TREA

Triazole compounds with dopamine-D3-receptor affinity

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Information

  • Patent Grant
  • 6602867
  • Patent Number
    6,602,867
  • Date Filed
    Wednesday, July 11, 2001
    23 years ago
  • Date Issued
    Tuesday, August 5, 2003
    21 years ago
Information
Abstract
Triazole compounds of the following formula where R1, R2, 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 D3 receptor and can therefore be used for treating diseases which respond to the influence of dopamine D3 ligands.
Description




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 D


3


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 D


3


receptor ligands. U.S. Pat. Nos. 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


46 (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 1990, two subtypes of dopamine receptor had been clearly defined pharmacologically, namely the D


1


and D


2


receptors.




More recently, a third subtype has been found, namely the D


3


receptor, which appears to mediate some of the effects of the antipsychotic and anti-Parkinson agents (J. C. Schwartz et al., The Dopamine D


3


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 D


3


receptors are chiefly expressed in the limbic system, it is assumed that while a selective D


3


ligand would probably have the properties of known antipsychotic agents, it would not have their dopamine D


3


receptor-mediated neurological side-effects (P. Sokoloff et al., Localization and Function of the D


3


Dopamine Receptor,


Arzneim. Forsch./Drug Res


. 42(1), 224 (1992); P. Sokoloff et al. Molecular Cloning and Characterization of a Novel Dopamine Receptor (D


3


) 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 D


3


receptor and a low affinity for the D


2


receptor. These compounds are consequently selective D


3


ligands.




The present invention relates, therefore, to the compounds of the formula I:











where




R


1


is H, C


1


-C


6


-alkyl, which may be substituted by OH, OC


1


-C


6


-alkyl, halogen or phenyl, C


3


-C


6


-cycloalkyl or phenyl;




R


2


is H, C


1


-C


6


-alkyl, which may be substituted by OH, OC


1


-C


6


-alkyl, halogen or phenyl, C


1


-C


6


-alkoxy, C


1


-C


6


-alkylthio, C


2


-C


6


-alkenyl, C


2


-C


6


-alkynyl, C


3


-C


6


-cycloalkyl, halogen, CN, COOR


3


, CONR


3


R


4


, NR


3


R


4


, SO


2


R


3


, SO


2


NR


3


R


4


, 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 C


1


-C


6


-alkyl, which may be substituted by OH, OC


1


-C


6


-alkyl, halogen or phenyl, C


1


-C


6


-alkoxy, C


2


-C


6


-alkenyl, C


2


-C


6


-alkynyl, C


3


-C


6


-cycloalkyl, halogen, CN, COR


3


, NR


3


R


4


, NO


2


, SO


2


R


3


, SO


2


NR


3


R


4


and phenyl which may be substituted by one or two radicals which are selected, independently of each other, from C


1


-C


6


-alkyl, C


1


-C


6


-alkoxy, NR


3


R


4


, CN, CF


3


, CHF


2


or halogen;




R


3


and R


4


are, independently of each other, H, C


1


-C


6


-alkyl, which may be substituted by OH, OC


1


-C


6


-alkyl, halogen or phenyl, or phenyl;




A is C


4


-C


10


-alkylene or C


3


-C


10


-alkylene which comprises at least one group Z which is selected from O, S, CONR


3


, COO, CO, C


3


-C


6


-cycloalkyl and a double or triple bond;




B is a radical of the following formula:











 where




X is CH


2


or CH


2


CH


2


;




R


6


, R


7


and R


8


are, independently of each other, selected from H, C


1


-C


6


-alkyl, which may be substituted by OH, OC


1


-C


6


-alkyl, which may be substituted by amino, mono- or di-C


1


-C


4


-alkylamino; C


1


-C


6


-alkylthio, halogen or phenyl; OH, C


1


-C


6


-alkoxy, OCF


3


, OSO


2


CF


3


, SH, C


1


-C


6


-alkylthio, C


2


-C


6


-alkenyl, C


2


-C


6


-alkynyl, halogen, CN, NO


2


, CO


2


R


3


, SO


2


R


3


, SO


2


NR


3


R


4


, where R


3


and R


4


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, CONR


3


R


4


, NHSO


2


R


3


, NR


3


R


4


, 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 C


1


-C


6


-alkyl, phenyl, phenoxy, halogen, C


1


-C


6


-alkoxy, OH, NO


2


, CF


3


and CHF


2


, and with two of the substituents R


6


, R


7


and R


8


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 CH


2


groups in the fused ring being replaced by a nitrogen atom, a NH or a N—(C


1


-C


6


-alkyl) group;




and the salts thereof with physiologically tolerated acids.




The compounds according to the invention are selective dopamine D


3


receptor ligands which act in the limbic system in a regioselective manner and which, as a result of their low affinity for the D


2


receptor, have fewer side-effects than do the classic neuroleptic agents, which are D


2


receptor antagonists. The compounds can therefore be used for treating diseases which respond to dopamine D


3


ligands, i.e. they are effective for treating those diseases in which affecting (modulating) the dopamine D


3


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.




The 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:




Alkyl (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. The alkyl group can have one or more substituents which are selected, independently of each other, from OH, OC


1


-C


6


-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 α or ω position. CF


3


, CHF


2


, CF


2


Cl or CH


2


F 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, C


3


-C


6


-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 CONR


2


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—C


3


-C


6


-alkylene, in particular —Z—CH


2


CH


2


CH


2


—, —Z—CH


2


CH


2


CH


2


CH


2


—, —Z—CH


2


CH═CHCH


2


—, —Z—CH


2


C(CH


3


)═CHCH


2


—,











—Z—CH


2


CH(CH


3


)CH


2


— or a linear —Z—C


7


-C


10


-alkylene radical, with Z being bonded to the triazole ring. Z is preferably CH


2


, O and, in particular, S. Preference is additionally given to A being —(CH


2


)


4


—, —(CH


2


)


5


—, —CH


2


CH


2


CH═CHCH


2


—,











—CH


2


CH


2


C(CH


3


)═CHCH


2


— or —CH


2


CH


2


CH(CH


3


)CH


2


—.




Halogen is F, Cl, Br or I, preferably F or Cl.




X is preferably —CH


2


-CH


2


—.




R


1


is preferably H, C


1


-C


6


-alkyl or C


3


-C


6


-cycloalkyl.




If R


2


is an aromatic radical, this radical is then preferably one of the following radicals:











where




R


9


to R


11


are H or the abovementioned substituents of the aromatic radical,




R


12


is H, C


1


-C


6


-alkyl or phenyl, and T is N or CH.




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 R


9


, R


10


and R


12


have the abovementioned meanings. The indicated phenyl, pyridine, thiazolyl and pyrrole radicals are particularly preferred.




The radicals R


9


to R


11


are preferably H, C


1


-C


6


-alkyl, OR


3


, CN, phenyl, which may be substituted by C


1


-C


6


-alkyl, C


1


-C


6


-alkoxy or halogen, CF


3


and halogen, and are, in particular, H, C


1


-C


6


-alkyl, OR


3


and halogen. In this context, R


3


has the abovementioned meanings.




Particularly preferably, R


2


is H, C


1


-C


6


-alkyl, NR


3


R


4


(R


3


and R


4


are, independently of each other, H or C


1


-C


6


-alkyl), phenyl or a 5-membered aromatic heterocyclic radical which has 1 or 2 heteroatoms which are independently selected from N, S and O. The heterocyclic radical is preferably a pyrrole radical or a pyridine radical.




A is preferably C


4


-C


10


-alkylene or C


3


-C


10


-alkylene which comprises at least one group Z which is selected from O, S, COO, CO, a double bond and cyclohexyl.




Preferably, at least one of the radicals R


6


, R


7


and R


8


is H.




The radicals R


6


, R


7


and R


8


are preferably, and independently of each other, selected from H, C


1


-C


6


-alkyl, OH, C


1


-C


6


-alkoxy, C


1


-C


6


-alkylthio-C


1


-C


6


-alkyl, halogen, CN, NO


2


, SO


2


R


3


, SO


2


NR


3


R


4


and CONR


3


R


4


. Particularly preferably, the fused phenyl group has one or two substituents, i.e. one or two of the radicals R


6


, R


7


and R


8


is/are C


1


-C


6


-alkyl, halogen, CN, NO


2


, SO


2


R


3


and, in particular, SO


2


NR


3


R


4


, where R


3


and R


4


, 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, O or S besides the nitrogen atom and which may be substituted, e.g. pyrrolidine, piperidine, morpholine or azepine.




If one of the radicals R


6


, R


7


and R


8


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 R


6


, R


7


and R


8


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




R


1


is H, C


1


-C


6


-alkyl or phenyl,




R


2


is H, C


1


-C


6


-alkyl, phenyl, thienyl, furanyl, pyridyl, pyrrolyl, thiazolyl or pyrazinyl,




A is —SC


3


-C


10


-alkylene which can comprise a double bond, and




R


6


, R


7


and R


8


are selected from H, C


1


-C


6


-alkyl, C


1


-C


6


-alkoxy, halogen, SO


2


NR


3


R


4


, CN, NO


2


, CF


3


, CONR


3


R


4


, CHF


2


, OSO


2


CF


3


, OCF


3


and NHSO


2


-C


1


-C


6


-alkyl.




In here X is especially CH


2


CH


2


.




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., Birkhäuser 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


1


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






HB  (III);






or




b) reacting a compound of the formula (IV)











where Z


1


is O or S, and A


1


is C


1


-C


10


-alkylene or a bond, with a compound of the formula (V)






Y


1


—A


2


—B  (V)






where Y


1


has the abovementioned meaning and A


2


is C


2


-C


10


-alkylene, with A


1


and A


2


together having from 3 to 10 C atoms and A


1


and/or A


2


where appropriate comprising at least one group Z; or




c) reacting a compound of the formula (VI)











where Y


1


and A


1


have the abovementioned meanings, with a compound of the formula (VII)






H—Z


1


—A—B  (VII)






where Z


1


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, 39, 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, 45, 7643




Martin et al.


Synthesis


1979, 633,




 to give the products (VIIIa) (using 1,3-propanedithiol by way of example)











 and then chain-elongating with compounds of the formula (IX)






Y


1


—A


3


—B  (IX)






where Y


1


has the abovementioned meaning and A


3


is C


3


-C


9


-alkylene which can contain a group Z,




 with compounds of the formula (Ia)











where Z


2


is CO or a methylene group, and Z


2


and A


2


have together from 4 to 10 C atoms, being obtained after deprotecting or reducing, or




e) reacting a compound of the formula (VIII) with a compound of the formula (X)






Y


2


—A—B  (X)






where Y


2


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/1b p. 383 ff, or Vol. V/1c p. 575 ff, or




f) reacting a compound of the formula (XI)











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, 50, 1927; or WO 92/20655.




The process for preparing a compound of the formula I where A comprises the groups COO or CONR


3


consists in reacting a compound of the formula (XII)











where Y


3


is OH, OC


1


-C


4


-alkyl, Cl or, together with CO, an activated carboxyl group, and A


4


is C


0


-C


9


-alkylene, with a compound of the formula (XIII)






B—A—Z


3


  (XIII)






where Z


3


is OH or NHR


3


.




Compounds of the formula B—H can be prepared as described, for example, in




Synth. Commun. 1984, 14, 1221;




S. Smith et al.,


Bioorg. Med. Chem. Lett


. 1998, 8, 2859;




WO 97/47602 or WO 920655, or






J. Med. Chem


. 1987, 30, 2111 and 2208 and 1999, 42, 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, R


1


, R


2


, R


6


, R


7


, R


8


, A, B and 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 500 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-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline




1A Preparation of the Starting Materials 2-(3-Chloropropyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline




7.2 g (37 mmol) of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline were heated together with 4.05 ml (40 mmol) of 1-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.






1


H-NMR (CDCl


3


): δ=2.0 (m, 2H); 2.6-2.8 (m, 6H); 3.5 (s, 2H); 3.6 (t, 2H); 3.8 (2s, 6H); 6.5 (s, 1H); 5.6 (s, 1H). C


14


H


20


ClNO


2


(269).




1B Preparation of the Final Product




380 mg (1.7 mmol) of 3-mercapto-4-methyl-5-phenyl-1,2,4(4H)-triazole were heated with 450 mg (1.7 mmol) of the chlorinated base 1A and 40 mg (1.7 mmol) of lithium hydroxide in 5 ml of DMF while stirring at 100° C. 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);


1


H-NMR (CDCl


3


): δ=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, 1H); 6.5 (s, 1H); 7.5 (m, 3H); 7.8 (m, 2H).




The title compound was obtained by treatment with ethereal hydrochloric acid C


23


H


28


N


4


O


2


S×HCl Melting point: 180-183° C.




EXAMPLE 2




6-Methoxy-2-{3-[(4-methyl-5-pyrrol-2-yl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline




2A Preparation of the Starting Compound 2-(3-Chloropropyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline




The above substance was prepared using 6-methoxy-1,2,3,4-tetrahydroisoquinoline in a manner analogous to 1A.






1


H-NMR (CDCl


3


): δ=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, 1H); 6.7 (dd, 1H); 6.9 (d, 1H).




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. C


20


H


25


N


5


OS (383.5); Melting point: 179-181° C.




EXAMPLE 3




2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-6-methoxy-1,2,3,4-tetrahydroisoquinoline




3A Preparation of the Starting Material 3-(3-Chloropropylmercapto)-4-methyl-5-phenyl-1,2,4(4H)-triazole




A suspension of 2.6 g (16.5 mmol) of 1-bromo-3-chloropropane, 0.22 g (1.5 mmol) of sodium iodide, 2.7 g (15 mmol) of 3-mercapto-4-methyl-5-phenyl-1,2,4(4H)-triazole and 2.1 g (15 mmol) of potassium carbonate in 70 ml of ethanol 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;


1


H-NMR (CDCl


3


): δ=2.3 (q, 2H); 3.4 (t, 2H); 3.6 (s, 3H); 3.7 (t, 2H); 7.5-7.7 (m, 5H). C


12


H


14


ClN


3


S (267.8); Melting point: 137-141° C.




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-1,2,3,4-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 120° C. 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 crude product was chromatographed on silica gel (mobile phase: methylene chloride with 0-3% methanol). 110 mg of a white solid were isolated.




C


22


H


26


N


4


OS (394.5) MS (m/z): 395 [M]


+


.




EXAMPLE 4




2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-7-(piperidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline




4A Preparation of N-Acetyl-7-(piperidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline




21.1 g (77 mmol) of 2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride (prepared as described in G. Grunewald et al. J. Med. Chem 1999, 42, 118-134) in 50 ml of THF were added dropwise to a solution of 6.0 g (70 mmol) of piperidine and 10.9 g (84 mmol) of diisopropylethylamine in 230 ml of THF, and the mixture was heated under reflux for two hours. After the reaction was complete, the solvent was removed in vacuo, the residue was taken up in dichloromethane/water and, after making alkaline with 10% strength sodium hydroxide solution and separating the phases, the organic phase was dried over sodium sulfate. The crude product remaining after filtration and removal of the solvent was purified by column chromatography on silica gel (mobile phase: methylene chloride with 3% methanol).




Yield: 18.6 g (57.6 mmol); 82%; Melting point:171-174° C.




4B 7-(Piperidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline




The compound described above was heated to boiling with 50% concentrated hydrochloric acid for two hours. The product formed a white precipitate on cooling. The residue was isolated, washed with water, digested in diethyl ether and dried in vacuo.




Yield: 12.1 g (38.2 mmol) 56% of theory.




4C 2-(3-Chloropropyl)-7-(piperidin-4-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline




12.1 g (38.2 mmol) of 7-(piperidin-1-ylsulfonyl)-1,2,3,4-tetra-hydroisoquinoline and 8.4 g (84 mmol) of triethylamine were dissolved in DMF at 40° C., 9.0 g (57.2 mmol) of 1-bromo-3-chloropropane were added dropwise, and the mixture was stirred at 50° C. for 7 h. For workup, the mixture was concentrated, and the residue was taken up in water and extracted with dichloromethane. Drying over sodium sulfate, filtration and removal of the solvent were followed by purification by chromatography (silica gel; mobile phase: methylene chloride with 3% methanol) to result in 11.7 g (323.7 mmol) of a yellowish oil.




Yield: 86% of theory.




4D Preparation of the Final Compound




10.0 g (28.0 mmol) of the chlorinated base 4C described above, 6.4 g (28 mmol) of 3-mercapto-4-methyl-5-phenyl-4H-1,2,4-triazole and 0.7 g (28.0 mmol) of lithium hydroxide were heated in 77 ml of DMF at 100° C. for three hours. After the reaction was complete, the solvent was removed, and the residue was mixed with water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Chromatography of the crude product (silica gel; mobile phase: methylene chloride with 0-5% methanol) afforded 3.9 g (7.5 mmol) of a white solid.




Yield: 27% of theory;


1


H-NMR (CDCl


3


): δ=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); 7.2 (d, 1H); 7.4 (s, 1H); 7.5 (m, 4H); 7.7 (m, 2H). C


26


H


33


N


5


O


2


S


2


(511.7) MS (m/z): 512.3 [M+H]


+


; Melting point: 105-108° C.




EXAMPLE 5




2-[4-(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)butyl]-7-(morpholin-4-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline Hydrochloride




Preparation of the Starting Compound




5A N-Acetyl-7-(morpholin-4-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline




was obtained as described in Example 4A by reacting morpholine with 2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride in the presence of diisopropylamine in THF and by heating with 50% concentrated hydrochloric acid and, after alkaline workup, converted into the corresponding 7-(morpholin-4-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline.




C


13


H


18


N


2


O


3


S (282) MS (m/z): 283 [M+H]


+


.




5B 2-(3-Chloropropyl)-7-(morpholin-4-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline




1.2 g (4.4 mmol) of 7-(morpholin-4-ylsulfonyl)-1,2,3,4-tetra-hydroisoquinoline and 1.0 g (10 mmol) of triethylamine were dissolved in DMF at 40° C., 1.1 g (6.6 mmol) of 1-bromo-3-chloropropane were added dropwise, and the mixture was stirred at 40° C. 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.


1


H-NMR (CDCl


3


): δ=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, 1H); 7.4 (s, 1H); 7.5 (d, 1H). C


16


H


23


N


2


O


3


S (359).




Preparation of the Final Compound




280 mg (1 mmol) of 2-[4-methyl-5-phenyl-1,2,4-(4H)-triazol-3-yl]-1,3-dithiane (described in WO 9902503) were dissolved in 2.5 ml of dry THF and, at −70° C., 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 −70+ C. for 45 min, 0.37 g (1 mmol) of 2-[3-chloropropyl]-7-(morpholin-4-yl-sulfonyl)-1,2,3,4-tetrahydroisoquinoline 5B dissolved in THF 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); 1H-NMR (CDCl


3


): δ=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, 1H); 7.4 (s, 1H); 7.5 (m, 4H); 7.7 (m, 2H).




The title compound was obtained by adding ethereal HCl C


26


H


33


N


5


O


3


S.HCl (531.6); Melting point: 87-89° C.




The following were obtained in an analogous way:




EXAMPLE 6




1-(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)-4-(7-(piperidin-1-yl-sulfonyl)-1,2,3,4-tetrahydroisoquinolin-2-yl)butan-1-one




C


27


H


33


N


5


O


3


S (507.7) MS: 508.3 [M+H]


+


.




EXAMPLE 7




2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline-7-carbonitrile




C


22


H


23


N


5


S (389.5); Melting point: 116-118° C.




EXAMPLE 8




5-[2-(Diethylammonio)ethoxy]-2-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline Dihydrochloride




C


27


H


37


N


5


OS.2HCl (552.6); Melting point: 110-112° C.




EXAMPLE 9




N-Benzyl-2-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide




C


26


H


30


N


6


O


2


S


3


(554.8); Melting point: 67-70° C.




EXAMPLE 10




N-Benzyl-2-{3-[(4-methyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide




C


27


H


30


N


6


O


2


S


2


.2HCl (607.6); Melting point: 81-84° C.




EXAMPLE 11




5-Methoxy-2-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline




C


22


H


26


N


4


OS (394.5); Melting point: 73-75° C.




EXAMPLE 12




2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-7-nitro-1,2,3,4-tetrahydroisoquinoline




C


21


H


24


ClN


5


O


2


S (446); Melting point: 190-192° C.




EXAMPLE 13




2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline






1


H-NMR (CDCl


3


): δ=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, 1H); 7.2 (m, 3H); 7.5 (m, 3H); 7.7 (m, 2H). C


21


H


24


N


4


S (365.5).




EXAMPLE 14




2-(3-{[4-Methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1,2,3,4-tetrahydroisoquinoline






1


H-NMR (CDCl


3


): δ=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, 1H); 7.1 (m, 3H); 8.9 (s, 1H). C


19


H


23


N


5


S


2


(386.5).




EXAMPLE 15




2-{3-[(4-Methyl-5-pyridinium-3-yl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline Dihydrochloride




C


20


H


23


N


5


S.2HCl (438.4); Melting point: 87-89° C.




EXAMPLE 16




7-[(Dimethylamino)sulfonyl]-2-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline






1


H-NMR (CDCl


3


): δ=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, 1H); 7.4-7.6 (m, 7H). C


23


H


29


N


5


O


2


S


2


(472.6).




EXAMPLE 17




7-[(Dimethylamino)sulfonyl]-2-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1,2,3,4-tetrahydroisoquinoline




1H-NMR (CDCl


3


): δ=2.1 (q, 2H); 2.5 (s, 3H); 2.6-2.8 (m, 10H); 2.9 (m, 2H); 3.4 (t, 2H); 3.5 (s, 3H); 3.7 (s, 2H); 7.2 (m, 1H); 7.5 (m, 2H); 8.9 (s, 1H). C


21


H


28


N


6


O


2


S


3


(493.7).




EXAMPLE 18




Methyl 2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline-7-carboxylate Oxalate




C


23


H


27


N


4


O


2


S.C


2


HO


4


(512.6); Melting point: 160-163° C.




EXAMPLE 20




2-(3-{[4-Methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-7-(piperidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline






1


H-NMR (CDCl


3


): δ=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, 1H); 7.45 (s, 1H); 7.5 (d, 1H); 8.9 (s, 1H).




C


24


H


32


N


6


O


2


S


3


(532.8).




EXAMPLE 21




2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-7-(phenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline






1


H-NMR (CDCl


3


): δ=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, 1H); 7.4-7.7 (m, 10H); 7.9 (d, 2H). C


27


H


28


N


4


O


2


S


2


(504.7).




EXAMPLE 22




2-(3-{(4-Methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1,2,3,4-tetrahydroisoquinolin-7-yl Phenylsulfone






1


H-NMR (CDCl


3


): δ=2.1 (q, 2H); 2.5 (s, 3H); 2.7 (t, 2H); 2.8 (t, 2H); 2.95 (t, 2H); 3.4 (t, 2H); 3.5 (s, 3H); 3.65 (m, 2H); 7.2 (d, 1H); 7.4-7.7 (m, 5H); 7.9 (d, 2H); 8.9 (s, 1H). C


25


H


29


N


5


O


2


S


3


(525.7).




EXAMPLE 23




2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-7-(morpholin-4-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline






1


H-NMR (CDCl


3


): δ=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, 1H); 7.4-7.6 (m, 5H); 7.9 (d, 2H). C


25


H


31


N


5


O


3


S


2


(525.7).




EXAMPLE 24




2-[4-(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)butyl]-7-(phenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline




C


28


H


30


N


4


O


2


S (486.6).




EXAMPLE 25




2-{3-[(4-Methyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-yl)sulfanyl]-propyl}-N-phenyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide






1


H-NMR (CDCl


3


): δ=1.3 (m, NH); 2.1 (q, 2H); 2.6 (m, 4H); 2.8 (t, 2H); 3.3 (t, 2H); 3.6 (s, 3H); 3.7 (m, 6H); 7.3 (m, 1H); 7.4-7.6 (m, 5H); 7.9 (d, 2H). C


26


H


28


N


6


O


2


S


2


(520.7). Melting point: 58-61° C.




EXAMPLE 26




2-(3-{[4-Methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-N-phenyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide






1


H-NMR (CDCl


3


): δ=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, 1H). C


25


H


28


N


6


O


2


S


3


(540.7); Melting point: 77-81° C.




EXAMPLE 27




2-(3-{[5-(2,4-Dimethoxy)phenyl)-4-methyl-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-7-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline






1


H-NMR (CDCl


3


): δ=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, 1H); 6.65 (d, 1H); 7.25 (d, 1H); 7.3 (d, 1H); 7.7 (s, 1H); 7.8 (d, 1H). C


24


H


30


N


4


O


4


S


2


(502.7) MS: 503.5 [M+H]


+


.




EXAMPLE 28




6,7-Dichloro-2-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline




C


21


H


22


Cl


2


N


4


S (433.4); Melting point: 138-139° C.




EXAMPLE 29




7,8-Dichloro-2-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline Hydrochloride




1H-NMR (CDCl


3


): δ=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, 1H); 7.2 (d, 1H); 7.5 (m, 3H); 7.7 (m, 2H), [free base].




Salt precipitation with ethereal HCl led to the title compound C


21


H


22


Cl


2


N


4


S.×HCl (469.9); Melting point: 109° C.




EXAMPLE 30




7-Cyano-2-[4-(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)butyl]-1,2,3,4-tetrahydroisoquinoline Hydrochloride




C


23


H


25


N


5


.HCl(407.9); Melting point: 175° C.




EXAMPLE 31




2-{3-[(4-Methyl-5-thien-3-yl-4H-1,2,4-triazol-3-yl)sulfanyl]-propyl}-6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline Hydrochloride




C


20


H


21


F


3


N


4


S


2


.Cl×HCl (475); Melting point: 184-185° C.




EXAMPLE 32




1-{2-[3-({4-Methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}ethanone






1


H-NMR (CDCl


3


): δ=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, 1H); 7.6-7.8 (m, 6H). C


24


H


25


F


3


N


4


OS (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




1H-NMR (CDCl


3


): δ=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, 1H); 7.2 (s, 1H); 7.3 (d, 2H); 7.5 (d, 2H); [free base].




The title compound was obtained by treatment with ethereal hydrochloric acid C


22


H


24


Cl


2


N


4


S.HCl (483.9) Melting point: 207-210° C.




EXAMPLE 34




6-Chloro-2-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline Hydrochloride






1


H-NMR (CDCl


3


): δ=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, 1H); 7.1 (m, 2H); 7.5 (d, 3H); 7.5 (d, 2H); [free base].




Salt precipitation with ethereal HCl led to the title compound C


21


H


23


ClN


4


S.HCl (435.4); Melting point: 188-191° C.




EXAMPLE 35




2-(3-{[4-Methyl-5-(1-methyl-1H-pyrrol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-7-(piperidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline






1


H-NMR (CDCl


3


): δ=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, 1H); 6.4 (m, 1H); 6.8 (m, 1H); 7.2 (d, 1H); 7.4 (s, 1H); 7.5 (m, 2H). C


25


H


34


N


6


O


2


S


2


(514.7); Melting point: 96-100° C.




EXAMPLE 36




2-[4-(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)butyl]-7-(piperidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline




C


27


H


35


N


5


O


2


S (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






1


H-NMR (CDCl


3


): δ=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, 1H); 7.4 (s, 1H); 7.5 (m, 3H); 7.7 (s, 1H). C


24


H


31


N


5


O


2


S


3


(517.7) MS: 518.3 [M+H]


+


; Melting point: 192-195° C.




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






1


H-NMR (CDCl


3


): δ=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). C


27


H


29


N


5


O


2


S


2


(519.7) MS: 520.3 [M+H]


+


.




EXAMPLE 39




6-Chloro-2-{3-[(4-methyl-5-thien-3-yl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline




C


19


H


21


ClN


4


S


2


(405); Melting point: 99-100° C.




EXAMPLE 40




7-[(Diethylammonio)methyl]-2-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline Dihydrochloride




C


26


H


35


N


5


S.2HCl (522.6); Melting point: 75° C.




EXAMPLE 41




2-{3-[(4-Methyl-5-thien-3-yl-4H-1,2,4-triazol-3-yl)sulfanyl]-propyl}-7-(trifluoromethyl)-1,2,3,4-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 ice-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-tetrahydroisoquinoline 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.


1


H-NMR (CDCl


3


): δ=2.0 (sbr, 1H); 2.9 (t, 2H); 3.2 (t, 2H); 4.0 (s, 2H); 7.2 (d, 1H); 7.3 (s, 1H); 7.4 (s, 1H).




41B 2-(3-Chloropropyl)-7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline




0.95 g (4.7 mmol) of the compound described above was reacted with 1-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.


1


H-NMR (CDCl


3


): δ=2.0 (m, 2H); 2.65 (m, 2H); 2.75 (m, 2H); 2.9 (m, 2H); 3.65 (m, 4H); 7.2 (dd, 1H); 7.3 (d, 1H); 7.4 (dd, 1H).




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-1,2,4-triazole 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.


1


H-NMR (CDCl


3


): δ=2.1 (m, 2H); 2.7 (t, 2H); 2.8 (t, 2H); 3.0 (m, 2H); 3.35 (t, 2H); 3.7 (m, 5H); 7.1 (d, 1H); 7.2 (s, 1H); 7.3 (d, 1H); 7.5 (m, 2H); 7.7 (s, 1H); [free base].




The title compound was obtained by treatment with ethereal HCl C


20


H


21


F


3


N


4


S


2


.HCl (475); Melting point: 192-194° C.




EXAMPLE 42




2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-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 22 ml of glacial acetic acid and 30 ml of concentrated sulfuric acid. After 18 hours at room temperature, the reaction mixture was poured into 350 ml of ice-water 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):




F1 1.2 g (5.7 mmol) 32% of theory of 8-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline


1


H-NMR (CDCl


3


): δ=1.9 (sbr, 1H); 2.8 (t, 2H); 3.1 (t, 2H); 4.2 (s, 2H); 7.2 (m, 2H); 7.5 (d, 1H).




F2 1.4 g (6.8 mmol) 38% of theory of 6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline


1


H-NMR (CDCl


3


): δ=1.8 sbr, 1H); 2.8 (t, 2H); 3.1 (t, 2H); 4.0 (s, 2H); 7.1 (d, 1H); 7.4 (m, 2H).




42 B 2-(3-Chloropropyl)-8-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline




2-(3-Chloropropyl)-8-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline was obtained in 73% yield by reacting 42-A F1 with bromochloropropane in a manner analogous to the description in Example 4C.






1


H-NMR (CDCl


3


): δ=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, 1H).




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-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline [42B1] in 10 ml of DMF in the presence of 70 mg of lithium hydroxide at 100° C. 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


1


H-NMR (CDCl


3


): δ=2.1 (q, 2H); 2.6-2.7 (m, 4H); 2.9 (t, 2H); 3.4 (t, 2H); 3.6 (s, 3H); 3.8 (s, 2H); 7.1 (t, 1H); 7.25 (d, 1H); 7.4 (d, 1H), 7.5 (m, 3H); 7.6 (m, 2H).




The title compound was obtained by treatment with ethereal HCl. C


22


H


23


F


3


N


4


S.HCl (469); Melting point: 118° C.




EXAMPLE 43




2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-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-tetrahydroisoquinoline




2-(3-Chloropropyl)-6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline was obtained in 96% yield by reacting 6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline [42AF2] (obtained as described in 42A) with bromochloropropane in a manner analogous to that described for 4C.






1


H-NMR (CDCl


3


): δ=2.0 (m, 2H); 2.6-2.8 (m, 4H); 2.9 (t, 2H); 3.6 (m, 4H); 7.1 (d, 1H); 7.4 (m, 2H).




43C 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 100° C. 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;


1


H-NMR (CDCl


3


): δ=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, 1H); 7.3 (m, 2H); 7.5 (m, 3H); 7.7 (m, 2H); [free base].




The title compound was obtained by treatment with ethereal HCl C


22


H


23


F


3


N


4


S.HCl (469); Melting point: 200-202° C.




EXAMPLE 44




2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline Hydrochloride




C


22


H


23


F


3


N


4


S.HCl (469); Melting point: 205-207° C.




EXAMPLE 45




2-{3-[(4-Methyl-5-(thien-3-yl)-4H-1,2,4-triazol-3-yl)sulfanyl]-propyl}-7-(4-methylpiperazin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline






1


H-NMR (CDCl


3


): δ=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, 1H). C


24


H


32


N


6


O


2


S


3


(538.8).




EXAMPLE 46




2-{3-[(4-Methyl-5-(phenyl)-4H-1,2,4-triazol-3-yl)sulfanyl]-propyl}-7-(4-methylpiperazin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline






1


H-NMR (CDCl


3


): δ=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, 1H); 7.5 (m, 5H); 7.6 (m, 2H). C


26


H


34


N


6


O


2


S


3


(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-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline






1


H-NMR (CDCl


3


): δ=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, 1H); 7.4-7.6 (m, 4H); 7.7 (m, 1H). C


28


H


31


N


5


O


2


S


3


(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-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline






1


H-NMR (CDCl


3


) δ=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, 1H); 7.4-7.6 (m, 3H); 8.0 (m, 1H); 8.7 (m, 1H); 8.9 (m, 1H). C


29


H


32


N


6


O


2


S


2


(558).




EXAMPLE 49




7-[(3,3-Dimethylpiperidin-1-yl)sulfonyl]-2-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline




C


28


H


37


N


5


O


2


S


2


(539.8); Melting point: 75-76° C.




EXAMPLE 50




2-{3-[(4-Cyclopropyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]-propyl}-7-[(3,3-dimethylpiperidin-1-yl)sulfonyl]-1,2,3,4-tetrahydroisoquinoline




C


30


H


39


N


5


O


2


S


2


(558).




EXAMPLE 51




2-[(4-{[(4-Methyl-5-(1-methyl-1H-pyrrol-3-yl)-4H-1,2,4-triazol-3-yl)sulfanyl]methyl}cyclohexyl)methyl]-7-nitro-1,2,3,4-tetrahydroisoquinoline




C


26


H


31


N


5


O


2


S (477.6); Melting point: 160° C.




EXAMPLE 52




2-{(E)-4-[(4-Methyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-yl)-sulfanyl]but-2-enyl}-7-nitro-1,2,3,4-tetrahydroisoquinoline




C


21


H


22


N


6


O


2


S (422) MS: 423 [M+H]


+


.




EXAMPLE 53




2-[(4-{[(4-Methyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-yl)sulfanyl]-methyl}cyclohexyl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-carbonitrile




C


27


H


31


N


5


S (457.6); Melting point: 156-158° C.




EXAMPLE 54




1-(2-{3-[(4-Methyl-5-(3-cyano)phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)ethanone Hydrochloride




C


24


H


25


N


5


OS×HCl (468); Melting point: 185° C.




EXAMPLE 55




7-Nitro-2-[(4-{[(4-methyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-yl)-sulfanyl]-methyl}cyclo-hexyl)methyl]-1,2,3,4-tetrahydroisoquinoline




C


26


H


31


N


6


O


2


S (477.6); Melting point: 160° C.




EXAMPLE 56




1-{2-[3-({4-Methyl-5-phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)-propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}ethanone Hydrochloride




C


23


H


27


N


4


OS×HCl (443); Melting point: 165° C.




EXAMPLE 57




7,8-Dichloro-2-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline




C


21


H


22


ClN


4


S (399); Melting point: 72-75° C.




EXAMPLE 58




1-{2-[3-({5-(2,4-Dinitrophenyl)-4-methyl]-4H-1,2,4-triazol-3-yl}-sulfanyl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}ethanone Hydrochloride




C


23


H


25


N


6


O


5


S×HCl (500.6); Melting point: 193° C.




EXAMPLE 59




2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-7-(octahydroisoquinolin-2(1H)-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline




C


30


H


39


N


5


O


2


S


2


(565.8) MS: 567 [M+H]


+


.




EXAMPLE 60




2-{3-[(4-Methyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-yl)sulfanyl]-propyl}-7-(octahydroisoquinolin-2(1H)-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline




C


29


H


38


N


6


O


2


S


2


(566.8) MS: 568 [M+H]


+


.




EXAMPLE 61




2-{3-[(4-Cyclopropyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]-propyl}-7-(azepan-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline




C


29


H


37


N


5


O


2


S


2


(551.8) MS: 552 [M]


+


.




EXAMPLE 62




2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-7-(pyrrolidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline




C


25


H


31


N


5


O


2


S


2


(497.7).




EXAMPLE 63




2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-7-(azepan-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline




C


27


H


35


N


5


O


2


S


2


(525.7).




EXAMPLE 64




7-Chlor-2-(3-{[4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl]sulfanyl}-but-2-en-yl)-1,2,3,4-tetrahydroisoquinoline




C


21


H


23


ClN


4


S (399); Melting point: 72-75° C.




EXAMPLE 65




2-(3-{[4-Methyl-5-methylamino-4H-1,2,4-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-dihydroisoquinolin-2(1H)-yl)propyl]sulfanyl}-4H-1,2,4-triazol-3-amine




EXAMPLE 67




7-tert-Butyl-2-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1,2,3,4-tetrahydroisoquinoline




EXAMPLE 68




2-{3-[(4-Methyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-yl)sulfanyl]-propyl}-7-(azepan-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline




EXAMPLE 69




7-({4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}sulfonyl)-2-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline




EXAMPLE 70




8-Brom-2-(3-{[5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}but-2-en-yl)-1,2,3,4-tetrahydroisoquinoline




EXAMPLE 71




4-Methyl-5-phenyl-N-[4-(7-(pyrrolidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-2-yl)butyl]-4H-1,2,4-triazole-3-carboxamide




EXAMPLE 72




6-Methyl-2-(3-{[4-methyl-5-(1-methyl-1H-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-1,2,4-triazol-3-yl)-sulfanyl]-methyl}-cyclopropyl)methyl]-1,2,3,4-tetrahydroisoquinoline




EXAMPLE 74




1-(2-{3-[(4-Methyl-5-(3-methoxy)phenyl-4H-1,2,4-triazol-3-yl)-oxy]propyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)ethanone




EXAMPLE 75




4-(7-(Pyrrolidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-2-yl)butyl-4-methyl-5-phenyl-4H-1,2,4-triazole-3-carboxylate




EXAMPLE 76




2-[2-({[5-(N-Methyl)pyrrol-2-yl)-4-methyl-4H-1,2,4-triazol-3-yl]-sulfanyl}methyl)prop-2-enyl]-1,2,3,4-tetrahydroisoquinolin-7-carboxamide




EXAMPLE 77




2-{3-[(4-Cyclopropyl-5-(4-methylsulfonyl)phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-7-(pyrrolidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline




EXAMPLE 78




6-tert-Butyl-2-(3-{[5-(2,4-dinitrophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1,2,3,4-tetrahydroisoquinoline




EXAMPLE 79




N-[2-(8-{[5-(Dimethylamino)-4-butyl-4H-1,2,4-triazol-3-yl]sulfanyl}octyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]methansulfonamide




EXAMPLE 80




2-{3-[(4-Methyl-5-pyrazin-2-yl-4H-1,2,4-triazol-3-yl)sulfanyl]-propyl}-7-(octahydroisoquinolin-2(1H)-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline




EXAMPLE 81




7-Cyano-2-{3-[(4-methyl-5-(2-methyloxazol-4-yl)-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1,2,3,4-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-tetrahydroisoquinoline




EXAMPLE 83




2-[2-({[4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-prop-2-enyl]-7-nitro-1,2,3,4-tetrahydroisoquinoline Hydrochloride




C


22


H


23


N


5


O


2


S×HCl (460); Melting point: 146-150° C.




EXAMPLE 84




N-[2-(3-{[4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl]sulfanyl}-propyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]methansulfonamide




C


22


H


27


N


5


O


2


S


2


×HCl (494.1); Melting point: 90° C.




The following compounds can be prepared in an analogous way in principle:












TABLE 1











































Ex.




R


1






R


2






A




R


6






R


7






R


8






















85




Me




Ethoxycarbonyl




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-




8-methyl











nyl)






86




Me




N,N-Dimethyla-




S—CH


2


—CH═CH—CH


2


—




6-methyl




7-cyano








mino-






87




Et




tert.Butyl




(CH


2


)


4


—




7-cyano






88




Butyl




Methylsulfanyl




(CH


2


)


4


—




6-fluoro






89




cycProp




Methyl




S—(CH


2


)


3


—




6-chloro




7-chloro






90




Me




2,5-Di-methyl-fu-




S—CH


2


—CH═CH—CH


2


—




7-(piperidin-1-yl-sulfo-








ranyl-3-





nyl)






91




Me




3-Thienyl




COO—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






92




Me




Phenyl-




(CH


2


)


4


—




7-(3,3-dimethyl-piperi-










din-1-yl-sulfonyl)






93




Me




2,4-Dimethoxyphe-




S—(CH


2


)


3


—




7-methansulfonamid








nyl






94




Me




Amino-




S—CH


2


—C(═CH


2


)—CH


2






7-(piperidin-1-yl-sulfo-










nyl)






95




Prop




Phenyl




S—CH


2


—C(CH


3


)═CH—CH


2


—




8-trifluoromethyl






96




Me




2-Me-4-Oxazolyl-




S—(CH


2


)


3


—




7-(dimethylamino-sulfonyl)






97




Me




3-Benzthienyl-




S—(CH


2


)


6


—




7-(pyrolidin-1-yl-sulfo-










nyl)






98




Me




Phenyl-




S—(CH


2


)


7


—




7-(pyrolidin-1-yl-sulfo-










nyl)






99




Me




Phenyl




CONH—(CH


2


)


4


—




7-(piperidin-1-yl-sulfo-










nyl)






100




Me




2-Pyrazinyl-




S—(CH


2


)


3


—




7-trifluoromethyl






101




Phenyl




Methyl




(CH


2


)


4


—




7-(morpholin-1-yl-sulfo-










nyl)






102




Me




Tetrazolyl-




S—(CH


2


)


3


—




7-methoxy






103




Et




4-Methylthia-




S—(CH


2


)


3


—




7-methylsulfonyl








zol-5-yl






104




Et




3-Jod-phenyl




S—(CH


2


)


3


—




7-methansulfonamid






105




Et




4-Methylphenyl




S—CH


2


—C(═CH


2


)—CH


2






7-(piperidin-1-yl-sulfo-










nyl)






106




Me




N-Methyl-2-Pyrro-




S—(CH


2


)


3


—




7-(dimethylamino-sulfonyl)








lyl-






107




Me




4-Methylthia-




S—CH


2


—C(═CH


2


)—CH


2






7-(pyrrolidin-1-yl-sulfo-








zol-5-yl





nyl)






108




Me




2,5-Di-methyl-fu-




S—(CH


2


)


3


—




7-phenylsulfonyl








ranyl-3-






109




Me




2-Me-4-Oxazolyl-




(CH


2


)


2


—CH(CH


3


)—CH


2


—CH


2


—




7-(morpholin-1-yl-sulfo-










nyl)






110




Me




Phenyl-




S—(CH


2


)


7


—




7-(pyrolidin-1-yl-sulfo-










nyl)






111




Hexyl




3-Pyridyl-




S—(CH


2


)


3


—




6-chloro




7-chloro






112




Me




3-Cyano-phenyl




S—(CH


2


)


3


—




7-(dimethylamino-sulfonyl)






113




Me




2-Pyrazinyl-




CO—(CH


2


)


3


—




7-(morpholin-1-yl-sulfo-










nyl)






114




Prop




Phenyl




S—(CH


2


)


4


—




7-(morpholin-1-yl-sulfo-










nyl)






115




Me




3-Metoxyphenyl




(CH


2


)


4


—




6-triflourmethyl






116




Me




3-Pyrrolyl




S—(CH


2


)


3


—




7-nitro






117




Et




3-Pyridyl




S—(CH


2


)


7


—




6-methyl




7-cyano






118




Me




4-Methylthia-




O—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-








zol-5-yl





nyl)






119




Me




Phenyl




CONH—(CH


2


)


4


—




7-cyano






120




Et




2,5-Di-methyl-fu-




S—(CH


2


)


3


—




7-nitro








ranyl-3-






121




Et




N-Methyl-2-Pyrro-




S—(CH


2


)


3


—




7-nitro








lyl-






122




Prop




Phenyl-




S—(CH


2


)


3


—




6-methyl




7-(aze-











pan-1-yl-











sulfonyl)






123




Et




N-Propyl-tetrazo-




S—(CH


2


)


3


—




7-cyano








lyl-






124




Me




3-Thienyl




S—(CH


2


)


3


—




7-methylsulfonyl






125




Me




4-Methoxyphenyl




S—(CH


2


)


3


—




4-methoxy






126




Me




Tetrazolyl-




S—(CH


2


)


3


—




7-(dimethylamino-sulfonyl)






127




Me




4-Methylthia-




S—CH


2


-cycHex-CH


2


—




7-phenylsulfonyl








zol-5-yl




CH


2


—






128




Me




2-Chloro-phenyl




CO—(CH


2


)


3


—




7-trifluoromethoxy






129




Et




Phenyl-




S—(CH


2


)


3


—




6-CH


2


—CH


2


—CH


2


—CH


2


-7






130




Et




4-Methoxyphenyl




(CH


2


)


2


—CH(CH


3


)—CH


2


—CH


2


—




7-(piperidin-1-yl-sulfo-










nyl)






131




Et




4-Methylthia-




S—CH


2


—C(═CH


2


)—CH


2






7-(azepan-1-yl-sulfonyl)








zol-5-yl






132




Me




2-Me-4-Oxazolyl-




S—(CH


2


)


6


—




7-nitro






133




Me




5-Methyl imida-




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-








zol-4-yl-





nyl)






134




Me




3-Jod-phenyl




S—(CH


2


)


3


—




7-(dimethylamino-sulfonyl)






135




Me




Phenylmethyl




S—CH


2


—CH═CH—CH


2


—




7-(azepan-1-yl-sulfonyl)






136




Et




Phenyl-




S—(CH


2


)


3


—




6-CH(CH


3


)CH


2


—N(CH


3


)-7






137




Et




3-Thienyl




S—(CH


2


)


3


—




7-(dimethylamino-sulfonyl)






138




Me




3-Jod-phenyl




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






139




Et




Phenyl




S—(CH


2


)


3


—




8-trifluoromethyl






140




Me




Phenyl




CONH—(CH


2


)


5


—




8-triflouromethyl






141




Me




Phenyl-




S—CH


2


—CH═CH—CH


2


—




7-(piperidin-1-yl-sulfo-










nyl)






142




Me




Cyclohexyl-




S—(CH


2


)


3


—




7-nitro






143




iProp




3-Pyridyl




S—(CH


2


)


7


—




7-chloro




8-chloro






144




Me




Amino-




S—(CH


2


)


3


—




7-cyano






145




Me




2-Aminothia-




S—(CH


2


)


3


—




7-cyano








zol-4yl-






146




Me




3-Pyrrolyl




S—CH


2


-cycProp-CH


2


—




6-triflourmethyl






147




cycProp




Phenyl-




S—(CH


2


)


3


—




6-CH


2


—CH


2


—CH


2


—CH


2


-7






148




Me




2-Pyrazinyl-




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






149




Me




Cyclohexyl-




S—(CH


2


)


3


—




7-cyano






150




Me




5-Methyl imida-




(CH


2


)


2


—CH(CH


3


)—CH


2


—CH


2


—




tert-Butyl








zol-4-yl-






151




Me




Methylamino-




S—(CH


2


)


3


—




7-cyano






152




Me




3-Benzthienyl-




S—(CH


2


)


3


—




7-(dimethylamino-sulfonyl)






153




Me




Phenyl




S—CH


2


-cycHex-CH


2


—




5-methoxy









CH


2


—






154




Me




Pyridin-4-yl-




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






155




Prop




Phenyl-




S—CH


2


—C(═CH


2


)—CH


2






7-(azepan-1-yl-sulfonyl)






156




Me




3-Pyridinyl




S—(CH


2


)


8


—




7-CHF


2








157




Me




Tetrazolyl-




(CH


2


)


4


—




7-(pyrolidin-1-yl-sulfo-










nyl)






158




Me




4-Phenyl




S—CH


2


-cyc-




7-bromo









Prop-(CH


2


)


2


—






159




Me




4-Methylphenyl




COO—(CH


2


)


4


—




7-nitro






160




Et




3-Cyano-phenyl




S—CH


2


-cycHex-CH


2


—




6-Methyl









CH


2


—






161




Et




2-Aminothia-




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-








zol-4yl-





nyl)






162




Et




Phenyl-




(CH


2


)


4


—




7-(3,3-dimethyl-piperi-










din-1-yl-sulfonyl)






163




Me




4-Methylthia-




S—(CH


2


)


3


—




7-trifluoromethyl








zol-5-yl






164




Me




Oxadiazol-2-yl




S—(CH


2


)


3


—




7-(dimethylamino-sulfonyl)






165




Me




6-Chloro-biphe-




S—(CH


2


)


3


—




7-methylsulfonyl








nyl-2-






166




Et




3-Pyridinyl




S—(CH


2


)


8


—




7-CHF


2








167




Me




Pyridin-3-yl-




S—(CH


2


)


3


—




7-methylsulfonyl






168




Me




Phenyl




CONH—(CH


2


)


4


—




7-Phenylsulfonyl






169




Et




2-Me-4-Oxazolyl-




S—(CH


2


)


3


—




8-trifluoromethyl






170




Me




5-Methyl imida-




S—(CH


2


)


3


—




7-nitro








zol-4-yl-






171




iProp




Phenyl




S—(CH


2


)


3


—




6-bromo






172




Prop




4-Imidazolyl-




S—(CH


2


)


3


—




7-methoxy






173




Me




Tetrazolyl-




S—(CH


2


)


3


—




7-cyano






174




Et




Phenyl




CONH—(CH


2


)


4


—




6-chloro




7-chloro






175




Me




2-Pyrazinyl-




S—(CH


2


)


3


—




7-methoxy






176




Prop




Phenyl-




S—(CH


2


)


3


—




6-methyl




7-nitro






177




Me




4-Jod-phenyl




COO—(CH


2


)


4


—




7-cyano






178




iProp




4-Imidazolyl-




S—CH


2


—CH═CH—CH


2


—




7-(azepan-1-yl-sulfonyl)






179




Et




4-Methylsulfonyl-




S—(CH


2


)


8


—




7-(piperidin-1-yl-sulfo-








phenyl





nyl)






180




Butyl




N-Propyl-tetrazo-




S—(CH


2


)


3


—




7-cyano








lyl-






181




Me




2-Me-4-Oxazolyl-




S—CH


2


—C(CH


3


)═CH—CH


2


—




7-(azepan-1-yl-sulfonyl)






182




Et




3-Pyrrolyl




S—(CH


2


)


3


—




7-nitro






183




Me




N-Propyl-tetrazo-




S—CH


2


—C(═CH


2


)—CH


2






7-(piperidin-1-yl-sulfo-








lyl-





nyl)






184




Me




Propyl




CO—(CH


2


)


3


—




5-methoxy






185




Me




2-Pyrazinyl-




O—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






186




Me




Oxadiazol-2-yl




S—(CH


2


)


3


—




7-nitro






187




Prop




2-Me-4-Oxazolyl-




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






188




Hexyl




Phenyl




(CH


2


)


4


—




8-nitro






189




Prop




Phenyl




O—(CH


2


)


3


—




7-methoxy






190




Me




3-Pyridyl




S—(CH


2


)


7


—




7-chloro




8-chloro






191




Et




Oxadiazol-2-yl




S—(CH


2


)


3


—




7-nitro






192




Et




Phenyl-




S—(CH


2


)


3


—




6-CH(CH


3


)CH


2


—NH-7






193




Me




3-Jod-phenyl




S—(CH


2


)


3


—




7-methansulfonamid






194




Me




Pyridin-4-yl-




S—(CH


2


)


3


—




7-nitro






195




Me




4-Imidazolyl-




S—(CH


2


)


3


—




7-(dimethylamino-sulfonyl)






196




Me




Phenyl




(CH


2


)


4


—




8-nitro






197




Me




4-Methylphenyl




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






198




cycProp




Phenyl




S—(CH


2


)


3


—




7-Carboxamid






199




Me




3-Jod-phenyl




O—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






200




Me




Cyclohexyl-




S—(CH


2


)


6


—




7-(piperidin-1-yl-sulfo-










nyl)






201




Me




3-Jod-phenyl




S—CH


2


—C(CH


3


)═CH—CH


2


—




7-(piperidin-1-yl-sulfo-










nyl)






202




Me




3-Jod-phenyl




S—(CH2)


3


—




7-phenylsulfonyl






203




Butyl




Pyridin-3-yl-




O—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






204




cycProp




2,4-Dimethoxyphe-




S—(CH


2


)


3


—




7-methansulfonamid








nyl






205




Me




N-Propyl-tetrazo-




S—(CH


2


)


3


—




7-cyano








lyl-






206




Et




4-Methoxyphenyl




S—CH


2


—CH═CH—CH


2


—




7-(piperidin-1-yl-sulfo-










nyl)






207




Et




Phenyl-




S—(CH


2


)


3


—




6-methyl




7-nitro






208




Et




Phenyl-




(CH


2


)


2


—CH(CH


3


)—CH


2


—CH


2


—




6-methoxy






209




Me




3-Br-Pyri-




S—(CH


2


)


3


—




7-nitro








din-5-yl-






210




Me




Methylamino-




S—CH


2


-cycHex-CH


2


—




7-cyano









CH


2


—






211




Et




tert.-Butyl




CO—(CH


2


)


3


—




6-methoxy






212




Me




Phenyl




S—(CH


2


)


3


—




6-Fluoro






213




Me




Phenylmethyl




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






214




iProp




4-Methoxyphenyl




S—CH


2


—CH═CH—CH


2


—




7-(piperidin-1-yl-sulfo-










nyl)






215




iProp




4-Cyano-phenyl




S—CH


2


—C(CH


3


)═CH—CH


2


—




7-(piperidin-1-yl-sulfo-










nyl)






216




Me




3-Br-Pyri-




S—(CH


2


)


3


—




7-(dimethylamino-sulfonyl)








din-5-yl-






217




Me




Phenyl-




S—(CH


2


)


3


—




6-CH


2


—CH


2


—CH


2


—CH


2


-7






218




Me




3-Cyano-phenyl




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






219




Me




3-Thienyl




S—(CH


2


)


3


—




7-(dimethylamino-sulfonyl)






220




Et




Phenyl




(CH


2


)


4


—




8-nitro






221




Me




Amino




S—(CH


2


)


3


—




7-nitro






222




Me




4-Methylsulfonyl-




S—(CH


2


)


8


—




7-(piperidin-1-yl-sulfo-








phenyl





nyl)






223




Me




4-Methylsulfonyl-




S—(CH


2


)


3


—




7-(dimethylamino-sulfonyl)








phenyl






224




Me




4-Methylthia-




S—(CH


2


)


3


—




7-methoxy








zol-5-yl






225




Me




2-Me-4-oxazolyl-




S—(CH


2


)


3


—




7-methylsulfonyl






226




Me




2,5-Di-methyl-fu-




S—(CH


2


)


3


—




7-methoxy








ranyl-3-






227




Me




3-Pyrrolyl




S—(CH


2


)


3


—




7-cyano






228




Phenyl




Cyano




S—(CH


2


)


3


—




7-(pyrrolidin-1-yl-sulfo-










nyl)






229




Me




Tetrazolyl-




O—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






230




Me




Phenyl-




S—(CH


2


)


3


—




6-methyl




7-cyano






231




Et




Carboxamido




S—(CH


2


)


3


—




7-cyano






232




Me




Pyridin-3-yl-




S—CH


2


—C(CH


3


)═CH—CH


2


—




7-(azepan-1-yl-sulfonyl)






233




Et




Phenyl




S—(CH


2


)


3


—




6-bromo






234




Prop




2-Aminothia-




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-








zol-4yl-





nyl)






235




Me




Pyridin-4-yl-




S—(CH


2


)


3


—




7-(dimethylamino-sulfonyl)






236




Me




4-Methylthia-




S—(CH


2


)


3


—




7-cyano








zol-5-yl






237




cycProp




Phenyl-




S—(CH


2


)


3


—




6-CH


2


—CH


2


—CH


2


-7






238




Me




Pyridin-3-yl-




S—CH


2


—C(═CH


2


)—CH


2






7-(azepan-1-yl-sulfonyl)






239




Et




5-Methyl imida-




S—(CH


2


)


10


—




7-(piperidin-1-yl-sulfo-








zol-4-yl-





nyl)






240




Me




Methylamino




S—(CH


2


)


3


—




7-nitro






241




Me




Pyridin-4-yl-




S—(CH


2


)


6


—




7-(piperidin-1-yl-sulfo-










nyl)






242




Butyl




Phenyl-




S—(CH


2


)


3


—




6-methyl




7-cyano






243




Phenyl




3-Pyridyl-




S—(CH


2


)


6


—




7-(piperidin-1-yl-sulfo-










nyl)






244




Me




Tetrazolyl-




O—(CH


2


)


3


—




7-cyano






245




Hexyl




3-Jodphenyl-




S—(CH


2


)


3


—




6-chloro




7-chloro






246




Me




4-Methylsulfonyl-




S—CH


2


-cycProp-CH


2


—




7-cyano








phenyl






247




Phenyl




tert-Butyl




S—(CH


2


)


3


—




7-(pyrrolidin-1-yl-sulfo-










nyl)






248




Me




tert.-Butyl




(CH


2


)


4


—




6-methoxy






249




cycProp




tert.-Butyl




CO—(CH


2


)


3


—




6-methoxy






250




Me




Amino-




S—(CH


2


)


3


—




7-methylsulfonyl






251




Me




Amino-




S—(CH


2


)


3


—




6-methoxy






252




Et




N-Methyl-2-Pyrro-




S—(CH


2


)8—




7-cyano








lyl-






253




Me




Methylamino-




S—(CH


2


)


3


—




7-methoxy






254




Me




Phenyl




S—(CH


2


)


3


—




8-ethenyl






255




Et




Phenyl




S—CH


2


-cycHex-CH


2


—




7-trifluoromethoxy






256




Me




N-Methyl-2-Pyrro-




S—CH


2


-cycProp-CH


2


—




8-triflourmethyl








lyl-






257




Prop




3-Jod-phenyl




S—(CH


2


)


3


—




7-methansulfonamid






258




Me




Methylamino-




S—(CH


2


)


3


—




7-trifluoromethyl






259




Me




Tetrazolyl-




S—CH


2


-cycHex-CH


2


—




7-(morpholin-1-yl-sulfo-










nyl)






260




Me




Methylamino-




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






261




Me




N-Methyl-2-Pyrro-




S—(CH


2


)


3


—




7-trifluoromethyl








lyl-






262




Me




2-Aminothia-




S—(CH


2


)


3


—




7-(dimethylamino-sulfonyl)








zol-4yl-






263




Me




3-Pyrrolyl




S—(CH


2


)


3


—




7-methylsulfonyl






264




Me




4-Imidazolyl-




S—CH


2


—CH═CH—CH


2


—




7-(azepan-1-yl-sulfonyl)






265




Me




Propyl




(CH


2


)


4


—




5-methoxy






266




Me




Oxadiazol-2-yl




S—(CH


2


)


3


—




6-trifluoromethyl






267




Me




4-Methylphenyl




O—(CH


2


)


3


—




7-cyano






268




cycProp




Phenyl




(CH


2


)


4


—




8-nitro






269




Me




3-Br-Pyri-




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-








din-5-yl-





nyl)






270




iProp




Phenyl




S—(CH


2


)


3


—




7-Acetyl






271




Me




4-Methylsulfonyl-




S—(CH


2


)


8


—




7-(piperidin-1-yl-sulfo-








phenyl





nyl)






272




Me




3-Cyano-phenyl




S—(CH


2


)


3


—




7-nitro






273




Me




4-Methylthia-




S—(CH


2


)


3


—




7-methansulfonamid








zol-5-yl






274




Me




3-Cyano-phenyl




S—(CH


2


)


3


—




7-cyano






275




Me




Oxadiazol-2-yl




S—(CH


2


)


3


—




7-cyano






276




Me




Phenyl-




S—(CH


2


)


7


—




6-methyl




7-(pyroli-











din-1-yl-











sulfonyl)






277




Me




Phenyl-




CO—(CH


2


)


3


—




7-cyano






278




cycProp




4-Methoxyphenyl




(CH


2


)


4


—




8-ethenyl






279




Me




Phenyl




S—CH


2


—C(CH


3


)═CH—CH


2


—




7-(piperidin-1-yl-sulfo-










nyl)






280




Me




6-Chloro-biphe-




S—(CH


2


)


3


—




7-nitro








nyl-2-






281




Me




4-Imidazolyl-




S—(CH


2


)


3


—




8-trifluoromethyl






282




Me




3-Br-Pyri-




S—(CH


2


)


3


—




7-cyano








din-5-yl-






283




Pentyl




3-Pyridyl-




S—(CH


2


)


3


—




6-chloro




7-chloro






284




Me




Pyridin-3-yl-




O—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






285




Me




3-Pyrrolyl




S—(CH


2


)


3


—




7-methoxy






286




Me




2-Pyrazinyl-




O—(CH


2


)


3


—




7-cyano






287




Et




Phenyl-




CO—(CH


2


)


3


—




7-cyano






288




Me




2-Me-4-Oxazolyl-




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






289




Me




4-Methylsulfonyl-




S—(CH


2


)


3


—




7-methylsulfonyl








phenyl






290




Me




Phenyl




COO—(CH


2


)


4


—




7-(piperidin-1-yl-sulfo-










nyl)






291




Me




Oxadiazol-2-yl




S—(CH


2


)


3


—




7-methylsulfonyl






292




Me




2-Aminothia-




S—(CH


2


)


3


—




7-methoxy








zol-4yl-






293




Me




4-Methylphenyl




CONH—(CH


2


)


4


—




7-cyano






294




Me




3-Pyrrolyl




S—CH


2


—CH═CH—CH


2


—




7-(piperidin-1-yl-sulfo-










nyl)






295




Me




3-Cyano-phenyl




S—(CH


2


)


3


—




7-methansulfonamid






296




Me




2-Pyrazinyl-




S—CH


2


-cyc-




7-(pyrolidin-1-yl-sulfo-









Prop-(CH


2


)


2


—




nyl)






297




Me




Pyridin-3-yl-




S—CH


2


—C(═CH


2


)—CH


2






7-(piperidin-1-yl-sulfo-










nyl)






298




Me




2-Me-4-Oxazolyl-




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






299




Et




3-Br-Pyri-




S—(CH


2


)


3


—




7-cyano








din-5-yl-






300




Me




6-Chloro-biphe-




S—(CH


2


)


3


—




7-trifluoromethyl








nyl-2-






301




iProp




Phenyl-




S—(CH


2


)


7


—




6-methyl




7-(pyroli-











din-1-yl-











sulfonyl)






302




Me




3-Benzthienyl-




S—(CH


2


)


3


—




7-nitro






303




Me




Phenyl




CONH—(CH


2


)


4


—




7-nitro






304




Me




Cyclohexyl-




S—(CH


2


)


6


—




7-(piperidin-1-yl-sulfo-










nyl)






305




Me




3-Pyrrolyl




S—CH


2


—CH═CH—CH


2


—




6-chloro






306




Et




2-Pyrazinyl-




O—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






307




Me




4-Imidazolyl-




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






308




Me




3-Pyridinyl




S—(CH


2


)


8


—




7-CHF


2








309




Me




3-Pyridyl




COO—(CH


2


)


3


—




7-cyano






310




Me




3-Benzthienyl-




S—(CH


2


)


3


—




7-cyano






311




Me




3-Pyrrolyl




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






312




Me




4-Methoxyphenyl




(CH


2


)


2


—CH(CH


3


)—CH


2


—CH


2


—




5-hydroxy






313




Me




Amino-




S—(CH


2


)


3


—




7-trifluoromethyl






314




Me




4-Methylthia-




S—CH


2


-cycProp-CH


2


—




7-(piperidin-1-yl-sulfo-








zol-5-yl





nyl)






315




Me




Tetrazolyl-




S—(CH


2


)


3


—




7-phenylsulfonyl






316




Me




Phenyl




S—CH


2


-cycHex-CH


2


—




7-trifluoromethoxy






317




Phenyl




3-Thienyl




S—(CH


2


)


3


—




7-nitro






318




Me




Pyridin-3-yl-




S—(CH


2


)


3


—




7-(dimethylamino-sulfonyl)






319




Me




4-Methylphenyl




S—CH


2


—C(═CH


2


)—CH


2






7-(piperidin-1-yl-sulfo-










nyl)






320




Prop




3-Benzthienyl-




S—(CH


2


)


3


—




7-(dimethylamino-sulfonyl)






321




Me




4-Methylthia-




S—(CH


2


)


3


—




7-methylsulfonyl








zol-5-yl






322




Me




4-Methoxyl-phenyl




S—(CH


2


)


8


—




7-(piperidin-1-yl-sulfo-










nyl)






323




Me




Oxadiazol-2-yl




S—(CH


2


)


7


—




7-azepan-1-yl-sulfonyl)






324




Me




Methylamino-




S—CH


2


—cycProp-CH


2


—




7-(piperidin-1-yl-sulfo-










nyl)






325




Me




4-methoxyphenyl




S—(CH


2


)


3


—




7-cyano






326




Butyl




2-Aminothia-




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-








zol-4yl-





nyl)






327




iProp




3-Pyrrolyl




S—CH


2


—CH═CH—CH


2


—




7-(piperidin-1-yl-sulfo-










nyl)






328




Me




Phenyl




CONH—(CH


2


)


4


—




7-chloro






329




Butyl




Phenyl-




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-




8-chloro










nyl)






330




Et




4-Imidazolyl-




S—(CH


2


)


3


—




7-methoxy






331




Me




Phenyl




S—CH


2


-cycProp-CH


2


—




6-methoxy






332




Me




3-Furanyl




S—CH


2


-cycprop-CH


2


—




7-(N-methylanilin-1-sulfo-










nyl)






333




Me




2-Pyrazinyl-




S—(CH


2


)


3


—




7-cyano






334




cycProp




2-Pyrazinyl-




O—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






335




Et




Phenyl




S—(CH


2


)


4


—




7-(morpholin-1-yl-sulfo-










nyl)






336




Me




Phenyl-




S—(CH


2


)


3


—




7-methylsulfonyl






337




Me




4-Methylphenyl




O—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






338




Butyl




Phenyl




S—(CH


2


)


3


—




7-acetyl






339




Et




4-Cyano-phenyl




S—CH


2


—C(CH


3


)═CH—CH


2


—




7-(piperidin-1-yl-sulfo-










nyl)






340




Butyl




Phenyl-




S—(CH


2


)


3


—




6-Methyl




7-(pyroli-











din-1-yl-











sulfonyl)






341




Butyl




Phenyl




S—(CH


2


)


3


—




8-chloro






342




Et




Pyridin-3-yl-




O—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






343




Me




3-Thienyl




S—(CH


2


)


3


—




7-methoxy






344




Me




N-Methyl-2-Pyrro-




S—CH


2


-cycHex-CH


2


—




5-methoxy








lyl-




CH


2


—






345




Me




4-Imidazolyl-




S—(CH


2


)


3


—




7-methoxy






346




cycProp




Phenyl




CONH—(CH


2


)


5


—




8-trifluoromethyl






347




Me




6-Chloro-biphe-




S—(CH


2


)


3


—




7-(dimethylamino-sulfonyl)








nyl-2-






348




Et




3-Pyridyl




S—(CH


2


)


7


—




7-chloro




8-chloro






349




Me




4-Methylsulfonyl-




S—CH


2


-cycHex-CH


2


—




6-methoxy








phenyl






350




Me




Methylamino-




S—(CH


2


)


3


—




7-methylsulfonyl






351




Et




2-Me-4-Oxazolyl-




S—(CH


2


)


3


—




7-methoxy






352




Et




Phenyl-




S—(CH


2


)


3


—




6-CH


2


—CH


2


—CH


2


-7






353




Et




Phenyl




S—(CH


2


)


4


—




7-(pyrrolidin-1-yl-sulfo-










nyl)






354




Butyl




2-Pyrazinyl-




O—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






355




Me




4-Methoxyl-phenyl




S—(CH


2


)


8


—




7-(piperidin-1-yl-sulfo-










nyl)






356




Me




Phenyl-




(CH


2


)


2


—CH(CH


3


)—CH


2


—CH


2


—




6-methoxy






357




Me




2-Aminothia-




S—(CH


2


)


3


—




7-trifluoromethyl








zol-4yl-






358




Prop




Phenyl




S—(CH


2


)


3


—




7-Acetyl






359




Me




4-Methylphenyl




COO—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






360




Et




2-Me-4-Oxazolyl-




(CH


2


)


2


—CH(CH


3


)—CH


2


—CH


2


—




7-(morpholin-1-yl-sulfo-










nyl)






361




Butyl




Carboxamido




S—(CH


2


)


3


—




7-cyano






362




Me




Pyridin-4-yl-




S—(CH


2


)


3


—




6-trifluoromethyl






363




Hexyl




3-Pyridyl-




S—(CH


2


)


3


—




7-chloro




8-chloro






364




Me




N-Propyl-tetrazo-




S—(CH


2


)


3


—




7-methylsulfonyl








lyl-






365




Et




Phenyl-




S—CH


2


—C(═CH


2


)—CH


2






7-(azepan-1-yl-sulfonyl)






366




cycProp




Phenyl-




(CH


2


)


4


—




7-(3,3-dimethyl-piperi-










din-1-yl-sulfonyl)






367




Me




Phenyl




CONH—(CH


2


)


4


—




6-chloro




7-chloro






368




Et




4-Imidazolyl-




S—CH


2


—CH═CH—CH


2


—




7-(azepan-1-yl-sulfonyl)






369




Me




Cyclohexyl-




S—(CH


2


)


3


—




7-methoxy






370




Me




2-Pyrazinyl-




S—(CH


2


)


3


—




7-(dimethylamino-sulfonyl)






371




Prop




2-Me-4-Oxazolyl-




S—(CH


2


)


3


—




8-trifluoromethyl






372




Me




2,4-Dimethoxy-




S—CH


2


—C(CH


3


)═CH—CH


2


—




7-(piperidin-1-yl-sulfo-








phenyl





nyl)






373




Me




Cyclohexyl-




S—(CH


2


)


3


—




7-(dimethylamino-sulfonyl)






374




Me




Pyridin-3-yl-




S—(CH


2


)


3


—




7-methoxy






375




Me




Phenyl-




S—(CH


2


)


3


—




7-methoxy






376




Me




2-Pyrazinyl-




S—CH


2


-cycHex-CH


2


—




7-(morpholin-1-yl-sulfo-










nyl)






377




Me




N-Propyl-tetrazo-




S—(CH


2


)


3


—




7-nitro








lyl-






378




Me




Phenyl-




(CH


2


)


4


—




8-triflourmethyl






379




Prop




4-Methoxyphenyl




(CH


2


)


4


—




6-ethenyl






380




Me




Phenyl-




S—(CH


2


)


7


—




7-(pyrolidin-1-yl-sulfo-










nyl)






381




iProp




4-Methylthia-




S—(CH


2


)


3


—




7-methylsulfonyl








zol-5-yl






382




iProp




Phenyl-




S—(CH


2


)


7


—




7-(piperidin-1-yl-sulfo-




8-chloro










nyl)






383




iProp




Phenyl




S—(CH


2


)


3


—




7-carboxamid






384




Me




Phenyl




S—CH


2


—C(CH


3


)═CH—CH


2


—




7-trifluoromethyl






385




Et




Phenyl




CONH—(CH


2


)


5


—




8-trifluoromethyl






386




iProp




3-Pyrrolyl




S—(CH


2


)


6


—




7-cyano






387




Me




Phenyl-




S—(CH


2


)


7


—




7-(piperidin-1-yl-sulfo-




8-chloro










nyl)






388




Et




3-Benzthienyl-




S—(CH


2


)


3


—




7-(dimethylamino-sulfonyl)






389




Me




2-Me-4-Oxazolyl-




S—(CH


2


)


3


—




7-methoxy






390




Me




2-Aminothia-




S—(CH


2


)


3


—




7-nitro








zol-4yl-






391




Prop




3-Br-Pyri-




S—(CH


2


)


3


—




7-cyano








din-5-yl-






392




Me




3-Thienyl




S—(CH


2


)


3


—




7-nitro






393




Et




Phenyl




CONH—(CH


2


)


4


—




7-chloro






394




Me




4-Methylthia-




S—(CH


2


)


3


—




7-nitro








zol-5-yl






395




Me




2-Me-4-Oxazolyl-




S—(CH


2


)


3


—




7-(dimethylamino-sulfonyl)






396




Me




6-Chloro-biphe-




S—(CH


2


)


3


—




7-cyano








nyl-2-






397




Me




Tetrazolyl-




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






398




Me




3-Benzthienyl-




S—(CH


2


)


3


—




7-methylsulfonyl






399




Me




3-Thienyl




S—CH


2


—CH═CH—CH


2


—




7-(pyrrolidin-1-yl-sulfo-










nyl)






400




Hexyl




Phenyl-




S—(CH


2


)


3


—




6-methyl




7-cyano






401




Me




3-Pyridyl




S—(CH


2


)


7


—




6-methyl




7-cyano






402




Me




2-Me-4-Oxazolyl-




S—(CH


2


)


3


—




7-methylsulfonyl






403




Me




3-Thienyl




O—(CH


2


)


3


—




7-cyano






404




Prop




Phenyl-




S—(CH


2


)


3


—




6-methyl




7-(piperi-











din-1-yl-











sulfonyl)






405




Et




2,4-Dimethoxyphe-




S—(CH


2


)


3


—




7-methansulfonamid








nyl






406




Me




Phenyl-




S—(CH


2


)


3


—




7-trifluoromethyl






407




Me




4-Methoxyphenyl




(CH


2


)


2


—CH(CH


3


)—




7-(piperidin-1-yl-sulfo-









CH


2


—CH


2


—




nyl)






408




Me




Phenyl




S—CH


2


-cyc-




5-methoxy









Prop-(CH


2


)


2


—






409




Phenyl




3-Thienyl




(CH


2


)


4


—




7-(piperidin-1-yl-sulfo-










nyl)






410




Me




3-Thienyl




S—(CH


2


)


3


—




7-methansulfonamid






411




Me




Pyridin-3-yl-




S—(CH


2


)


3


—




7-trifluoromethyl






412




Phenyl




tert-Butyl




O—(CH


2


)


3


—




7-(pyrrolidin-1-yl-sulfo-










nyl)






413




Me




3-Pyrrolyl




S—(CH


2


)


3


—




7-trifluoromethyl






414




Me




N-Methyl-2-Pyrro-




S—(CH


2


)


3


—




7-nitro








lyl-






415




iProp




Phenyl




S—(CH


2


)


3


—




8-trifluoromethyl






416




Butyl




3-Thienyl




S—(CH


2


)


8


—




7-(pyrrolidin-1-yl-sulfo-










nyl)






417




Me




Phenyl-




S—CH


2


—C(═CH


2


)—CH


2






7-(piperidin-1-yl-sulfo-










nyl)






418




Me




2-Me-4-Oxazolyl-




S—(CH


2


)


3


—




7-nitro






419




Me




2-Aminothia-




S—(CH


2


)


3


—




7-phenylsulfonyl








zol-4yl-






420




Me




4-Methylthia-




O—(CH


2


)


3


—




7-cyano








zol-5-yl






421




Me




4-Methylsulfonyl-




S—(CH


2


)


3


—




7-trifluoromethyl








phenyl






422




Me




4-methylsulfonyl-




O—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-








phenyl





nyl)






423




Butyl




3-Pyridyl-




S—(CH


2


)


3


—




7-chloro




8-chloro






424




Me




Methylamino-




S—CH


2


—C(CH


3


)═CH—CH


2


—




7-(piperidin-1-yl-sulfo-










nyl)






425




Me




Carboxamido




S—(CH


2


)


3


—




7-cyano






426




Me




4-Methoxyphenyl




S—(CH


2


)


3


—




7-phenylsulfonyl






427




Et




3-Pyrrolyl




S—CH


2


—CH═CH—CH


2


—




7-(piperidin-1-yl-sulfo-










nyl)






428




Me




3-Cyano-phenyl




S—(CH


2


)


3


—




7-trifluoromethyl






429




Me




5-Methyl imida-




S—(CH


2


)


3


—




7-cyano








zol-4-yl-






430




Prop




N-Propyl-tetrazo-




S—(CH


2


)


3


—




7-cyano








lyl-






431




Me




2,5-Di-methyl-fu-




S—(CH


2


)


3


—




7-(dimethylamino-sulfonyl)








ranyl-3-






432




Prop




Pyridin-3-yl-




S—CH


2


—C(═CH


2


)—CH


2






7-(azepan-1-yl-sulfonyl)






433




Me




4-Methylsulfonyl-




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-








phenyl





nyl)






434




Butyl




Phenyl




(CH


2


)


4


—




8-nitro






435




Me




4-Methylphenyl




COO—(CH


2


)


4


—




7-(piperidin-1-yl-sulfo-










nyl)






436




Me




3-Furanyl




S—CH


2


-cycHex-CH


2


—




7-phenylsulfonyl









CH


2


—






437




Me




3-Jod-phenyl




S—(CH


2


)


3


—




7-trifluoromethyl






438




Et




2-Pyrazinyl-




O—(CH


2


)


3


—




8-ethenyl






439




Me




3-Benzthienyl-




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






440




Me




Cyclohexyl-




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






441




Me




Pyridin-3-yl-




S—CH


2


-cycHex-CH


2


—




6-methoxy






442




Me




2-Me-4-Oxazolyl-




S—(CH


2


)


3


—




7-nitro






443




Me




2-Pyrazinyl-




(CH


2


)


4


—




7-(morpholin-1-yl-sulfo-










nyl)






444




Prop




2-Pyrazinyl-




S—(CH


2


)


3


—




8-ethenyl






445




Me




4-Methoxyphenyl




S—(CH


2


)


3


—




7-trifluoromethyl






446




Me




4-Imidazolyl-




S—(CH


2


)


3


—




7-methylsulfonyl






447




Me




Phenyl-




S—(CH


2


)


7


—




7-(pyrolidin-1-yl-sulfo-










nyl)






448




Me




Cyclohexyl-




S—(CH


2


)


3


—




7-trifluoromethyl






449




Butyl




Phenyl-




(CH


2


)


4


—




7-(3,3-dimethyl-piperi-










din-1-yl-sulfonyl)






450




Et




Phenyl




S—(CH


2


)


3


—




8-ethenyl






451




Me




4-Methoxyphenyl




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






452




iProp




Phenyl




S—(CH


2


)


4


—




7-(morpholin-1-yl-sulfo-










nyl)






453




Me




Cyano




S—(CH


2


)


8


—




6,7-dimethoxy






454




Me




2-Aminothia-




S—CH


2


—CH═CH—CH


2


—




7-(piperidin-1-yl-sulfo-








zol-4yl-





nyl)






455




Et




Phenyl




COO—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






456




Me




3-Cyano-phenyl




S—(CH


2


)


3


—




7-methylsulfonyl






457




Me




2-Pyrazinyl-




S—(CH


2


)


3


—




7-nitro






458




Me




3-Cyano-phenyl




S—CH


2


—C(═CH


2


)—CH


2






7-(piperidin-1-yl-sulfo-










nyl)






459




cycProp




N-Methyl-2-Pyrro-




S—(CH


2


)


8


—




7-cyano








lyl-






460




Me




4-Methoxyphenyl




S—(CH


2


)


3


—




7-nitro






461




Me




Oxadiazol-2-yl




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






462




Me




Tetrazolyl-




S—(CH


2


)


7


—




7-(piperidin-1-yl-sulfo-










nyl)






463




Butyl




Phenyl




(CH


2


)


4


—




7-(pyrrolidin-1-yl-sulfo-










nyl)






464




Prop




4-Methylphenyl




S—CH


2


—C(═CH


2


)—CH


2






7 (piperidin-1-yl-sulfo-










nyl)






465




Me




Phenyl-




S—(CH


2


)


3


—




6-CH


2


—CH


2


—CH


2


-7






466




Me




N-Methyl-2-Pyrro-




S—(CH


2


)


3


—




7-methylsulfonyl








lyl-






467




Me




3-Thienyl




S—(CH


2


)


3


—




7-trifluoromethyl






468




Et




Cyano




S—(CH


2


)


8


—




6-methoxy




7-methoxy






469




cycProp




Phenyl-




S—(CH


2


)


3


—




6-CH(CH


3


)CH


2


—NH-7






470




Me




3-Br-Pyri-




S—(CH


2


)


3


—




7-methylsulfonyl








din-5-yl-






471




Me




Phenyl-




S—(CH


2


)


3


—




6-CH(CH


3


)CH


2


—N(CH


3


)-7






472




Et




4-Methoxyphenyl




(CH


2


)


4


—




8-ethenyl






473




Me




Tetrazolyl-




S—(CH


2


)


3


—




7-trifluoromethyl






474




Me




6-Chloro-biphe-




S—(CH


2


)


3


—




7-methoxy








nyl-2-






475




Me




4-Pyridyl-




(CH


2


)


4


—




7-(pyrolidin-1-yl-sulfo-










nyl)






476




cycProp




Phenyl




CONH—(CH


2


)


4


—




6-chloro




7-chloro






477




Me




2-Me-4-Oxazolyl-




S—(CH


2


)


6


—




7-nitro






478




Me




2-Me-4-Oxazolyl-




S—(CH


2


)


3


—




7-methoxy






479




Me




4-Methoxyphenyl




S—CH


2


—CH═CH—CH


2


—




7-(piperidin-1-yl-sulfo-










nyl)






480




Me




Cyano




S—(CH


2


)


8


—




6-methoxy




7-methoxy






481




Me




tert.-Butyl




CO—(CH


2


)


3






6-methoxy






482




Et




3-Cyano-phenyl




S—(CH


2


)


3


—




7-methansulfonamid






483




Prop




Cyano




S—(CH


2


)


8


—




6-methoxy




7-methoxy






484




Me




3-Pyrrolyl




S—CH


2


-cycHex-CH


2


—




7-cyano









CH


2


—






485




Me




Methylamino-




S—(CH


2


)


3


—




7-(dimethylamino-sulfonyl)






486




Me




2,5-Di-methyl-fu-




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-








ranyl-3-





nyl)






487




Me




2,5-Dimethyl-fu-




S—(CH


2


)


3


—




7-nitro








ranyl-3-






488




iProp




4-Methoxyphenyl




(CH


2


)


4


—




8-ethenyl






489




Et




Tetrazolyl-




S—(CH


2


)


3


—




7-nitro






490




Me




Phenyl




COO—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






491




Me




4-Imidazolyl-




S—(CH


2


)


3


—




7-nitro






492




Me




3-Thienyl




O—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






493




Et




Phenyl




S—CH


2


—C(CH


3


)═CH—CH


2


—




8-trifluoromethyl






494




Me




Pyridin-4-yl-




S—(CH


2


)


6


—




7-nitro






495




Me




N-Methyl-2-Pyrro-




S—(CH


2


)


3


—




7-methansulfonamid








lyl-






496




Et




Phenyl-




S—(CH


2


)


3


—




6-methyl




7-cyano






497




Prop




4-Methylthia-




S—(CH


2


)


3


—




7-trifluoromethyl








zol-5-yl






498




Me




Phenyl




O—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






499




Me




4-Cyano-phenyl




S—CH


2


—C(CH


3


)═CH—CH


2


—




7-(piperidin-1-yl-sulfo-










nyl)






500




Et




Phenyl




S—(CH


2


)


3


—




7-Carboxamid






501




Me




N-Propyl-tetrazo-




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-








lyl-





nyl)






502




Me




Amino-




S—(CH


2


)


3


—




7-(dimethylaminosulfonyl)






503




Me




2,4-Dimethoxy-




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-








phenyl





nyl)






504




Me




3-Benzthienyl-




CO-(CH


2


)


3


—




7-phenylsulfonyl






505




Me




4-Imidazolyl-




S—(CH


2


)


3


—




7-cyano






506




Et




Phenyl




S—CH


2


-cycHex-CH


2


—




5-methoxy









CH


2


—






507




Et




3-Pyrrolyl




S—(CH


2


)


6


—




7-cyano






508




Me




3-Pyrrolyl




S—(CH


2


)


3


—




7-methansulfonamid






509




Me




Tetrazolyl-




S—(CH


2


)


7


—




7-(piperidin-1-yl-sulfo-










nyl)






510




Me




Tetrazolyl-




S—(CH


2


)


3


—




7-methansulfonamid






511




Me




3-Thienyl




COO—(CH


2


)


4


—




7-(piperidin-1-yl-sulfo-










nyl)






512




Et




2-Me-4-Oxazolyl-




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






513




Me




Pyridin-4-yl-




S—(CH


2


)


3


—




7-methylsulfonyl






514




Butyl




N-Methyl-2-Pyrro-




S—(CH


2


)


8


—




7-cyano








lyl-






515




Me




Phenyl-




S—(CH


2


)


3


—




6-CH(CH


3


)CH


2


—NH-7






516




Me




Pyridin-4-yl-




S—(CH


2


)


3


—




7-cyano






517




Me




3-Thienyl




S—CH


2


-cyc-




7-(3,3-dimethyl-piperi-









Prop-(CH


2


)


2


—




din-1-yl-sulfonyl)






518




Me




2,4-Dimethoxyphe-




O—(CH


2


)


3


—




7-cyano








nyl






519




Me




4-Methylsulfonyl-




O—(CH


2


)


3


—




7-cyano








phenyl






520




Me




4-Methylthia-




S—CH


2


—C(═CH


2


)—CH


2






7-(azepan-1-yl-sulfonyl)








zol-5-yl






521




Me




Amino-




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






522




Prop




N-Methyl-2-Pyrro-




S—(CH


2


)


8


—




7-cyano








lyl-






523




Me




5-Methyl imida-




S—(CH


2


)


3


—




7-trifluoromethyl








zol-4-yl-






524




Me




Cyclohexyl-




S—(CH


2


)


3


—




7-methylsulfonyl






525




Et




Pyridin-3-yl-




S—CH


2


—C(═CH


2


)—CH


2






7-(azepan-1-yl-sulfonyl)






526




Prop




Phenyl




S—(CH


2


)


3


—




8-ethenyl






527




Me




5-Methyl imida-




S—CH


2


—C(CH


3


)═CH—CH


2


—




7-(pyrrolidin-1-yl-sulfo-








zol-4-yl-





nyl)






528




Me




Tetrazolyl-




S—CH


2


-cycProp-CH


2


—




6-methoxy






529




Me




Phenyl-




S—CH


2


—C(═CH


2


)—CH


2






7-(azepan-1-yl-sulfonyl)






530




Me




6-Chloro-biphe-




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-








nyl-2-





nyl)






531




Et




Phenyl-




S—(CH


2


)


7


—




6-methyl




7-(pyroli-











din-1-yl-











sulfonyl)






532




Me




Pyridin-3-yl-




S—(CH


2


)


3


—




7-methansulfonamid






533




Me




2-Pyrazinyl-




S—CH


2


—C(═CH


2


)—CH


2






7-(piperidin-1-yl-sulfo-










nyl)






534




Et




3-Jod-phenyl




O—(CH


2


)


3


—




7-cyano






535




Me




3-Benzthienyl-




S—(CH


2


)


3


—




6-methoxy






536




Me




Oxadiazol-2-yl




S—(CH


2


)


3


—




7-methoxy






537




Me




6-Chloro-biphe-




S—CH


2


—C(CH


3


)═CH—CH


2


—




7-(piperidin-1-yl-sulfo-








nyl-2-





nyl)






538




cycProp




4-Methylthia-




S—CH


2


—C(═CH


2


)—CH


2






7-(azepan-1-yl-sulfonyl)








zol-5-yl






539




Me




Pyridin-3-yl-




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






540




Et




4-Methylthia-




S—(CH


2


)


3


—




7-trifluoromethyl








zol-5-yl






541




Me




3-Pyrrolyl




S—(CH


2


)


3


—




7-(dimethylamino-sulfonyl)






542




Me




3-Pyridyl




COO—(CH


2


)


4


—




7-(piperidin-1-yl-sulfo-










nyl)






543




Prop




Carboxamido




S—(CH


2


)


3


—




7-cyano






544




Me




4-Jod-phenyl




COO—(CH


2


)


3


—




7-cyano






545




Hexyl




Phenyl-




(CH


2


)


4


—




7-(3,3-dimethyl-piperi-










din-1-yl-sulfonyl)






546




Me




2-Me-4-Oxazolyl-




S—(CH


2


)


3


—




7-trifluoromethyl






547




Et




Phenyl-




S—(CH


2


)


7


—




7-(piperidin-1-yl-sulfo-




8-chloro










nyl)






548




Prop




Phenyl




S—(CH


2


)


4


—




7-(pyrrolidin-1-yl-sulfo-










nyl)






549




Me




N-Propyl-tetrazo-




S—(CH


2


)


3


—




7-methoxy








lyl-






550




Me




2-Pyrazinyl-




S—(CH


2


)


3


—




7-methylsulfonyl






551




Me




Phenyl




S—CH


2


—C(CH


3


)═CH—CH


2


—




8-trifluoromethyl






552




Butyl




tert.-Butyl




CO—(CH


2


)


3


—




6-methoxy






553




Prop




5-Methyl imida-




S—(CH


2


)


10


—




7-(piperidin-1-yl-sulfo-








zol-4-yl-





nyl)






554




Me




4-Jod-phenyl




S—(CH


2


)


3


—




7-cyano






555




Me




5-Methyl imida-




S—(CH


2


)


3


—




7-(dimethylamino-sulfonyl)








zol-4-yl-






556




Me




3-Benzthienyl-




(CH


2


)


4


—




7-phenylsulfonyl






557




Me




Pyridin-3-yl-




O—(CH


2


)


3


—




7-cyano






558




Me




Tetrazolyl-




S—(CH


2


)


3


—




7-nitro






559




Me




3-Benzthienyl-




S—(CH


2


)


6


—




7-(pyrolidin-1-yl-sulfo-










nyl)






560




cycProp




Phenyl




S—(CH


2


)


3


—




7-Acetyl






561




iProp




Phenyl




S—(CH


2


)


4


—




7-(pyrrolidin-1-yl-sulfo-










nyl)






562




Me




Phenyl-




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






563




Me




2-Me-4-Oxazolyl-




S—(CH


2


)


3


—




7-cyano






564




Me




5-Methyl imida-




S—(CH


2


)


3


—




7-methoxy








zol-4-yl-






565




Prop




Phenyl-




S—(CH


2


)


3


—




6-CH(CH


3


)CH


2


—N(CH


3


)-7






566




Me




N-Propyl-tetrazo-




S—(CH


2


)


3


—




7-trifluoromethyl








lyl-






567




Me




2,5-Di-methyl-fu-




S—(CH


2


)


3


—




7-trifluoromethyl








ranyl-3-






568




Me




Phenyl




O—(CH


2


)


3


—




7-cyano






569




Me




4-Jod-phenyl




S—(CH


2


)


3


—




7-nitro






570




Me




N-Methyl-2-Pyrro-




S—(CH


2


)


3


—




7-cyano








lyl-






571




Prop




3-Pyridyl




S—(CH


2


)


7


—




6-methyl




7-cyano






572




Me




2,5-Di-methyl-fu-




S—(CH


2


)


3


—




7-cyano








ranyl-3-






573




Me




2-Pyrazinyl-




S—(CH


2


)


3


—




7-methansulfonamid






574




Me




2-Me-4-Oxazolyl-




S—(CH


2


)


3


—




7-cyano






575




Et




Phenyl




O—(CH


2


)


3


—




7-cyano






576




Me




Methylamino-




S—(CH


2


)


3


—




7-methansulfonamid






577




Me




3-Thienyl




S—(CH


2


)


3


—




7-cyano






578




Me




2-Chloro-phenyl




(CH


2


)


4


—




7-trifluoromethoxy






579




Butyl




3-Pyrrolyl




S—CH


2


—CH═CH—CH


2


—




7-(piperidin-1-yl-sulfo-










nyl)






580




cycProp




3-Cyano-phenyl




S—(CH


2


)


3


—




7-methansulfonamid






581




Me




N-Propyl-tetrazo-




S—(CH


2


)


3


—




7-(dimethylamino-sulfonyl)








lyl-






582




Me




4-Methylphenyl




COO—(CH


2


)


4


—




7-trifluoromethyl






583




Me




5-Methyl imida-




S—(CH


2


)


3


—




7-methylsulfonyl








zol-4-yl-






584




Me




3-Br-Pyri-




S—(CH


2


)


3


—




7-methoxy








din-5-yl-






585




Me




3-Thienyl




S—CH


2


-cycHex-CH


2


—




7-trifluoromethoxy






586




Me




Pyridin-3-yl-




S—(CH


2


)


3


—




7-nitro






587




Et




3-Thienyl




COO—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






588




Prop




3-Thienyl




S—(CH


2


)


3


—




7-(dimethylaminosulfonyl)






589




Butyl




3-Br-Pyri-




S—(CH


2


)


3


—




7-cyano








din-5-yl-






590




Me




Pyridin-3-yl-




S—(CH


2


)


3


—




7-cyano






591




Et




3-Cyano-phenyl




S—(CH


2


)


3


—




7-nitro






592




Prop




Phenyl




S—(CH


2


)


10


—




7-Carboxamid






593




Et




3-Furanyl




S—CH


2


-cycHex-CH


2


—




7-phenylsulfonyl









CH


2


—






594




Me




N-Methyl-2-Pyrro-




S—(CH


2


)


3


—




7-methoxy








lyl-






595




Me




3-Cyano-phenyl




S—CH


2


-cycHex-CH


2


—




6-Methyl









CH


2


—






596




Me




4-Methylsulfonyl-




S—(CH


2


)


3


—




7-methansulfonamid








phenyl






597




Me




2-Aminothia-




S—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-








zol-4yl-





nyl)






598




Prop




Phenyl




S—(CH


2


)


3


—




6-bromo






599




Prop




4-Methylthia-




S—(CH


2


)


3


—




7-methylsulfonyl








zol-5-yl






600




Me




2,4-Dimethoxyphe-




O—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-








nyl





nyl)






601




Et




Pyridin-4-yl-




S—(CH


2


)


3


—




7-nitro






602




Me




N-Methyl-2-Pyrro-




S—CH


2


—C(CH


3


)═CH—CH


2


—




7-(piperidin-1-yl-sulfo-








lyl-





nyl)






603




Me




3-Br-Pyri-




S—(CH


2


)


6


—




7-(piperidin-1-yl-sulfo-








din-5-yl-





nyl)






604




iProp




Phenyl-




S—(CH


2


)


3


—




6-methyl




7-cyano






605




Et




2-Pyrazinyl-




CO—(CH


2


)


3


—




7-(morpholin-1-yl-sulfo-










nyl)






606




Me




Phenyl-




S—(CH


2


)


3


—




6-methyl




7-nitro






607




Butyl




4-Methylthia-




S—CH


2


—C(═CH


2


)—CH


2






7-(azepan-1-yl-sulfonyl)








zol-5-yl






608




Me




4-Methoxyphenyl




S—(CH


2


)


3


—




7-(dimethylamino-sulfonyl)






609




Me




3-Br-Pyri-




S—(CH


2


)


6


—




7-(piperidin-1-yl-sulfo-








din-5-yl-





nyl)






610




Me




Pyridin-4-yl-




S—(CH


2


)


3


—




7-methoxy






611




cycProp




Pyridin-3-yl-




O—(CH


2


)


3


—




7-(piperidin-1-yl-sulfo-










nyl)






612




Me




3-Br-Pyri-




S—(CH


2


)


3


—




7-trifluoromethyl








din-5-yl-






613




Me




2-Me-4-Oxazolyl-




S—(CH


2


)


3


—




8-trifluoromethyl






614




Prop




Phenyl




S—(CH


2


)


3


—




8-trifluoromethyl






615




Me




3-Benzthienyl-




S—(CH


2


)


3


—




7-trifluoromethyl






616




Et




Phenyl




S—(CH


2


)


3


—




7-acetyl






617




Me




Pyridin-3-yl-




S—CH


2


-cycProp-CH


2


—




7-(pyrolidin-1-yl-sulfo-










nyl)






618




Me




Oxadiazol-2-yl




S—(CH


2


)


7


—




7-(piperidin-1-yl-sulfo-










nyl)






619




Phenyl




3-Thienyl




S—(CH


2


)


3


—




7-cyano






620




Me




3-Jod-phenyl




O—(CH


2


)


3


—




7-cyano






621




Me




Phenyl




CONH—(CH


2


)


4


—




6-methoxy




8-methyl






622




Me




3-Thienyl




S—(CH


2


)


3


—




6-CH(CH


3


)CH


2


—NH-7





5-methyl






623




Me




3-Thienyl




S—(CH


2


)


3


—




6-CH


2


—CH


2


—CH


2


—CH


2


-7





8-bromo






624




Me




4-Pyridyl




S—(CH


2


)


3


—




6-CH


2


—CH


2


—CH


2


-7





8-ethe-












nyl






625




Me




3-Pyridyl-




S—(CH


2


)


3


—




5-methoxy




7-chloro




8-chloro






626




Me




3-Phenyl-




O—(CH


2


)


3


—




6-chloro




7-chloro




8-methyl














If no meaning is given, R


7


and R


8


are hydrogen.




Here and in the following tables is:




Me=methyl




Et=ethyl




cycProp=cyclopropyl




Prop=n−propyl




iProp=isopropyl




cycHex=cyclohexyl




The following compounds can be prepared in an analogous way in principle:












TABLE 2









































Ex.




R


1






R


2






A




R


6











627




Me




Phenyl




CONH—(CH


2


)4—




5-nitro






628




Butyl




Methylamino




S—(CH


2


)


3


—




5-fluoro






629




Me




Oxadiazol-2-yl




S—(CH


2


)


7


—




5-(piperidin-1-yl-sulfonyl)






630




Me




Tetrazolyl-




S—(CH


2


)


7


—




5-(piperidin-1-yl-sulfonyl)






631




Me




3-Cyano-phenyl




S—(CH


2


)


3


—




5-fluoro






632




Et




3-Thienyl




S—(CH


2


)


3


—




5-methoxy






633




Me




Carboxamid




S—CH


2


—C(CH


3


)═CH—CH


2


—




5-methoxy






634




Butyl




Cyclohexyl-




S—CH


2


—cycProp-(CH2)


2


—




5-chloro






635




Me




3-Pyrrolyl




S—(CH


2


)


3


—




5-nitro






636




Me




2-Pyrazinyl-




S—(CH


2


)


3


—




5-nitro






637




Pentyl




tert.-Butyl




CO—(CH


2


)


3


—




6-methoxy






638




Me




Pyridin-3-yl-




CO—(CH


2


)


3


—




5-fluoro






639




Me




4-Jod-phenyl




S—(CH


2


)


3


—




5-fluoro






640




Me




4-Methylsulfonyl-phenyl




S—(CH


2


)


8


—




5-(piperidin-1-yl-sulfonyl)






641




iProp




N-Propyl-tetrazolyl-




S—(CH


2


)


3


—




5-fluoro






642




cycProp




tert.-Butyl




CO—(CH


2


)


3


—




6-methoxy






643




Me




2-Aminothiazol-4yl-




S—(CH


2


)


3


—




5-fluoro






644




cycProp




4-Methylsulfonyl-phenyl




S—(CH


2


)


8


—




5-(piperidin-1-yl-sulfonyl)






645




Me




Pyridin-3-yl-




S—CH


2


—CH═CH—CH


2


—




5-methoxy






646




Me




N-Propyl-tetrazolyl-




S—CH


2


—CH═CH—CH


2


—




5-nitro






647




cycProp




Carboxamido




S—(CH


2


)


3


—




5-fluoro






648




Me




N-Methyl-2-Pyrrolyl-




S—(CH


2


)


3


—




5-nitro






649




Me




2-Me-4-Oxazolyl-




S—(CH


2


)


3


—




5-nitro






650




Me




Pyridin-4-yl-




S—(CH


2


)


3


—




5-nitro






651




Me




3-Br-Pyridin-5-yl-




S—CH


2


—CH═CH—CH


2


—




5-methoxy






652




Me




Phenyl-




S—(CH


2


)


3


—




5-fluoro






653




Me




4-Jod-phenyl




S—(CH


2


)


3


—




5-methoxy






654




Me




3-Pyrrolyl




S—(CH


2


)


3


—




5-methoxy






655




Me




Phenyl-




S—CH


2


—CH═CH—CH


2


—




5-(piperidin-1-yl-sulfonyl)






656




Me




3-Cyano-phenyl




S—(CH


2


)


3


—




5-methoxy






657




Me




N-Methyl-2-Pyrrolyl-




S—CH


2


-cycProp-(CH2)


2


—




5-methoxy






658




Me




Phenyl




O—(CH


2


)


3


—




5-cyano






659




Pentyl




Cyclohexyl-




S—(CH


2


)


3


—




5-chloro






660




Me




3-Benzthienyl-




S—CH


2


-cycProp-(CH


2


)


2


—




5-fluoro






661




Pentyl




Carboxamido




S—(CH


2


)


3


—




5-chloro






662




Et




5-Methyl imidazol-4-yl-




S—CH


2


—CH═CH—CH


2


—




5-methoxy






663




iProp




Cyclohexyl-




S—(CH


2


)


3


—




5-fluoro






664




Me




3-Benzthienyl-




S—(CH


2


)


3


—




5-nitro






665




Butyl




Cyclohexyl-




S—CH


2


—cycProp-(CH


2


)


2


—




5-methoxy






666




Me




4-Methoxyphenyl




S—(CH


2


)


3


—




5-methoxy






667




Prop




N-Propyl-tetrazolyl-




S—CH


2


—CH═CH—CH


2


—




5-fluoro






668




Pentyl




Phenyl




CONH—(CH


2


)


4


—




5-cyano






669




Me




Phenyl-




CO—(CH


2


)


3


—




5-methoxy






670




Prop




Cyclohexyl-




S—(CH


2


)


3


—




5-fluoro






671




Butyl




Methylamino




S—(CH


2


)


3


—




5-methoxy






672




Me




4-Methylthiazol-5-yl




S—(CH


2


)


3


—




5-cyano






673




cycProp




N-Propyl-tetrazolyl-




S—CH


2


—CH═CH—CH


2


—




5-nitro






674




cycProp




Propyl




CO—(CH


2


)


3


—




5-methoxy






675




Me




Oxadiazol-2-yl




S—CH


2


—CH═CH—CH


2


—




5-nitro






676




Me




3-Pyridyl




S—(CH


2


)


7


—




5-chloro






677




Me




5-Methyl imidazol-4-yl-




S—(CH


2


)


3


—




5-fluoro






678




Me




5-Methyl imidazol-4-yl-




S—CH


2


—C(CH


3


)═CH—CH


2


—




5-(pyrrolidin-1-yl-sulfonyl)






679




Me




3-Pyrrolyl




S—(CH


2


)


3


—




5-fluoro






680




Me




Cyclohexyl-




O-(CH


2


)


3


—




5-nitro






681




Me




Methylamino-




S—CH


2


—C(CH


3


)═CH—CH


2


—




5-(piperidin-1-yl-sulfonyl)






682




iProp




6-Chloro-biphenyl-2-




S—(CH


2


)


3


—




5-fluoro






683




Me




3-Cyano-phenyl




S—(CH


2


)


3


—




5-nitro






684




Pentyl




N-Propyl-tetrazolyl-




S—CH


2


—CH═CH—CH


2


—




5-chloro






685




Me




Phenyl




CONH—(CH


2


)


4


—




5-cyano






686




cycProp




Phenyl




COO—(CH


2


)


3


—




5-(piperidin-1-yl-sulfonyl)






687




Me




Amino




S—(CH


2


)


3


—




5-nitro






688




Me




Phenyl




CONH—(CH


2


)


4


—




5-chloro






689




Me




2-Pyrazinyl-




S—(CH


2


)


3


—




5-fluoro






690




Me




4-Jod-phenyl




S—CH


2


—CH═CH—CH


2


—




5-nitro






691




Me




2-Pyrazinyl-




S—CH


2


-cycProp-(CH


2


)


2


—




5-(pyrolidin-1-yl-sulfonyl)






692




Me




Pyridin-4-yl-




S—(CH


2


)


3


—




5-methoxy






693




Pentyl




4-Methylsulfonyl-phenyl




S—(CH


2


)


8


—




5-(piperidin-1-yl-sulfonyl)






694




Pentyl




N-Methyl-2-Pyrrolyl-




S—(CH


2


)


3


—




5-chloro






695




cycProp




Phenyl




O—(CH


2


)


3


—




5-cyano






696




Me




4-Imidazolyl-




S—(CH


2


)


3


—




5-nitro






697




Me




3-Pyrrolyl




S—CH


2


—CH═CH—CH


2


—




6-chloro






698




Me




Oxadiazol-2-yl




(CH2)


2


—CH(CH


3


)—CH


2


—CH


2


—




5-fluoro






699




Me




6-Chloro-biphenyl-2-




S—(CH


2


)


3


—




5-nitro






700




Butyl




4-Methoxyphenyl




S—(CH


2


)


3


—




5-methoxy






701




Me




3-Br-Pyridin-5-yl-




S—(CH


2


)


3


—




5-nitro






702




Prop




N-Propyl-tetrazolyl-




S—CH


2


—CH═CH—CH


2


—




5-chloro






703




Me




5-Methyl imidazol-4-yl-




(CH


2


)


2


—CH(CH


3


)—CH


2


—CH


2


—




tert-Butyl






704




Pentyl




Carboxamido




S—(CH


2


)


3


—




5-fluoro






705




Me




2-Pyrazinyl-




S—(CH


2


)


3


—




5-methoxy






706




Pentyl




Phenyl-




CO—(CH


2


)


3


—




6-methoxy






707




Me




4-Imidazolyl-




S—(CH


2


)


3


—




5-methoxy






708




Me




Phenyl-




CO—(CH


2


)


3


—




6-methoxy






709




Me




Tetrazolyl-




S—CH


2


—C(═CH


2


)—CH


2






5-nitro






710




cycProp




N-Methyl-2-Pyrrolyl-




S—(CH


2


)


3


—




5-chloro






711




cycProp




Cyclohexyl-




S—(CH


2


)


3


—




5-nitro






712




cycProp




Carboxamido




S—(CH


2


)


3


—




5-chloro






713




iProp




2,5-Di-methyl-furanyl-3-




S—(CH


2


)


3


—




5-fluoro






714




Me




Amino




S—CH


2


-cycProp-(CH


2


)


2


—




5-fluoro






715




Me




3-Thienyl




(CH


2


)


2


—CH(CH


3


)—CH


2


—CH


2


—




5-fluoro






716




Me




3-Thienyl




O—(CH


2


)


3


—




5-nitro






717




Me




tert.-Butyl




CO—(CH


2


)


3


—




6-methoxy






718




Me




Amino




S—(CH


2


)


3


—




5-methoxy






719




Me




2-Me-4-Oxazolyl-




S—(CH


2


)


3


—




5-fluoro






720




Et




Tetrazolyl-




S—CH


2


—C(CH


3


)═CH—CH


2


—




5-methoxy






721




Prop




Carboxamido




S—(CH


2


)


3


—




5-chloro






722




Et




4-Methylthiazol-5-yl




S—(CH


2


)


3


—




5-methoxy






723




Me




4-Imidazolyl-




S—(CH


2


)


3


—




5-fluoro






724




Me




4-Methylthiazol-5-yl




S—(CH


2


)


3


—




5-fluoro






725




Et




2-Me-4-Oxazolyl-




S—(CH


2


)


3


—




5-methoxy






726




Butyl




4-Methoxyphenyl




S—(CH


2


)


3


—




5-fluoro






727




Me




2,5-Di-methyl-furanyl-3-




S—(CH


2


)


3


—




5-methoxy






728




Me




3-Br-Pyridin-5-yl-




S—(CH


2


)


3


—




5-fluoro






729




Pentyl




N-Methyl-2-Pyrrolyl-




S—(CH


2


)


3


—




5-fluoro






730




cycProp




N-Methyl-2-Pyrrolyl-




S—(CH


2


)


3


—




5-nitro






731




Prop




Cyclohexyl-




S—(CH


2


)


3


—




5-chloro






732




cycProp




3-Pyridyl




S—(CH


2


)


7


—




5-chloro






733




cycProp




Cyclohexyl-




S—(CH


2


)


3


—




5-chloro






734




Me




N-Propyl-tetrazolyl-




S—(CH


2


)


3


—




5-methoxy






735




Me




Methylamino




S—(CH


2


)


3


—




5-nitro






736




Me




Pyridin-3-yl-




S—(CH


2


)


3


—




5-nitro






737




Me




2-Aminothiazol-4yl-




S—(CH


2


)


3


—




5-nitro






738




Et




Oxadiazol-2-yl




S—(CH


2


)


3


—




5-methoxy






739




Me




3-Cyano-phenyl




S—CH


2


—C(═CH


2


)—CH


2






5-(piperidin-1-yl-sulfonyl)






740




cycProp




Phenyl-




CO—(CH


2


)


3


—




6-methoxy






741




Me




2-Me-4-Oxazolyl-




(CH


2


)


2


—CH(CH


3


)—CH


2


—CH


2


—




5-(morpholin-1-yl-sulfonyl)






742




Et




2-Aminothiazol-4yl-




S—CH


2


—CH═CH—CH


2


—




5-methoxy






743




Me




2,5-Di-methyl-furanyl-3-




S—(CH


2


)


3


—




5-nitro






744




Me




Phenyl




COO—(CH


2


)


3


—




5-(piperidin-1-yl-sulfonyl)






745




Me




2-Me-4-Oxazolyl-




S—(CH


2


)


3


—




5-fluoro






746




iProp




Pyridin-4-yl-




S—(CH


2


)


3


—




5-fluoro






747




Me




Methylamino




S—CH


2


-cycProp-(CH


2


)


2


—




5-methoxy






748




Me




5-Methyl imidazol-4-yl-




S—(CH


2


)


3


—




5-nitro






749




Me




2-Me-4-Oxazolyl-




S—(CH


2


)


3


—




5-cyano






750




cycProp




Carboxamido




S—(CH


2


)


3


—




5-cyano






751




Me




Tetrazolyl-




S—(CH


2


)


3


—




5-fluoro






752




Pentyl




Cyclohexyl-




S—(CH


2


)


3


—




5-fluoro






753




Prop




N-Methyl-2-Pyrrolyl-




S—(CH


2


)


3


—




5-chloro






754




Me




N-Methyl-2-Pyrrolyl-




S—(CH


2


)


3


—




5-fluoro






755




cycProp




N-Propyl-tetrazolyl-




S—CH


2


—CH═CH—CH


2


—




5,6-dichloro






756




Pentyl




Propyl




CO—(CH


2


)


3


—




5-methoxy






757




Me




4-Methoxyphenyl




S—(CH


2


)


3


—




5-nitro






758




Me




Propyl




CO—(CH


2


)


3


—




5-methoxy






759




Me




2-Me-4-Oxazolyl-




S—(CH


2


)


3


—




5-methoxy






760




cycProp




Phenyl




CONH—(CH


2


)


4


—




5-cyano






761




Me




Carboxamido




S—(CH


2


)


3


—




5-cyano






762




Et




tert.Butyl




S—CH


2


-cycProp-(CH


2


)


2


—




5-methoxy






763




cycProp




N-Methyl-2-Pyrrolyl-




S—(CH


2


)


3


—




5-fluoro














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 acetate 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 tablets which have been prepared in this way are then provided with an enteric coating.




Biological Investigations—Receptor Binding Studies




D


3


binding test




Cloned human D


3


-receptor-expressing CCL 1,3 mouse fibroblasts, obtainable from Res. Biochemicals Internat. One Strathmore Rd., Natick, Mass. 01760-2418 USA, were used for the binding studies.




Cell Preparation




The D


3


-expressing cells were multiplied in RPMI-1640 containing 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 incubated 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 300 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 incubated, at 4° C. for 30 min, at a concentration of 10


7


cells/ml of lysis buffer. The cells were centrifuged at 200 g for 10 min and the pellet was stored in liquid nitrogen.




Binding Tests




For the D


3


-receptor binding test, the membranes were suspended in incubation buffer (50 mM Tris-HCl, pH 7.4, containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl


2


, 2 mM MgCl


2


, 10 μM quinolinol, 0.1% ascorbic acid and 0.1% BSA), at a concentration of approx. 10


6


cells/250 μl of test mixture, and incubated at 30° C. with 0.1 nM


125


iodosulpiride in the presence and absence of the test substance. The nonspecific binding was determined using 10


−6


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 ice-cold Tris-HCl buffer, pH 7.4. The radioactivity which had collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.




The K


i


values were determined by means of nonlinear regression analysis using the LIGAND program.




2) D


2


binding test




Cell Culture




HEK-293 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 μg/ml of streptomycin/ml. The cells were maintained at 37° C. in a moist atmosphere containing 5% CO


2


.




The cells were prepared for the binding studies by trypsinizing them (0.05% solution of trypsin) at room temperature for 3-5 minutes. After that, the cells were centrifuged at 250 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 centrifuging at 250 g for 10 minutes, the residue was stored at −20° C. until used.




Receptor Binding Tests




Low affinity state dopamine D


2


receptor using


125


I-spiperone (81 TBq/mmol, Du Pont de Nemours, Dreieich)




The test mixtures (1 ml) consisted of 1×10


5


cells in incubation buffer (50 mM Tris, 120 mM NaCl, 5 mM KCl, 2 mM MgCl


2


and 2 mM CaCl


2


, pH 7.4 with HCl) and 0.1 mM


125


I-spiperone (total binding) or additionally 1 μM 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 ice-cold 50 mM Tris-HCl buffer, pH 7.4. The radioactivity which had collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.




The results were evaluated as described in a).




The K


i


values were determined by way of nonlinear regression analysis using the LIGAND program or by converting the IC


50


values using the Cheng and Prusoff formula.




In these tests, the compounds according to the invention exhibit very good affinities for the D


3


receptor (<1 μmolar, in particular <100 nmolar) and bond selectively to the D


3


receptor.




In table 3 pK


i


(D


3


) values (negative logarithm of the affinity constant for the D


3


receptor) and selectivity versus D


2


receptor (K


i


(D


2


)/K


i


(D


3


)) are given for the compounds of the examples 3, 4 and 7.














TABLE 3









Example




pK


i


(D


3


)




Selectivity











3




8,02




78






4




7,96




67






7




8,37




81













Claims
  • 1. A triazole compound of the formula I whereR1 is H, C1-C6-alkyl, which may be substituted by OH, OC1-C6-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-C6-alkoxy, C1-C6-alkylthio, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, halogen, CN, COOR3, CONR3R4, NR3R4, SO2R3, SO2NR3R4 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, C3-C6-cycloalkyl, halogen, CN, COR3, 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, CONR3, COO, CO, C3-C6-cycloalkyl and a double or triple bond; B is a radical of the following formula: whereX is CH2 or CH2CH2; 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, C(O)CH3, CO2R3, SO2R3, SO2NR3R4, 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, CONR3R4, 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 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 R6, R7 and R8 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; or a salt thereof with a physiologically tolerated acid.
  • 2. A compound as claimed in claim 1 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 O, S, COO, CO, a double bond or triple bond and C3-C6-cycloalkyl.
  • 3. A compound as claimed in claim 1 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 O, S, a double bond and cyclohexyl.
  • 4. A compound as claimed in claim 1 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.
  • 5. A compound as claimed in claim 1 of the formula I, where R2 is H, C1-C6-alkyl, phenyl, thienyl, furanyl, tetrazolyl, pyrrolyl, pyridyl or pyrazinyl.
  • 6. A compound as claimed in claim 1 of the formula I, where R1 is H, C1-C6-alkyl or C3-C6-cycloalkyl.
  • 7. A compound as claimed in claim 1 of the formula I, where R6, R7 and R8 are selected, independently of each other, from H, C1-C6-alkyl, OH, C1-C6-alkoxy, C1-C6-akylthio-C1-C6-alkyl, halogen, CN, C(O)CH3, NO2, SO2R3, SO2NR3R4 and CONR3R4.
  • 8. A compound as claimed in claim 1 of the formula I, whereR1 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 R6, R7 and R8 are selected from H, C1-C6-alkyl, C1-C6-alkoxy, halogen, SO2NR3R4, CN, C(O)CH3, NO2, CF3, CONR3R4, CHF2, OSO2CF3, OCF3 and NHSO2—C1-C6-alkyl.
  • 9. A pharmaceutical which comprises at least one compound as claimed in claim 1, optionally together with physiologically acceptable excipients and/or adjuvants.
  • 10. A triazole compound of formula I whereR1 is H, C1-C6-alkyl, which may be substituted by OH, OC1-C6-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-C6-alkoxy, C1-C6-alkylthio, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, halogen, CN, COOR3, CONR3R4, NR3R4, SO2R3, SO2NR3R4 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, C3-C6-cycloalkyl, halogen, CN, COR3, 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, CONR3, COO, CO, C3-C6-cycloalkyl and a double or triple bond; B is a radical of the following formula: whereX is CH2CH2; 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, C(O)CH3, CO2R3, SO2R3, SO2NR3R4, 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, CONR3R4, 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 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 R6, R7 and R8 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; or a salt thereof with a physiologically tolerated acid.
  • 11. The compound defined in claim 10, wherein A is C4-C10-alkylene or C3-C10-alkylene which comprises at least one group Z selected from the group consisting of O, S, COO, CO, a double bond, a triple bond and C3-C6-cycloalkyl.
  • 12. The compound defined in claim 10, wherein A is C4-C10-alkylene or C3-C10-alkylene which comprises at least one group Z selected from the group consisting of O, S, a double bond and cyclohexyl.
  • 13. The compound defined in claim 10, wherein 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.
  • 14. The compound defined in claim 10, wherein R2 is H, C1-C6-alkyl, phenyl, thienyl, furanyl, tetrazolyl, pyrrolyl, pyridyl or pyrazinyl.
  • 15. The compound defined in claim 10, wherein R1 is H, C1-C6-alkyl or C3-C6-cycloalkyl.
  • 16. The compound defined in claim 10, wherein R6, R7 and R8 are selected, independently of each other, from H, C1-C6-alkyl, OH, C1-C6-alkoxy, C1-C6-akylthio-C1-C6-alkyl, halogen, CN, C(O)CH3, NO2, SO2R3, SO2NR3R4 and CONR3R4.
  • 17. The compound defined in claim 10, whereinR1 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 R6, R7 and R8 are selected from H, C1-C6-alkyl, C1-C6-alkoxy, halogen, SO2NR3R4, CN, C(O)CH3, NO2, CF3, CONR3R4, CHF2, OSO2CF3, OCF3 and NHSO2—C1-C6-alkyl.
  • 18. A pharmaceutical which comprises at least one compound as defined in claim 10, optionally together with physiologically acceptable excipients and/or adjuvants.
Priority Claims (1)
Number Date Country Kind
199 00 811 Jan 1999 DE
PCT Information
Filing Document Filing Date Country Kind
PCT/EP00/00177 WO 00
Publishing Document Publishing Date Country Kind
WO00/42036 7/20/2000 WO A
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