include psychic disorders and behavioral disorders due to the abuse of psychotropic substances, such as drugs or drugs, as well as other addiction diseases, such as addiction to gambling ("impulse control disorders"). else here classified "). Substances that cause addiction are, for example: opioids (eg, morphine, heroin, codeine); cocaine; nicotine; alcohol; substances that interact with the GABA chloride channel complex, sedatives, hypnotics or tranquilizers, for example, benzodiazepines; LSD; cannabinoids; psychomotor stimulants, such as 3, 4-methylenedioxy-N-methylanfetamiha (Ecstasy); amphetamines and amphetamine-type substances such as methylphenidate or other stimulants including caffeine. Substances that cause addiction include, especially, opioids, cocaine, amphetamine, or amphetamine-type substances, nicotine and alcohol. Preferably the compounds according to the invention are used for the treatment of affective disorders, neurotic, stress and somatoform disorders and psychoses, e.g. , schizophrenia. In the context of the present invention, the following terms have the meanings indicated below: Alkyl (also in moieties such as alkoxy, alkylthio, alkylamino, etc.) means a straight or branched chain alkyl group with 1 to 4 carbon atoms and especially 1 to 4 carbon atoms. The alkyl group may have one or more substituents, independently selected from OH, alkyl OC-C, halogen or phenyl. In the case of a halogen substituent the alkyl group may especially comprise 1, 2, 3 or 4 halogen atoms, which may be found in one or more C atoms, preferably in the a or position. Especially preferred are CF3, CHF2, CF2C1 or CH2F. Examples of an alkyl group are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, etc.

Cycloalkyl means especially C3-C6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Alkylene means straight or branched chain residues. When A does not have a group Z, A comprises 4 to 10 carbon atoms, preferably 4 to 8 carbon atoms. The chain between triazole nucleus and group B then has at least four carbon atoms. When A has at least one of the mentioned Z groups, A comprises 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms. When the alkylene groups comprise at least one of the Z groups, they may be ordered in the alkylene chain at any place or in the 1 or 2 position of group A (as seen from the triazole moiety). The remains CONR2 and COO are preferably arranged in such a way that the carbonyl group is facing the triazoi ring. Especially preferred are compounds of the formula I, wherein A represents alkylene -Z-C3-C6, especially an alkylene radical -Z-CH2CH2CH2, -Z-CH2CH2CH2CH2, -Z-CH2CH = CHCH2, -Z-CH2C (CH3) = CHCH2-, -Z-CH2-0-CH2-, -Z-CH2CH (CH3) CH2, or a linear alkylene residue -Z-C7-C10, Z being bound to the triazole ring. Z preferably represents CH2, O and especially S. More preferably A represents - (CH2) 4-, - (CH2) 5-, -CH2CH2CH = CHCH2-, -CH2-CD-CH2-, -CH2CH2C (CH3) = CHCH2- or -CH2CH2CH (CH3) CH2-. Halogen means F, Cl, Br or I, preferably F or Cl. X preferably represents -CH2-CH2-. R1 preferably represents H, Ci-C6 alkyl or C3-C6 cycloalkyl. When R2 represents an aromatic moiety, it is preferably one of the following residues: wherein: R to R represent H or the above-mentioned substituents of the aromatic moiety, R12 represents H, Cx-C6 alkyl or phenyl and T represents N or CH. When the phenyl moiety is substituted, the substituents are preferably in the m or p position.

More preferably, in the case of the aromatic moiety, it is a group of the formula: where R9, R10 and R12 have the meanings indicated above. The indicated phenyl, pyridyl, thiazolyl and pyrrole radicals are especially preferred. The radicals R9 to R11 preferably represent H, alkyl d-Cg, OR3, CN, phenyl optionally substituted by C? -C6 alkyl, Cx-Cg alkoxy, or halogen, CF3 and halogen and especially, H, alkyl CL-Cg, OR3 and halogen. R3 has the meanings indicated above. More preferably R2 represents H, alkyl d-Cg, NR3R4 (R3 and R4 independently of each other H or Cx-C6 alkyl), phenyl or a 5-membered aromatic heterocyclic residue, having 1 or 2 heteroatoms, independently selected from N , S and 0. Preferably the heterocyclic moiety is a pyrrole or pyridine moiety. A preferably represents C4-C10 alkylene or C3_C10 alkylene, comprising at least one group Z, selected from O, S, COO, CO, a double bond and cyclohexyl. Preferably at least one of the radicals Rs, R7 and R8 represents H. The radicals R.sup.6, R.sup.7 and R.sup.s are preferably independently selected from H, C.sub.12-C.sub.6 alkyl, OH, C.sub.x-C.sub.12 alkoxy, C.sub.thylthio Cg-alkyl CL-C6, halogen, CN, NC2, S02R3, S02NR3R4 and CONR3R4. More preferably the fused phenyl group has one or two substituents, ie one or two of the radicals R6, R7 and R8 represent alkyl dC, halogen, CN, N02, S02R3 and especially S02NR3R4, where R3 and R4 together with the N atom to which they are attached, can also represent a 5, 6 or 7 membered heterocycle, which apart from the nitrogen atom may also have one or two other heteroatoms, selected from N, O or S and / or may be substituted, e.g. , pyrrolidine, piperidine, morpholine or azepine. When one of the radicals R6, R7 and R8 represents a 5- or 6-membered heterocyclic ring, it is, for example, a pyrrolidine, piperidine, morpholine, pyridine, pyrimidine, triazine, pyrrole, thiophene or pyrazole moiety, with a pyrrole moiety being preferred. , pyrrolidine, pyrazole or thienyl. When one of the radicals R6, R7 and R8 represents a carbocyclic radical, it is especially attached to a phenyl, cyclopentyl or cyclohexyl radical.

Especially preferred are compounds of Formula I, wherein: R 1 represents H, C) alkyl- Cg or phenyl, R 2 represents H, dC alkyl, phenyl, thienyl, furanyl, pyridyl, pyrrolyl, thiazolyl or pyrazinyl, A represents alkylene -SC3-C10, which may optionally comprise a double bond, R5, R7 and R8 are selected from H, C] .- C6 alkyl, Ci-Cg alkoxy, halogen, S02NR3R4, CN, N02, CF3, CONR3R4, CHF2, 0S02CF3 , 0CF3 and NHS02-Cj-Cg alkyl. Here X more preferably represents CH2CH2. The invention also comprises the acid addition salts of the compounds of Formula I, with physiologically compatible acids. Suitable physiologically compatible organic and inorganic acids are, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid or benzoic acid. Other useful acids are described in Fortschritte der Arzneimittelforschung, Vol. 10, pgs. 224 ff., Birkháuser Verlag, Basel and Stuttgart, 1966. The compounds of Formula I may have one or more asymmetric centers. The invention therefore comprises not only the racemates but also the corresponding enantiomers and diastereomers. The invention also comprises the corresponding tautomeric forms. The process for the preparation of the compounds of the Formula I comprises: a) transforming a compound of the general Formula (II): N-N '/ Y R2 (II) Rl wherein Y1 represents a usual leaving group, such as, for example, Hal, alkylsulfonyloxy, arylsulfonyloxy, etc., with a compound of the general Formula (III): HB (III) or b) transforming a compound of the general Formula (IV) : NN Rl wherein Z1 represents 0 or S and A1 represents alkylene dC ^ c a bond, with a compound of the general Formula (V): Y1-A2-B (V) wherein Y1 has the meaning indicated above and A2 represents C2- alkylene C10, wherein A1 and A2 together have 3 to 10 C atoms and A1 and / or A2 optionally comprise at least one Z group; or c) a compound of the general formula (VI) is converted: N-N '/ R2 l N Al / (VI) Rl wherein Y1 and A1 have the meanings indicated above, with a compound of the general Formula (VII): H-Za-A-B (VII) wherein Z1 has the meanings indicated above; or d) the polarity of the compound of the general Formula (VIII) is inverted: N-N R2 N "-CH0 (VIII) I Rl with reagents known in the literature, such as eg. , 1,3-propanedithiol, KCN / water, TMSCN (trimethylsilyl cyanide) or KCN / morpholine, as described, e.g. , in: Albright, Tetrahedron, 1983, 23., 3207 or 6. Seebach, Synthesis, 1969, 17 and 1979, 19 or H. Stetter, Angew. Chem. Int. Ed. 1976, 1¿, 639 or van Niel et al., Tetrahedron 1989, 4_5_, 7643, Martin et al., Synthesis 1979, 633, to products (Villa) (in illustrative form with 1.3 -propanodithiol): R2 (Villa) and then the chain is prolonged with compounds of the general formula (IX): Y1-A3-B (IX) wherein Y1 has the meaning indicated above and A3 represents C3-C9 alkylene, which may contain a group Z, obtaining after deprotection or reduction, compounds of the formula (la): wherein Zz represents CO or a methylene group and Z2 and A2 present together 4 to 10 C atoms, or e) a compound of the general Formula (VIII) is transformed with a compound of the general Formula (X): Y2-A - B (X) wherein Y2 represents a phosphorane or an ester of phosphonic acid, analogously to the usual methods, as described, for example, in Houben Weyl "Handbuch der Organischen Chemie", 4th. edition, Thieme Verlag Stuttgart, Vol. V / lb, p. 383 ss. or Vol. V / lc p. 575 ff., Or f) a compound of the general formula (XI) is transformed: wherein Q represents H or OH, with a compound of Formula III under reducing conditions analogously to the methods known from the literature, as described, e.g. in J. Org. Chem. 1986, Q; 1927; or WO 92/20655. The process for the preparation of a compound of the Formula I, wherein A comprises the group COO or CONR3, consists in transforming a compound of the general Formula (XII): N-N wherein Y3 represents OH, alkyl, or, together with CO, an activated carboxyl group, and A4 represents C0-C9 alkylene, with a compound of the formula (XIII): B-A-Z3 (XIII) in where Z3 represents OH or NHR3. The compounds of the general Formula B-H can be prepared as described, e.g. , in: Synth. Commun. 1984, 14, 1221; S. Smith et al., Bioorg. Med. Chem. Lett. 1998, £, 2859; WO 97/47602 or WO 920655 or J. Med. Chem. 1987, _3_Q, 2111 and 2208 and 1999, 42, 118. Compounds of the type of the formula (IV) are known or can be prepared according to known procedures, such as describe, eg. , in A.R. Katritzky, C.W. Rees (ed.), "Comprehensive Heterocyclic Chemistry", Pergamon Press, or The Chemistry of Heterocyclic Compounds, "J. Wiley &Sons Inc. NY and the literature therein mentioned, or in S. Kubota et al., Chem. Pharm. Bull. 1975, 2Z, 555 or Vosilevskii et al., Izv. Akad. Nauk. SSSR Ser. Khim. 15 ~ 5, 22., 955. In the above-mentioned formulas R1, R2, R6, R7, R8, A , B and X have the meanings indicated in relation to Formula I. The preparation of the compounds according to the invention and the starting materials and intermediates can also be carried out analogously to the procedures described in the patent publications. mentioned above The transformations described above are generally carried out in a solvent at a temperature between room temperature and the boiling temperature of the solvent used Useful solvents are, for example, esters, such as ethyl acetate, ethers, ether or ether. diethyl or tetrahydrofura no, dimethylformamide, dimethylsulfoxide, dimethoxyethane, toluene, xylene, acetonitrile, ketones, such as acetone or methyl ethyl ketone, or alcohols, such as ethanol or butanol. If desired, work in the presence of an acid binding agent. Suitable acid-binding agents are inorganic bases, such as sodium or potassium carbonate, sodium or potassium hydrogen carbonate, sodium methylate, sodium ethylate, sodium hydride or organometallic compounds, such as butyllithium or alkylmagnesium compounds, or organic bases. , such as triethylamine or pyridine. The latter can serve at the same time as solvents. The procedure (f) is carried out under reducing conditions, eg. , using sodium borohydride, sodium cyanoborohydride or triacetoxyborohydride, optionally in an acidic medium or in the presence of a Lewis acid, as for example. , zinc chloride or by means of catalytic hydration. . The isolation of the crude product is carried out in a conventional manner, for example, by filtration, removal of the solvent by distillation or extraction from the reaction mixture, etc. The purification of the compounds obtained can be carried out in the usual manner, for example, by recrystallization from a solvent, chromatography or transformation into an acid addition compound.

The acid addition salts are prepared in a customary manner by mixing the free base with the corresponding acid, optionally in solution in an organic solvent, for example, a lower alcohol, such as methanol, ethanol or propanol, an ether, such as methyl alcohol. t-butyl ether, a ketone, such as acetone or methyl ethyl ketone or an ester, such as ethyl acetate. For the treatment of the above-mentioned diseases, the compounds according to the invention are administered in a conventional manner in oral or parenteral form (subcutaneous, intravenous, intramuscular, intraperitoneal). Administration can also be done by nebulizations or sprays in the nasopharyngeal cavity. The dosage depends on the age, condition and weight of the patient, as well as the type of administration. In general, the daily effective dose comprises of approx. 10 to 1000 mg per patient and per day in the oral administration and approx. 1 to 500 mg per patient and per day in parenteral administration. The invention also comprises pharmaceutical products containing the compounds according to the invention. These products are presented in the usual galenic administration forms in solid or liquid form, for example, as tablets, coated tablets, capsules, powders, granules, dragees, suppositories, solutions or sprays. The active substances can be prepared with the usual galenic auxiliaries, such as tablet binders, fillers, preservatives, tablet dispersants, lubricants, plasticizers, crosslinking agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellant gases ( see H. Sucker et al., "Pharmazeutische Technologie", Thieme-Verlag, Stuttgart, 1978). The administration forms thus obtained contain the active substance normally in an amount of 1 to 99% by weight. The following examples are intended to clarify the invention without limiting it. Example 1 6,7-Dimethoxy-2-f 3'-((4-met il-5-phenyl-4H-1,2-, 4-triazol-3-yl) sulfanyl propi11-1, 2.3.4-te ahydroisoquinoline 1A Preparation of the starting substances 2- (3-chloropropyl) -6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline. 7.2 g (37 mmol) were heated at 70 ° C. 6,7-dimethoxy-1,2,4,4-tetrahydroisoquinoline together with 4.05 ml (40 mmol) of l-bromo-3-chloropropane, 11.3 g (81 mmol) of potassium carbonate and 610 mg ( 40 mmoles) of sodium iodide in 250 ml of acetonitrile for four hours. After the reaction was complete, the solvent was removed by distillation, the residue was taken up in water and extracted with methylene chloride. The combined organic phases were dried, concentrated and the crude product was purified by chromatography on silica gel (eluent: methylene chloride / methanol = 9/1). 4.8 g (45% of theory) of a yellowish oil were obtained. - M (CDC13): d = 2.0 (m, 2H); 2.6-2.8 (m, 6H); 3.5 (s, 2H); 3.6 (t, 2H); 3.8 (2s, 6H); 6.5 (s, 1H); 5.6 (s, ÍH). C14H20ClNO2 (269) IB Preparation of the final product: 380 mg (1.7 mmol) of 3-mercapto-4-methyl-5-phenyl-1,2,4 (4H) were heated at 100 ° C for 5 hours with stirring. triazole with 450 mg (1.7 mmoles) of the chlorine base IA and 40 mg (1.7 mmoles) of lithium hydroxide in 5 ml of DMF. For working up, 50 ml of water were added, the mixture was extracted several times with methyl tert-butyl ether, the combined organic phases were dried, evaporated and purified by chromatography on silica gel (eluent: methylene chloride / 2-). 5% methanol). Yield: 0.2 g (49% of theory). XH-NMR (CDCl 3): d = 2.1 (q, 2H); 2.6 (m, 2H); 2.7 (m, 2H); 2.8 '(m, 2H); 3.3 (t, 2H); 3.5 (m, 2H); 3.6 (s, 3H); 3.8 (2s, 6H); 6.3 (s, ÍH); 6.5 (s, ÍH); 7.5 (m, 3H); 7.8 (m, 2H). The title compound was obtained by treatment with ethereal hydrochloric acid.

C23H28N402S x HCl P.F .: 180-183 ° C. Example 2 6-methoxy -2-f 3-? (4-Methyl-5-pyrrol-2-yl-4H-l. 2,4-ylazol-3-yl-suifayl-1-propyl-1-1.2.3.4-tetrahydroisoquinoline 2A Preparation of the starting compound 2- (3-Chloropropyl) -6-methoxy-l, 2,3,4-tetrahydro-isoquinoline Analogously to IA, the above-mentioned substance was prepared using 6-methoxy-1,2,3,4-tetrahydroisoquinoline. XH-NMR (CDC13): d = 2.0 (q, 2H); 2.5-2.6 (m, 4H); 2.9 (m, 2H); 3.5 (s, 2H); 3.6 (m, 2H); 3.8 (s, 3H); 6.6 (d, ÍH); 6.7 (dd, ÍH); 6, 9 (d, 1H). The preparation was carried out analogously to Example 1 by reaction of the chlorine base prepared under 2A and 3-mercapto-4-methyl-5- (2-pyrrolyl) -1,2,4 (4H) -tpazole. Yield: 52% of the theoretical. C20H25N5OS (383.5) P.'i .: 179-181 ° C. Example 3 2-f 3- ((4-methyl-5-phenyl-H-1.2.4-triazol-3-yl) sulfanyl-1-propyl} -6-methoxy-1,2,3,4-tetrahydroisoquinoline 3A Preparation of the starting material 3- (3-Chloropropylmercapto) 4-methyl-5-phenyl-1,2,4 (4H) -triazole A suspension of 2.6 g (16.5 mmol) of l-bromo-3-chloropropane, 0.22 g (1.5 mmol) of sodium iodide, 2.7 g (15 mmol) of 3-mercapto- 4-Methyl-5-phenyl-1,2,4 (4H) -triazole and 2.1 g (15 mmol) of potassium carbonate in 70 ml of ethanol was heated to boiling for one hour. After filtration in hot, the filtrate was concentrated, taken up in water and extracted with dichloromethane. The combined organic phases were dried, filtered, concentrated and the residue was chromatographed (eluent: methylene chloride / 2% methanol). Yield: 1.35 g (34% of theory) of a white solid. H1-NMR (CDC13): d = 2.3 (q, 2H); 3.4 (t, 2H); 3.6 (s, 3H); 3.7 (t, 2H); 7.5-7.7 (m, 5H). C12H14C1N3S (267.8) P.i. : "137-141 ° C. 3B Preparation of the final product 0.7 g (2.5 mmol) of the compound 3A described above were stirred with 0.6 g (2.5 mmol) of 6-methoxy-1,2, 3, 4-tetrahydroisoquinoline-salt of oxalic acid in the presence of 1.1 ml (7.5 mmol) of triethylamine and catalytic amounts of sodium iodide in 6 ml of butanol at 120 ° C for four hours. The reaction was carried out with water and methyl tert-butyl ether with extraction, dried over sodium sulfate, concentrated and the crude product was chromatographed on silica gel (eluent: methylene chloride with 0-3% methanol). 110 mg of a white solid.

C22H26N4OS (394.5) MS (m / z): 395 [M] + Example 4 2-f-r (4-methyl-5-phenyl-4H-2,4-triazole-3-yl) sulphanil- propyl-7- (piperidin-1-yl sulfonyl -1.2.3.4 -tetrahydro-isoquinoline 4A Preparation of N-acetyl-7- (piperidin-1-ylsulfonyl) -1,2,3,4-tetrahydroisoquinoline. of 6.0 g (70 mmol) of piperidine and 10.9 g (84 mmol) of diisopropylethylamine in 230 ml of THF were added dropwise 21.1 g (77 mmol) of 2-acetyl-l, 2, 3 , 4-tetrahydroisoquinoline-7-sulfonylchloride (prepared as described in G. Grunewald et al., J. Med. Chem. 1999, 42, 118-134) in 50 ml of THF, and heated at reflux for two hours. After the reaction was complete, the solvent was removed under vacuum, taken up with dichloromethane / water, made basic with 10% sodium hydroxide, and the organic phase was dried over sodium sulfate after phase separation. remained after the filtration and the elimination of the solvent was purified by means of column chromatography on silica gel (eluent: methylene chloride with 3% methanol). Yield: 18.6 g (57.6 mmol); 82% P.f .: 171-174 ° C. 4B 7- (Piperidin-1-ylsulfonyl) -l, 2,3,4-tetrahydro-isoquinoline The compound described above was heated to boiling for two hours with semi-concentrated hydrochloric acid. Upon cooling the product precipitated as a white precipitate. The residue was isolated, washed with water, digested in diethyl ether and dried in vacuo. Yield: 12.1 g (38.2 mmol) 56% of theory. 4C 2- (3-Chloropropyl) -7- (piperidin-4-ylsulfonyl) -1, 2, 3, 4-tetrahydroisoquinoline 12.1 g (38.2 mmol) of 7- (piperidin-1-ylsulfonyl) were dissolved -1, 2, 3, 4-tetrahydroisoquinoline and 8.4 g (84 mmoles) of triethylamine in DMF at 40 ° C, 9.0 g (57.2 mmol) of 1,3-bromo- were added dropwise. chloropropane and stirred for 7 h at 50 ° C. For working up, the mixture was concentrated, the residue was taken up in water, and extracted with dichloromethane. After drying over sodium sulfate, filtration and removal of the solvent, it was purified chromatographically (silica gel; eluent: methylene chloride with 3% methanol) and 11.7 g (323.7 mmol) of a yellowish oil were obtained. Performance: 86% of the theoretical. 4D Preparation of the final compound: 10.0 g (28.0 mmol) of the chlorine base described above 4 C, 6.4 g (28 mmol) of 3-mercapto-4-methyl were heated at 100 ° C for three hours. 5-phenyl-4H-1,2,4-triazole and 0.7 g (28.0 mmol) of lithium hydroxide in 77 ml of DMF.

After the end of the reaction, the solvent was removed, the residue was mixed with water and extracted with ethyl acetate.

The combined organic phases were dried over sodium sulfate, filtered and evaporated. Chromatography of the crude product (silica gel; eluent: methylene chloride with 0-5% methanol) gave 3.9 g (7.5 mmol) of a white solid. Performance: 27% of the theoretical. XH-NMR (CDC13): d = 1.4 (m, 2H); 1.7 (na, 4H); 2.1 (q, 2H); 2.7 (t, 2H); 2.8 (t, 2H); 3.0 (m, 6H); 3.35 (t, 2H); 3.6 (s, 3H); 3.7 (s, 2H); 7.2 (d, ÍH); 7.4 (s, ÍH); 7.5 (m, 4H); 7.7 (m, 2H). C 26 H 33 N 502 S 2 (511.7) MS (m / z): 512.3 [M + H] t Pf: 105-108 ° C Example 5 Hydrochloride = 2- \ 4- f 4-methyl-5-fer? Il-4H -l > 2, - riazQl-3-yl butyl -7- (morpholin-4-ylsulfonyl) -1,2,3, 4 -ethohydro-isoquinoline 5A N-acetyl-7- (morpholin-4-ylsulfonyl) - 1, 2, 3, 4-tetrahydro-isoquinoline was obtained as described in Example 4A by transformation of morpholine with 2-acetyl-1,2,4,4-tetrahydroisoquinoline-7-sulfonic acid chloride in the presence of diisopropylamine in THF and was transformed by heating with semiconcentrated hydrochloric acid and after alkaline processing in the corresponding 7- (morpholin-4-ylsulfonyl) -1,2,3,4-tetrahydro-isoquinoline. C13H18N20S (282) MS (m / z): 283 [M + H] + 5B 2- (3-Chloropropyl) -7- (morpholin-4-ylsulfonyl) -1,2,3,4-tetrahydroisoquinoline 1.2 g (4.4 mmoles) of 7- (morpholin-4-ylsulfonyl) were dissolved -1, 2, 3, 4-tetrahydroisoquinoline and 1.0 g (10 mmoles) of triethylamine in DMF at 40 ° C, 1.1 g (6.6 mmol) of 1,3-bromo- were added dropwise. chloropropane and stirred at 40 ° C for 3 h. For working up, the mixture was concentrated, the residue was taken up in water and extracted with ethyl tert-butyl ether. After drying over sodium sulfate, filtration and elimination of the solvent was chromatographically purified (silica gel, eluent: methylene chloride with 2% methanol) and 0.7 g (2 mmol) of a clear oil were obtained. Performance: 46% of the theoretical. XH-NMR (CDC13): d = 2.0 (q, 2H); 2.7 (t, 2H); 2.8 (t, 2H); 3.0 (m, 6H); 3.6-3.8 (m, 8H); 7.3 (d, ÍH); 7.4 (s, ÍH); 7.5 (d, 1H). C16H23N203S (359) Preparation of the final compound 280 mg (1 mmol) of 2- [4-methyl-5-phenyl-1,2,4- (4H) -triazol-3-yl] -1,3-dithiane was dissolved. (described in WO 9902503) in 2.5 ml of dry DMF and treated at -70 ° C under the addition of 0.15 g of sodium iodide, with 0.75 ml (1.2 mmol) of a solution of butyllithium in 15% n-hexane. After stirring for 45 min at -70 ° C, 0.37 g (1 mmol) of 2- [3-chloropropyl] -7- (morpholin-4-ylsulfonyl) -1, 2, 3, 4 were added dropwise. -tetrahydro-isoquinoline 5B in THF. It was warmed slowly to room temperature and was still heated 90 min at 40 ° C, to obtain a complete reaction, for working up it was poured onto ice / water and extracted several times with methylene chloride. After drying and concentrating, 0.5 g (82% of theory) of the substituted dithian remained, which was then hydrated with Raney nickel at 40 ° C in the course of 3 hours in tetrahydrofuran. After separating the catalyst, the residue was chromatographically purified (silica gel, methylene chloride with 5% methanol). Yield: 120 mg (29% of theory). Hí-NMR (CDC13): d = 1.8 (m, 2H); 2.0 (q, 2H); 2.6 (m, 2H); 2.7 (t, 2H); 2.9 (t, 2H); 3.0 (m, 6H); 3.6 (s, 3H); 3.7 (m, 6H); 7.2 (d, ÍH); 7.4 (s, ÍH); 7.5 (m, 4H); 7.7 (m, 2H). Mixing with ethereal HCl gave the title compound C26H33N503S. HC1 (531, 6) Pf. : 87 -89 ° C. Analogously, the following were obtained: Example 6 l- (4-Methyl-5-phenyl-4H-1,?, 4-triazol-3-yl) -4- (7- (piperidin-1-yl-sulfonyl -1.2, 3,4-dihydroisoquinolin-2-yl) utan-1-one C27H33N503S (507.7) MS: 508.3 [M + H] + Example 7 2-. { 3- [(4-Methyl-5-phenyl-4H-1,2,2-triazol-3-yl) sulfanyl] -propyl} -l, 2,3,4 -tetrahydroisoquinolin-7 -carboni trilo C22H23N5S (389.5) Mp .: 116-118 ° C. Example 8 5- [2-] dihydrochloride { Diethylammonium) ethoxy] -2-. { 3- [(4-Methyl-5-phenyl-4H-l, 2,4-triazol-3-yl) sulfanyl] -propyl} -1, 2, 3, 4-tetrahydroisoquinoline C27H37N50S.2HC1 (552.6) P.f. : 110-112 ° C. Example 9 N-benzyl-2-. { 3- [(4-Methyl-5- (4-methyl-1,3-thiazol-5-yl) -4 H -1,2,4-triazol-3-yl) sulfanyl] -propyl} -l, 2, 3, 4-tetrahydroisoquinolin-7-sulfonamide C26H3o g02S3 (554.8) P.f .: 67-70 ° C. Example 10 N-benzyl-2-. { 3- [(4-Methyl-5-pyridin-3-yl-4H-1, 2, -triazol-3-yl) sulfanyl] -propyl} -l, 2, 3, 4-tetrahydroisoquinolin-7-sulfonamide C27H30N6O2S2. HCl (607, 6) M.p .: 81-84 ° C.

Example 11 5 -Me toxi -2 -. { 3- [(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl) sulfanyl] -propyl} -l, 2,3-tetrahydroisoquinoline C22H26N4OS (394.5) P.f .: 73-75 ° C. Example 12 2-. { 3- [(4-Methyl-5-phenyl-4H-1, 2,4-triazol-3-yl) sulfanyl] -propyl} -7-nitro-l, 2,3,4-tetrahydroisoquinoline C21H24C1N502S (446) M.p .: 190-192 ° C. Example 13 2-. { 3- [(4-Methyl-5-phenyl-4H-1, 2,4-triazol-3-yl) sulfanyl] -propyl} -l, 2, 3, 4-tetrahydroisoquinoline XH-NMR (CDC13): d = 2.1 (q, 2H); 2.65 (t, 2H); 2.7 (t, 2H); 3.4 (t, 2H); 3.5 (s, 3H); 3.7 (s, 2H); 7.0 (m, ÍH); 7.2 (m, 3H); 7.5 (m, 3H); 7.7 (m, 2H). C21H24N4S (365.5). Example 14 2-. { 3- [(4-Methyl-5- (4-methyl-l, 3-thiazol-5-yl) -4 H-1, 2,4-triazol-3-yl) sulfanyl] -propyl} -1,2,3, 4-tetrahydroisoquinoline XH-NMR (CDC13): d = 2.1 (q, 2H); 2.55 (s, 3H); 2.7 (t, 2H); * 2.75 (t, 2H); 2.9 (t, 2H); 3.4 (t, 2H); 3.5 (s, 3H); 3.65 (s, 2H); 7.0 (m, ÍH); 7.1 (m, 3H); 8.9 (s, ÍH). C19H23N5S2 (386.5). EXAMPLE 1 2- Hydrochloride. { 3- [(4-Methyl-5-pyridinium-3-yl-4 H -1,2,4-triazol-3-yl) sulfanyl] -propyl} -l, 2, 3, 4-tetrahydroisoquinoline C20H23N5S.2HC1 (438.4) P.f .: 87-89 ° C. Example 16 7- [(Dimethylamino) sulfonyl] -2-. { 3- [(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl) sulfanyl] -propyl} -l, 2, 3, 4-tetrahydroisoquinoline * H-NMR (CDC1,): d = 2.1 (q, 2H); 2.65 (m, 8H); 2.75 (t, 2H); 3.0 (t, 2H); 3.3 (t, 2H); 3.6 (s, 3H); 3.7 (s, 2H); 7.2 (d, ÍH); 7.4-7.6 (m, 7H). C23H29N502S2 (472, 6). Example 17 7- [(Dimethylamino) sulf onyl] -2-. { 3- . { [4 -Met il-5- (4-methyl-l, 3-thiazol-5-yl) -4 H -1,2,4-triazol-3-yl] sulfanyl} -propyl) -1,2,3,4-tetrahydroisoquinoline '• H-NMR (CDC13): d = 2.1 (q, 2H); 2.5 (s, 3H); 2.6-2.8 (m, 10H); 2.9 (m, 2H); 3.4 (t, 2H); 3.5 (s, 3H); 3.7 (s, 2H); 7.2 (m, ÍH); 7.5 (m, 2H); 8.9 (s, ÍH). C21H28N602S3 (493.7). EXAMPLE 18 Oxalate of 2- methyl acid ester. { 3- [(4-Methyl-5-f-enyl-H-1,2,4-triazol-3-yl) sulfanyl] -propyl} -l, 2,3,4-tetrahydro-isoquinolin-7 -carboxylic C23H27N402S.C2H04 (512.6) P.f. : 160-163 ° C.

Example 2Q 2-. { 3-. { [4-Methyl-5- (4-methyl-1,3-thiazol-5-yl) -4 H -1,2,4-triazol-3-yl] sulfanyl} -propyl) -7- (piper idin-1-lsulf onyl) -1,2,3,4-tetrahydroisoquinoline 2 H-NMR (CDC13): 'd = 1.4 (m, 2H); 1.7 (m, 4H); 2.1 (q, '2H); 2.5 (s, 3H); 2.6 (t, 2H); 2.7 (t, 2H); 3.0 (m, 6H); 3.3 (t, 2H); 3.5 (s, 3H); 3.6 (s, 2H); 7.2 (d, ÍH); 7.45 (s, ÍH); 7.5 (d, ÍH); 8.9 (s, ÍH). C24H32N602S3 (532.8). Example 21 2-. { 3-. { [4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl) sulfanyl] -propyl} -7- (phenylsulfonyl) -1,2,3, -tetrahydroisoquinoline : H-NMR (CDCl 3): d = 2.1 (q, 2H); 2.6 (t, 2H); 2.7 (t, 2H); 2.9 (t, 2H); 3.35 (t, 2H); 3.5 (s, 3H); 3.6 (m, 2H); 7.2 (d, ÍH); 7.4-7.7 (m, 10H); 7.9 (d, 2H). C27H28N402S2 (504.7). Example 22 2-. { 3-. { [4-Methyl-5- (4-methyl-1,3-thiazol-5-yl) -4H-1, 2,4-t-riazol-3-yl] sulfanyl} -propyl) -1,2,3,4-tetrahydroisoquinolin-7-yl f-enylsulfone XH-NMR (CDCl 3): d = 2.1 (q, 2H); 2.5 (s, 3H); 2.7 (t, 2H); 2.8 * (t, 2H); 2.95 (t, 2H); 3.4 (t, 2H); 3.5 (s, 3H); 3.65 (m, 2H); 7.2 (d, 1H); 7.4-7.7 (m, 5H); 7.9 (d, 2H); 8.9 (s, ÍH).

C25H29N502S3 (525.7). Example 23 2-. { 3-. { [4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl) sulfanyl] -propyl} -7- (morpholin-4-ylsulfonyl) -l, 2,3,4-tetrahydro-isoquinoline 'H-NMR (CDC13): d = 2.1 (q, 2H); 2.7 (t, 2H); 2.8 (t, 2H); 3.0 (t, 4H); 3.35 (t, 2H); 3.6 (s, 3H); 3.7 (m, 6H); 7.3 (m, ÍH); 7.4-7.6 (m, 5H); 7.9 (d, 2H). C25H31N503S2 (525.7). Example 24 2- [4- (4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl) butyl] -7- (phenylsulfonyl) -1,2,3,4-tetrahydroisoquinoline C28H30N4O2S (486.6). Example 25 2-. { 3-: (4-Methyl-5-pyridin-3-yl-4H-l, 2,4-triazol-3-yl) sulfanyl] -propyl} -N-phenyl-1, 2, 3, 4-tetrahydroisoquinoline 'H-NMR (CDCl 3): d = 1.3 (m, NH); 2.1 (q, 2H); 2.6 (m, 4H); 2.8 (t, 2H); 3.3 (t, 2H); 3.6 (s, 3H); 3.7 (m, 6H); 7.3 (m, 1H); 7.4-7.6 (m, 5H); 7.9 (d, 2H). C26H28N602S2 (520.7) P.f .: 58-61 ° C. Example 26 2-. { 3-. { [4-Methyl-5- (4-methyl-1,3-thiazol-5-yl) -4 H -1,2,4-t-riazol-3-yl] sulfanyl} -propyl) -N-phenyl-1, 2, 3, 4-tetrahydro-isoquinoline XH-NMR (CDCI3): d = 2.1 (q, 2H); 2.5 (s, 3H); 2.7 (m, 4H); 2.9 (m, 2H); 3.3 (t, 2H); 3.5 (s, 3H); 3.6 (s, 32H); 7.0-7.2 (m, 6H); 7.5 (m, 2H); 8, 9 (s, ÍH). C25H28N602S3 (540.7) M.p .: 77-81 ° C. Example 27 2-. { 3-. { [5- (2,4-Dimethoxy) phenyl) -4-methyl-H-1,2,4-triazol-3-yl] sulfanyl} -propyl) -7- (methyl-sulfonyl) -1,2,3,4-tetrahydro-isoquinoline -NMR (CDC13): d = 2.2 (q, 2H); 2.9 (m, 2H); 3.0 (m, 2H); 3.05 (s, 3H); 3.1 (m, 2H); 3.3 (m, 5H); 3.7 (s, 3H); 3.85 (s, 3H); 3.9 (s, 2H); 6.5 (s, ÍH); 6.65 (d, ÍH); 7.25 (d, ÍH); 7.3 (d, ÍH); 7.7 (s, ÍH); 7.8 (d, ÍH). C 24 H 30 N 4 O 4 S 2 (502.7) MS: 503.5 [M + H] + Example 28 6,7-Dichloro-2-. { 3- [(4-methyl-5-f-enyl-4H-1, 2,4-triazol-3-yl) sulfanyl] -propyl} -1, 2, 3, 4-tetrahydroisoquinoline C21H22C12N4S (433.4) M.p .: 138-139 ° C. EXAMPLE 29 Hydrochloride of 7,8-Dichloro-2-. { 3- [(4-methyl-5-f-enyl-4H-1,2,4-triazol-3-yl) sulfanyl] -propyl} -l, 2, 3, 4-tetrahydroisoquinoline > H-NMR (CDCl 3): d = 2.1 (q, 2H); 2.7 'm, 4H); 2.9 (t, 2H); 3.3 '(t, 2H); 3.6 (s, 3H); 3.7 (s, 2H); 6.95 (d, ÍH); 7.2 (d, ÍH); 7.5 (m, 3H); 7.7 (m, 2H), [free base]. Precipitation of salt with ethereal HCl led to the title compound.

C21H22C12N4S x HCl (469.9) M.p .: 109 ° C. Example 3Q 7-Cyano-2- [4- (4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl) butyl] -1,2,3,4-tetrahydroisoquinoline C23H25N5 Hydrochloride. HC1 (407.9) Mp: 175 ° C. Example 31 2- Hydrochloride. { 3- [(4-Methyl-5-thien-3-yl-4H-l, 2,4-triazol-3-yl) sulfanyl] -propyl} -6- (trifluoromethyl) -1, 2, 3, 4-tetrahydroisoquinoline C20H21F3N4S2.C1 x HCl (475) M.p .: 184-185 ° C. l-. { 2- [3- ( { 4-Methyl-5- [4- (trifluoromethyl) phenyl] -4H-1, 2,4-triazol-3-yl} sulfanyl) -propyl] -1,2, 3,4-tetrahydroisoquinolin-7-yl} -etanone H-NMR (CDC13): d = 2.15 (q, 2H); 2.4 (s, 3H); 2.7 (t, 2H); 2.8 (t, 2H); 3.0 (t, 2H); 3.3 (t, 2H); 3.6 (s, 3H); 3.75 (s, 2H); 7.1 (d, ÍH); 7.6-7.8 (m, 6H). C24H25F3N40S (474.5). The hydrochloride of the title compound was obtained by treatment with ethereal hydrochloric acid: M.p .: 183 ° C. Example 33 Hydrochloride of 6-dichloro-2- (3 { [4-methyl-5- [4- (methylphenyl] -4H-1, 2,4-triazol-3-yl] sulfanyl.} - propyl) -1, 2, 3, 4 -tetrahydroisoquinoline Hí-NMR (CDC13): d = 2.1 (q, 2H), 2.4 (s, 3H), 2.7 (m, 4H), 2.8 ( t, 2H), 3.3 (t, 2H), 3.5 (s, 3H), 3.6 (s, 3H), 7.1 (s, ÍH), 7.2 (s, ÍH); 7.3 (d, 2H); 7.5 (d, 2H); [free base] By treatment with ethereal hydrochloric acid, the title compound C22H24C12N4S.HC1 (483.9) PF was obtained: 207-210 ° C EXAMPLE 34 6-Chloro-2-. {3- [4-methyl-5-phenyl] -4H-1,2,4-triazol-3-yl) sulfanyl] -propyl hydrochloride} -1, 2, 3, 4-tetrahydroisoquinoline? -NMR (CDC13): d = 2.1 (q, 2H); 2.4 (s, 3H); 2.7 (t, 2H); 2.8 (t, 2H); 3.3 (t, 2H); 3.5 (s, 2H); 3.6 (m, 5H); 6.9 (d, ÍH); 7.1 (m, 2H); 7.5 (d, 3H); 7.5 (d, 2H); [free base] Precipitation of the salt with ethereal HCl led to the title compound C21H23C1N4S.HC1 (435.4) M.p .: 188-191 ° C. Example 35 2- (3-. {[4-Methyl-5- (l-methyl-lH-pyrrol-2-yl) -4 H -l, 2,4-triazol-3-yl] sulfanyl}. propyl) -7- (piperidin-1-yl sulfonyl) -1,2,3,4-tetrahydroisoquinoline 'H-NMR (CDCl 3): d = 1.4 (m, 2H); 1.7 (m, 4H); 2.1 (q, 2H); 2.7 (t, 2H); 2.8 (t, 2H); 3.0 (m, 6H); 3.35 (t, 2H); 3.6 (s, 3H); 3.7 (s, 2H); 3.9 (s, 3H); 6.2 (m, ÍH); 6.4 (m, ÍH); 6.8 (m, ÍH); 7.2 (d, 1H); 7.4 (s, ÍH); 7.5 (m, 2H). C25H34N602S2 (514.7) P.f. : 96-100 ° C. Example 36 2- [4-. { 4-Methyl-5-phenyl-4H-l, 2,4-triazol-3-yl) butyl] -7- (piperidin-1-ylsulfonyl) -1,2,3,4-tetrahydroisoquinoline C27H35N502S (493.7) MS: 494.3 [M + H] + Example 37 2- (3 { [4-Methyl-5-thien-3-yl) -4 H-1,2,4-triazol-3-yl] sulfanil } -propyl) -7- (piperidin-1-ylsulfonyl) -1, 2, 3, 4-tetrahydro-isoquinoline? -NMR (CDC13): d = 1.4 (m, 2H); 1.7 (m, 4H); 2.15 (q, 2H); 2.7 (t, 2H); 2.8 (t, 2H); 3.0 (m, 6H); 3.3 (t, 2H); 3.7 (m, 5H); 7.2 (d, ÍH); 7.4 (s, 1H); 7.5 (m, 3H); 7.7 (s, ÍH). C 24 H 31 N 502 S 3 (517.7) MS: 518.3 [M + H] + P.f. : 192-195 ° C. Example 38 2-. { 3- [(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl) sulfanyl] -propyl} -N-f eni 1-1, 2,3,4-tetrahydroisoquinolin-7-sulfonamide ^ -NMR (CDCl 3): d = 2.1 (q, 2H); 2.6 (t, 2H); 2.7 (t, 2H); 2.9 (t, 2H); 3.3 (t, 2H); 3.55 (s, 2H); 3.6 (s, 3H); 7.0 (m, 2H); 7.2 (m, 4H); 7.5 (m, 5H); 7.7 (m, 2H). C27H29N502S2 (519.7) MS: 520.3 [M + H] + Example 39 6-Chloro-2-. { 3- [(4-methyl-5-thien-3-yl-4H-l, 2,4-triazol-3-yl) sulfanyl] propyl} -1, 2, 3, 4-tetrahydroisoquinoline C19H21C1N4S2 (405) P.f .: 99-100 ° C. Example 4Q 7- [(diethylammonium) -methyl] -2- dihydrochloride. { 3- [(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl) sulfanyl] propyl} -1, 2, 3, 4-tetrahydroisoquinoline C26H35N5S.2HC1 (522.6) P.f .: 75 ° C. Example 41 2- Hydrochloride. { 3- [(4-Methyl-5-thien-3-yl-4 H -1,2,4-triazol-3-yl) sulfanyl] -propyl} -7- (trifluoromethyl) -1, 2, 3, 4 -tetrahydroisoquinoline Preparation of starting material 41A 7-Trifluoromethyl-1, 2,3,4-tetrahydroisoquinoline To a solution of 1.77 g (6.2 mmol) of N-trifluoroacetyl-2- (4-trifluorophenyl) ethylamine [prepared from 2- (4-trifluorophenyl) ethylamine and trifluoroacetic acid anhydride at -5 ° C] in 7.5 ml of glacial acetic acid were added dropwise slowly 10.0 ml of concentrated sulfuric acid was added dropwise under ice-cooling with 2 ml of formalin solution. After 18 hours at room temperature, the reaction mixture was poured into 130 ml of ice water, extracted with dichloromethane, the combined organic phases were washed with sodium hydrogen carbonate solution, then with water. After drying over sodium sulfate, filtration and evaporation, 1.7 g of 2-trifluoroacetyl-7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline were isolated, which were transformed by refluxing in ethanol / 3N HCl ( 1: 1) and alkaline work-up, in 7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline. Yield: 1.0 (4.7 mmol), 75% of theory. LH-NMR (CDC13): d = 2.0 (sbr, ÍH); 2.9 (t, 2H); 3.2 (t, 2H); 4.0 (s, 2H); 7.2 (d, ÍH); 7.3 (s, ÍH); 7.4 (s, ÍH). 41B 2- (3-Chloropropyl) -7-trifluoromethyl-1, 2,3,4-tetrahydro-isoquinoline 0.95 g (4.7 mmol) of the compound described above was transformed in a manner similar to that described in Example 4B with l-bromo-3-chloropropane at room temperature and purified chromatographically (silica gel, eluent: dichloromethane with 2% methanol). Yield: 0.9 g (3.2 mmol), 69% of theory. ? -NMR (CDCI3): d = 2.0 (m, 2H); 2.65 (m, 2H); 2.75 (m, 2H); 2.9 (m, 2H); 3.65 (m, 4H); 7.2 (dd, 1H); 7.3 (d, ÍH); 7.4 '(dd, ÍH). 41C Preparation of the final product 0.45 g (1.6 mmol) of 2- (3-chloropropyl) -7-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline were stirred at 100 ° C for 4 hours. , 36 g (1.6 mmoles) of 3-mercapto-4-methyl-5-thien-3-yl-4H-l, 2,4-triazole and 40 mg of lithium hydroxide in 6 ml of DMF. For working up, the mixture was poured onto ice / water, extracted with methyl tert-butyl ether, dried over sodium sulfate and purified after filtration and evaporation in column chromatography (silica gel, eluent dichloromethane with 3-5% strength). methanol). Yield: 0.3 g (0.7 mmol), 42% of theory. ? -NMR (CDC13): d = 2.1 (m, 2H); 2.7 (t, 2H); 2.8 (t, 2H); 3.0 (m, 2H); 3.35 (t, 2H); 3.7 (m, 5H); 7.1 (d, 1H); 7.2 (s, ÍH); 7.3 (d, ÍH); 7.5 (, 2H); 7.7 (s, ÍH); [free base] Treatment with ethereal HCl gave the title compound C20H21F3N4S2.HC1 (475) M.p .: 192-194 ° C. In emplo 42 Hydrochloride 2-. { 3- [(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl) sulfanyl] -propyl} -8- (trifluoromethyl) -1,2,3,4-tetrahydro-isoquinoline Preparation of starting material 42A 6/8-Trifluoromethyl-1, 2,3,4-tetrahydroisoquinoline 5.3 g (18.6 mmol) were added ) of N-trifluoroacetyl-2- (3-trifluorophenyl) ethylamine [prepared from 2- (3-trifluorophenyl) ethylamine and trifluoroacetic acid anhydride at -5 ° C] and 0.9 g (29 mmol) of paraformaldehyde, to a mixture of 22 ml of glacial acetic acid and 30 ml of concentrated sulfuric acid. After 18 hours at room temperature, the reaction mixture was poured into 350 ml of ice water, extracted with ethyl acetate, the combined organic phases were washed with sodium hydrogen carbonate solution, then with water. After drying over sodium sulfate, filtration and evaporation, 5.4 g of a mixture of 2-trifluoroacetyl-6- or 8-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline was isolated. Heating the mixture to reflux in ethanol / 3N HCl (1: 1). After working-up and chromatographic purification (silica gel, eluent: dichloromethane and 2-4% methanol) the two isomers were separated: Fl 1.2 g (5.7 mmol), 32% of theory. 8-Trifluoromethyl-1,2,3,4-tetrahydroisoquinoline XH-NMR (CDC13): d = 1.9 (sbr, 1H); 2.8 (t, 2H); 3.1 (t, 2H); 4.2 (s, 2H); 7.2 (m, 2H); 7.5 (d, ÍH). F2 1.4 g (6.8 mmol), 38% of theory. 6-Trifluoromethyl-1,2,3,4-tetrahydroisoquinoline? -NMR (CDC13): d = 1.8 (sbr, 1H); 2.8 (t, 2H); 3.1 (t, 2H); 4.0 (s, 2H); 7.1 (d, ÍH); 7.4 (m, 2H). 2B 2- (3-Chloropropyl) -8-trifluoromethyl-1, 2,3,4-tetrahydro-isoquinoline. 2- (3-Chloropropyl) -8-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline was obtained by transformation. of 42-A Fl with bromochloropropane in a manner analogous to that described under Example 4C with a yield of 73%. XH-NMR (CDC13): d = 2.0 (q, 2H); 2.7-2.8 (m, 4H); 3.0 (t, 2H); 3.6 (t, 2H); 3.8 (s, 2H); 7.2-7.3 (m, 2H); 7.4 (d, ÍH). 42C Preparation of the final compound The transformation of 0.7 g (3.0 mmol) of 3-mercapto -4-methyl-5-phenyl-l, 2,4 (4H) -triazole with 0.83 g (3.0 mmoles) of 2- (3-chloropropyl) -8-trifluoromethyl-1, 2,3,4-tetrahydro-isoquinoline [42B1] in 10 ml of DMF in the presence of 70 mg of lithium hydroxide at 100 ° C gave, then of working-up as described under 4D, 0.84 g (1.9 mmol) of the final compound. Yield: 0.84 g (1.9 mmol), 65% of theory. XH-NMR (CDCl 3): d = 2.1 (q, 2H); 2.6-2.7 (m, 4H); 2.9 (t, 2H); 3.4 (t, 2H); 3.6 (s, 3H); 3.8 (s, 2H); 7.1 (t, 1H); 7.25 (d, ÍH); 7.4 (d, ÍH); 7.5 (m, 3H); 7.6 (m, 2H). Treatment with ethereal HCl gave the title compound C22H23F3N4S.HC1 (469) M.p .: 118 ° C. Example 43 2- hydrochloride. { 3- [(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl) sulfanyl] -propyl} -6- (trifluoromethyl) -1,2,3,4-tetrahydro-isoquinoline Preparation of starting material 43A 2- (3-Chloropropyl) -6-trifluoro-r.ethyl-1, 2, 3, 4-tetrahydro- Isoquinoline 2- (3-Chloropropyl) -6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline was obtained by transformation of 6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline (42AF2) (obtained as described under 42A) with bromochloropropane in a manner analogous to that described under 4C with a yield of 96%. '• H-NMR (CDC13): d = 2.0 (m, 2H); 2.6-2.8 (m, 4H ); 2.9 (t, 2H); 3.6 (m, 4H); 7.1 (d, ÍH); 7.4 (m, 2H). 43C Preparation of the final compound The transformation of 0.7 g (3.0 mmol) of 3-mercapto-4-methyl-5-phenyl-1,2,4 (4H) -triazole with 0.83 g (3.0 mmoles) of 2- (3-chloropropyl) -8-trifluoromethyl-1,2,4,4-tetrahydro-isoquinoline in 10 ml of DMF in the presence of 70 mg of lithium hydroxide at 100 ° C gave, after processing as described under 4D, 0.75 g (1.7 mmol) of the final compound. Yield: 0.75 g (1.7 mmol), 58% of theory. ? -NMR (CDCI3): d = 2.1 (q, 2H); 2.6 (t, 2H); 2.7 (t, 2H); 2.9 (t, 2H); 3.3 (t, 2H); 3.6 (s, 3H); 3.7 (s, 2H); 7.1 (d, ÍH); 7.3 (m, 2H); 7.5 (m, 3H); 7.7 (m, 2H); [free base] Treatment with ethereal HCl gave the title compound C22H23F3N4S.HC1 (469) P.f. : 200-202 ° C. Example 44 2- Hydrochloride. { 3- [(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl) sulfanyl] -propyl} -7- (trifluoromethyl) -1, 2, 3, 4-tetrahydro-isoquinoline C22H23F3N4S.HC1 (469) M.p .: 205-207 ° C. Example 45 2-. { 3- [(4-Methyl-5- (thien-3-yl) -4 H -1,2,4-triazol-3-yl) sulfanyl] -propyl} -7- (4-methyl-piperazin-1-ylsulfonyl) -1,2,4,4-tetrahydroisoquinoline Hl-NMR (CDC13): d = 2.1 (q, 2H); 2.2 (s, 3H); 2.4 (m, 4H); 2.7 (t, 2H); 2.8 (t, 2H); 2.9 (t, 2H); 3.0 (m, 4H); 3.3 (t, 2H); 3.6 (m, 5H); 7.2 (d, 2H); 7.45 (m, 4H); 7.7 (m, ÍH). C24H32Ng02S3. HCl (538, 8) 2-. { 3- [(4-Methyl-5- (phenyl) -4 H-1,2,4-triazol-3-yl) sulfanyl] -propyl} -7- (4-methyl-piperazin-1-ylsulfonyl) -1, 2, 3, 4-tetrahydroisoquinoline? -NMR (CDCl 3): d = 2.1 (q, 2H); 2.2 (s, 3H); 2.5 (m, 4H); 2.7 (t, 2H); 2.8 (t, 2H); 2.9-3.0 (m, 6H); 3.3 (t, 2H); 3.6 (s, 3H); 3.7 (s, 2H); 7.2 (d, ÍH); 7.5 (m, 5H); 7.6 (m, 2H). C2gH34NgO = S3.HCl (564.8) Example 47 2-. { 3 - [(4-Methyl-5- (thien-3-yl) -4H-1, 2,4-triazol-3-yl) sulfanyl] -propyl} -7- (1, 2, 3, 4-tetrahydroisoquinoline 1-ylsulfonyl) -1,2,3,4-tetrahydroisoquinoline XH-NMR (CDC13): d = 2.1 (q, 2H); 2.7 (t, 2H); 2.8 (t, 2H); 2.9 (t, 2H); 3.2-3.3 (m, 4H); 3.6 (m, 2H); 3.7 (m, 5H); 4.2 (m, 2H); 7.1 (m, 4H); 7.2 (d, ÍH); 7.4-7.6 (m, 4H); 7.7 (m, ÍH). C28H31N502S3 (565) Example 48 2-. { 3- [(4 -Met i 1-5- (pyrid-3-yl) -4 H -l, 2,4-triazol-3-yl) -sulfanyl] -propyl} -7- (1,2,3,4-tetrahydroisoquinolin 1-ylsulfonyl) -1,2,3,4-tetrahydroisoquinoline 'H-NMR (CDCl 3): d = 2.1 (q, 2H); 2.7 (t, 2H); 2.8 (t, 2H); 2.9 (m, 4H); 3.3 (, 4H); 3.6 (s, 3H); 3.7 (s, 2H); 4.2 (s, 2H); 7.0-7.2 (m, 5H); 7.2 (m, ÍH); 7.4-7.6 (m, 3H); 8.0 (m, ÍH); 8.7 (m, ÍH); 8.9 (m, 1H). C 29 H 32 N 602 S2 (558) Example 49 7- [(3,3-dimethylpiperidin-1-yl) sulfonyl] -2-. { 3- [(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl) sulfanyl] -propyl} -1,2, 3,4-tetrahydroisoquinoline C28H37N502S2 (539.8) P.f .: 75-76 ° C. fcj emplo 50 2-. { 3- [(4-Cyclopropyl-5-phenyl-4H-1,2,4-triazol-3-yl) sulfanyl] -propyl} -7- [(3,3-dimethylpiperidin-1-yl) sulfonyl] -! 2, 3, 4-tetrahydroisoquinoline C30H39N5O2S2 (558) 2 - [(4- { [(4-Methyl-5- (l-methyl-lH-pyrrol-3-yl) -4 H -l, 2,4-triazol-3-yl) sulfanyl] methyl. cyclohexyl) methyl] -7-nitro-l, 2, 3, 4-tetrahydroisoquinoline C26H31N502S (477.6) Mp: 160 ° C. Example 52 2-. { (E) -4- [(4-Methyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-yl) sulfanyl] but-2-enyl} -7-nitro-l, 2,3,4-tetrahydro-isoquinoline C21H22N602S (422) MS: 423 [M + H] + Example 53 2- [(4- {[[4-Methyl-5-pyridin- 3-yl-4H-l, 2,4-triazol-3-yl) sulfanelyl] methyl.} Cyclohexyl) methyl] -1,2,4,4-tetrahydro-isoquinoline C27H31N5S (457.6) Mw: 156- 158 ° C. EXAMPLE 54 1- (2- {3 - [(4-Methyl-5- (3-cyano) f-4H-L, 2,4-triazol-3-yl) sulfanyl] propyl} hydrochloride. -1, 2,3,4-tetrahydroisoquinolin- "? -il) ethanone C24H25N5OS (468) Mp: 185 ° C Example 55 7-Nitro- 2- [(4- {[[4-Methyl-5- pyridin-3-yl-4H-1,2,4-triazol-3-yl) sulfanyl] methyl.} cyclohexyl) methyl] -1,2,4,4-tetrahydro-isoquinoline C26H31N602S (477.6) Pf: 160 ° C. Example 56 L-. {2- [3- ((4-Methyl-5-phenyl] -4H-1, 2,4-triazol-3-yl} sulfanyl) propyl] - hydrochloride 1,2,3,4-tetrahydroisoquinoline C23H27N40S (443) Mp: 165 ° C Example 57 7,8-Dichloro-2-. {3- [4-methyl-5-phenyl-4H-1, 2, 4-triazol-3-yl) sulfanyl] propyl.! -!, 2,3,4-tetrahydroisoquinoline C21H22C1N4S (399) Mp: 72-75 ° C Example 58 L-. {2- 2- 3- Hydrochloride (. {5- (2,4-dinitrophenyl) -4-methyl] -4H- 1,2,4-triazol-3-yl} sulfanyl) propyl] -1,2,3,4-tetra hydro -isoquinolin-7-yl.} ethanone C23H25N605S x HCl (500.6) Mp: 193 ° C. Example 59 2-. 3- [(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl) sulfanyl] -propyl} -7- (Octahydroisoquinolin-2 (1 H) -i lsulf onyl) -1,2,3,4-tetrahydroisoquinoline C 30 H 39 N 5 O 2 S 2 (565.8) MS: 567 [M + H] + Example 60 2-. { 3- [(4-Methyl-5-pyridin-3-yl-4H-1, 2,4-triazol-3-yl) -sulfanyl] propyl} -7- (Octahydroisoquinolin-2 (1H) -ylsulfonyl) -1,2,3,4-tetrahydroisoquinoline C29H38N602S2 (566.8) MS: 568 [M + H] + Example 61 2-. { 3- [(4-Cyclopropyl-5-phenyl-4H-1,2,2-triazol-3-yl) sulfanyl] -propyl} -7- (aze-an-ilsulfonyl) -1,2,3, 4-tetrahydroisoquinoline C29H37N502S2 (551.8) MS: 552 [M] + Example 62 2-. { 3- [(4-Methyl-5-phenyl-4H-l, 2,4-triazol-3-yl) -sulfanyl] propyl} -7- (pyrrolidin-1-ylsulfonyl) -1,2,4,4-tetrahydroisoquinoline C25H31N502S2 (497.7) Example 63 2-. { 3- [(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl) sulfanyl] -proyl} -7- (azepan-1-ylsulfonyl) -1, 2, 3, 4-tetrahydro-isoquinoline C27H35N502S2 (525.7) EXAMPLE 64 V-Chloro-2- (3 { [4-Methyl-5-f-4H-L, 2,4-triazole- 3-yl] -sulfanyl.} But-2-en-yl) -1,2,3,4-tetrahydroisoquinoline C21H23C1N4S (399) Mp: 72-75 ° C Example 65 2-. { 3- [(4-Methyl-5-methylamino-4H-l, 2,4-triazol-3-yl] -sulfanyl} propyl) -7-azepan-1-ylsulfonyl) -1,2,3, 4 -tetrahydro-isoquinoline Example 66 N, 4-Dimethyl-5-. { (3- (7-piperidin-1-ylsulfonyl) -3,4-dihydro-isoquinolin-2 (1H) -yl) propyl] sulfanyl} -4H-1, 2,4-triazol-3-amine Example 67 7-tert-Butyl-2-. { 3- [(4-Methyl-5- (4-methyl-l, 3-thiazol-5-yl) -4 H- 1,2,4-triazol-3-yl] -sulfanyl} propyl) -1, 2,3,4-tetrahydro-ispquinoline Example 68 2-. { 3- [(4-Methyl-5-pyridin-3-yl-4H-1, 2,4-triazol-3-yl) -sulfanyl] propyl} -7- (azepan-1-ylsulfonyl) -1,2,3,4-tetrahydro-isoquinpline Example 69 7- (. {4- [2-tert-Butyl-6- (trifluoromethyl) pyrimidin-4-yl) ] piperazin-1-yl.] sulfonyl) -2-. { 3- [(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl) -sulfanyl] propyl} -1,2,3, -tetrahydroisoquinoline EXAMPLE 70 8-Bromo-2-. { 3-. { [5-cyclohexyl-4-methyl-4H-1, 2,4-triazol-3-yl] -sulfanyl} but-2-en-yl) -1,2,3, 4-tetrahydroisoquinoline Example 71 4-Methyl-5-phenyl-N- [4- (7- (pyrrolidin-1-ylsulfonyl) -1,2,3, 4- tetrahydroisoquinolin-2-yl) butyl] -4H-1,2,4-triazole-3-carboxamide Example 72 6-Methyl-2-. { 3-. { [4-methyl-5- (l-methyl-lH-pyrrol-3-yl) -4 H-1,2,4-triazol-3-yl] -sulfanyl} prcpil) -7- (pyrrolidin-1-ylsulfonyl) -1,2,3-tetrahydroisoquinoline Example 7 7-Cyano-2- [(2- {[[4-Methyl-5-pyridin-3-yl- 4H-1, 2,4-triazol-3-yl) -sulfanyl] -methyl] -cyclopropyl) methyl] -1,2,4,4-tetrahydroisoquinoline Example 74 1- (2-. {3- [3- (4-Methyl-5- (3-methoxy) phenyl-4H-1,2,4-triazol-3-yl] -oxy] propyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) ethanone Example 7 4- (7- (Pyrrolidin-1-ylsulfonyl) -1,2,3,4-tetrahydroisoquinolin-2-yl) butyl-4-methyl-5-phenyl-4H-1, 2,4-triazole-3 -carboxylate Example 76 2- [2-. { . { [5- (N-Methylpyrrol-2-yl) -4-methyl-4H-l, 2,4-triazol-3-yl] -sulfanyl} methyl) prop-2-enyl] -1,2,3,4-tetrahydro-isoquinoline-7-carboxamide Example 77 2- (3- [(4-Cyclopropyl-5- (4-methylsulfonyl) phenyl-4H-1, 2,4-triazol-3-yl) -sulfanyl] propyl.} - 7 - (pyrrolidin-1-ylsulfonyl) -1,2,3,4-tetrahydroisoquinoline Example 78 6-tert-Butyl-2- (3- { [5- (2,4-dinitrofenyl) -4-methyl-4H-1,2,4-triazol-3-yl] sulfanyl} propyl) -1,2,3,4-tetrahydroisoquinoline Example 79 N- [2- (8-. {(5- (dimethylamino) -4-butyl-4H-1,2,4-triazol-3-yl] -sulfanyl} -octyl) -1, 2 , 3,4-tetrahydroisoquinoline, Example 80 2- (3- [(4-Methyl-5-pyrazin-2-yl-4H-1, 2,4-triazol-3-yl) -sulfanyl] -propyl.}. -7- (Octahydro-isoquinolin-2 / lH) -ylsulf onyl) -1,2,3,4-tetrahydroisoquinoline Example 81 7-Cyano-2- (3- [(4-methyl) 1-5- (2- methyloxazol-4-yl) -4 H-1,2,4-triazol-3-yl) sulfanyl] propyl.] - l, 2,3,4-tetrahydroisoquinoline Example 82 2-. { 6- [(5- (2,5-Dimethyl-furan-3-yl) -4-methyl-4H-1,2,4-triazol-3-yl) sulfanyl] hexyl} -7-trif luoromethanesulfoniumloxy-1, 2,3,4-tetrahydroisoquinoline Example 83 2- [2- ( { [4-Methyl-5-phenyl-4H-1, 2,4-triazole-3-hydrochloride - il] -sulfanyl.}. - methyl) prop-2-enyl] -7-nitro-1,2,4,4-tetrahydroisoquinoline C22H23Ns02S x HCl (460) Mp: 146-150 ° C Example 84 N- [- 2- (3- { [4-Methyl-5-phenyl-4H-l, 2,4-triazol-3-yl] sulfanyl.} - propyl) -1,2,3,4-tetrahydroisoquinoline-7 -yl] -methanesulfonamide C22H27N502S2 x HCl (494, I! Pf: 90 ° C.

Ol Kl or H O In analogous ways, they can be prepared: Table 1 ^ (L? To or H lzt \ to Lp H O Lp O Lp in -or t Lp O Ln oo to Lp t or L? I-1 or to t Lp or Lp O or t Lp t O s t to L? H O H Lp O t to Lp O O to L? t or H o ^ to Lp to o H Lp to Lp t O H H Lp O Lp t t H Ul or H L? or to L? to o H H p O oo to L? t O M O Lp H.H to to Lp O l o to Lp O Lp O Ln t to Lp H O j to to Lp to H O Lp H O vj L to Lp O H O Lp to t H O Lp vj to to l o ~ O -v4 NJ IO Ul or O to to L? or H? -4 oo to to Lp O H H Lp O ^ 1 NJ? NJ s 00 or to? NJ or Lp O oo Lp L? oo t 00 LO NJ NJ Ul O Ooo NJ to Lp l- > Or L? o 00 NJ to Lp or Lp 00 NJ L? NJ OR L? L? 00 vj t NJ Lp O H O oo oo NJ t Lp O H Lp O R and R represent hydrogen, as long as no other meaning is indicated in this Table. The following abbreviations are used in this and in the following Table: Me = Methyl Et = Ethyl cicProp = Cyclopropyl Prop = n-Propyl iProp = Isopropyl 00 cicHex = Ciciohexyl VD NJ Lp NJ O Lp H O In analogous manner, the following can be prepared: Table 2: NJ L? NJ O Lp H O O NJ NJ L? o o VO to to Ul t o H L? OR VO OJ VO ^ / NJ NJ H Lp O? O VO VO Examples of galenic administration forms A) Tablets Tablets with the following composition are compressed in a tablet press in the usual manner: 40 mg of the substance of Example 1 120 mg of corn starch 13, 5 mg of gelatin 45 mg of lactose 2.25 mg of Aerosil (R) (chemically pure silicic acid with fine submicroscopic distribution) 6.75 mg of potato starch (as a 6% paste) B) Dragees 20 mg of the Example 3 substance 60 mg core dough 70 mg dough for sweetening The core dough is composed of 9 parts of corn starch, 3 parts of lactose and 1 part of vinyl pyrrolidone-vinyl acetate 60:40 polymer blend. The dough to sugar is composed of 5 parts of cane sugar, 2 parts of corn starch, 2 parts of calcium carbonate and 1 part of talc. The tablets thus prepared are then provided with a coating resistant to gastric juices. Biological tests - ligation studies to receptors 1) D3 ligation test For ligation studies, cloned 1,3 CCL mouse fibroblasts expressing the human D3 receptor, which can be obtained from Res. Biochemicals Internat, were used. One Strathmore Rd., Natick, MA 01760-2418 USA Cell preparation Cells expressing D3 were multiplied in RPMI-1640 with 10% fetal calf serum (GIBCO No. 041-32400 N); 100 U / ml penicillin and 0.2% streptomycin (GIBCO BRL, Gaithersburg, MD, USA). After 48 hours the cells were washed with PBS and incubated with 0.05% PBS containing trypsin for 5 min. Then it was neutralized with medium and the cells were collected by centrifugation at 300 g. For lysis of the cells the pellet was briefly washed with lysis buffer (5 mM Tris-HCl, pH 7.4 with 10% glyceria) and then incubated at 4 ° C for 30 min at a concentration of 10 7 cells / ml of lysis buffer. The cells were centrifuged at 200 g for 10 min and the pellet was stored in liquid nitrogen. Ligation tests For the ligation test of the D3 receptor the membranes were suspended in incubation buffer (50 mM tris-HCl, pH 7.4 with 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, 10 μM quinolinol, 0.1% ascorbic acid and 0.1% BSA) in a concentration of approx. 106 cells / 250 μl of test mixture and incubated at 30 ° C with 0.1 nM 125 Iodo-sulpiride in the presence and absence of test substance. Non-specific ligation was determined with 10"6 Spiperon, after 60 min, free radioligand and ligand were separated by filtration through a GF / B glass fiber filter (Whn, England) in a Skatron cell harvester (Skatron , Lier, Norway) and the filters were washed with ice-cold Tris-HCl buffer, pH 7.4 The radioactivity collected on the filters was quantified with a Packard 2200 CA liquid scintillation counter. The determination of the Kx values was carried out by means of of non-linear regression analysis with the LIGAND program 2) Ligation test. Cell culture HEK-293 cells with stable expressed human dopamine D2A receptors were cultured in RPMI 1640 with Glutamax I * ® and 25 mM HEPES with 10 % fetal calf serum albumin All media contained 100 units per ml penicillin and 100 μg / ml streptomycin The cells were kept in a humid sphere with 5% C02 at 37 ° C.

Cell preparation for ligation studies was performed by trypsinization (0.05% trypsin solution) for 3-5 minutes at room temperature. The cells were then centrifuged at 250 g for 10 minutes and treated for 30 minutes at 4 ° C with lisis buffer (5 mM Tris-HCl, 10% glycerol, pH 7.4). After centrifugation at 250 g for 10 minutes the residue was stored at -20 ° C until use. Ligation tests of the receptor Dopamine D2 receptor "low affinity state" with 125I-Spiperon (81 TBq / mmoles, Du Pont de Nemours, Dreieich). The mixtures (1 ml) were composed of 1 x 10 5 cells in incubation buffer (50 mM Tris, 120 mM NaCl, 5 mM KCl, 2 mM MgCl 2 and 2 mM CaCl 2, pH 7.4 with HCl) and 0.1 nM of 125 I-Spiperon (total ligation) or in addition 1 μM of haloperidol (nonspecific ligation) or test substance. After incubation at 25 ° C for 60 minutes, the mixtures were filtered through a GF / B glass fiber filter (Whatman, England) in a Skatron cell harvester (Zinsser firm, Frankfurt) and the filters were washed with 50 mM Tris-HCl buffer, pH 7.4. The radioactivity collected on the filters was quantified with a Packard 2200 CA liquid scintillation counter. The evaluation was carried out as under a). The determination of the K values was carried out by non-linear regression analysis with the LIGAND program or by calculation of the CI5Q values with the help of the Cheng and Prusoff formula. The compounds according to the invention show in these tests very good affinities for the D3 receptor (< 1 μmolar, especially < 100 nmolar) and selectively bind to the D3 receptor. Table 3 lists the compounds of Examples 3, 4 and 7, the pKx- (D3) values (negative deciaml logarithm of the binding constant to the D3 receptor) and the selectivity with respect to the binding to the D2A receptor (Kx). (D2) / Kx (D3)). Table 3:

Claims (8)

CLAIMS Triazole compounds of the general Formula I: wherein: R1 represents H, CX-C6 alkyl, optionally substituted by OH, OCx-Cg alkyl, halogen or phenyl, C3-C6 cycloalkyl or phenyl; R2 represents H, CX-C6 alkyl, optionally substituted by OH, OCi-Cg alkyl, halogen or phenyl, Ci-C alkoxy, CX-Cß alkylthio, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, halogen, CN, COOR3, CONR3R4, NR3R4, S02R3, S02NR3R ", or an aromatic moiety, selected from phenyl, naphthyl and a 5- or 6-membered heterocyclic moiety with 1, 2, 3 or 4 heteroatoms, independently selected from each other between O, N and S, the aromatic moiety may have one or two substituents, independently selected from C 1 -C 6 alkyl, optionally substituted by OH, OCi-C alkyl, halogen or phenyl, C 2 -C 6 alkoxy, C 2 - alkenyl C6, C2-C6 alkynyl, C3-C6 cycloalkyl, halogen, CN, COR3, NR3R4, N02, S02R3, S02NR3R4 and phenyl, optionally substituted by one or two residues independently selected from Cx-C6 alkyl, Cj-Cg alkoxy , NR3R4, CN, CF3, CHF2 or halogen; R3 and R4 independently represent one of another H, alkyl
1. Cx-Cg optionally substituted by OH, alkyl OCj-Cg, halogen or phenyl, or phenyl; A represents C4-C10 alkylene or C3-C10 alkylene, comprising at least one group Z, selected from O,
2. S, CONR3, COO, CO, C3-C6 cycloalkyl and a double or triple bond; B means a remainder of the following formula: wherein: X represents CH2 or CH2CH2; R6, R7 and R8 selected independently from each other from H, Ci-C alkyl optionally substituted by OH, OCi-C alkyl optionally substituted by amino, mono- or di-C1-C4 alkylamino, CX-C6 alkylthio, halogen or phenyl; OH, C ^ Cg alkoxy, OCF3, OS02CF3, SH, CX-Cg alkylthio, C2-C6 alkenyl, C2-C6 alkynyl, halogen, CN, N02, C02R3, S02R3, S02NR3R4, wherein R3 and R4 have the above-mentioned meaning and together with the N atom, to which they are bound, they can also form a saturated or unsaturated heterocycle with 5 to 7 ring atoms and 1 or 2 N heteroatoms; CONR3R4, NHS02R3, NR3R4, a 5- or 6-membered aromatic or non-aromatic carbocyclic ring and a 5- or 6-membered aromatic or non-aromatic heterocyclic ring with 1 or 2 heteroatoms, independently selected from 0, N and S, may be selected present the carbocyclic or heterocyclic ring one or two substituents, selected independently from each other between CX-C6 alkyl, phenyl, phenoxy, halogen, Cx-C6 alkoxy, OH, N02, CF3 and CHF2, and two of the substituents R6, R7 can be present and R8 together with the carbon atom of the phenyl ring, to which they are attached, form a phenyl, cyclopentyl or cyclohexyl ring fused to the phenyl ring, wherein one or two of the CH or CH2 groups can be replaced by a nitrogen atom, or an NH or N-C 1 Cg alkyl group; as well as their salts with physiologically compatible acids. 2. Compounds according to claim 1 of Formula I, wherein X represents CH2CH2. 3. Compounds according to claim 1 or 2 of the
3. Formula I, wherein A represents C4-C10 alkylene or C3-C10 alkylene, comprising at least one Z group, selected from 0, S, COO, CO, a double or triple bond and C3-C6 cycloalkyl.
4. 4. Compounds according to one of the preceding claims of Formula I, wherein A represents C4-C10 alkylene or C3-C10 alkylene, comprising at least one Z group, selected from 0, S, a double bond and cyclohexyl.
5. 5. Method according to one of the preceding claims of Formula I, wherein R2 represents an aromatic moiety, unsubstituted or having one or two substituents, independently selected from Ci-Cg alkyl, OH, Ci-Cg alkoxy, phenyl, CN and halogen.
6. 6. Compounds according to one of the preceding claims of Formula I, wherein R2 represents H, CX-C6 alkyl, phenyl, thienyl, furanyl, tetrazolyl, pyrrolyl, pyridyl or pyrazinyl.
7. 7. Compounds according to one of the preceding claims of Formula I, wherein R1 represents H, CX-C6 alkyl or C3-C6 cycloalkyl.
8. 8. Compounds according to one of the preceding claims of Formula I, wherein R6, R Ra independently of one another are selected from H, Ci-Cg alkyl, OH, Ci-C alkoxy, Ci-Cg alkylthio-Ci alkyl -Cg, halogen, CN, N02, S02R3, S02NR3R4 and CONR3R4. 9 *. Compounds according to claim 1 of the Formula I, wherein: R 1 represents H, C) alkyl- C 6 or phenyl, R 1 represents H, C x C 6 alkyl, phenyl, thienyl, furanyl, tetrazolyl, pyrrolyl, thiazolyl or pyrazinyl, A represents alkylene -SC 3 -C 10 , which may optionally comprise a double bond, and R6, R7 and R8 are selected from H, CX-C6 alkyl, d-Cg alkoxy, halogen, S02NR3R4, CN, N02, CF3, CONR3R4, CHF2, OS02CF3, OCF3 and NHS02-C6-C6 alkyl. 10. Pharmaceutical product containing at least one compound according to one of claims 1 to 9, optionally together with vehicles and / or physiologically acceptable auxiliary substances. 11. Use of at least one compound according to one of claims 1 to 9 for the preparation of a pharmaceutical product for the treatment of diseases responsive to the action of agonists and / or antagonists of the dopamine D3 receptors.