Indian Patents. 225611:TRIAZOLE COMPOUNDS WITH DOPAMINE-D3-RECEPTOR AFFINITY

Title of Invention	TRIAZOLE COMPOUNDS WITH DOPAMINE-D3-RECEPTOR AFFINITY
Abstract	Triazole compounds of the following formula where R,SUP>l</SUP>, R<SUP>2</SUP>, A and B have the meanings given in the description are described. The compounds according to the invention possess a high affinity for the dopamine 03 receptor and can therefore be used for treating diseases which respond to the influence of do- pamine 03 ,ligands.

Full Text	Triazole compounds and their use The invention relates to triazole compounds and to the use of these compounds. These compounds possess valuable therapeutic properties and can be used for treating diseases which respond to the influence of dopamine D3 receptor ligands. Compounds of the type which is under discussion here and which possess 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 which act on the dopamine receptors. DE 44 25 144 A, WO 96/30333, WO 97/25324, WO 97/40015, WO 97/47602, WO 97/17326, EP 887 350, EP 779 284 A and Bioorg. & Med, Chem. Letters 9 (1999) 2059-2064 disclose further compounds which possess activity as dopamine D3 receptor ligands. US 4,338,453; 4,408,049 and 4,577,020 disclose triazole compounds which possess antiallergic or antipsychotic activity. WO 93/08799 and WO 94/25013 describe compounds of the type which is under discussion here and which constitute endothelin receptor antagonists. Additional triazole compounds, which inhibit blood platelet aggregation and which have a hypotensive effect are described in Pharmazie 16, (1991), 109-112. Further triazole compounds which possess physiological activity are disclosed in EP 691 342, EP 556 119, WO 97/10210, WO 98/24791, WO 96/31512 and WO 92/20655. Neurons obtain their information by way of G protein-coupled receptors, inter alia. There are a large number of substances which exert their effect by way of these receptors. One of them is dopamine. A number of facts about the presence of dopamine, and its physiological function as a neuron transmitter, are known with certainty. Disturbances of the dopaminergic transmitter system result in diseases such as schizophrenia, depression and Parkinson's disease. These, and other, diseases are treated with drugs which interact with the dopamine receptors. By 199 0, two subtypes of dopamine receptor had been clearly defined pharmacologically, namely the Di and D2 receptors. More recently, a third subtype has been found, namely the D3 receptor, which appears to mediate some of the effects of the antipsychotic and anti-Parkinson agents (J.C. Schwartz et al., The Dopamine D3 Receptor as a Target for Antipsychotics, in Novel Antipsychotic Drugs, H.Y. Meltzer, Ed. Raven Press, New York 1992, pages 135-144; M. Dooley et al,. Drugs and Aging 1998, 12, 495-514) . Since D3 receptors are chiefly expressed in the limbic system, it is assumed that while a selective D3 ligand would probably have the properties of known antipsychotic agents, it would not have their dopamine D3 receptor-mediated neurological side-effects (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, 347, 146 (1990)). Surprisingly, it has now been found that certain triazole compounds exhibit a high affinity for the dopamine D3 receptor and a low affinity for the D2 receptor. These compounds are consequently selective D3 ligands. The present invention relates, therefore, to the compounds of the formula I: R1 is H, C1-C6-alkyl, which may be substituted by OH, OC1-C6-alkyl, halogen or phenyl, C6-C6-cycloalkyl or phenyl; R2 is H, C1-C6-alkyl, which may be substituted by OH, OC1-C6-alkyl, halogen or phenyl, C1-C6-alkoxy, C1-C6-alkylthio, C2-C6-alkenyl, C2-C6-alkynyl, C3_C6-cycloalkyl, halogen, CN, C00R3, C0NR3R4, NR3R4, SO2R3, S02NR3R4,or an aromatic radical which is selected from phenyl, naphthyl and a 5- or 6-membered heterocyclic radical having 1, 2, 3 or 4 heteroatoms which are selected, independently of each other, from O, N and S, with it being possible for the aromatic radical to have one or two substituents which are selected, independently of each other, from C1-C6-alkyl, which may be substituted by OH, OC1-C6-alkyl, halogen or phenyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C6-C6-cycloalkyl, halogen, CN, COR2, NR2R2, NO2, SO2R3, S02NR3R'1 and phenyl which may be substituted by one or two radicals which are selected, independently of each other, from C1-C6-alkyl, C1-C6-alkoxy, NR3R4, CN, CF3, CHF2 or halogen; R3 and R4 are, independently of each other, H, C1-C6-alkyl, which may be substituted by OH, OC1-C6-alkyl, halogen or phenyl, or phenyl; A is C4-C10-alkylene or Ca-Cio-alkylene which comprises at least one group Z which is selected from 0, S, C0NR3, COO, CO, Ca-C6-cycloalkyl and a double or triple bond; R6, R7 and R2 are, independently of each other, selected from H, C1-C6-alkyl, which may be substituted by OH, OC1-C6-alkyl, which may be substituted by amino, mono- or di-C1-C4-alkylamino; C1-C6-alkylthio, halogen or phenyl; OH, C1-C6-alkoxy, OCF3, OSO2CF3, SH, C1-C6-alkylthio, C2-C6-alkenyl, C2-C6-alkynyl, halogen, CN, NO2, C02R2, SO2R3, S02NR3R4, where R2 and R' have the abovementioned meanings and may also form together with the N atom to which they are bonded a saturated or unsaturated heterocycle with 5 to 7 ring atoms and 1 or 2 N and/or O heteroatoms, CONR2R2, NHS02R2, NR3R4, a 5- or 6-membered carbocyclic, aromatic or nonaromatic ring and a 5- or 6-membered heterocyclic, aromatic or nonaromatic ring with 1 or 2 heteroatoms which are selected, independently of each other, from O, N and S, with the carbocyclic or heterocyclic ring being able to have one or two substituents which are selected, independently of each other, from C1-C6-alkyl, phenyl, phenoxy, halogen, C1-C6-alkoxy, OH, NO2, CF3 and CHF2, and with two of the substituents R2, R2 and R2 being able to form, together with the carbon atoms of the phenyl ring to which they are bonded, a phenyl, cyclopentyl or cyclohexyl ring which is fused to the phenyl ring with the possibility for one or two of the CH or CH2 groups in the fused ring being replaced by a nitrogen atom, a NH or a N-(C1-C6-alkyl) group; and the salts thereof with physiologically tolerated acids. The compounds according to the invention are selective dopamine D3 receptor ligands which act in the limbic system in a regioselective manner and which, as a result of their low affinity for the D2 receptor, have fewer side-effects than do the classic neuroleptic agents, which are D2 receptor antagonists. The compounds can therefore be used for treating diseases which respond to dopamine D3 ligands, i.e. they are effective for treating those diseases in which affecting (modulating) the dopamine D3 receptors leads to an improvement in the clinical picture or to the disease being cured. Examples of such diseases are diseases of the cardiovascular system and the kidneys, diseases of the central nervous system, in particular schizophrenia, affective disorders, neurotic stress and somatoform disorders, psychoses. Parkinsonism, attention deficit disorders, hyperactivity in children, epilepsy, amnesic and cognitive disorders such as learning and memory impairment (impaired cognitive function), anxiety states, dementia, delirium, personality disorders, sleep disturbances (for example restless legs syndrome), disorders of the sex life (male impotence), eating disorders and addictive disorders. Moreover they are useful in the treatment of stroke. Addictive disorders include the psychological disorders and behavioral disturbances caused by the abuse of psychotropic substances such as pharmaceuticals or drugs, and other addictive disorders such as, for example, compulsive gambling (impulse control disorders not elsewhere classified). Addictive substances are, for example: opioids (for example morphine, heroin, codeine); cocaine; nicotine; alcohol; substances which interact with the GABA chloride channel complex, sedatives, hypnotics or tranquilizers, for example benzodiazepines; LSD; cannabinoids; psychomotor stimulants such as 3,4-methylenedioxy-N-methyl-amphetamine (ecstasy); amphetamine and amphetamine-like substances such as methylphenidate or other stimultants including caffeine. Addictive substances of particular concern are opioids, cocaine, amphetamine or amphetamine-like substances, nicotine and alcohol. rhe compounds according to the invention are preferably used for treating affective disorders; neurotic, stress and somatoform disorders and psychoses, e.g. schizophrenia. within the context of the present invention, the following expressions have the meanings given in conjunction with them: Akyl (also in radicals such as alkoxy, alkylthio, alkylamino etc.) is a straight-chain or branched alkyl group having from 1 to 6 carbon atoms and, in particular from 1 to 4 carbon atoms, rhe alkyl group can have one or more substituents which are selected, independently of each other, from OH, OC1-C6-alkyl, halogen or phenyl, in the case of a halogen substituent, the alkyl group can, in particular, encompass, 1, 2, 3 or 4 halogen atoms which can be located on one or more C atoms, preferably in the a or co position. CF3, CHF2, CF2CI or CH2F are particularly preferred. Examples of an alkyl group are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, etc. Cycloalkyl is, in particular, Ca-C6-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Alkylene radicals are straight-chain or branched. If A does not have a group Z, A then comprises from 4 to 10 carbon atoms, preferably from 4 to 8 carbon atoms. The chain between the triazole nucleus and group B then has at least four carbon atoms. If A has at least one of said Z groups, A then comprises from 3 to 10 carbon atoms, preferably from 3 to 8 carbon atoms. If the alkylene groups comprise at least one of the Z groups, this or these groups can then be arranged in the alkylene chain at an arbitrary site or in position 1 or 2 of the A group (seen from the triazole radical). The radicals CONR2 and COO are preferably arranged such that the carbonyl group is in each case facing the triazole ring. Particular preference is given to the compounds of the formula I in which A is -Z-Ca-C6-alkylene, in particular -Z-CH2CH2CH2-, -Z-CH2CH2CH2CH2-, -Z-CH2CH=CHCH2-, -Z-CH2C(CH3)=CHCH2-, -Z-CH2- -CH2- Halogen is F, Cl, Br or I, preferably F or CI. X is preferably -CH2-CH2- . Ri is preferably H, C1-C6-alkyl or C6-C6-cycloalkyl. If R2 is an aromatic radical, this radical is then preferably one of the following radicals: If the phenyl radical is substituted, the substituents are preferably in the m position or the p position. The aromatic radical is particularly preferably a group of the formula: where R2, R2o and Ri2 have the abovementioned meanings. The indicated phenyl, pyridine, thiazolyl and pyrrole radicals are particularly preferred. The radicals R2 to Ri are preferably H, C1-C6-alkyl, 0R3, CN, phenyl, which may be substituted by C1-C6-alkyl, C1-C6-alkoxy or halogen, CF3 and halogen, and are, in particular, H, C1-C6-alkyl, 0R3 and halogen. In this context, R3 has the abovementioned meanings. Particularly preferably, R2 is H, C1-C6-alkyl, NR2R2 (R3 and R2 are, independently of each other, H or C1-C6-alkyl), phenyl or a 5-membered aromatic heterocyclic radical which has 1 or 2 heteroatoms which are independently selected from N, S and 0. The heterocyclic radical is preferably a pyrrole radical or a pyridine radical. A is preferably C4-Cio-alkylene or Ca-Cio-alkylene which comprises at least one group Z which is selected from 0, S, COO, CO, a double bond and cyclohexyl. Preferably, at least one of the radicals R2, R' and R2 is H. The radicals R2, R? and R2 are preferably, and independently of each other, selected from H, C1-C6-alkyl, OH, C1-C6-alkoxy, C;L-C6-alkylthio-C1-C6-alkyl, halogen, CN, NO2, SO2R3, S02NR3R4 and C0NR3R4. Particularly preferably, the fused phenyl group has one or two substituents, i.e. one or two of the radicals R2, R7 and R2 is/are C1-C6-alkyl, halogen, CN, NO2, SO2R3 and, in particular, S02NR3R4, where R2 and R'*, together with the N atom to which they are attached, can also be a 5-, 6- or 7-membered heterocycle, which may contain one or two additional heteroatoms being selected from N, 0 or S besides the nitrogen atom and which may be substituted, e.g. pyrrolidine, piperidine, morpholine or azepine. If one of the radicals R6, R7 and R2 is a 5- or 6-membered heterocyclic ring, this ring is then, for example, a pyrrolidine, piperidine, morpholine, pyridine, pyrimidine, triazine, pyrrole, thiophene or pyrazole radical, with a pyrrole, pyrrolidine, pyrazole or thienyl radical being preferred. If one of the radicals R2, R? and R2 is a carbocyclic radical, this radical is then, in particular, a phenyl, cyclopentyl or cyclohexyl radical. Particular preference is given to the compounds of formula I where Ri is H, C1-C6-alkyl or phenyl, R2 is H, C1-C6-alkyl, phenyl, thienyl, furanyl, pyridyl, pyrrolyl, thiazolyl or pyrazinyl, A is -SCa-Cio-alkylene which can comprise a double bond, and R6, R7 and R2 are selected from H, C1-C6-alkyl, C1-C6-alkoxy, halogen, S02NR3R4 , CN, NO2, CF3, CONR3R4 , CHF2, OSO2CF3, OCF3 and NHSOa-C1-C6-alkyl. In here X is especially CH2CH2. The invention also encompasses the acid addition salts of the compounds of the formula I with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid or benzoic acid. Other acids which can be used are described in Fortschritte der Arzneimittelforschung [Advances in pharmaceutical research]. Volume 10, pages 224 ff., Birkhauser Verlag, Basle and Stuttgart, 1966. The compounds of the formula I can exhibit one or more centers of asymmetry. The invention therefore includes not only the racemates but also the relevant enantiomers and diastereomers. The respective tautomeric forms are also included in the invention. The process for preparing the compounds of the formula I consist in a) reacting a compound of the formula (II) where Y is a customary leaving group, such as Hal, alkylsulfonyloxy, arylsulfonyloxy, etc., with a compound of the formula (III) where Y and A have the abovementioned meanings, with a compound of the formula (VII) where Z has the abovementioned meanings; or d) reversing the polarity of a compound of the formula (VIII) using reagents which are known from the literature, such as 1,3-propanedithiol, KCN/water, TMSCN (trimethylsilyl cyanide) or KCN/morpholine, as described, for example, in Albright Tetrahedron, 1983, H, 3207 or D. Seebach Synthesis 1969, 17 und 1979, 19 or H. Stetter Angew. Chem. Int. Ed. 1976, 15., 639 or van Niel et al. Tetrahedron 1989, 15, 7643 Martin et al. Synthesis 1979, 633, to give the products (Villa) (using 1,3-propanedithiol by way of example) and then chain-elongating with compounds of the formula (IX) yi - A3 - B (IX) where Y has the abovementioned meaning and A is Ca-C6-alkylene which can contain a group Z, where Z2 is CO or a methylene group, and Z and A have together from 4 to 10 C atoms, being obtained after deprotecting or reducing, or ) reacting a compound of the formula (VIII) with a compound of the formula (X) where Y2 is a phosphorane or a phosphonic ester, in analogy with customary methods, as described, for example, in Houben Weyl "Handbuch der Organischen Chemie" [Textbook of Organic Chemistry], 4th Edition, Thieme Verlag Stuttgart, Volume V/lb p. 383 ff, or vol. V/lc p. 575 ff, or where Q is H or OH, with a compound of the formula III under reductive conditions in analogy with methods known from the literature, for example as described in J. Org. Chem. 1986, M, 1927; or WO 92/20655. The process for preparing a compound of the formula I where A comprises the groups COO or CONR2 consists in reacting a compound of the formula (XII) Compounds of the formula B-H can be prepared as described, for example, in Synth. Commun. 1984, M, 1221 S. Smith et al., Bioorg. Med. Chem. Lett. 1998, 8., 2859; WO 97/47602 or WO 920655, or J. Med. Chem. 1987, M, 2111 and 2208 and 1999, 41, 118. The compounds of the formula (IV) type are either known or can be prepared using known methods, as described, for example, 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 which is cited therein, or in S. Kubota et al. Chem. Pharm. Bull. 1975, 23, 955 or Vosilevskii et al. Izv. Akad. Nauk. SSSR Ser. Khim. 1975, 23., 955. In the above formulae, Ri, R2, R6, R7, R8 g d X have the meanings given in connection with formula I. The compounds according to the invention, and the starting materials and the intermediates, can also be prepared in analogy with the methods which are described in the patent publications which were mentioned at the outset. The above-described reactions are generally effected in a solvent at temperatures of between room temperature and the boiling temperature of the solvent employed. Examples of solvents which can be used are esters, such as ethyl acetate, ethers, such as diethyl ether or tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, dimethoxyethane, toluene, xylene, acetonitrile, ketones, such as acetone or methyl ethyl ketone, or alcohols, such as ethanol or butanol. If desired, the reactions can be carried out in the presence of an acid-binding agent. Suitable acid-binding agents are inorganic bases, such as sodium carbonate or potassium carbonate, or sodium hydrogencarbonate or potassium hydrogencarbonate, sodium methoxide, sodium ethoxide, sodium hydride, or organometallic compounds, such as butyl lithium or alkyl magnesium compounds, or organic bases, such as triethylamine or pyridine. The latter can also simultaneously serve as the solvent. Process (f) is effected under reducing conditions, e.g. using sodium borohydride, sodium cyanoborohydride or triacetoxy borohydride, where appropriate in an acid medium or in the presence of a Lewis acid, such as zinc chloride, or by way of catalytic hydrogenation. The crude product is isolated in a customary manner, for example by means of filtering, distilling off the solvent or extracting from the reaction mixture, etc. The resulting compounds can be purified in a customary manner, for example by recrystallization from a solvent, by chromatography or by converting into an acid addition compound. The acid addition salts are prepared in a customary manner by-mixing the free base with the corresponding acid, where appropriate in solution in an organic solvent, for example a lower alcohol, such as methanol, ethanol or propanol, an ether, such as methyl tert-butyl ether, a ketone, such as acetone or methyl ethyl ketone, or an ester, such as ethyl acetate. For treating the abovementioned diseases, the compounds according to the invention are administered orally or parenterally (subcutaneously, intravenously, intramuscularly or intraperitoneally) in a customary manner. The administration can also be effected through the nasopharyngeal space using vapors or sprays. The dosage depends on the age, condition and weight of the patient and on the type of administration. As a rule, the daily dose of active compound is from about 10 to 1000 mg per patient and day when administered orally and from about 1 to above 50 0 mg per patient and day when administered parenterally. The invention also relates to pharmaceuticals which comprise the compounds according to the invention. In the customary pharmacological administration forms, these pharmaceuticals are present in solid or liquid form, for example as tablets, film tablets, capsules, powders, granules, sugar-coated tablets, suppositories, solutions or sprays. In this context, the active compounds can be worked up together with the customary pharmacological auxiliary substances, such as tablet binders, fillers, preservatives, tablet disintegrants, flow-regulating agents, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retarding agents, antioxidants and/or propellent gases (cf. H. Sucker et al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The resulting administration forms normally comprise the active compound in a quantity of from 1 to 99% by weight. The following examples serve to explain the invention without limiting it. Example 1 6,7-Dimethoxy-2-{3-[(4-methyl-5-phenyl-4H-l,2,4-triazol-3-yl)- sulfanyl]propyl}-!,2,3,4-tetrahydroisoquinoline lA Preparation of the starting materials 2-(3-Chloropropyl)-6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline 7.2 g (37 mmol) of 6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline were heated together with 4.05 ml (40 mmol) of l-bromo-3-chloropropane, 11.3 g (81 mmol) of potassium carbonate and 610 mg (40 mmol) of sodium iodide in 250 ml of acetonitrile with stirring at 70°C for four hours. After the reaction was complete, the solvent was distilled off, and the residue was taken up in water and extracted with methylene chloride. The combined organic phases were dried and concentrated, and the crude product was purified by chromatography on silica gel (mobile phase: methylene chloride/methanol = 9/1). 4.8 g (45% of theory) of a yellowish oil were obtained. iH-NMR (CDCI3): 8 = 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, IH); 5.6 (s, IH). C14H20CINO2 (269) IB Preparation of the final product 380 mg (1.7 mmol) of 3-mercapto-4-methyl-5-phenyl-l,2,4(4H)-triazole were heated with 450 mg (1.7 mmol) of the chlorinated base lA and 40 mg (1.7 mmol) of lithium hydroxide in 5 ml of DMF while stirring at lOQoc for five hours. Workup entailed addition of 50 ml of water, extraction several times with methyl tert-butyl ether, drying of the combined organic phases, evaporation and purification by chromatography on silica gel (mobile phase: methylene chloride/2-5% methanol). Yield: 0.2 g (49% of theory) iH-NMR (CDCI3): 6 = 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, IH); 6.5 (s, IH); 7.5 (m, 3H); 7.8 (m, 2H). The title compound was obtained by treatment with ethereal hydrochloric acid C23H28N4O2S x HCl Melting point: 180-183OC Example 2 6-Methoxy-2-{3-[(4-methyl-5-pyrrol-2-yl-4H-l,2,4-triazol-3-yl)- sulfanyl]propyl}-l,2,3,4-tetrahydroisoquinoline 2A Preparation of the starting compound 2-(3-Chloropropyl)-6-methoxy-l,2,3,4-tetrahydroisoquinoline The above substance was prepared using 6-methoxy- 1,2,3,4-tetrahydroisoquinoline in a manner analogous to lA. IH-NMR (CDCI3): 6 = 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, IH); 6.7 (dd, IH); 6.9 (d, IH). i 2B Preparation of the final product Preparation took place in analogy to Example 1 by reacting the chlorinated base prepared in 2A with 3-mercapto-4-methyl-5-(2-pyrrolyl)-1,2,4(4H)-triazole. Yield: 52% of theory. C20H25N5OS (383.5) Melting point: 179-18loc Example 3 2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-6-inethoxy-l, 2, 3,4-tetrahydroisoquinoline 3A Preparation of the starting material 3-(3-Chloropropylmercapto)-4-methyl-5-phenyl-l,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-l,2,4(4H)-triazole and 2.1 g (15 mmol) of potassium carbonate in 70 ml of ethanol were heated to boiling for one hour. After filtration hot, the filtrate was concentrated, taken up in water and extracted with dichloromethane. The combined orgainc phases were dried, filtered and concentrated, and the residue was chromatographed (mobile phase: methylene chloride/2% methanol). Yield: 1.35 g (34% of theory) of white solid iH-NMR (CDCI3): 8 = 2.3 (q, 2H); 3.4 (t, 2H); 3.6 (s, 3H); 3.7 (t, 2H); 7.5-7.7 (m, 5H). C12H14CIN3S (267.8) Melting point: 137-1410C 3B Preparation of the final product 0.7 g (2.5 mmol) of Compound 3A described above was stirred with 0.6 g (2.5 mmol) of 6-methoxy-l,2,3,4-tetrahydroisoquinoline oxalic acid salt in the presence of 1.1 ml (7.5 mmol) of triethylamine and catalytic amounts of sodium iodide in 6 ml of butanol at 120oc for four hours. After the reaction was complete it was worked up by extraction with water and methyl tert-butyl ether, drying over sodium sulfate and concentrating, and the 1.2 g (4.4 mmol) of 7-(morpholin-4-ylsulfonyl)-l,2,3,4-tetra-hydroisoquinoline and 1.0 g (10 mmol) of triethylamine were dissolved in DMF at 400, 1.1 g (6.6 mmol) of l-bromo-3-chloropropane were added dropwise, and the mixture was stirred at 40oc for 3 h. For workup, the mixture was concentrated, and the residue was taken up in water and extracted with methyl tert-butyl ether. Drying over sodium sulfate, filtration and removal of the solvent were followed by purification by chromatography (silica gel; mobile phase: methylene chloride with 2% methanol) to afford 0.7 g (2 mmol) of a pale oil. Yield: 46% of theory. iH-NMR (CDCI3): 6 = 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, IH); 7.4 (s, IH); 7.5 (d, IH). C16H23N2O3S (359) Preparation of the final compound 280 mg (1 mmol) of 2-[4-methyl-5-phenyl-l,2,4-(4H)-triazol-3-yl]-l,3-dithiane (described in WO 9902503) were dissolved in 2.5 ml of dry THE and, at -70oc, with the addition of 0.15 g of sodium iodide, treated with 0.75 ml (1.2 mmol) of a 15% strength solution of butyllithium in n-hexane. After stirring at -70oc for 45 min, 0.37 g (1 mmol) of 2-[3-chloropropyl]-7-(morpholin-4-yl-sulfonyl)-l,2,3,4-tetrahydroisoquinoline 5B dissolved in THE was added dropwise. The mixture was then slowly warmed to room temperature and subsequently heated at 40°C for 90 min in order to achieve complete conversion. Workup entailed addition to ice/water and extraction several times with methylene chloride. After drying and concentration, 0.5 g (82% of theory) of the substituted dithiane remained and was then hydrogenated with Raney nickel and hydrogen in tetrahydrofuran at 40°C over the course of 3 hours. After removal of the catalyst, the residue was purified by chromatography (silica gel, methylene chloride with 5% methanol). Yield: 120 mg (29% of theory) iH-NMR (CDCI3): 8 = 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, IH); 7.4 (s, IH); 7.5 (m, 4H); 7.7 (m, 2H). The title compound was obtained by adding ethereal HCl C26H33N503S-HC1 (531.6) Melting point: 87-89°C The following were obtained in an analogous way: Example 6 1-(4-Methyl-5-phenyl-4H-l,2,4-triazol-3-yl)-4-(7-(piperidin-1-yl- sulfonyl)-1,2,3,4-tetrahydroisoquinolin-2-yl)butan-l-one C27H33N5O3S (507.7) MS: 508.3 [M+HJ+ Example 7 2-{3-[(4-Methyl-5-phenyl-4H-l,2,4-triazol-3-yl)sulfanyl]propyl}- 1,2,3,4-tetrahydroisoquinoline-7-carbonitrile C22H23N5S (389.5) Melting point: II6-II80C Example 8 5-[2-(Diethylammonio)ethoxy]-2-{3-[(4-methyl-5-phenyl-4H-l,2,4- triazol-3-yl)sulfanyl]propyl}-l,2,3,4-tetrahydroisoquinoline dihydrochloride C27H37N50S-2HC1 (552.6) Melting point: 110-H2OC Example 9 N-Benzyl-2-(3-{[4-methyl-5-(4-methyl-l,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide C26H30N6O2S3 (554.8) Melting point: 67-70OC Example 10 N-Benzyl-2-{3-[(4-methyl-5-pyridin-3-yl-4H-l,2,4-triazol-3-yl)-sulf anyl ]propyl}-l , 2,3,4-tetrahydroisoquinoline-7-sulfonamide C27H30N6O2S2-2HC1 (607.6) Melting point: 81-840C Example 11 5-Methoxy-2-{3-[(4-methyl-5-phenyl-4H-l,2,4-triazol-3-yl)- sulfanyl]propyl}-l,2,3,4-tetrahydroisoquinoline C22H26N4OS (394.5) Melting point: 12-1S°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 C21H24CIN5O2S (446) Melting point: 190-192oc Example 13 2-{3-[(4-Methyl-5-phenyl-4H-l,2,4-triazol-3-yl)sulfanyl]propyl}- 1,2,3,4-tetrahydroisoquinoline IH-NMR (CDCI3): 6 = 2.1 (q, 2H); 2.65 (t, 2H); 2.7 (t, 2H); 2.9 (t, 2H); 3.4 (t, 2H); 3.5 (s, 3H); 3.7 (s, 2H); 7.0 (m, IH); 7.2 (m, 3H); 7.5 (m, 3H); 7.7 (m, 2H) . C21H24N4S (365.5) Example 14 2-(3-{[4-Methyl-5-(4-inethyl-l,3-thiazol-5-yl)-4H-1,2,4-triazol- 3-yl]sulfanyl}propyl)-1,2,3,4-tetrahydroisoquinoline iH-NMR (CDCI3): 6 = 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, IH); 7.1 (m, 3H); 8.9 (s, IH). C19H23N5S2 (386.5) Example 15 2-{3-[(4-Methyl-5-pyridinium-3-yl-4H-l,2,4-triazol-3-yl)- sulfanyl]propyl}-l,2,3,4-tetrahydroisoquinoline dihydrochloride C20H23N5S-2HC1 (438.4) Melting point: 87-890C Example 16 7-[(Dimethylamino)sulfonyl]-2-{3-[(4-methyl-5-phenyl-4H-l,2,4- tria2ol-3-yl)sulfanyl]propyl}-l,2,3,4-tetrahydroisoquinoline iH-NMR (CDCI3): 6 = 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, IH); 7.4-7.6 (m, 7H). C23H29N5O2S2 (472.6) Example 17 7-[(Dimethylamino)sulfonyl]-2-(3-{[4-methyl-5-(4-methyl-l,3- thiazol-5-yl)-4H-l,2,4-triazol-3-yl]sulfanyl}propyl)-1,2,3,4- tetrahydroisoquinoline IH-NMR (CDCI3): 8 = 2.1 (q, 2H) ; 2.5 (s, 3H); 2.6-2.8 (m, lOH); 2.9 (m, 2H); 3.4 (t, 2H); 3.5 (s, 3H); 3.7 (s, 2H); 7.2 (m, IH); 7.5 (m, 2H); 8.9 (s, IH) . C21H28N6O2S3 (493.7) Example 18 Methyl 2-{3-[(4-methyl-5-phenyl-4H-l,2,4-triazol-3-yl)- sulfanyl]propyl}-l,2,3,4-tetrahydroisoquinoline-7-carboxylate oxalate C23H27N402S-C2H04 (512.6) Melting point: 160-163°C Example 20 2-(3-{[4-Methyl-5-(4-methyl-l,3-thiazol-5-yl)-4H-l,2,4-triazol-3-yl]sulfanyl}propyl)-7-(piperidin-1-ylsulfonyl)-1,2,3,4-tetra-hydroisoquinoline iR-NMR (CDCI3): 8 = 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, IH); 7.45 (s, IH); 7.5 (d, IH); 8.9 (s, IH) . C24H32N6O2S3 (532.8) Example 21 2-{3-[(4-Methyl-5-phenyl-4H-l,2,4-triazol-3-yl)sulfanyl]propyl}- 7-(phenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline iH-NMR (CDCI3): 8 = 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, IH); 7.4-7.7 (m, lOH); 7.9 (d, 2H). C27H28N4O2S2 (504.7) Example 22 2-(3-{[4-Methyl-5-(4-methyl-l,3-thiazol-5-yl)-4H-1,2,4-triazol- 3-yl]sulfanyl}propyl)-1,2,3,4-tetrahydroisoquinolin-7-yl phenyl sulfone iH-NMR (CDCI3): 8 = 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, IH); 7.4-7.7 (m, 5H); 7.9 (d, 2H); 8.9 (s, IH). C25H29N5O2S3 (525.7) Example 23 2-{3-[(4-Methyl-5-phenyl-4H-l,2,4-triazol-3-yl)sulfanyl]propyl}- 7-(morpholin-4-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline iH-NMR (CDCI3): 8 = 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, IH); 7.4-7.6 (m, 5H); 7.9 (d, 2H). C25H31N5O3S2 (525.7) Example 24 2-[4-(4-Methyl-5-phenyl-4H-l,2,4-triazol-3-yl)butyl]- 7-(phenylsulfonyl)-l,2,3,4-tetrahydroisoquinoline C28H30N4O2S (486.6) Example 25 2-{3-[(4-Methyl-5-pyridin-3-yl-4H-l,2,4-triazol-3-yl)sulf anyl ] - propyl}-N-phenyl-l,2,3,4-tetrahydroisoquinoline-7-sulfonamide iR-NMR (CDCI3): 8 = 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, IH); 7.4-7.6 (m, 5H); 7.9 (d, 2H) . C26H28N6O2S2 (520.7) Melting point: 58-61°C Example 26 2-(3-{[4-Methyl-5-(4-methyl-l,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-N-phenyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide iH-NMR (CDCI3): 8 = 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, IH). C25H28N6O2S3 (540.7) Melting point: 77-81°C Example 27 2-(3-{[5-(2,4-Dimethoxy)phenyl)-4-methyl-4H-l,2,4-triazol-3-yl]-sulfanyl}propyl)-7-(methylsulfonyl)-1,2,3,4-tetrahydroiso¬quinoline IH-NMR (CDCI3): 8 = 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, IH); 6.65 (d, IH); 7.25 (d, IH); 7.3 (d, IH); 7.7 (s, IH); 7.8 (d, IH). C24H30N4O4S2 (502.7) MS: 503.5 [M+H] + Example 28 6,7-Dichloro-2-{3-[(4-methyl-5-phenyl-4H-l,2,4-triazol-3-yl)- sulfanyl]propyl}-l,2,3,4-tetrahydroisoquinoline C21H22CI2N4S (433.4) Melting point: 138-1390C Example 29 7,8-Dichloro-2-{3-[(4-methyl-5-phenyl-4H-l,2,4-triazol-3-yl)-sulf anyl]propyl}-l,2, 3,4-tetrahydroisoquinoline hydrochloride IH-NMR (CDCI3): 8 = 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, IH); 7.2 (d, IH); 7.5 (m, 3H); 7.7 (m, 2H), [free base]. Salt precipitation with ethereal HCl led to the title compound C2iH22Cl2N4S-x HCl (469.9) Melting point: IO90C Example 30 7-Cyano-2-[4-(4-methyl-5-phenyl-4H-l,2,4-triazol-3-yl)butyl]- 1,2,3,4-tetrahydroisoquinoline hydrochloride C23H25N5-HC1(407.9) Melting point: 175°C Example 31 2-{3-[(4-Methyl-5-thien-3-yl-4H-l,2,4-triazol-3-yl)sulfanyl]- propyl}-6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride C20H2lF3N4S2-Cl X HCl (475) Melting point: 184-185°C Example 32 l-{2-[3-({4-Methyl-5-[4-(trifluoromethyl)phenyl]- 4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1,2,3,4-tetrahydroiso- quinolin-7-yl}ethanone iH-NMR (CDCI3): 8 = 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, IH); 7.6-7.8 (m, 6H). C24H25F3N4OS (474.5) The hydrochloride of the title compound was obtained by treatment with ethereal hydrochloric acid: Melting point: 183°C Example 33 6,7-Dichloro-2-(3-{[4-methyl-5-(4-methylphenyl)-4H-1,2,4-triazol- 3-yl]sulfanyl}propyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride iH-NMR (CDCI3): 8 = 2.1 (q, 2H) ; 2.4 (s, 3H); 2.7 (m, 4H); 2.8 (t, 2H); 3.3 (t, 2H); 3.5 (s, 2H); 3.6 (s, 3H); 7.1 (s, IH); 7.2 (s, IH); 7.3 (d, 2H); 7.5 (d, 2H); [free base]. The title compound was obtained by treatment with ethereal hydrochloric acid C22H24C12N4S-HC1 (483.9) Melting point: 207-210OC Example 34 6-Chloro-2-{3-[(4-methyl-5-phenyl-4H-l,2,4-triazol-3-yl)- sulfanyl]propyl}-l,2,3,4-tetrahydroisoquinoline hydrochloride iR-NMR (CDCI3): 8 = 2.1 (q, 2H); 2.4 (s, 3H); 2.7 (m, 4H); 2.8 (t, 2H); 3.3 (t, 2H); 3.5 (s, 2H); 3.6 (m, 5H); 6.9 (d, IH); 7.1 (m, 2H); 7.5 (d, 3H); 7.5 (d, 2H); [free base]. Salt precipitation with ethereal HCl led to the title compound C2iH23ClN4S-HCl (435.4) Melting point: 188-191°C Example 35 2-(3-{[4-Methyl-5-(l-methyl-lH-pyrrol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-7-(piperidin-l-ylsulfonyl)-l,2,3,4-tetra¬hydroisoquinoline IH-NMR (CDCI3): 6 = 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, IH); 6.4 (m, IH); 6.8 (m, IH); 7.2 (d, IH); 7.4 (s, IH); 7.5 (m, 2H). C25H34N6O2S2 (514.7) Melting point: 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 C27H35N5O2S (493.7) MS: 494.3 [M+H] + Example 37 2-(3-{[4-Methyl-5-thien-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}- propyl)-7-(piperidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline iH-NMR (CDCI3): 8 = 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, IH); 7.4 (s, IH); 7.5 (m, 3H); 7.7 (s, IH). C24H31N5O2S3 (517.7) MS: 518.3 [M+H]+ Melting point: 192-1950C Example 38 2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}- N-phenyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide iH-NMR (CDCI3): 8 = 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). C27H29N5O2S2 (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}-l,2,3,4-tetrahydroisoquinoline C19H21CIN4S2 (405) Melting point: 99-lOOoc Example 40 7-[(Diethylammonio)methyl]-2-{3-[(4-methyl-5-phenyl-4H-1,2,4- triazol-3-yl)sulfanyl]propyl}-l,2,3,4-tetrahydroisoquinoline dihydrochloride C26H35N5S-2HC1 (522.6) Melting point: 75°C Example 41 2-{3-[(4-Methyl-5-thien-3-yl-4H-l,2,4-triazol-3-yl)sulfanyl]- propyl}-7-(trifluoromethyl)-!,2,3,4-tetrahydroisoquinoline hydrochloride Preparation of the starting material 41A 7-Trifluoromethyl-1,2,3,4-tetrahydroisoquinoline 10.0 ml of concentrated sulfuric acid were slowly added dropwise to a solution of 1.77 g (6.2 mmol) of N-trifluoroacetyl-2-(4-trifluoromethylphenyl)ethylamine [prepared from 2-(4-trifluoromethylphenyl)ethylamine and trifluoroacetic anhydride at -5°C] in 7.5 ml of glacial acetic acid, and, while cooling in ice, 2 ml of formalin solution were added dropwise. After 18 hours at room temperature, the reaction mixture was poured into 130 ml of iC6-water and extracted with dichloromethane, and the combined organic phases were washed with sodium bicarbonate solution and then with water. After drying over sodium sulfate, filtration and evaporation, 1.7 g of 2-trifluoroacetyl-7-trifluoromethyl-1,2,3,4-tetrahydroiso¬quinoline were isolated and were converted into 7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline by heating under reflux in ethanol/3N HCl (1:1) and alkaline workup. Yield: 1.0 g (4.7 mmol) 75% of theory. iH-NMR (CDCI3): 6 = 2.0 (sbr, IH); 2.9 (t, 2H); 3.2 (t, 2H); 4.0 (s, 2H); 7.2 (d, IH); 7.3 (s, IH); 7.4 (s, IH). 4 IB 2-(3-Chloropropyl)-7-trifluoromethyl-1,2,3,4-tetrahydroiso¬quinoline 0.95 g (4.7 mmol) of the compound described above was reacted with l-bromo-3-chloropropane in the same way as described in Example 4B at room temperature, and purified by chromatography (silica gel, mobile phase dichloromethane with 2% methanol). Yield: 0.9 g (3.2 mmol) 69% of theory. iH-NMR (CDCI3): 6 = 2.0 (m, 2H); 2,65 (m, 2H); 2.75 (m, 2H); 2.9 (m, 2H); 3.65 (m, 4H); 7.2 (dd, IH); 7.3 (d, IH); 7.4 (dd, IH). 41C Preparation of the final product 0.45 g (1.6 mmol) of 2~(3-chloropropyl)-7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline, 0.36 g (1.6 mmol) of 3-mercapto-4-methyl-5-thien-3-yl-4H-l,2,4-tria2ole and 40 mg of lithium hydroxide were stirred in 6 ml of DMF at 100°C for 4 hours. Workup entailed pouring into ice/water, extraction with methyl tert-butyl ether, drying over sodium sulfate and purification after filtration and evaporation by column chromatography (silica gel, mobile phase dichloromethane with 3-5% methanol). Yield: 0.3 g (0.7 mmol) 42% of theory. iH-NMR (CDCI3): 8 = 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, IH); 7.2 (s, IH); 7.3 (d, IH); 7.5 (m, 2H); 7.7 (s, IH); [free base]. The title compound was obtained by treatment with ethereal HCl C2oH2iF3N4S2-HCl (475) Melting point: 192-194°C Example 42 2-{3-[(4-Methyl-5-phenyl-4H-l,2,4-triazol-3-yl)sulfanyl]propyl}- 8-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride Preparation of the starting materials 42A 6/8-Trifluoromethyl-1,2,3,4-tetrahydroisoquinoline 5.3 g (18.6 mmol) of N-trifluoroacetyl-2-(3-trifluoromethyl-phenyl)ethylamine [prepared from 2-(3-trifluoromethylphenyl)-ethylamine and trifluoroacetic anhydride at -5°C] and 0.9 g (29 mmol) of paraformaldehyde were added to a mixture of 2 2 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 iC6-water and extracted with ethyl acetate, and the combined organic phases were washed with sodium bicarbonate solution and then with water. After drying over sodium sulfate, filtration and evaporation, 5,4 g of a mixture of 2-trifluoroacetyl-6- and -8-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline were isolated. The protective group was eliminated by heating in ethanol/3N HCl (1:1) under reflux. The two isomers were separated after workup and purification by chromatography (silica gel, mobile phase dichloromethane with 2-4% methanol): Fl 1.2 g (5.7 mmol) 32% of theory of 8-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline iH-NMR (CDCI3): 8 = 1.9 (sbr, IH); 2.8 (t, 2H); 3.1 (t, 2H) ; 4.2 (s, 2H); 7.2 (m, 2H); 7.5 (d, IH), F2 1.4 g (6,8 mmol) 38% of theory of 6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline iH-NMR (CDCI3): 8 = 1,8 (sbr, IH); 2,8 (t, 2H); 3.1 (t, 2H); 4.0 (s, 2H); 7.1 (d, IH); 7,4 (m, 2H). 42 B 2-(3-Chloropropyl)~8-trifluoromethyl-l,2,3,4-tetrahydro¬ isoquinoline 2-(3-Chloropropyl)-8-trifluoromethyl-1,2,3,4-tetrahydroiso¬quinoline was obtained in 73% yield by reacting 42-A Fl with bromochloropropane in a manner analogous to the description in Example 4C. iR-NMR (CDCI3): 8 = 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, IH), 42C Preparation of the final compound Reaction 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 mmol) of 2-(3-chloropropyl)-8-trif luoromethyl-1,2,3, 4-tetrahydroisoquinoline [42B1] in 10 ml of DMF in the presence of 70 mg of lithium hydroxide at lOQoc afforded, after workup as described under 4D, 0.84 g (1.9 mmol) of the final compound. Yield: 0.84 g (1.9 mmol) 65% of theory iH-NMR (CDCI3): 8 = 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, IH); 7.25 (d, IH); 7.4 (d, IH), 7.5 (m, 3H); 7,6 (m, 2H), The title compound was obtained by treatment with ethereal HCl, C22H23F3N4S-HC1 (469) Melting point: 1180 Example 43 2-{3-[(4-Methyl-5-phenyl-4H-l,2,4-triazol-3-yl)sulfanyl]propyl}- 6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride Preparation of the starting materials 43 B2 2-(3-Chloropropyl)-6-trifluoromethyl-1,2,3,4-tetrahydro¬ isoquinoline 2-(3-Chloropropyl)-6-trifluoromethyl-1,2,3,4-tetrahydroiso-quinoline was obtained in 96% yield by reacting 6-trifluoro-methyl-1,2,3,4-tetrahydroisoquinoline [42AF2] (obtained as described in 42A) with bromochloropropane in a manner analogous to that described for 4C. iH-NMR (CDCI3): 8 = 2.0 (m, 2H); 2.6-2.8 (m, 4H); 2.9 (t, 2H) ; 3.6 (m, 4H) 7.1 (d, IH); 7.4 (m, 2H). 4 3C Preparation of the final compound Reaction 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 mmol) of 2-(3-chloropropyl)-6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline in 10 ml of DMF in the presence of 70 mg of lithium hydroxide at lOQoc afforded, after workup as described under 4D, 0.75 g (1.7 mmol) of the final compound. Yield: 0.75 g (1.7 mmol) 58% of theory iH-NMR (CDCI3): 8 = 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, IH); 7.3 (m, 2H); 7.5 (m, 3H); 7.7 (m, 2H); [free base]. The title compound was obtained by treatment with ethereal HCl C22H23F3N4S-HC1 (469) Melting point: 200-202°C Example 44 2-{3-[(4-Methyl-5-phenyl-4H-l,2,4-triazol-3-yl)sulfanyl]propyl}- 7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride C22H23F3N4S-HC1 (469) Melting point: 205-207OC Example 45 2-{3-[(4-Methyl-5-(thien-3-yl)-4H-1,2,4-triazol-3-yl)sulfanyl]-propyl}-7-(4-methylpipera2in-l-ylsulfonyl)-1,2,3,4-tetrahydroiso¬quinoline iH-NMR (CDCI3): 6 = 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, IH). C24H32N6O2S3 (538.8) Example 4 6 2-{3-[(4-MethYl-5-(phenyl)-4H-1,2,4-tria20l-3-yl)sulfanyl]-propyl}-7-(4-methylpiperazin-l-ylsulfonyl)-1,2,3,4-tetrahydroiso-quinoline iH-NMR (CDCI3): 6 = 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, IH); 7.5 (m, 5H); 7.6 (m, 2H). C26H34N6O2S3 (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-tetrahydroisoquinolin-l-ylsulfonyl)-1,2,3,4- tetrahydroisoquinoline iH-NMR (CDCI3): 6 = 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, IH); 7.4-7.6 (m, 4H); 7.7 (m, IH). C28H31N5O2S3 (565) Example 48 2-{3-[(4-Methyl-5-(pyrid-3-yl)-4H-1,2,4-triazol-3-yl)sulfanyl]-propyl}-7-(1,2,3,4-tetrahydroisoquinolin-l-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline iH-NMR (CDCI3) 6 = 2.1 (q, 2H) ; 2.7 (t, 2H) ; 2.8 (t, 2H); 2.9 (m, 4H); 3.3 (m, 4H); 3.6 (s, 3H); 3.7 (s, 2H) ; 4.2 (s, 2H); 7.0-7.2 (m, 5H); 7.2 (m, IH); 7.4-7.6 (m, 3H); 8.0 (m, IH); 8.7 (m, IH); 8.9 (m, IH). C29H32N6O2S2 (558) Example 49 7-[(3,3-Dimethylpiperidin-l-yl)sulfonyl]-2-{3-[(4-methyl-5-phenyl-4H-l,2,4-triazol-3-yl)sulfanyl]propyl}-1,2,3,4-tetra¬hydroisoquinoline C28H37N5O2S2 (539.8) I Melting point: 75-760C Example 50 2-{3-[(4-Cyclopropyl-5-phenyl-4H-l,2,4-triazol-3-yl)sulfanyl]-propyl}-7-[(3,3-dimethylpiperidin-l-yl)sulfonyl]-1,2,3,4-tetra-5 hydroisoquinoline C30H39N5O2S2 (558) Example 51 2-[(4-{[(4-Methyl-5-(l-methyl-lH-pyrrol-3-yl)-4H-1,2 , 4-tria2ol- 3-yl)sulfanyl]methyl}eyelohexyl)methyl]-7-nitro-l,2,3,4-tetra- hydroisoquinoline C25H31N5O2S (477.6) Melting point: I6OOC Example 52 2-{(E)-4-[(4-Methyl-5-pyridin-3-yl-4H-l,2,4-triazol-3-yl)- sulfanyl]but-2-enyl}-7-nitro-l,2,3,4-tetrahydroisoquinoline C21H22N6O2S (422) MS: 423 [M+H]+ Example 53 2-[(4-{[(4-methyl-5-pyridin-3-yl-4H-l,2,4-tria2ol-3-yl)sulfanyl]- methyl}cyclohexyl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-carbo- nitrile C27H31N5S (457.6) Melting point: 156-1580C Example 54 1-(2-{3-[(4-Methyl-5-(3-cyano)phenyl-4H-l,2,4-triazol-3-yl)sulfa- nyl]propyl}-!,2,3,4-tetrahydroisoquinolin-7-yl)ethanone hydrochloride C24H25N5OS X HCl (468) Melting point: 185°C Example 55 7-Nitro-2-[(4-{[(4-methyl-5-pyridin-3-yl-4H-l, 2,4-triazol-3-yl)-sulfanyl]-methyl}cyclo-hexyl)methyl]-1,2,3,4-tetrahydroiso¬quinoline C26H31N6O2S (477.6) Melting point: I6OOC Example 56 l_p_ [ 3_ ( {4-Methyl-5-phenyl ] -4H-1, 2 , 4-triazol-3-yl} sulf anyl) - propyl]-l,2,3,4-tetrahydroisoquinolin-7-yl}ethanone hydrochloride C23H27N4OS X HCl (443) Melting point: 165oc Example 57 7,8-Dichloro-2-{3-[(4-methyl-5-phenyl-4H-l,2,4-triazol-3-yl)-sulfanyl]propyl}-!,2,3,4-tetrahydroisoquinoline C21H22CIN4S (399) Melting point: 12-15'C Example 58 l-{2-[3-({5-{2,4-Dinitrophenyl)-4-methyl]-4H-l,2,4-triazol-3-yl}-sulfanyl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}ethanone hydrochloride C23H25N6O5S X HCl (500.6) Melting point: 193°C Example 59 2-{3~[(4-Methyl-5-phenyl-4H-l,2,4-triazol-3-yl)sulfanyl]propyl}- 7-(octahydroisoquinolin-2(IH)-ylsulfonyl)-1,2,3,4-tetrahydro- isoquinoline C30H39N5O2S2 (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}-?-(octahydroisoquinolin-2(lH)-ylsulfonyl)-l,2,3,4-tetra- hydroisoquinoline C29H3aN602S2 (566.8) MS: 568 [M+H] + Example 61 2-{3-[(4-Cyclopropyl-5-phenyl-4H-l,2,4-triazol-3-yl)sulfanyl]- propyl}-?-(azepan-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline C29H37N5O2S2 (551.8) MS: 552 [M] + Example 62 2-{3-[(4-Methyl-5-phenyl-4H-l,2,4-triazol-3-yl)sulfanylJpropyl}- 7-(pyrrolidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline C25H31N5O2S2 (497.7) Example 63 2_{3-[(4-Methyl-5-phenyl-4H-l,2,4-triazol-3-yl)sulfanyl]propyl}- 7-(azepan-l-ylsulfonyl)-l,2,3,4-tetrahydroisoquinoline C27H35N5O2S2 (525.7) Example 64 7-Chlor-2-(3-{[4-methyl-5-phenyl-4H-l,2,4-triazol-3-yl]sulfanyl}- but-2-en-yl)-1,2,3,4-tetrahydroisoquinoline C21H23CIN4S (399) Melting point: 12-15°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-tetrahydroisoquinoline Example 66 N,4-Dimethyl-5-{[3-(7-(piperidin-1-ylsulfonyl)-3,4-dihydroiso- quinolin-2(IH)-yl)propyl]sulfanyl}-4H-l,2,4-triazol-3-amine Example 67 7-tert-Butyl-2-(3-{[4-methyl-5-(4-methyl-l,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1,2,3,4-tetrahydroiso¬quinoline Example 68 2-{3-[(4-Methyl-5-pyridin-3-yl-4H-l,2,4-triazol-3-yl)sulfanyl]- propyl}-7-(azepan-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline Example 69 7-({4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-l-yl}sulfonyl)-2-{3-[(4-methyl-5-phenyl-4H-l,2,4-triazol-3-yl)-sulfanyl]propyl}-l,2,3,4-tetrahydroisoquinoline Example 70 8-Brom-2-(3-{[5-cyclohexyl-4-methyl-4H-l,2,4-triazol-3-yl]sulfa- nyl}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-l,2,4-triazole- 3-carboxamide Example 72 6-Methyl-2-(3-{[4-methyl-5-(l-methyl-lH-pyrrol-3-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}-propyl)-7-(pyrrolidin-1-ylsulfonyl)- 1,2,3,4-tetrahydroisoquinoline Example 73 7-Cyano-2-[(2-{[(4-Methyl-5-pyridin-3-yl-4H-l,2,4-triazol-3-yl)- sulfanyl]-methyl}-cyclopropy1)methyl]~1,2,3,4-tetrahydroiso- quinoline Example 74 1-(2-{3-[(4-Methyl-5-(3-methoxy)phenyl-4H-l,2 , 4-triazol-3-yl)- oxy]propyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)ethanone Example 75 4-(7-(Pyrrolidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline- 2-yl)butyl-4-methyl-5-phenyl-4H-l,2,4-triazole-3-carboxylate Example 7 6 2-[2-({[5-(N-Methylpyrrol-2-yl)-4-methyl-4H-l,2,4-triazol- 3-y1]-sulfanyl}methyl)prop-2-enyl]-1,2,3,4-tetrahydroiso- quinolin-7-carboxamide Example 77 2-{3-[(4-Cyclopropy1-5-(4-methylsulfonyl)phenyl-4H-1,2,4-triazol- 3-yl)sulfanyl]propyl}-7-(pyrrolidin-1-ylsulfonyl)-1,2,3,4-tetra- hydroisoquinoline Example 78 6-tert-Butyl-2-(3-{[5-(2,4-dinitrophenyl)-4-methyl-4H-l,2,4-tri- azol-3-yl]sulfanyl}propyl)- 1,2,3,4-tetrahydroisoquinoline Example 79 N-[2-(8-{[5-(dimethylamino)-4-butyl-4H-l,2,4-triazol-3-yl]sulfa- nyl}octyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]methansulfonamide Example 80 2-{3-[(4-Methyl-5-pyrazin-2-yl-4H-l,2,4-tria2ol-3-yl)sulfanyl]- propyl}-7-(octahydro-isoquinolin-2(IH)-ylsulfonyl)- 1,2,3,4-tetrahydroisoquinoline Example 81 7-Cyano-2-{3-[(4-methyl-5-(2-methyloxazol-4-yl)-4H-1,2,4-tria2ol- 3~yl)sulfanyl]propyl}-l,2,3,4-tetrahydroisoquinoline Example 82 2-{6-[(5-(2,5-Dimethylfuran-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]hexyl}-7-trifluormethansulfonyloxy-1,2,3,4-tetra¬hydroisoquinoline Example 83 2-[2-({[4-methyl-5-phenyl-4H-l,2,4-triazol-3-yl]sulfanyl}inethyl)- prop-2-enyl]-7-nitro-l,2,3,4-tetrahydroisoquinoline hydrochloride C22H23N5O2S X HCl (460) Melting point: 146-150OC Example 84 N-[2-(3-{[4-Methyl-5-phenyl-4H-l,2,4-tria2ol-3-yl]sulfanyl}- propyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]methansulfonamide C22H27N5O2S2 x HCl (494.1) Melting point: 90°C Examples of pharmaceutical administration forms A) Tablets Tablets of the following composition were pressed on a tabletting machine in the customary manner 40 mg of the substance from Example 1 120 mg of corn starch 13.5 mg of gelatin 45 mg of lactose 2.25 mg of Aerosil® (chemically pure silicic acid in a submicroscopically fine dispersion) 6.75 mg of potato starch (as a 6% paste) B) Sugar-coated tablets 20 mg of the substance from Example 3 60 mg of core composition 70 mg of sugar-coating composition The core composition consists of 9 parts of corn starch, 3 parts of lactose and 1 part of vinylpyrrolidone-vinyl ace¬tate 60:40 copolymer. The sugar-coating composition consists of 5 parts of cane sugar, 2 parts of corn starch, 2 parts of calcium carbonate and 1 part of talc. The sugar-coated ta¬blets which have been prepared in this way are then provided with an enteric coating. Biological investigations - receptor binding studies 1) D3 binding test Cloned human Da-receptor-expressing CCL 1,3 mouse fibro¬blasts, obtainable from Res. Biochemicals Internat. One Strathmore Rd,, Natick, MA 01760-2418 USA, were used for the binding studies. Cell preparation The D3-expressing cells were multiplied in RPMI-1640 contai¬ning 10% fetal calf serum (GIBCO No. 041-32400 N); 100 U of penicillin/ml and 0.2% streptomycin (GIBO BRL, Gaithersburg, MD, USA). After 48 h, the cells were washed with PBS and in¬cubated for 5 min with 0.05% trypsin-containing PBS. After that, the solution was neutralized with medium and the cells were collected by centrifuging at 3 00 g. In order to lyse the cells, the pellet was washed briefly with lysis buffer (5 mM Tris-HCl, pH 7.4, containing 10% glycerol) and after that in¬cubated, at 40c for 30 min, at a concentration of lO' cells/ml of lysis buffer. The cells were centrifuged at 200 g for 10 min and the pellet was stored in liquid nitrogen. Binding tests .For the D3-receptor binding test, the membranes were suspen¬ded in incubation buffer (50 mM Tris-HCl, pH 7.4, containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, 2 mM MgCl2, 10 \m quinoli-nol, 0.1% ascorbic acid and 0.1% BSA), at a concentration of approx. 10 cells/250 [il of test mixture, and incubated at 30°C with 0.1 nM i25iodosulpiride in the presence and absence of the test substance. The nonspecific binding was determined using 10- M spiperone. After 60 min, the free radioligand and the bound radioligand were separated by filtering through GF/B glass fiber filters (Whatman, England) on a Skatron cell harvester (Skatron, Lier, Norway), and the filters were washed with iC6-cold Tris-HCl buffer, pH 7.4- The radioactivity which had collec¬ted on the filters was quantified using a Packard 2200 CA li¬quid scintillation counter. The Ki values were determined by means of nonlinear regres¬sion analysis using the LIGAND program. 2) D2 binding test Cell culture HEK-2 93 cells possessing stably expressed human dopamine D2A receptors were cultured in RPMI 1640 containing Glutamix I' and 25 mM HEPES containing 10% fetal calf serum albumin. All the media contained 100 units of penicillin per mol and 100 ng/ml of streptomycin/ml. The cells were maintained at 370c in a moist atmosphere containing 5% CO2. The cells were prepared for the binding studies by trypsini-zing them (0.05% solution of trypsin) at room temperature for 3-5 minutes. After that, the cells were centrifuged at 2 50 g for 10 minutes and treated with lysis buffer (5 mM Tris-HCl, 10% glycerol, pH 7.4) at 4°C for 30 minutes. After centrifu-ging at 250 g for 10 minutes, the residue was stored at -20oc until used. Receptor binding tests Low affinity state dopamine D2 receptor using isj.gpipej-one (81 TBq/irunol, Du Pont de Nemours, Dreieich) The test mixtures (1 ml) consisted of 1 x 10 cells in incubation buffer (50 mM Tris, 120 mM NaCl, 5 mM KCl, 2 mM MgClj and 2 mM CaCl2, pH 7.4 with HCl) and 0.1 mM i25i_spiperone (total binding) or additionally 1 \|J,M haloperidol (nonspecific binding) or test substance. After the test mixtures had been incubated at 25°C for 60 minutes, they were filtered through GM/B glass filters (Whatman, England) on a Skatron cell harvester (from Zinsser, Frankfurt), and the filters were washed with iC6-cold 50 mM Tris-HCl buffer, pH 7.4. The radioactivity which had collected on the filters was quanti¬fied using a Packard 2200 CA liquid scintillation counter. The results were evaluated as described in a). The Ki values were determined by way of nonlinear regression ana¬lysis using the LIGAND program or by converting the IC50 values using the Cheng and Prusoff formula. In these tests, the compounds according to the invention exhibit very good affinities for the D3 receptor ( We claim: 1. A triazole compound of the formula I R1 is H, C1-C6-alkyl, which may be substituted by OH, OC1-C3-alkyl, halogen or phenyl, C3-C6-cycloalkyl or phenyl; R2 is H, C1-C6-alkyl, which may be substituted by OH, OC1-C6-alkyl, halogen or phenyl, C1-C3-alkoxy, C1-C6-alkylthio, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, halogen, CN, C00R3, CONR2R4, NR2R4/ SO2R3, SOZNR2R4 or an aromatic radical which is selected from phenyl, naphthyl and a 5- or 6-membered heterocyclic radical having 1, 2, 3 or 4 heteroatoms which are selected, independently of each other, from 0, N and S, with it being possible for the aromatic radical to have one or two substituents which are selected, independently of each other, from C1-C6-alkyl, which may be substituted by OH, OC1-C6-alkyl, halogen or phenyl, C1-C3-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, halogen, CN, C0R3, NR3R4, NO2, SO2R3, SO2NR3R4 and phenyl which may be substituted by one or two radicals which are selected, independently of each other, from C1-C6-alkyl, C1-C6-alkoxy, NR3R4, CN, CF3, CHF2 or halogen; R3 and R4 are, independently of each other, H, C1-C6-alkyl, which may be substituted by OH, OC1-C6-alkyl, halogen or phenyl, or phenyl; A is C4-C10-alkylene or C3-C10-alkylene which comprises at least one group Z which is selected from O, S, CONR2, COO, CO, C3-C6-cycloalkyl and a double or triple bond; B is a radical of the following formula: R6, R7 and R8 are, independently of each other, selected from H, C1-C6-alkyl, which may be substituted by OH, OC1-C6-alkyl, which may be substituted by amino, mono- or di~C1-C4-alkylamino; C1-C6-alkylthio, halogen or phenyl; OH, C1-C6-alkoxy, OCF3, OSO2CF3, SH, C1-C6-alkylthio, C2-C6-alkenyl, C2-C6-alkynyl, halogen, CN, NO2, CO2R3, SOaR2, S02NR3R4, where R3 and R4 have the abovementioned meanings and may also form together with the N atom to which they are bonded a saturated or unsaturated heterocycle with 5 to 7 ring atoms and 1 or 2 N heteroatoms, CONR2R4, NHSO2R3, NR3R4, a 5- or 6-membered carbocyclic, aromatic or nonaromatic ring and a 5- or 6-membered heterocyclic, aromatic or nonaromatic ring with 1 or 2 heteroatoms which are selected, independently of each other, from 0, N and S, with the carbocyclic or heterocyclic ring being able to have one or two substituents which are selected, independently of each other, from C1-C6-alkyl, phenyl, phenoxy, halogen, C1-C6-alkoxy, OH, NO2, CF3 and CHF2, and with two of the substituents R2, R' and R2 being able to form, together with the carbon atoms of the phenyl ring to which they are bonded, a phenyl, cyclopentyl or cyclohexyl ring which is fused to the phenyl ring, with the possibility for one or two of the CH or CH2 groups in the fused ring being replaced by a nitrogen atom, an NH or an N-C1-C6 alkyl group; and the salts thereof with physiologically tolerated acids. 2. The compound as claimed in claim 1 of the formula I, where X is CH2CH2. 3. The compound as claimed in claim 1 or 2 of the formula I, where A is C4-C10-alkylene or C3-C10-alkylene which comprises at least one group Z which is selected from 0, S, COO, CO, a double bond or triple bond and C3-C6-cycloalkyl. 4. The compound as claimed in one of the preceding claims of the formula I, where A is C4-C:o-alkylene of C3-C10-alkylene which comprises at least one group Z which is selected from 0, S, a double bond and cyclohexyl. 5. The compound as claimed in one of the preceding claims of the formula I, where R2 is an aromatic radical which is unsubstituted or has one or two substituents which are selected, independently of each other, from C1-C6-alkyl, OH, C1-C6-alkoxy, phenyl, CN and halogen. 6. The compound as claimed in one of the preceding claims of the formula I, where R2 is H, C1-C6-alkyl, phenyl, thienyl, furanyl, tetrazolyl, pyrrolyl, pyridyl or pyrazinyl. 7. The compound as claimed in one of the preceding claims of the formula I, where R2 is H, C1-C6-alkyl or C3-C6-cycloalkyl. 8. The compound as claimed in one of the preceding claims of the formula I, where R2, R7 and R2 are selected, independently of each other, from H, C1-C6-alkyl, OH, C1-C6-alkoxy, C1-C6-akylthio-C1-C6-alkyl, halogen, CN, NO2, SO2R3, SOZNR2RI and C0NR3R4. 9. The compound as claimed in claim 1 of the formula I, where R2 is H, C1-C6-alkyl or phenyl, R2 is H, C1-C6-alkyl, phenyl, thienyl, furanyl, tetrazolyl, pyrrolyl, thiazolyl or pyrazinyl, A is -SC3-C10-alkylene which may comprise a double bond, and' R5, R7 and R2 are selected from H, C1-C6-alkyl, C1-C3-alkoxy, halogen, SOzNR2R1, CN, NO2, CF3, CONR2R4, CHF2, OSO2CF3, OCF3 and NHS02-C1-C6-alkyl. 10 .The compound which is selected from l-{2-[3-({4-methyl-5-[4-{trifluoromethyl)phenyl]-4H-l,2,4-triazol-3-yl}sulfanyl)propyl]-l,2,3,4-tetrahydroisochino-lin-7-yl}-ethanon; l-{2-{3-[(4-methyl-5-(3-cyano)phenyl-4H-l,2,4-triazol-3-yl) sufanyl]propyl}-!,2,3,4-tetrahydroisochinolin-7-yl)ethanon; l-{2-[3-({4-methyl-5-phenyl-4H-l,2,4-triazol-3-yl>sul-fany1)propyl]-1,2,3,4-tetrahydroisochinolin-7-yl}ethanon; l-{2-[3-({5-(2,4-dinitrophenyl)-4-methyl]-4H-1,2,4-triazol-3-yl}-sulfanyl)propyl] -l,2,3,4-tetrahydroisochinolin-7-yl}-ethanon; l-{2-{3-[(4-methyl-5-(3-methoxy)phenyl-4H-l,2,4-triazol- 3-yl)-oxy]propyl}-1,2,3,4-tetrahydro-isochinolin-7-yl)etha-non; l-{2-[ 3-( {4-isopropyl-5-phenyl-4H-I,2,4-triazol-3-yl}sui-fanyl ) propyl] -1,2,3, 4-tetrahydroisochinolin-7-yI}ethanor. ; l-{2-[3-( {4-butyl-5-phenyl-4H-l,2,4-triazol-3-yl}oul-fanyl)propyl]~1,2,3,4-tetrahydroisochinolin-7-yl}ethanon; l-{2-[3-({5-pheny1-4-propyl-4H-1,2,4-triazol-3-yl}su1-fanyl)propyl]-1,2,3,4-tetrahydroisochinolin-7-yl}ethanon; l-{2-[3-({4-eyelopropyl-5-phenyl-4H-1,2,4-triazol-3-yl}sul-fanyl)propyl]-1,2,3,4-tetrahydroisochinolin-7-yl}ethanon; und l-{2-[3-( {4-ethyl-5-phenyl-4H-l,_2,4-triazol-3-yl}sul-fanyl)propyl]-1,2,3,4-tetrahydroisochinolin-7-yl}ethanon. 11. A pharmaceutical which comprises at least one compound as claimed in one of claims 1 to 9, where appropriate together with physiologically acceptable excipients and/or adjuvants.

Full Text

Triazole compounds and their use
The invention relates to triazole compounds and to the use of these compounds. These compounds possess valuable therapeutic properties and can be used for treating diseases which respond to the influence of dopamine D3 receptor ligands.
Compounds of the type which is under discussion here and which possess 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 which act on the dopamine receptors. DE 44 25 144 A, WO 96/30333, WO 97/25324, WO 97/40015, WO 97/47602, WO 97/17326, EP 887 350, EP 779 284 A and Bioorg. & Med, Chem. Letters 9 (1999) 2059-2064 disclose further compounds which possess activity as dopamine D3 receptor ligands. US 4,338,453; 4,408,049 and 4,577,020 disclose triazole compounds which possess antiallergic or antipsychotic activity. WO 93/08799 and WO 94/25013 describe compounds of the type which is under discussion here and which constitute endothelin receptor antagonists. Additional triazole compounds, which inhibit blood platelet aggregation and which have a hypotensive effect are described in Pharmazie 16, (1991), 109-112. Further triazole compounds which possess physiological activity are disclosed in EP 691 342, EP 556 119, WO 97/10210, WO 98/24791, WO 96/31512 and WO 92/20655.
Neurons obtain their information by way of G protein-coupled receptors, inter alia. There are a large number of substances which exert their effect by way of these receptors. One of them is dopamine.
A number of facts about the presence of dopamine, and its physiological function as a neuron transmitter, are known with certainty. Disturbances of the dopaminergic transmitter system result in diseases such as schizophrenia, depression and Parkinson's disease. These, and other, diseases are treated with drugs which interact with the dopamine receptors.
By 199 0, two subtypes of dopamine receptor had been clearly defined pharmacologically, namely the Di and D2 receptors.
More recently, a third subtype has been found, namely the D3 receptor, which appears to mediate some of the effects of the antipsychotic and anti-Parkinson agents (J.C. Schwartz et al., The Dopamine D3 Receptor as a Target for Antipsychotics, in Novel Antipsychotic Drugs, H.Y. Meltzer, Ed. Raven Press, New York

1992, pages 135-144; M. Dooley et al,. Drugs and Aging 1998, 12, 495-514) .
Since D3 receptors are chiefly expressed in the limbic system, it is assumed that while a selective D3 ligand would probably have the properties of known antipsychotic agents, it would not have their dopamine D3 receptor-mediated neurological side-effects (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, 347, 146 (1990)).
Surprisingly, it has now been found that certain triazole compounds exhibit a high affinity for the dopamine D3 receptor and a low affinity for the D2 receptor. These compounds are consequently selective D3 ligands.
The present invention relates, therefore, to the compounds of the formula I:

R1 is H, C1-C6-alkyl, which may be substituted by OH,
OC1-C6-alkyl, halogen or phenyl, C6-C6-cycloalkyl or phenyl;
R2 is H, C1-C6-alkyl, which may be substituted by OH, OC1-C6-alkyl, halogen or phenyl, C1-C6-alkoxy, C1-C6-alkylthio, C2-C6-alkenyl, C2-C6-alkynyl, C3_C6-cycloalkyl, halogen, CN, C00R3, C0NR3R4, NR3R4, SO2R3, S02NR3R4,or an aromatic radical which is selected from phenyl, naphthyl and a 5- or 6-membered heterocyclic radical having 1, 2, 3 or 4 heteroatoms which are selected, independently of each other, from O, N and S, with it being possible for the aromatic radical to have one or two substituents which are selected, independently of each other, from C1-C6-alkyl, which may be substituted by OH, OC1-C6-alkyl, halogen or phenyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C6-C6-cycloalkyl, halogen, CN, COR2, NR2R2, NO2, SO2R3, S02NR3R'1 and phenyl which may be substituted by one or two radicals which are selected, independently of each other, from C1-C6-alkyl, C1-C6-alkoxy, NR3R4, CN, CF3, CHF2 or halogen;

R3 and R4 are, independently of each other, H, C1-C6-alkyl, which
may be substituted by OH, OC1-C6-alkyl, halogen or phenyl, or
phenyl; A is C4-C10-alkylene or Ca-Cio-alkylene which comprises at least
one group Z which is selected from 0, S, C0NR3, COO, CO,
Ca-C6-cycloalkyl and a double or triple bond;

R6, R7 and R2 are, independently of each other, selected from H, C1-C6-alkyl, which may be substituted by OH, OC1-C6-alkyl, which may be substituted by amino, mono- or
di-C1-C4-alkylamino; C1-C6-alkylthio, halogen or phenyl; OH, C1-C6-alkoxy, OCF3, OSO2CF3, SH, C1-C6-alkylthio, C2-C6-alkenyl, C2-C6-alkynyl, halogen, CN, NO2, C02R2, SO2R3, S02NR3R4, where R2 and R' have the abovementioned meanings and may also form together with the N atom to which they are bonded a saturated or unsaturated heterocycle with 5 to 7 ring atoms and 1 or 2 N and/or O heteroatoms, CONR2R2, NHS02R2, NR3R4, a 5- or 6-membered carbocyclic, aromatic or nonaromatic ring and a 5- or 6-membered heterocyclic, aromatic or nonaromatic ring with 1 or 2 heteroatoms which are selected, independently of each other, from O, N and S, with the carbocyclic or heterocyclic ring being able to have one or two substituents which are selected, independently of each other, from C1-C6-alkyl, phenyl, phenoxy, halogen, C1-C6-alkoxy, OH, NO2, CF3 and CHF2, and with two of the substituents R2, R2 and R2 being able to form, together with the carbon atoms of the phenyl ring to which they are bonded, a phenyl, cyclopentyl or cyclohexyl ring which is fused to the phenyl ring with the possibility for one or two of the CH or CH2 groups in the fused ring being replaced by a nitrogen atom, a NH or a N-(C1-C6-alkyl) group;
and the salts thereof with physiologically tolerated acids.
The compounds according to the invention are selective dopamine D3 receptor ligands which act in the limbic system in a regioselective manner and which, as a result of their low affinity for the D2 receptor, have fewer side-effects than do the classic neuroleptic agents, which are D2 receptor antagonists. The

compounds can therefore be used for treating diseases which respond to dopamine D3 ligands, i.e. they are effective for treating those diseases in which affecting (modulating) the dopamine D3 receptors leads to an improvement in the clinical picture or to the disease being cured. Examples of such diseases are diseases of the cardiovascular system and the kidneys, diseases of the central nervous system, in particular schizophrenia, affective disorders, neurotic stress and somatoform disorders, psychoses. Parkinsonism, attention deficit disorders, hyperactivity in children, epilepsy, amnesic and cognitive disorders such as learning and memory impairment (impaired cognitive function), anxiety states, dementia, delirium, personality disorders, sleep disturbances (for example restless legs syndrome), disorders of the sex life (male impotence), eating disorders and addictive disorders. Moreover they are useful in the treatment of stroke.
Addictive disorders include the psychological disorders and behavioral disturbances caused by the abuse of psychotropic substances such as pharmaceuticals or drugs, and other addictive disorders such as, for example, compulsive gambling (impulse control disorders not elsewhere classified). Addictive substances are, for example: opioids (for example morphine, heroin, codeine); cocaine; nicotine; alcohol; substances which interact with the GABA chloride channel complex, sedatives, hypnotics or tranquilizers, for example benzodiazepines; LSD; cannabinoids; psychomotor stimulants such as 3,4-methylenedioxy-N-methyl-amphetamine (ecstasy); amphetamine and amphetamine-like substances such as methylphenidate or other stimultants including caffeine. Addictive substances of particular concern are opioids, cocaine, amphetamine or amphetamine-like substances, nicotine and alcohol.
rhe compounds according to the invention are preferably used for treating affective disorders; neurotic, stress and somatoform disorders and psychoses, e.g. schizophrenia.
within the context of the present invention, the following expressions have the meanings given in conjunction with them:
Akyl (also in radicals such as alkoxy, alkylthio, alkylamino etc.) is a straight-chain or branched alkyl group having from 1 to 6 carbon atoms and, in particular from 1 to 4 carbon atoms, rhe alkyl group can have one or more substituents which are selected, independently of each other, from OH, OC1-C6-alkyl, halogen or phenyl, in the case of a halogen substituent, the alkyl group can, in particular, encompass, 1, 2, 3 or 4 halogen

atoms which can be located on one or more C atoms, preferably in the a or co position. CF3, CHF2, CF2CI or CH2F are particularly preferred.
Examples of an alkyl group are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, etc.
Cycloalkyl is, in particular, Ca-C6-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Alkylene radicals are straight-chain or branched. If A does not have a group Z, A then comprises from 4 to 10 carbon atoms, preferably from 4 to 8 carbon atoms. The chain between the triazole nucleus and group B then has at least four carbon atoms. If A has at least one of said Z groups, A then comprises from 3 to 10 carbon atoms, preferably from 3 to 8 carbon atoms.
If the alkylene groups comprise at least one of the Z groups, this or these groups can then be arranged in the alkylene chain at an arbitrary site or in position 1 or 2 of the A group (seen from the triazole radical). The radicals CONR2 and COO are preferably arranged such that the carbonyl group is in each case facing the triazole ring. Particular preference is given to the compounds of the formula I in which A is -Z-Ca-C6-alkylene, in particular -Z-CH2CH2CH2-, -Z-CH2CH2CH2CH2-, -Z-CH2CH=CHCH2-, -Z-CH2C(CH3)=CHCH2-, -Z-CH2- -CH2- Halogen is F, Cl, Br or I, preferably F or CI.
X is preferably -CH2-CH2- .
Ri is preferably H, C1-C6-alkyl or C6-C6-cycloalkyl.
If R2 is an aromatic radical, this radical is then preferably one of the following radicals:

If the phenyl radical is substituted, the substituents are preferably in the m position or the p position.
The aromatic radical is particularly preferably a group of the formula:

where R2, R2o and Ri2 have the abovementioned meanings. The indicated phenyl, pyridine, thiazolyl and pyrrole radicals are particularly preferred.
The radicals R2 to Ri are preferably H, C1-C6-alkyl, 0R3, CN, phenyl, which may be substituted by C1-C6-alkyl, C1-C6-alkoxy or halogen, CF3 and halogen, and are, in particular, H, C1-C6-alkyl, 0R3 and halogen. In this context, R3 has the abovementioned meanings.
Particularly preferably, R2 is H, C1-C6-alkyl, NR2R2 (R3 and R2 are, independently of each other, H or C1-C6-alkyl), phenyl or a 5-membered aromatic heterocyclic radical which has 1 or 2 heteroatoms which are independently selected from N, S and 0. The heterocyclic radical is preferably a pyrrole radical or a pyridine radical.
A is preferably C4-Cio-alkylene or Ca-Cio-alkylene which comprises at least one group Z which is selected from 0, S, COO, CO, a double bond and cyclohexyl.
Preferably, at least one of the radicals R2, R' and R2 is H.
The radicals R2, R? and R2 are preferably, and independently of each other, selected from H, C1-C6-alkyl, OH, C1-C6-alkoxy, C;L-C6-alkylthio-C1-C6-alkyl, halogen, CN, NO2, SO2R3, S02NR3R4 and C0NR3R4. Particularly preferably, the fused phenyl group has one or two substituents, i.e. one or two of the radicals R2, R7 and R2 is/are C1-C6-alkyl, halogen, CN, NO2, SO2R3 and, in particular, S02NR3R4, where R2 and R'*, together with the N atom to which they are attached, can also be a 5-, 6- or 7-membered heterocycle, which may contain one or two additional heteroatoms being selected from N, 0 or S besides the nitrogen atom and which may

be substituted, e.g. pyrrolidine, piperidine, morpholine or azepine.
If one of the radicals R6, R7 and R2 is a 5- or 6-membered heterocyclic ring, this ring is then, for example, a pyrrolidine, piperidine, morpholine, pyridine, pyrimidine, triazine, pyrrole, thiophene or pyrazole radical, with a pyrrole, pyrrolidine, pyrazole or thienyl radical being preferred.
If one of the radicals R2, R? and R2 is a carbocyclic radical, this radical is then, in particular, a phenyl, cyclopentyl or cyclohexyl radical.
Particular preference is given to the compounds of formula I where
Ri is H, C1-C6-alkyl or phenyl,
R2 is H, C1-C6-alkyl, phenyl, thienyl, furanyl, pyridyl,
pyrrolyl, thiazolyl or pyrazinyl, A is -SCa-Cio-alkylene which can comprise a double bond, and R6, R7 and R2 are selected from H, C1-C6-alkyl, C1-C6-alkoxy,
halogen, S02NR3R4 , CN, NO2, CF3, CONR3R4 , CHF2, OSO2CF3, OCF3
and NHSOa-C1-C6-alkyl. In here X is especially CH2CH2.
The invention also encompasses the acid addition salts of the compounds of the formula I with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid or benzoic acid. Other acids which can be used are described in Fortschritte der Arzneimittelforschung [Advances in pharmaceutical research]. Volume 10, pages 224 ff., Birkhauser Verlag, Basle and Stuttgart, 1966.
The compounds of the formula I can exhibit one or more centers of asymmetry. The invention therefore includes not only the racemates but also the relevant enantiomers and diastereomers. The respective tautomeric forms are also included in the invention.
The process for preparing the compounds of the formula I consist in
a) reacting a compound of the formula (II)

where Y is a customary leaving group, such as Hal, alkylsulfonyloxy, arylsulfonyloxy, etc., with a compound of the formula (III)

where Y and A have the abovementioned meanings, with a compound of the formula (VII)

where Z has the abovementioned meanings; or d) reversing the polarity of a compound of the formula (VIII)

using reagents which are known from the literature, such as 1,3-propanedithiol, KCN/water, TMSCN (trimethylsilyl cyanide) or KCN/morpholine, as described, for example, in
Albright Tetrahedron, 1983, H, 3207 or
D. Seebach Synthesis 1969, 17 und 1979, 19 or
H. Stetter Angew. Chem. Int. Ed. 1976, 15., 639 or
van Niel et al. Tetrahedron 1989, 15, 7643
Martin et al. Synthesis 1979, 633,
to give the products (Villa) (using 1,3-propanedithiol by way of example)

and then chain-elongating with compounds of the formula (IX)
yi - A3 - B (IX)
where Y has the abovementioned meaning and A is Ca-C6-alkylene which can contain a group Z,

where Z2 is CO or a methylene group, and Z and A have together from 4 to 10 C atoms, being obtained after deprotecting or reducing, or
) reacting a compound of the formula (VIII) with a compound of the formula (X)

where Y2 is a phosphorane or a phosphonic ester, in analogy with customary methods, as described, for example, in Houben Weyl "Handbuch der Organischen Chemie" [Textbook of Organic Chemistry], 4th Edition, Thieme Verlag Stuttgart, Volume V/lb p. 383 ff, or vol. V/lc p. 575 ff, or

where Q is H or OH, with a compound of the formula III under reductive conditions in analogy with methods known from the literature, for example as described in J. Org. Chem. 1986, M, 1927; or WO 92/20655.
The process for preparing a compound of the formula I where A comprises the groups COO or CONR2 consists in reacting a compound of the formula (XII)

Compounds of the formula B-H can be prepared as described, for example, in
Synth. Commun. 1984, M, 1221
S. Smith et al., Bioorg. Med. Chem. Lett. 1998, 8., 2859;
WO 97/47602 or WO 920655, or
J. Med. Chem. 1987, M, 2111 and 2208 and 1999, 41, 118.
The compounds of the formula (IV) type are either known or can be prepared using known methods, as described, for example, 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 which is cited therein, or in S. Kubota et al. Chem. Pharm. Bull. 1975, 23, 955 or Vosilevskii et al. Izv. Akad. Nauk. SSSR Ser. Khim. 1975, 23., 955.
In the above formulae, Ri, R2, R6, R7, R8 g d X have the meanings given in connection with formula I.
The compounds according to the invention, and the starting materials and the intermediates, can also be prepared in analogy with the methods which are described in the patent publications which were mentioned at the outset.
The above-described reactions are generally effected in a solvent at temperatures of between room temperature and the boiling temperature of the solvent employed. Examples of solvents which can be used are esters, such as ethyl acetate, ethers, such as diethyl ether or tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, dimethoxyethane, toluene, xylene, acetonitrile, ketones, such as acetone or methyl ethyl ketone, or alcohols, such as ethanol or butanol.
If desired, the reactions can be carried out in the presence of an acid-binding agent. Suitable acid-binding agents are inorganic bases, such as sodium carbonate or potassium carbonate, or sodium hydrogencarbonate or potassium hydrogencarbonate, sodium methoxide, sodium ethoxide, sodium hydride, or organometallic compounds, such as butyl lithium or alkyl magnesium compounds, or organic bases, such as triethylamine or pyridine. The latter can also simultaneously serve as the solvent.
Process (f) is effected under reducing conditions, e.g. using sodium borohydride, sodium cyanoborohydride or triacetoxy borohydride, where appropriate in an acid medium or in the presence of a Lewis acid, such as zinc chloride, or by way of catalytic hydrogenation.
The crude product is isolated in a customary manner, for example by means of filtering, distilling off the solvent or extracting from the reaction mixture, etc. The resulting compounds can be purified in a customary manner, for example by recrystallization from a solvent, by chromatography or by converting into an acid addition compound.

The acid addition salts are prepared in a customary manner by-mixing the free base with the corresponding acid, where appropriate in solution in an organic solvent, for example a lower alcohol, such as methanol, ethanol or propanol, an ether, such as methyl tert-butyl ether, a ketone, such as acetone or methyl ethyl ketone, or an ester, such as ethyl acetate.
For treating the abovementioned diseases, the compounds according to the invention are administered orally or parenterally (subcutaneously, intravenously, intramuscularly or intraperitoneally) in a customary manner. The administration can also be effected through the nasopharyngeal space using vapors or sprays.
The dosage depends on the age, condition and weight of the patient and on the type of administration. As a rule, the daily dose of active compound is from about 10 to 1000 mg per patient and day when administered orally and from about 1 to above 50 0 mg per patient and day when administered parenterally.
The invention also relates to pharmaceuticals which comprise the compounds according to the invention. In the customary pharmacological administration forms, these pharmaceuticals are present in solid or liquid form, for example as tablets, film tablets, capsules, powders, granules, sugar-coated tablets, suppositories, solutions or sprays. In this context, the active compounds can be worked up together with the customary pharmacological auxiliary substances, such as tablet binders, fillers, preservatives, tablet disintegrants, flow-regulating agents, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retarding agents, antioxidants and/or propellent gases (cf. H. Sucker et al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The resulting administration forms normally comprise the active compound in a quantity of from 1 to 99% by weight.
The following examples serve to explain the invention without limiting it.
Example 1
6,7-Dimethoxy-2-{3-[(4-methyl-5-phenyl-4H-l,2,4-triazol-3-yl)-
sulfanyl]propyl}-!,2,3,4-tetrahydroisoquinoline
lA Preparation of the starting materials
2-(3-Chloropropyl)-6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline

7.2 g (37 mmol) of 6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline were heated together with 4.05 ml (40 mmol) of
l-bromo-3-chloropropane, 11.3 g (81 mmol) of potassium carbonate and 610 mg (40 mmol) of sodium iodide in 250 ml of acetonitrile with stirring at 70°C for four hours. After the reaction was complete, the solvent was distilled off, and the residue was taken up in water and extracted with methylene chloride. The combined organic phases were dried and concentrated, and the crude product was purified by chromatography on silica gel (mobile phase: methylene chloride/methanol = 9/1). 4.8 g (45% of theory) of a yellowish oil were obtained.
iH-NMR (CDCI3): 8 = 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, IH); 5.6 (s, IH). C14H20CINO2 (269)
IB Preparation of the final product
380 mg (1.7 mmol) of 3-mercapto-4-methyl-5-phenyl-l,2,4(4H)-triazole were heated with 450 mg (1.7 mmol) of the chlorinated base lA and 40 mg (1.7 mmol) of lithium hydroxide in 5 ml of DMF while stirring at lOQoc for five hours. Workup entailed addition of 50 ml of water, extraction several times with methyl tert-butyl ether, drying of the combined organic phases, evaporation and purification by chromatography on silica gel (mobile phase: methylene chloride/2-5% methanol). Yield: 0.2 g (49% of theory)
iH-NMR (CDCI3): 6 = 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, IH); 6.5 (s, IH); 7.5 (m, 3H); 7.8 (m, 2H).
The title compound was obtained by treatment with ethereal hydrochloric acid C23H28N4O2S x HCl Melting point: 180-183OC
Example 2
6-Methoxy-2-{3-[(4-methyl-5-pyrrol-2-yl-4H-l,2,4-triazol-3-yl)-
sulfanyl]propyl}-l,2,3,4-tetrahydroisoquinoline
2A Preparation of the starting compound
2-(3-Chloropropyl)-6-methoxy-l,2,3,4-tetrahydroisoquinoline
The above substance was prepared using 6-methoxy-
1,2,3,4-tetrahydroisoquinoline in a manner analogous to lA.

IH-NMR (CDCI3): 6 = 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, IH); 6.7 (dd, IH); 6.9 (d, IH).
i 2B Preparation of the final product Preparation took place in analogy to Example 1 by reacting the chlorinated base prepared in 2A with 3-mercapto-4-methyl-5-(2-pyrrolyl)-1,2,4(4H)-triazole. Yield: 52% of theory. C20H25N5OS (383.5) Melting point: 179-18loc
Example 3
2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-6-inethoxy-l, 2, 3,4-tetrahydroisoquinoline
3A Preparation of the starting material
3-(3-Chloropropylmercapto)-4-methyl-5-phenyl-l,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-l,2,4(4H)-triazole and 2.1 g (15 mmol) of potassium carbonate in 70 ml of ethanol were heated to boiling for one hour. After filtration hot, the filtrate was concentrated, taken up in water and extracted with dichloromethane. The combined orgainc phases were dried, filtered and concentrated, and the residue was chromatographed (mobile phase: methylene chloride/2% methanol). Yield: 1.35 g (34% of theory) of white solid
iH-NMR (CDCI3): 8 = 2.3 (q, 2H); 3.4 (t, 2H); 3.6 (s, 3H); 3.7 (t, 2H); 7.5-7.7 (m, 5H).
C12H14CIN3S (267.8)
Melting point: 137-1410C
3B Preparation of the final product
0.7 g (2.5 mmol) of Compound 3A described above was stirred with 0.6 g (2.5 mmol) of 6-methoxy-l,2,3,4-tetrahydroisoquinoline oxalic acid salt in the presence of 1.1 ml (7.5 mmol) of triethylamine and catalytic amounts of sodium iodide in 6 ml of butanol at 120oc for four hours. After the reaction was complete it was worked up by extraction with water and methyl tert-butyl ether, drying over sodium sulfate and concentrating, and the

1.2 g (4.4 mmol) of 7-(morpholin-4-ylsulfonyl)-l,2,3,4-tetra-hydroisoquinoline and 1.0 g (10 mmol) of triethylamine were dissolved in DMF at 400, 1.1 g (6.6 mmol) of
l-bromo-3-chloropropane were added dropwise, and the mixture was stirred at 40oc for 3 h. For workup, the mixture was concentrated, and the residue was taken up in water and extracted with methyl tert-butyl ether. Drying over sodium sulfate, filtration and removal of the solvent were followed by purification by chromatography (silica gel; mobile phase: methylene chloride with 2% methanol) to afford 0.7 g (2 mmol) of a pale oil. Yield: 46% of theory.
iH-NMR (CDCI3): 6 = 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, IH); 7.4 (s, IH); 7.5 (d, IH). C16H23N2O3S (359)
Preparation of the final compound
280 mg (1 mmol) of 2-[4-methyl-5-phenyl-l,2,4-(4H)-triazol-3-yl]-l,3-dithiane (described in WO 9902503) were dissolved in 2.5 ml of dry THE and, at -70oc, with the addition of 0.15 g of sodium iodide, treated with 0.75 ml (1.2 mmol) of a 15% strength solution of butyllithium in n-hexane. After stirring at -70oc for 45 min, 0.37 g (1 mmol) of 2-[3-chloropropyl]-7-(morpholin-4-yl-sulfonyl)-l,2,3,4-tetrahydroisoquinoline 5B dissolved in THE was added dropwise. The mixture was then slowly warmed to room temperature and subsequently heated at 40°C for 90 min in order to achieve complete conversion. Workup entailed addition to ice/water and extraction several times with methylene chloride. After drying and concentration, 0.5 g (82% of theory) of the substituted dithiane remained and was then hydrogenated with Raney nickel and hydrogen in tetrahydrofuran at 40°C over the course of 3 hours. After removal of the catalyst, the residue was purified by chromatography (silica gel, methylene chloride with 5% methanol).
Yield: 120 mg (29% of theory)
iH-NMR (CDCI3): 8 = 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, IH); 7.4 (s, IH); 7.5 (m, 4H); 7.7 (m, 2H).
The title compound was obtained by adding ethereal HCl C26H33N503S-HC1 (531.6) Melting point: 87-89°C
The following were obtained in an analogous way:

Example 6
1-(4-Methyl-5-phenyl-4H-l,2,4-triazol-3-yl)-4-(7-(piperidin-1-yl-
sulfonyl)-1,2,3,4-tetrahydroisoquinolin-2-yl)butan-l-one
C27H33N5O3S (507.7) MS: 508.3 [M+HJ+
Example 7
2-{3-[(4-Methyl-5-phenyl-4H-l,2,4-triazol-3-yl)sulfanyl]propyl}-
1,2,3,4-tetrahydroisoquinoline-7-carbonitrile
C22H23N5S (389.5)
Melting point: II6-II80C
Example 8
5-[2-(Diethylammonio)ethoxy]-2-{3-[(4-methyl-5-phenyl-4H-l,2,4-
triazol-3-yl)sulfanyl]propyl}-l,2,3,4-tetrahydroisoquinoline
dihydrochloride
C27H37N50S-2HC1 (552.6) Melting point: 110-H2OC
Example 9
N-Benzyl-2-(3-{[4-methyl-5-(4-methyl-l,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide
C26H30N6O2S3 (554.8) Melting point: 67-70OC
Example 10
N-Benzyl-2-{3-[(4-methyl-5-pyridin-3-yl-4H-l,2,4-triazol-3-yl)-sulf anyl ]propyl}-l , 2,3,4-tetrahydroisoquinoline-7-sulfonamide
C27H30N6O2S2-2HC1 (607.6) Melting point: 81-840C
Example 11
5-Methoxy-2-{3-[(4-methyl-5-phenyl-4H-l,2,4-triazol-3-yl)-
sulfanyl]propyl}-l,2,3,4-tetrahydroisoquinoline
C22H26N4OS (394.5)
Melting point: 12-1S°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

C21H24CIN5O2S (446)
Melting point: 190-192oc
Example 13
2-{3-[(4-Methyl-5-phenyl-4H-l,2,4-triazol-3-yl)sulfanyl]propyl}-
1,2,3,4-tetrahydroisoquinoline
IH-NMR (CDCI3): 6 = 2.1 (q, 2H); 2.65 (t, 2H); 2.7 (t, 2H); 2.9 (t, 2H); 3.4 (t, 2H); 3.5 (s, 3H); 3.7 (s, 2H); 7.0 (m, IH); 7.2 (m, 3H); 7.5 (m, 3H); 7.7 (m, 2H) .
C21H24N4S (365.5)
Example 14
2-(3-{[4-Methyl-5-(4-inethyl-l,3-thiazol-5-yl)-4H-1,2,4-triazol-
3-yl]sulfanyl}propyl)-1,2,3,4-tetrahydroisoquinoline
iH-NMR (CDCI3): 6 = 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, IH); 7.1 (m, 3H); 8.9 (s, IH).
C19H23N5S2 (386.5)
Example 15
2-{3-[(4-Methyl-5-pyridinium-3-yl-4H-l,2,4-triazol-3-yl)-
sulfanyl]propyl}-l,2,3,4-tetrahydroisoquinoline dihydrochloride
C20H23N5S-2HC1 (438.4) Melting point: 87-890C
Example 16
7-[(Dimethylamino)sulfonyl]-2-{3-[(4-methyl-5-phenyl-4H-l,2,4-
tria2ol-3-yl)sulfanyl]propyl}-l,2,3,4-tetrahydroisoquinoline
iH-NMR (CDCI3): 6 = 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, IH); 7.4-7.6 (m, 7H).
C23H29N5O2S2 (472.6)
Example 17
7-[(Dimethylamino)sulfonyl]-2-(3-{[4-methyl-5-(4-methyl-l,3-
thiazol-5-yl)-4H-l,2,4-triazol-3-yl]sulfanyl}propyl)-1,2,3,4-
tetrahydroisoquinoline

IH-NMR (CDCI3): 8 = 2.1 (q, 2H) ; 2.5 (s, 3H); 2.6-2.8 (m, lOH); 2.9 (m, 2H); 3.4 (t, 2H); 3.5 (s, 3H); 3.7 (s, 2H); 7.2 (m, IH); 7.5 (m, 2H); 8.9 (s, IH) .
C21H28N6O2S3 (493.7)
Example 18
Methyl 2-{3-[(4-methyl-5-phenyl-4H-l,2,4-triazol-3-yl)-
sulfanyl]propyl}-l,2,3,4-tetrahydroisoquinoline-7-carboxylate
oxalate
C23H27N402S-C2H04 (512.6) Melting point: 160-163°C
Example 20
2-(3-{[4-Methyl-5-(4-methyl-l,3-thiazol-5-yl)-4H-l,2,4-triazol-3-yl]sulfanyl}propyl)-7-(piperidin-1-ylsulfonyl)-1,2,3,4-tetra-hydroisoquinoline
iR-NMR (CDCI3): 8 = 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, IH); 7.45 (s, IH); 7.5 (d, IH); 8.9 (s, IH) .
C24H32N6O2S3 (532.8)
Example 21
2-{3-[(4-Methyl-5-phenyl-4H-l,2,4-triazol-3-yl)sulfanyl]propyl}-
7-(phenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline
iH-NMR (CDCI3): 8 = 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, IH); 7.4-7.7 (m, lOH); 7.9 (d, 2H).
C27H28N4O2S2 (504.7)
Example 22
2-(3-{[4-Methyl-5-(4-methyl-l,3-thiazol-5-yl)-4H-1,2,4-triazol-
3-yl]sulfanyl}propyl)-1,2,3,4-tetrahydroisoquinolin-7-yl phenyl
sulfone
iH-NMR (CDCI3): 8 = 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, IH); 7.4-7.7 (m, 5H); 7.9 (d, 2H); 8.9 (s, IH).
C25H29N5O2S3 (525.7)

Example 23
2-{3-[(4-Methyl-5-phenyl-4H-l,2,4-triazol-3-yl)sulfanyl]propyl}-
7-(morpholin-4-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline
iH-NMR (CDCI3): 8 = 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, IH); 7.4-7.6 (m, 5H); 7.9 (d, 2H).
C25H31N5O3S2 (525.7)
Example 24
2-[4-(4-Methyl-5-phenyl-4H-l,2,4-triazol-3-yl)butyl]-
7-(phenylsulfonyl)-l,2,3,4-tetrahydroisoquinoline
C28H30N4O2S (486.6)
Example 25
2-{3-[(4-Methyl-5-pyridin-3-yl-4H-l,2,4-triazol-3-yl)sulf anyl ] -
propyl}-N-phenyl-l,2,3,4-tetrahydroisoquinoline-7-sulfonamide
iR-NMR (CDCI3): 8 = 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, IH); 7.4-7.6 (m, 5H); 7.9 (d, 2H) .
C26H28N6O2S2 (520.7)
Melting point: 58-61°C
Example 26
2-(3-{[4-Methyl-5-(4-methyl-l,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-N-phenyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide
iH-NMR (CDCI3): 8 = 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, IH).
C25H28N6O2S3 (540.7)
Melting point: 77-81°C
Example 27
2-(3-{[5-(2,4-Dimethoxy)phenyl)-4-methyl-4H-l,2,4-triazol-3-yl]-sulfanyl}propyl)-7-(methylsulfonyl)-1,2,3,4-tetrahydroiso¬quinoline

IH-NMR (CDCI3): 8 = 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, IH); 6.65 (d, IH); 7.25 (d, IH); 7.3 (d, IH); 7.7 (s, IH); 7.8 (d, IH).
C24H30N4O4S2 (502.7) MS: 503.5 [M+H] +
Example 28
6,7-Dichloro-2-{3-[(4-methyl-5-phenyl-4H-l,2,4-triazol-3-yl)-
sulfanyl]propyl}-l,2,3,4-tetrahydroisoquinoline
C21H22CI2N4S (433.4)
Melting point: 138-1390C
Example 29
7,8-Dichloro-2-{3-[(4-methyl-5-phenyl-4H-l,2,4-triazol-3-yl)-sulf anyl]propyl}-l,2, 3,4-tetrahydroisoquinoline hydrochloride
IH-NMR (CDCI3): 8 = 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, IH); 7.2 (d, IH); 7.5 (m, 3H); 7.7 (m, 2H), [free base].
Salt precipitation with ethereal HCl led to the title compound
C2iH22Cl2N4S-x HCl (469.9) Melting point: IO90C
Example 30
7-Cyano-2-[4-(4-methyl-5-phenyl-4H-l,2,4-triazol-3-yl)butyl]-
1,2,3,4-tetrahydroisoquinoline hydrochloride
C23H25N5-HC1(407.9) Melting point: 175°C
Example 31
2-{3-[(4-Methyl-5-thien-3-yl-4H-l,2,4-triazol-3-yl)sulfanyl]-
propyl}-6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline
hydrochloride
C20H2lF3N4S2-Cl X HCl (475) Melting point: 184-185°C
Example 32
l-{2-[3-({4-Methyl-5-[4-(trifluoromethyl)phenyl]-
4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1,2,3,4-tetrahydroiso-
quinolin-7-yl}ethanone

iH-NMR (CDCI3): 8 = 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, IH); 7.6-7.8 (m, 6H).
C24H25F3N4OS (474.5)
The hydrochloride of the title compound was obtained by treatment with ethereal hydrochloric acid:
Melting point: 183°C
Example 33
6,7-Dichloro-2-(3-{[4-methyl-5-(4-methylphenyl)-4H-1,2,4-triazol-
3-yl]sulfanyl}propyl)-1,2,3,4-tetrahydroisoquinoline
hydrochloride
iH-NMR (CDCI3): 8 = 2.1 (q, 2H) ; 2.4 (s, 3H); 2.7 (m, 4H); 2.8 (t, 2H); 3.3 (t, 2H); 3.5 (s, 2H); 3.6 (s, 3H); 7.1 (s, IH); 7.2 (s, IH); 7.3 (d, 2H); 7.5 (d, 2H); [free base].
The title compound was obtained by treatment with ethereal hydrochloric acid
C22H24C12N4S-HC1 (483.9) Melting point: 207-210OC
Example 34
6-Chloro-2-{3-[(4-methyl-5-phenyl-4H-l,2,4-triazol-3-yl)-
sulfanyl]propyl}-l,2,3,4-tetrahydroisoquinoline hydrochloride
iR-NMR (CDCI3): 8 = 2.1 (q, 2H); 2.4 (s, 3H); 2.7 (m, 4H); 2.8 (t, 2H); 3.3 (t, 2H); 3.5 (s, 2H); 3.6 (m, 5H); 6.9 (d, IH); 7.1 (m, 2H); 7.5 (d, 3H); 7.5 (d, 2H); [free base].
Salt precipitation with ethereal HCl led to the title compound
C2iH23ClN4S-HCl (435.4)
Melting point: 188-191°C
Example 35
2-(3-{[4-Methyl-5-(l-methyl-lH-pyrrol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-7-(piperidin-l-ylsulfonyl)-l,2,3,4-tetra¬hydroisoquinoline

IH-NMR (CDCI3): 6 = 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, IH); 6.4 (m, IH); 6.8 (m, IH); 7.2 (d, IH); 7.4 (s, IH); 7.5 (m, 2H).
C25H34N6O2S2 (514.7) Melting point: 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
C27H35N5O2S (493.7) MS: 494.3 [M+H] +
Example 37
2-(3-{[4-Methyl-5-thien-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-
propyl)-7-(piperidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline
iH-NMR (CDCI3): 8 = 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, IH); 7.4 (s, IH); 7.5 (m, 3H); 7.7 (s, IH).
C24H31N5O2S3 (517.7) MS: 518.3 [M+H]+
Melting point: 192-1950C
Example 38
2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-
N-phenyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide
iH-NMR (CDCI3): 8 = 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).
C27H29N5O2S2 (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}-l,2,3,4-tetrahydroisoquinoline
C19H21CIN4S2 (405)
Melting point: 99-lOOoc
Example 40
7-[(Diethylammonio)methyl]-2-{3-[(4-methyl-5-phenyl-4H-1,2,4-
triazol-3-yl)sulfanyl]propyl}-l,2,3,4-tetrahydroisoquinoline
dihydrochloride

C26H35N5S-2HC1 (522.6) Melting point: 75°C
Example 41
2-{3-[(4-Methyl-5-thien-3-yl-4H-l,2,4-triazol-3-yl)sulfanyl]-
propyl}-7-(trifluoromethyl)-!,2,3,4-tetrahydroisoquinoline
hydrochloride
Preparation of the starting material
41A 7-Trifluoromethyl-1,2,3,4-tetrahydroisoquinoline
10.0 ml of concentrated sulfuric acid were slowly added dropwise to a solution of 1.77 g (6.2 mmol) of N-trifluoroacetyl-2-(4-trifluoromethylphenyl)ethylamine [prepared from 2-(4-trifluoromethylphenyl)ethylamine and trifluoroacetic anhydride at -5°C] in 7.5 ml of glacial acetic acid, and, while cooling in ice, 2 ml of formalin solution were added dropwise. After 18 hours at room temperature, the reaction mixture was poured into 130 ml of iC6-water and extracted with dichloromethane, and the combined organic phases were washed with sodium bicarbonate solution and then with water. After drying over sodium sulfate, filtration and evaporation, 1.7 g of 2-trifluoroacetyl-7-trifluoromethyl-1,2,3,4-tetrahydroiso¬quinoline were isolated and were converted into
7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline by heating under reflux in ethanol/3N HCl (1:1) and alkaline workup. Yield: 1.0 g (4.7 mmol) 75% of theory.
iH-NMR (CDCI3): 6 = 2.0 (sbr, IH); 2.9 (t, 2H); 3.2 (t, 2H); 4.0 (s, 2H); 7.2 (d, IH); 7.3 (s, IH); 7.4 (s, IH).
4 IB 2-(3-Chloropropyl)-7-trifluoromethyl-1,2,3,4-tetrahydroiso¬quinoline
0.95 g (4.7 mmol) of the compound described above was reacted with l-bromo-3-chloropropane in the same way as described in Example 4B at room temperature, and purified by chromatography (silica gel, mobile phase dichloromethane with 2% methanol). Yield: 0.9 g (3.2 mmol) 69% of theory.
iH-NMR (CDCI3): 6 = 2.0 (m, 2H); 2,65 (m, 2H); 2.75 (m, 2H); 2.9 (m, 2H); 3.65 (m, 4H); 7.2 (dd, IH); 7.3 (d, IH); 7.4 (dd, IH).
41C Preparation of the final product

0.45 g (1.6 mmol) of 2~(3-chloropropyl)-7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline, 0.36 g (1.6 mmol) of 3-mercapto-4-methyl-5-thien-3-yl-4H-l,2,4-tria2ole and 40 mg of lithium hydroxide were stirred in 6 ml of DMF at 100°C for 4 hours. Workup entailed pouring into ice/water, extraction with methyl tert-butyl ether, drying over sodium sulfate and purification after filtration and evaporation by column chromatography (silica gel, mobile phase dichloromethane with 3-5% methanol). Yield: 0.3 g (0.7 mmol) 42% of theory.
iH-NMR (CDCI3): 8 = 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, IH); 7.2 (s, IH); 7.3 (d, IH); 7.5 (m, 2H); 7.7 (s, IH); [free base].
The title compound was obtained by treatment with ethereal HCl
C2oH2iF3N4S2-HCl (475) Melting point: 192-194°C
Example 42
2-{3-[(4-Methyl-5-phenyl-4H-l,2,4-triazol-3-yl)sulfanyl]propyl}-
8-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride
Preparation of the starting materials
42A 6/8-Trifluoromethyl-1,2,3,4-tetrahydroisoquinoline
5.3 g (18.6 mmol) of N-trifluoroacetyl-2-(3-trifluoromethyl-phenyl)ethylamine [prepared from 2-(3-trifluoromethylphenyl)-ethylamine and trifluoroacetic anhydride at -5°C] and 0.9 g (29 mmol) of paraformaldehyde were added to a mixture of 2 2 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 iC6-water and extracted with ethyl acetate, and the combined organic phases were washed with sodium bicarbonate solution and then with water. After drying over sodium sulfate, filtration and evaporation, 5,4 g of a mixture of 2-trifluoroacetyl-6- and -8-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline were isolated. The protective group was eliminated by heating in ethanol/3N HCl (1:1) under reflux. The two isomers were separated after workup and purification by chromatography (silica gel, mobile phase dichloromethane with 2-4% methanol):
Fl 1.2 g (5.7 mmol) 32% of theory of 8-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline

iH-NMR (CDCI3): 8 = 1.9 (sbr, IH); 2.8 (t, 2H); 3.1 (t, 2H) ; 4.2 (s, 2H); 7.2 (m, 2H); 7.5 (d, IH),
F2 1.4 g (6,8 mmol) 38% of theory of 6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline
iH-NMR (CDCI3): 8 = 1,8 (sbr, IH); 2,8 (t, 2H); 3.1 (t, 2H); 4.0 (s, 2H); 7.1 (d, IH); 7,4 (m, 2H).
42 B 2-(3-Chloropropyl)~8-trifluoromethyl-l,2,3,4-tetrahydro¬
isoquinoline
2-(3-Chloropropyl)-8-trifluoromethyl-1,2,3,4-tetrahydroiso¬quinoline was obtained in 73% yield by reacting 42-A Fl with bromochloropropane in a manner analogous to the description in Example 4C.
iR-NMR (CDCI3): 8 = 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, IH),
42C Preparation of the final compound
Reaction 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 mmol) of 2-(3-chloropropyl)-8-trif luoromethyl-1,2,3, 4-tetrahydroisoquinoline [42B1] in 10 ml of DMF in the presence of 70 mg of lithium hydroxide at lOQoc afforded, after workup as described under 4D, 0.84 g (1.9 mmol) of the final compound. Yield: 0.84 g (1.9 mmol) 65% of theory
iH-NMR (CDCI3): 8 = 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, IH); 7.25 (d, IH); 7.4 (d, IH), 7.5 (m, 3H); 7,6 (m, 2H),
The title compound was obtained by treatment with ethereal HCl,
C22H23F3N4S-HC1 (469) Melting point: 1180
Example 43
2-{3-[(4-Methyl-5-phenyl-4H-l,2,4-triazol-3-yl)sulfanyl]propyl}-
6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride
Preparation of the starting materials
43 B2 2-(3-Chloropropyl)-6-trifluoromethyl-1,2,3,4-tetrahydro¬
isoquinoline

2-(3-Chloropropyl)-6-trifluoromethyl-1,2,3,4-tetrahydroiso-quinoline was obtained in 96% yield by reacting 6-trifluoro-methyl-1,2,3,4-tetrahydroisoquinoline [42AF2] (obtained as described in 42A) with bromochloropropane in a manner analogous to that described for 4C.
iH-NMR (CDCI3): 8 = 2.0 (m, 2H); 2.6-2.8 (m, 4H); 2.9 (t, 2H) ; 3.6 (m, 4H) 7.1 (d, IH); 7.4 (m, 2H).
4 3C Preparation of the final compound
Reaction 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 mmol) of 2-(3-chloropropyl)-6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline in 10 ml of DMF in the presence of 70 mg of lithium hydroxide at lOQoc afforded, after workup as described under 4D, 0.75 g (1.7 mmol) of the final compound. Yield: 0.75 g (1.7 mmol) 58% of theory
iH-NMR (CDCI3): 8 = 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, IH); 7.3 (m, 2H); 7.5 (m, 3H); 7.7 (m, 2H); [free base].
The title compound was obtained by treatment with ethereal HCl
C22H23F3N4S-HC1 (469) Melting point: 200-202°C
Example 44
2-{3-[(4-Methyl-5-phenyl-4H-l,2,4-triazol-3-yl)sulfanyl]propyl}-
7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride
C22H23F3N4S-HC1 (469) Melting point: 205-207OC
Example 45
2-{3-[(4-Methyl-5-(thien-3-yl)-4H-1,2,4-triazol-3-yl)sulfanyl]-propyl}-7-(4-methylpipera2in-l-ylsulfonyl)-1,2,3,4-tetrahydroiso¬quinoline
iH-NMR (CDCI3): 6 = 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, IH).
C24H32N6O2S3 (538.8)
Example 4 6

2-{3-[(4-MethYl-5-(phenyl)-4H-1,2,4-tria20l-3-yl)sulfanyl]-propyl}-7-(4-methylpiperazin-l-ylsulfonyl)-1,2,3,4-tetrahydroiso-quinoline
iH-NMR (CDCI3): 6 = 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, IH); 7.5 (m, 5H); 7.6 (m, 2H).
C26H34N6O2S3 (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-tetrahydroisoquinolin-l-ylsulfonyl)-1,2,3,4-
tetrahydroisoquinoline
iH-NMR (CDCI3): 6 = 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, IH); 7.4-7.6 (m, 4H); 7.7 (m, IH).
C28H31N5O2S3 (565)
Example 48
2-{3-[(4-Methyl-5-(pyrid-3-yl)-4H-1,2,4-triazol-3-yl)sulfanyl]-propyl}-7-(1,2,3,4-tetrahydroisoquinolin-l-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline
iH-NMR (CDCI3) 6 = 2.1 (q, 2H) ; 2.7 (t, 2H) ; 2.8 (t, 2H); 2.9 (m, 4H); 3.3 (m, 4H); 3.6 (s, 3H); 3.7 (s, 2H) ; 4.2 (s, 2H); 7.0-7.2 (m, 5H); 7.2 (m, IH); 7.4-7.6 (m, 3H); 8.0 (m, IH); 8.7 (m, IH); 8.9 (m, IH).
C29H32N6O2S2 (558)
Example 49
7-[(3,3-Dimethylpiperidin-l-yl)sulfonyl]-2-{3-[(4-methyl-5-phenyl-4H-l,2,4-triazol-3-yl)sulfanyl]propyl}-1,2,3,4-tetra¬hydroisoquinoline
C28H37N5O2S2 (539.8) I Melting point: 75-760C
Example 50
2-{3-[(4-Cyclopropyl-5-phenyl-4H-l,2,4-triazol-3-yl)sulfanyl]-propyl}-7-[(3,3-dimethylpiperidin-l-yl)sulfonyl]-1,2,3,4-tetra-5 hydroisoquinoline
C30H39N5O2S2 (558)

Example 51
2-[(4-{[(4-Methyl-5-(l-methyl-lH-pyrrol-3-yl)-4H-1,2 , 4-tria2ol-
3-yl)sulfanyl]methyl}eyelohexyl)methyl]-7-nitro-l,2,3,4-tetra-
hydroisoquinoline
C25H31N5O2S (477.6) Melting point: I6OOC
Example 52
2-{(E)-4-[(4-Methyl-5-pyridin-3-yl-4H-l,2,4-triazol-3-yl)-
sulfanyl]but-2-enyl}-7-nitro-l,2,3,4-tetrahydroisoquinoline
C21H22N6O2S (422) MS: 423 [M+H]+
Example 53
2-[(4-{[(4-methyl-5-pyridin-3-yl-4H-l,2,4-tria2ol-3-yl)sulfanyl]-
methyl}cyclohexyl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-carbo-
nitrile
C27H31N5S (457.6)
Melting point: 156-1580C
Example 54
1-(2-{3-[(4-Methyl-5-(3-cyano)phenyl-4H-l,2,4-triazol-3-yl)sulfa-
nyl]propyl}-!,2,3,4-tetrahydroisoquinolin-7-yl)ethanone
hydrochloride
C24H25N5OS X HCl (468) Melting point: 185°C
Example 55
7-Nitro-2-[(4-{[(4-methyl-5-pyridin-3-yl-4H-l, 2,4-triazol-3-yl)-sulfanyl]-methyl}cyclo-hexyl)methyl]-1,2,3,4-tetrahydroiso¬quinoline
C26H31N6O2S (477.6) Melting point: I6OOC
Example 56
l_p_ [ 3_ ( {4-Methyl-5-phenyl ] -4H-1, 2 , 4-triazol-3-yl} sulf anyl) -
propyl]-l,2,3,4-tetrahydroisoquinolin-7-yl}ethanone hydrochloride
C23H27N4OS X HCl (443) Melting point: 165oc
Example 57

7,8-Dichloro-2-{3-[(4-methyl-5-phenyl-4H-l,2,4-triazol-3-yl)-sulfanyl]propyl}-!,2,3,4-tetrahydroisoquinoline
C21H22CIN4S (399)
Melting point: 12-15'C
Example 58
l-{2-[3-({5-{2,4-Dinitrophenyl)-4-methyl]-4H-l,2,4-triazol-3-yl}-sulfanyl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}ethanone hydrochloride
C23H25N6O5S X HCl (500.6) Melting point: 193°C
Example 59
2-{3~[(4-Methyl-5-phenyl-4H-l,2,4-triazol-3-yl)sulfanyl]propyl}-
7-(octahydroisoquinolin-2(IH)-ylsulfonyl)-1,2,3,4-tetrahydro-
isoquinoline
C30H39N5O2S2 (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}-?-(octahydroisoquinolin-2(lH)-ylsulfonyl)-l,2,3,4-tetra-
hydroisoquinoline
C29H3aN602S2 (566.8) MS: 568 [M+H] +
Example 61
2-{3-[(4-Cyclopropyl-5-phenyl-4H-l,2,4-triazol-3-yl)sulfanyl]-
propyl}-?-(azepan-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline
C29H37N5O2S2 (551.8) MS: 552 [M] +
Example 62
2-{3-[(4-Methyl-5-phenyl-4H-l,2,4-triazol-3-yl)sulfanylJpropyl}-
7-(pyrrolidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline
C25H31N5O2S2 (497.7)
Example 63
2_{3-[(4-Methyl-5-phenyl-4H-l,2,4-triazol-3-yl)sulfanyl]propyl}-
7-(azepan-l-ylsulfonyl)-l,2,3,4-tetrahydroisoquinoline
C27H35N5O2S2 (525.7)

Example 64
7-Chlor-2-(3-{[4-methyl-5-phenyl-4H-l,2,4-triazol-3-yl]sulfanyl}-
but-2-en-yl)-1,2,3,4-tetrahydroisoquinoline
C21H23CIN4S (399)
Melting point: 12-15°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-tetrahydroisoquinoline
Example 66
N,4-Dimethyl-5-{[3-(7-(piperidin-1-ylsulfonyl)-3,4-dihydroiso-
quinolin-2(IH)-yl)propyl]sulfanyl}-4H-l,2,4-triazol-3-amine
Example 67
7-tert-Butyl-2-(3-{[4-methyl-5-(4-methyl-l,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1,2,3,4-tetrahydroiso¬quinoline
Example 68
2-{3-[(4-Methyl-5-pyridin-3-yl-4H-l,2,4-triazol-3-yl)sulfanyl]-
propyl}-7-(azepan-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline
Example 69
7-({4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-l-yl}sulfonyl)-2-{3-[(4-methyl-5-phenyl-4H-l,2,4-triazol-3-yl)-sulfanyl]propyl}-l,2,3,4-tetrahydroisoquinoline
Example 70
8-Brom-2-(3-{[5-cyclohexyl-4-methyl-4H-l,2,4-triazol-3-yl]sulfa-
nyl}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-l,2,4-triazole-
3-carboxamide
Example 72
6-Methyl-2-(3-{[4-methyl-5-(l-methyl-lH-pyrrol-3-yl)-4H-
1,2,4-triazol-3-yl]sulfanyl}-propyl)-7-(pyrrolidin-1-ylsulfonyl)-
1,2,3,4-tetrahydroisoquinoline

Example 73
7-Cyano-2-[(2-{[(4-Methyl-5-pyridin-3-yl-4H-l,2,4-triazol-3-yl)-
sulfanyl]-methyl}-cyclopropy1)methyl]~1,2,3,4-tetrahydroiso-
quinoline
Example 74
1-(2-{3-[(4-Methyl-5-(3-methoxy)phenyl-4H-l,2 , 4-triazol-3-yl)-
oxy]propyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)ethanone
Example 75
4-(7-(Pyrrolidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-
2-yl)butyl-4-methyl-5-phenyl-4H-l,2,4-triazole-3-carboxylate
Example 7 6
2-[2-({[5-(N-Methylpyrrol-2-yl)-4-methyl-4H-l,2,4-triazol-
3-y1]-sulfanyl}methyl)prop-2-enyl]-1,2,3,4-tetrahydroiso-
quinolin-7-carboxamide
Example 77
2-{3-[(4-Cyclopropy1-5-(4-methylsulfonyl)phenyl-4H-1,2,4-triazol-
3-yl)sulfanyl]propyl}-7-(pyrrolidin-1-ylsulfonyl)-1,2,3,4-tetra-
hydroisoquinoline
Example 78
6-tert-Butyl-2-(3-{[5-(2,4-dinitrophenyl)-4-methyl-4H-l,2,4-tri-
azol-3-yl]sulfanyl}propyl)- 1,2,3,4-tetrahydroisoquinoline
Example 79
N-[2-(8-{[5-(dimethylamino)-4-butyl-4H-l,2,4-triazol-3-yl]sulfa-
nyl}octyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]methansulfonamide
Example 80
2-{3-[(4-Methyl-5-pyrazin-2-yl-4H-l,2,4-tria2ol-3-yl)sulfanyl]-
propyl}-7-(octahydro-isoquinolin-2(IH)-ylsulfonyl)-
1,2,3,4-tetrahydroisoquinoline
Example 81
7-Cyano-2-{3-[(4-methyl-5-(2-methyloxazol-4-yl)-4H-1,2,4-tria2ol-
3~yl)sulfanyl]propyl}-l,2,3,4-tetrahydroisoquinoline
Example 82
2-{6-[(5-(2,5-Dimethylfuran-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]hexyl}-7-trifluormethansulfonyloxy-1,2,3,4-tetra¬hydroisoquinoline

Example 83
2-[2-({[4-methyl-5-phenyl-4H-l,2,4-triazol-3-yl]sulfanyl}inethyl)-
prop-2-enyl]-7-nitro-l,2,3,4-tetrahydroisoquinoline hydrochloride
C22H23N5O2S X HCl (460) Melting point: 146-150OC
Example 84
N-[2-(3-{[4-Methyl-5-phenyl-4H-l,2,4-tria2ol-3-yl]sulfanyl}-
propyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]methansulfonamide
C22H27N5O2S2 x HCl (494.1) Melting point: 90°C

Examples of pharmaceutical administration forms
A) Tablets
Tablets of the following composition were pressed on a tabletting machine in the customary manner
40 mg of the substance from Example 1
120 mg of corn starch
13.5 mg of gelatin
45 mg of lactose
2.25 mg of Aerosil® (chemically pure silicic acid in a
submicroscopically fine dispersion)
6.75 mg of potato starch (as a 6% paste)
B) Sugar-coated tablets
20 mg of the substance from Example 3
60 mg of core composition
70 mg of sugar-coating composition
The core composition consists of 9 parts of corn starch, 3 parts of lactose and 1 part of vinylpyrrolidone-vinyl ace¬tate 60:40 copolymer. The sugar-coating composition consists of 5 parts of cane sugar, 2 parts of corn starch, 2 parts of calcium carbonate and 1 part of talc. The sugar-coated ta¬blets which have been prepared in this way are then provided with an enteric coating.
Biological investigations - receptor binding studies
1) D3 binding test
Cloned human Da-receptor-expressing CCL 1,3 mouse fibro¬blasts, obtainable from Res. Biochemicals Internat. One Strathmore Rd,, Natick, MA 01760-2418 USA, were used for the binding studies.
Cell preparation
The D3-expressing cells were multiplied in RPMI-1640 contai¬ning 10% fetal calf serum (GIBCO No. 041-32400 N); 100 U of penicillin/ml and 0.2% streptomycin (GIBO BRL, Gaithersburg, MD, USA). After 48 h, the cells were washed with PBS and in¬cubated for 5 min with 0.05% trypsin-containing PBS. After that, the solution was neutralized with medium and the cells were collected by centrifuging at 3 00 g. In order to lyse the

cells, the pellet was washed briefly with lysis buffer (5 mM Tris-HCl, pH 7.4, containing 10% glycerol) and after that in¬cubated, at 40c for 30 min, at a concentration of lO' cells/ml of lysis buffer. The cells were centrifuged at 200 g for 10 min and the pellet was stored in liquid nitrogen.
Binding tests
.For the D3-receptor binding test, the membranes were suspen¬ded in incubation buffer (50 mM Tris-HCl, pH 7.4, containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, 2 mM MgCl2, 10 \m quinoli-nol, 0.1% ascorbic acid and 0.1% BSA), at a concentration of approx. 10 cells/250 [il of test mixture, and incubated at 30°C with 0.1 nM i25iodosulpiride in the presence and absence of the test substance. The nonspecific binding was determined using 10- M spiperone.
After 60 min, the free radioligand and the bound radioligand were separated by filtering through GF/B glass fiber filters (Whatman, England) on a Skatron cell harvester (Skatron, Lier, Norway), and the filters were washed with iC6-cold Tris-HCl buffer, pH 7.4- The radioactivity which had collec¬ted on the filters was quantified using a Packard 2200 CA li¬quid scintillation counter.
The Ki values were determined by means of nonlinear regres¬sion analysis using the LIGAND program.
2) D2 binding test
Cell culture
HEK-2 93 cells possessing stably expressed human dopamine D2A receptors were cultured in RPMI 1640 containing Glutamix I' and 25 mM HEPES containing 10% fetal calf serum albumin. All the media contained 100 units of penicillin per mol and 100 ng/ml of streptomycin/ml. The cells were maintained at 370c in a moist atmosphere containing 5% CO2.
The cells were prepared for the binding studies by trypsini-zing them (0.05% solution of trypsin) at room temperature for 3-5 minutes. After that, the cells were centrifuged at 2 50 g for 10 minutes and treated with lysis buffer (5 mM Tris-HCl, 10% glycerol, pH 7.4) at 4°C for 30 minutes. After centrifu-ging at 250 g for 10 minutes, the residue was stored at -20oc until used.

Receptor binding tests
Low affinity state dopamine D2 receptor using isj.gpipej-one (81 TBq/irunol, Du Pont de Nemours, Dreieich)
The test mixtures (1 ml) consisted of 1 x 10 cells in incubation buffer (50 mM Tris, 120 mM NaCl, 5 mM KCl, 2 mM MgClj and 2 mM CaCl2, pH 7.4 with HCl) and 0.1 mM i25i_spiperone (total binding) or additionally 1 |J,M haloperidol (nonspecific binding) or test substance.
After the test mixtures had been incubated at 25°C for 60 minutes, they were filtered through GM/B glass filters (Whatman, England) on a Skatron cell harvester (from Zinsser, Frankfurt), and the filters were washed with iC6-cold 50 mM Tris-HCl buffer, pH 7.4. The radioactivity which had collected on the filters was quanti¬fied using a Packard 2200 CA liquid scintillation counter.
The results were evaluated as described in a).
The Ki values were determined by way of nonlinear regression ana¬lysis using the LIGAND program or by converting the IC50 values using the Cheng and Prusoff formula.
In these tests, the compounds according to the invention exhibit very good affinities for the D3 receptor (

We claim:
1. A triazole compound of the formula I

R1 is H, C1-C6-alkyl, which may be substituted by OH, OC1-C3-alkyl, halogen or phenyl, C3-C6-cycloalkyl or phenyl;
R2 is H, C1-C6-alkyl, which may be substituted by OH, OC1-C6-alkyl, halogen or phenyl, C1-C3-alkoxy, C1-C6-alkylthio, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, halogen, CN, C00R3, CONR2R4, NR2R4/ SO2R3, SOZNR2R4 or an aromatic radical which is selected from phenyl, naphthyl and a 5- or 6-membered heterocyclic radical having 1, 2, 3 or 4 heteroatoms which are selected, independently of each other, from 0, N and S, with it being possible for the aromatic radical to have one or two substituents which are selected, independently of each other, from C1-C6-alkyl, which may be substituted by OH, OC1-C6-alkyl, halogen or phenyl, C1-C3-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, halogen, CN, C0R3, NR3R4, NO2, SO2R3, SO2NR3R4 and phenyl which may be substituted by one or two radicals which are selected, independently of each other, from C1-C6-alkyl, C1-C6-alkoxy, NR3R4, CN, CF3, CHF2 or halogen;
R3 and R4 are, independently of each other, H, C1-C6-alkyl, which may be substituted by OH, OC1-C6-alkyl, halogen or phenyl, or phenyl;
A is C4-C10-alkylene or C3-C10-alkylene which comprises at least one group Z which is selected from O, S, CONR2, COO, CO, C3-C6-cycloalkyl and a double or triple bond;
B is a radical of the following formula:

R6, R7 and R8 are, independently of each other, selected from H, C1-C6-alkyl, which may be substituted by OH, OC1-C6-alkyl, which may be substituted by amino, mono- or di~C1-C4-alkylamino; C1-C6-alkylthio, halogen or phenyl; OH, C1-C6-alkoxy, OCF3, OSO2CF3, SH, C1-C6-alkylthio, C2-C6-alkenyl, C2-C6-alkynyl, halogen, CN, NO2, CO2R3, SOaR2, S02NR3R4, where R3 and R4 have the abovementioned meanings and may also form together with the N atom to which they are bonded a saturated or unsaturated heterocycle with 5 to 7 ring atoms and 1 or 2 N heteroatoms, CONR2R4, NHSO2R3, NR3R4, a 5- or 6-membered carbocyclic, aromatic or nonaromatic ring and a 5- or 6-membered heterocyclic, aromatic or nonaromatic ring with 1 or 2 heteroatoms which are selected, independently of each other, from 0, N and S, with the carbocyclic or heterocyclic ring being able to have one or two substituents which are selected, independently of each other, from C1-C6-alkyl, phenyl, phenoxy, halogen, C1-C6-alkoxy, OH, NO2, CF3 and CHF2, and with two of the substituents R2, R' and R2 being able to form, together with the carbon atoms of the phenyl ring to which they are bonded, a phenyl, cyclopentyl or cyclohexyl ring which is fused to the phenyl ring, with the possibility for one or two of the CH or CH2 groups in the fused ring being replaced by a nitrogen atom, an NH or an N-C1-C6 alkyl group;
and the salts thereof with physiologically tolerated acids.
2. The compound as claimed in claim 1 of the formula I, where X is
CH2CH2.
3. The compound as claimed in claim 1 or 2 of the formula I, where
A is C4-C10-alkylene or C3-C10-alkylene which comprises at least one group Z which is selected from 0, S, COO, CO, a double bond or triple bond and C3-C6-cycloalkyl.

4. The compound as claimed in one of the preceding claims of the
formula I, where A is C4-C:o-alkylene of C3-C10-alkylene which comprises at least one group Z which is selected from 0, S, a double bond and cyclohexyl.
5. The compound as claimed in one of the preceding claims of the
formula I, where R2 is an aromatic radical which is unsubstituted or has one or two substituents which are selected, independently of each other, from C1-C6-alkyl, OH, C1-C6-alkoxy, phenyl, CN and halogen.
6. The compound as claimed in one of the preceding claims of the
formula I, where R2 is H, C1-C6-alkyl, phenyl, thienyl, furanyl, tetrazolyl, pyrrolyl, pyridyl or pyrazinyl.
7. The compound as claimed in one of the preceding claims of the
formula I, where R2 is H, C1-C6-alkyl or C3-C6-cycloalkyl.
8. The compound as claimed in one of the preceding claims of the
formula I, where R2, R7 and R2 are selected, independently of each other, from H, C1-C6-alkyl, OH, C1-C6-alkoxy, C1-C6-akylthio-C1-C6-alkyl, halogen, CN, NO2, SO2R3, SOZNR2RI and C0NR3R4.
9. The compound as claimed in claim 1 of the formula I, where
R2 is H, C1-C6-alkyl or phenyl,
R2 is H, C1-C6-alkyl, phenyl, thienyl, furanyl, tetrazolyl,
pyrrolyl, thiazolyl or pyrazinyl, A is -SC3-C10-alkylene which may comprise a double bond,
and' R5, R7 and R2 are selected from H, C1-C6-alkyl, C1-C3-alkoxy,
halogen, SOzNR2R1, CN, NO2, CF3, CONR2R4, CHF2, OSO2CF3,
OCF3 and NHS02-C1-C6-alkyl.
10 .The compound which is selected from
l-{2-[3-({4-methyl-5-[4-{trifluoromethyl)phenyl]-4H-l,2,4-triazol-3-yl}sulfanyl)propyl]-l,2,3,4-tetrahydroisochino-lin-7-yl}-ethanon;
l-{2-{3-[(4-methyl-5-(3-cyano)phenyl-4H-l,2,4-triazol-3-yl) sufanyl]propyl}-!,2,3,4-tetrahydroisochinolin-7-yl)ethanon; l-{2-[3-({4-methyl-5-phenyl-4H-l,2,4-triazol-3-yl>sul-fany1)propyl]-1,2,3,4-tetrahydroisochinolin-7-yl}ethanon; l-{2-[3-({5-(2,4-dinitrophenyl)-4-methyl]-4H-1,2,4-triazol-3-yl}-sulfanyl)propyl] -l,2,3,4-tetrahydroisochinolin-7-yl}-ethanon; l-{2-{3-[(4-methyl-5-(3-methoxy)phenyl-4H-l,2,4-triazol-

3-yl)-oxy]propyl}-1,2,3,4-tetrahydro-isochinolin-7-yl)etha-non; l-{2-[ 3-( {4-isopropyl-5-phenyl-4H-I,2,4-triazol-3-yl}sui-fanyl ) propyl] -1,2,3, 4-tetrahydroisochinolin-7-yI}ethanor. ; l-{2-[3-( {4-butyl-5-phenyl-4H-l,2,4-triazol-3-yl}oul-fanyl)propyl]~1,2,3,4-tetrahydroisochinolin-7-yl}ethanon; l-{2-[3-({5-pheny1-4-propyl-4H-1,2,4-triazol-3-yl}su1-fanyl)propyl]-1,2,3,4-tetrahydroisochinolin-7-yl}ethanon; l-{2-[3-({4-eyelopropyl-5-phenyl-4H-1,2,4-triazol-3-yl}sul-fanyl)propyl]-1,2,3,4-tetrahydroisochinolin-7-yl}ethanon; und l-{2-[3-( {4-ethyl-5-phenyl-4H-l,_2,4-triazol-3-yl}sul-fanyl)propyl]-1,2,3,4-tetrahydroisochinolin-7-yl}ethanon.
11. A pharmaceutical which comprises at least one compound as claimed in one of claims 1 to 9, where appropriate together with physiologically acceptable excipients and/or adjuvants.

Documents:

2001-950.rtf

in-pct-2001-0950-che abstract-duplicate.pdf

in-pct-2001-0950-che abstract.jpg

in-pct-2001-0950-che abstract.pdf

in-pct-2001-0950-che assignment.pdf

in-pct-2001-0950-che claims-duplicate.pdf

in-pct-2001-0950-che claims.pdf

in-pct-2001-0950-che correspondence-others.pdf

in-pct-2001-0950-che correspondence-po.pdf

in-pct-2001-0950-che description (complete)-duplicate.pdf

in-pct-2001-0950-che description (complete).pdf

in-pct-2001-0950-che form-1.pdf

in-pct-2001-0950-che form-13.pdf

in-pct-2001-0950-che form-19.pdf

in-pct-2001-0950-che form-26.pdf

in-pct-2001-0950-che form-3.pdf

in-pct-2001-0950-che form-5.pdf

in-pct-2001-0950-che form-6.pdf

in-pct-2001-0950-che others.pdf

in-pct-2001-0950-che pct.pdf

in-pct-2001-0950-che petition.pdf

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Patent Number

225611

Indian Patent Application Number

IN/PCT/2001/950/CHE

PG Journal Number

52/2008

Publication Date

26-Dec-2008

Grant Date

19-Nov-2008

Date of Filing

06-Jul-2001

Name of Patentee

ABBOTT GMBH & CO. KG

Applicant Address

65205 WIESBADEN, MAX-PLANCK-RING 2,

Inventors:

#	Inventor's Name	Inventor's Address
1	STARCK, DOROTHEA	KAISER-WILHELM-STR., 31 D-67059 LUDWIGSHAFEN,
2	treiber, hans-jorg	sperberweg 1, d-68782 bruhl,
3	NEUMANN-SCHULTZ BARBARA	RHEINGAUSTR. 42, D-68526 LADENBURG,
4	BLUMBACH, KAI	KATHARINENBERG 26, D-97337 DETTELBACH,
5	SCHOBEL, DIETMAR	WEISSBUCHENWEG 9, D-68167 MANNHEIM,
6	UNGER, LILIANE	WOLLSTR.129, D-67065 LUDWIGSHAFEN,

PCT International Classification Number

C07D401/12

PCT International Application Number

PCT/EP00/00177

PCT International Filing date

2000-01-12

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	199 00 811.6	1999-01-12	Germany