AU2002356689A1 - Substituted 4-phenyltetrahydroisoquinolines, method for the production thereof, the use thereof as medicaments, in addition to a medicament containing same - Google Patents

Substituted 4-phenyltetrahydroisoquinolines, method for the production thereof, the use thereof as medicaments, in addition to a medicament containing same Download PDF

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AU2002356689A1
AU2002356689A1 AU2002356689A AU2002356689A AU2002356689A1 AU 2002356689 A1 AU2002356689 A1 AU 2002356689A1 AU 2002356689 A AU2002356689 A AU 2002356689A AU 2002356689 A AU2002356689 A AU 2002356689A AU 2002356689 A1 AU2002356689 A1 AU 2002356689A1
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methyl
tetrahydro
dichloro
isoquinolin
phenyl
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Markus Bleich
Michael Gekle
Uwe Heinelt
Armin Hofmeister
Hans-Jochen Lang
Klaus Wirth
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Sanofi Aventis Deutschland GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • A—HUMAN NECESSITIES
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
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    • A61P11/00—Drugs for disorders of the respiratory system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Chemistry (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pulmonology (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Nutrition Science (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Vascular Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Indole Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Description

IN THE MATTER OF an Australian Application corresponding to PCT Application PCT/EPO2/12990 RWS Group plc, of Europa House, Marsham Way, Gerrards Cross, Buckinghamshire, England, hereby solemnly and sincerely declares that, to the best of its knowledge and belief, the following document, prepared by one of its translators competent in the art and conversant with the English and German languages, is a true and correct translation of the PCT Application filed under No. PCT/EP02/12990. Date: 30 January 2004 S. ANTHONY Director For and on behalf of RWS Group plc (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International publication date (10) International publication number 12 June 2003 (12.06.2003) PCT WO 03/048129 Al (51) International patent classification : CO7D 217/22, (81) Designated states (national): AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, 401/12,403/12, 417/12, 409/12, A61K 31/47, A61P 9/12 'U, , D , , , Z, C, , , CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, J'P, (21) International application number: PCTIEPO2/12990 , G, , , , , , , L, , , , KE, KG, KP, KR Z,KZ, LC K, LR, LS, LT, LU, LV, (22) International filing date: 20 November 2002 (20.11.2002) MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, OM, PH, PL, PT, RO, RU, SC, SD, SE, SG, SI, SK, SL, TJ, TM, TN, TR, TT, TZ, UA, UG, UZ, VC, VN, (25) Language of filing: German Y ZA, ZM, Z YU, ZA, 2M, ZW. (26) Language of publication: German (26) Language of publication: man (84) Designated states (regional): ARIPO Patent (GH, GM, (30) Data relating to the priority: KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW), (3 10) 59714.2 Dat reln t t: Eurasian Patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, 101 59 714.2 5 December 2001 (05.12.2001) DE' TM), European Patent (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, (71) Applicant: AVENTIS PHARMA DEUTSCHLAND GMBH SE, SK, TR), OAPI Patent (BF, B'J, CF CG, CI, CM, [DE/DE]; Brtiningstrasse 50, 65929 Frankfurt am Main (DE). GA, GN, GQ, GW, P, MR N, , T G, TG). GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (72) Inventors: HOFMEISTER, Armin; Pfaugasse 16, 55276 Published: Published: Oppenheim (DE). HEINELT, Uwe; Mosbacher Strasse 54, - With the International Search Report. 65187 Wiesbaden (DE). LANG, Hans-Jochen; Rildesheimer St-asse 7, 65719 Hofheim (DE). BLEICH, Markus; Eufinger For an explanation of the two-letter codes and the other Strasse 73, 65597 Hiunfelden-Dauborn (DE). WIRTH, Klaus; abbreviations, reference is made to the explanations abbreviations, reference is made to the explanations Robert-Schumann-Ring 104, 65830 Kriftel (DE). GEKLE, ("Guidance Notes on Codes and Abbreviations") at the Michael; Schiesshausstrasse 11, 97072 Wilrzburg (DE). beginning of each regular edition of the PCT Gazette. As printed (54) Title: SUBSTITUTED 4-PHENYLTETRAHYDROISOQUINOLINES, METHOD FOR THE PRODUCTION THEREOF, THE USE THEREOF AS MEDICAMENTS, IN ADDITION TO A MEDICAMENT CONTAINING SAME (54) Bezeichnung: SUBSTITUIERTE 4-PHENYLTETRAHYDROISOCHINOLINE, VERFAHREN ZU IHRER HERSTEL LUNG, IHRE VERWENDUNG ALS MEDIKAMENT, SOWIE SIE ENTHALTENDES MEDIKAMENT (57) Abstract: The invention relates to compounds of formula (T), wherein R8 RI - R9 which have the meaning as cited in the claims, are extremely suit Rable as antihypertensives for reducing or preventing ischemically induced R9 R7 injuries, as medicaments for operative intervention for the treatment of is chemics of the nervous system, strokes and swelling of the brain, shocks, Ri disturbed respiratory functions, for the treatment of snorers, as a laxative, R6 as agents against ectopic parasites, for the prevention of gallstones, as an R2 (I) tiatherosclerotic agents, agents against diabetic late complications, cancer, fibrotic diseases, endothelial dysfunctions, organ hypertrophia and hyper N* plasia. Said compounds are also inhibitors of the cellular sodium-proton-an R3 R5 tiponrters, they influence serum lipoproteins and can be used in the prophy '4 R4 laxis of and for the regression of atherosclerotic alterations. (57) Zusammenfassung: Verbindungen derFormel (I), worin RI bis R9 die in den Ansprtichen gegebenen Bedeutungen haben, sind hervorragend geeignetals Antihypertensiva, zur Veningerung oder Verhinderung ischamisch induzierter Scheden, als Arzneimittel fir operative Eingriffe zur Behandlung van Ischimien des Nervensystems, des Schlaganfalls und des Hirnm6dems, des Schocks, des gest6nrten Atemantriebs, zur Behandlung des Schnarchens, als Abfihnnrmittel, als Mittel gegen Ektoparasiten, zur Vorbeugung ge gen Gallenstein-Bildung, als Antiatherosklerotika, Miael gegn diabetische Spitkomplikationen, Krebserkrankungen, fibrotische Erkrankungen. endotheliale Dysfa.ii-tion, Organhypertrophimn und -hyperplasien. Sie sind Inhibitoren des 7ellilaren Natrium-Pro- WO 03/048129 PCT/EPO2/12990 1 Description Substituted 4-phenyltetrahydroisoquinolines, process for their preparation, their use as medicament, and medicament containing them 5 The invention relates to compounds of the formula I R8 R9 R7 R1 I R6 R2 R3 'R5 R4 in which the meanings are: R1, R2, R3 and R4 10 independently of one another H, F, CI, Br, I, CN, NO 2 , OH, NH 2 , CaH2a+1, CqqH2qq- 1 , OCbH2b+1, COOR10, OCOR10, COR10 or Ox-(CH2)y-phenyl; a and b in the groups CaH2a+1 and OCbH2b+1 independently of one another 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be 15 replaced by F atoms; qq 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms; R10 H or CcH2c+1; c 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H 20 atoms to be replaced by F atoms, x zero or 1; y zero, 1,2, 3 or 4; where the phenyl ring in the group Ox-(CH2)y-phenyl is unsubstituted or substituted by 1-3 substituents selected from 25 the group consisting of F, Cl, Br, CN, NO 2 , OH, NH 2 or CdH2d+l; 2 d 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms, or R1, R2, R3 and R4 5 independently of one another heteroaryl, it being possible for zero, 1, 2, 3 or 4 N atoms, zero or 1 oxygen atom or zero or 1 S atom to be present as ring atoms; or R1, R2, R3 and R4 10 independently of one another CONR11R12 or NR11R12; R11 and R12 independently of one another H, CeH2e+l, CrrH2rr-1; e 1,2, 3, 4, 5, 6, 7 or 8, rr 3, 4, 5, 6, 7, or 8, 15 it being possible for one or more H atoms in the groups CeH2e+1 and CrrH2rr-1 to be replaced by F atoms and for one or more CH 2 groups to be replaced by O or NR13; R13 H or CfH2f+1; f 1, 2, 3 or 4, it being possible for one or more H 20 atoms to be replaced by F atoms; or R13 and a CH 2 group of R11 or R12 together with the N atom to which they are bonded a 5- or 6-membered ring; or 25 Rll and R12 together with the N atom to which they are bonded a 5-, 6- or 7-membered ring; or R11 and R12 30 independently of one another COR14, CSR14 or SO 2 R14; R14 CgH2g+1
;
3 g 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms, and it being possible for one or more CH 2 groups to be replaced by O or NR13, 5 or R1, R2, R3 and R4 independently of one another -Oh-SOj-R15, with h zero or 1; j zero, 1 or 2; 10 R15 CkH2k+l, OH, OClH 2 1
+
1 or NR17R18; k 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms; I 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms; 15 R17 and R18 independently of one another H or CmH2m+1 m 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms in the group CmH2m+ 1 to be replaced by F atoms and for one or more CH 2 groups to be replaced 20 by O, CO, CS or NR19; R19 H or CnH2n+1; n 1,2, 3 or 4; it being possible for one or more H atoms in CnH2n+1 to be replaced by F atoms; 25 or R17 and R18 together with the N atom to which they are bonded a 5-, 6- or 7-membered ring; or 30 R19 and a CH 2 group of R17 or R18 together with the N atom to which they are bonded a 5- or 6-membered ring; 4 but where R2 must always not be equal to H, R5 H, CpH 2 p+l, CssH 2 ss-1, COR20 or SO 2 R20; p 1, 2, 3, 4, 5, 6, 7 or 8, ss 3, 4, 5, 6, 7 or 8, 5 R20 CqH2q+1; q 1,2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms in the groups CpH 2 p+ 1 , CssH 2 ss- 1 and CqH2q+1 to be replaced by F atoms and for one or more CH 2 groups to be replaced by O or NR21; 10 R21 H or CrH2r+1; r 1, 2, 3 or 4; it being possible for one or more H atoms in CrH2r+1 to be replaced by F atoms; R6 H, F, Cl, Br, I, CsH 2 s+ 1 , CddH2dd-1, OH, OCtH2t+1 or OCOR22; 15 s and t independently of one another 1, 2, 3, 4, 5, 6, 7 or 8; dd 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms in CsH 2 s+ 1 , CddH2dd-1 and OCtH2t+1 to be replaced by F atoms; R22 CuH2u+1 20 u 1, 2, 3 or 4; it being possible for one or more H atoms in CuH2u+1 to be replaced by F atoms; R7, R8 and R9 independently of one another -Ov-SOw-R23; 25 v zero or 1; w zero, 1 or 2; R23 CnnH2nn+1, CmmH2mm-1, OH, OCppH2pp+1 or NR25R26; nn and pp independently of one another 1, 2, 3, 4, 5, 6, 7 or 8, 30 mm 3, 4, 5, 6, 7 or 8, 5 it being possible for one or more H atoms in CnnH2nn+l, CmmH2mm-1 and OCpH 2 pp+ 1 to be replaced by F atoms; R25 and R26 independently of one another H, CN or CzH2z+1, CzzH2zz-1; 5 z 1,2,3,4,5,6, 7 or8; zz 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms and, in CzH2z+1, it being possible for one or more H atoms to be replaced by F atoms and it being possible for 10 one or more CH 2 groups to be replaced by O, CO, CS or NR27; R27 H or CaaH2aa+1; aa 1,2, 3 or 4; it being possible for one or more H atoms in 15 CaaH2aa+1 to be replaced by F atoms; or R25 and R26 together with the N atom to which they are bonded a 5-, 6- or 7-membered ring, 20 or R27 and a CH 2 group of R25 or R26 together with the N atom to which they are bonded a 5- or 6-membered ring; or R7, R8 and R9 25 independently of one another NR32COR30, NR32CSR30 or NR32SObbR30; R30 H, CccH2cc+1, CyyH2yy- 1 , pyrrolidinyl or piperidinyl, in which rings a
CH
2 group may be replaced by O or NR33; R32 and R33 independently of one another H or ChH2h+1; bb 2 or 3; 30 cc 1, 2, 3, 4, 5, 6, 7 or 8; yy 3,4,5,6, 7 or8; 6 h 1,2,3,4,5,6, 7 or8, it being possible for one or more H atoms in ChH2h+1 to be replaced by F atoms, and it being possible for one or more H atoms in the groups CccH2cc+1 and CyyH2yy-1 to be replaced by F atoms and for one or more 5 CH 2 groups to be replaced by NR31 and for a CH2 group to be replaced by O; R31 H, CkkH2kk+1, COR65 or SO2R65; kk 1,2, 3, or 4; it being possible for one or more H atoms to be replaced by F atoms, 10 R65 H, CxxH2xx+1; xx 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; or R31 forms together with a CH 2 group of R30 a 5-, 6- or 7-membered ring; 15 or R30 a 5- or 6-membered heteroaryl with 1, 2, 3 or 4 N atoms, zero or 1 S atoms and zero or 1 0 atoms, which is unsubstituted or substituted by up to three substituents selected from the group consisting of F, Cl, Br, I, 20 CooH 2 oo+ 1 , NR70R71; R70 and R71 independently of one another H, CuuH2uu+1 and COR72; R72 H, CvvH2vv+1; 25 oo, uu and vv independently of one another 1, 2, 3, 4, 5, 6, 7 or 8; it being possible for one ormore H atoms in the groups CooH 2 oo+ 1 , CuuH2uu+1 or CwH2vvw+1 to be 30 replaced by F atoms; 7 or R7, R8 and R9 independently of one another H, F, CI, Br, I, NO 2 , CN, OH, NH 2 , CeeH2ee+1, CwwH 2 ww-1, OCffH2ff+1, NR40R41, CONR40R41, COOR42, COR42 or 5 OCOR42, ee and ff independently of one another 1, 2, 3, 4, 5, 6, 7 or 8; ww 3, 4, 5, 6, 7 or 8; it being possible for one or more H atoms in the groups CeeH2ee+1, 10 CwwH 2 ww- 1 and OCffH2ff+1 to be replaced by F atoms; R40 and R41 H,CttH 2 tt+ 1 or C(NH)NH 2 ; tt 1,2, 3, 4, 5, 6, 7 or 8; it being possible for one or more H atoms in the group CttH2tt+1 to be 15 replaced by F atoms and for one or more CH 2 groups to be replaced by O or NR44; R44 H or CggH2gg+1; gg 1, 2, 3, 4, 5, 6, 7 or 8; it being possible for one or more H atoms in the group 20 CggH2gg+1 to be replaced by F atoms, and it being possible for R44 together with a (CH 2 ) group of R40 or R41 and the N atom to which they are jointly bonded to form a 5- or 6 membered ring, or 25 R40 and R41 with the N atom to which they are bonded a 5- or 6-membered ring; R42 H or ChhH2hh+1; hh 1,2,3,4,5,6, 7 or8; it being possible for one or more H atoms in the group ChhH2hh+1 to 30 be replaced by F atoms; 8 but where two substituents from the group of R7, R8 and R9 may not simultaneously be OH or OCH 3 and where at least one of the radicals R7, R8 or R9 must be selected from the group consisting of CONR40R41, -OvSOwR 2 3, NR32COR30, NR32CSR30 5 and NR32SObbR30; and the pharmaceutically acceptable salts and trifluoroacetates thereof. Preference is given to compounds of the formula I in which the meanings are: R1, R2, R3 and R4 10 independently of one another, H, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , CaH2a+1, cycloalkyl with 3, 4, 5 or 6 C atoms, OCbH2b+1, COOR10; a and b independently of one another 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; 15 R10 H or CcH2c+1; c 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; or R1, R2, R3 and R4 20 independently of one another 5- or 6-membered heteroaryl selected from the group consisting of pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl and oxazolyl; or R1, R2, R3 and R4 25 independently of one another CONR 11R12 or NR 11R12; R11 and R12 independently of one another H, CeH2e+1, CrrH2rr-1; e 1,2, 3or4, rr 3, 4, 5 or 6, 30 it being possible for one or more H atoms in the groups CeH2e+1 and CrrH2rr-1 to be replaced by F atoms 9 or R11 and R12 independently of one another hydroxyethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, 5 piperazinoethyl, morpholinoethyl or piperidinoethyl; or R11 and R12 together with the N atom to which they are bonded a pyrrolidine, piperidine, N-methylpiperazine, piperazine or morpholine ring; 10 or R11 and R12 independently of one another COR14, CSR14, CONHR14, CSNHR14 or SO 2 R14; R14 CgH2g+ 1 ; 15 g 1,2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; or R1, R2, R3 and R4 independently of one another OSO 3 H, SO 3 H, SO 2
R
15 , with 20 R15 CkH2k+1, OCIH 2 1
+
1 or NR17R18; k 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; I 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; 25 R17 and R18 independently of one another H, CmH2m+1, in which the first
CH
2 group bonded to the nitrogen is replaced by CO and the second CH 2 group is replaced by NR19; m 1, 2, 3, 4 or 5, it being possible for one or more H 30 atoms in the group CmH2m+1 to be replaced by F atoms; 10 R19 H or CnH2n+1; n 1, 2, 3 or 4; it being possible for one or more H atoms in CnH2n+ 1 to be replaced by F atoms; 5 or R17 and R18 together with the N atom to which they are bonded a 5- or 6-membered ring; but where R2 must always not be equal to H, 10 R5 H, CpH2p+l; p 1,2, 3 or 4; it being possible for one or more H atoms in CpH 2 p+ 1 to be replaced by F atoms; R6 H, CsH 2 s+ 1 , OCtH2t+ 1 or OCOR22; 15 s and t independently of one another 1, 2, 3 or 4; it being possible for one or more H atoms in CsH 2 s+ 1 and OCtH2t+1 to be replaced by F atoms; R22 CuH2u+1; 20 u 1, 2, 3 or 4; it being possible for one or more H atoms in CuH2u+1 to be replaced by F atoms; R7, R8 and R9 independently of one another OSO 3 H, SO 3 H or SO 2 R23; 25 R23 CnnH2nn+1, CmmH2mm-1, OCppH2pp+1 or NR25R26; nn and pp independently of one another 1, 2, 3, 4 or 5, mm 3, 4, 5 or 6, it being possible for one or more H atoms in CnnH2nn+l, 30 CmmH2mm-1 and OCppH2pp+ 1 to be replaced by F atoms; 11 R25 and R26 independently of one another H, CN, CzH2z+1, in which the first CH 2 group bonded to the nitrogen is replaced by CO or CS and the second CH 2 is replaced by NR27; 5 z 1,2,3,4, 5 or6; it being possible for one or more H atoms in CzH2z+1 to be replaced by F atoms; R27 H or CaaH2aa+1; aa 1, 2, 3 or 4; 10 it being possible for one or more H atoms in CaaH2aa+1 to be replaced by F atoms; or R25 and R26 together with the N atom to which they are bonded a 5- or 15 6-membered ring; or R27 and a CH 2 group of R25 or R26 together with the N atom to which they are bonded a 5- or 6-membered ring; or 20 R7, R8 and R9 independently of one another NR32COR30, NR32CSR30 or NR32SO 2 R30; R30 H, OH, CccH2cc+1, CyyH2yy- 1 , pyrrolidinyl or piperidinyl, in which rings a CH 2 group may be replaced by O or NR33; R32 and R33 independently of one another H or ChH2h+1; 25 cc 1,2,3,4,5,6, 7 or8; yy 3,4, 5 or6; h 1,2, 3 or 4; it being possible for one or more H atoms in ChH2h+1 to be replaced by F atoms, and it being possible for one or more H atoms in the groups 12 CccH2cc+1 and CyyH2yy-1 to be replaced by F atoms and for one or more
CH
2 groups to be replaced by NR31 and for a CH 2 group to be replaced by O; R31 H, CkkH2kk+1, COR65 or SO 2 R65; kk 1,2, 3, or 4; 5 it being possible for one or more H atoms to be replaced by F atoms, R65 H, CxxH 2 xx+ 1 ; xx 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; or 10 R31 together with a CH 2 group of R30 and the N atom to which they are jointly bonded form a 5- or 6-membered ring; or R30 a 5- or 6-membered heteroaromatic system selected from the group consisting of pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, 15 thienyl, thiazolyl and oxazolyl, which are unsubstituted or substituted by up to three substituents selected from the group consisting of F, Cl, Br, I, CooH 2 oo+ 1 , NR70R71, R70 and R71 20 independently of one another H, CuuH2uu+1 or COR72; R72 H, CvvH2vv+1; oo, uu and wvv independently of one another 1, 2, 3 or 4; it being possible for one or more H atoms in the groups 25 CooH 2 oo+ 1 , CuuH2uu+1 or CvvH2wvv+1 to be replaced by F atoms; or R7, R8 and R9 independently of one another H, F, Cl, Br, I, NO 2 , CN, OH, NH 2 , CeeH2ee+l, 30 CwwH 2 ww- 1 , OCffH2ff+1, NR40R41, CONR40R41, COOR42, COR42 or OCOR42; 13 ee and ff independently of one another 1, 2, 3 or 4; ww 3,4, 5or6, it being possible for one or more H atoms in the groups CeeH2ee+1, 5 CwwH2ww-1 and OCffH2ff+1 to be replaced by F atoms; R40 and R41 H, CttH2tt+1 or C(NH)NH 2 ; tt 1, 2, 3,4, 5, 6, 7 or 8; it being possible for one or more H atoms in the group CttH2tt+1 to be 10 replaced by F atoms; or R40 and R41 to be selected independently of one another hydroxyethyl,, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, 15 N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl; or R40 and R41 together with the N atom to which they are bonded form a ring selected 20 from the group consisting of pyrrolidine, piperidine, N-methyl piperazine, piperazine and morpholine; R42 H or ChhH2hh+1; hh 1,2, 3 or 4; it being possible for one or more H atoms in the group ChhH2hh+1 to 25 be replaced by F atoms; but where two substituents from the group of R7, R8 and R9 may not simultaneously be OH or OCH 3 and where at least one of the radicals R7, R8 or R9 must be selected from the group consisting of CONR40R41, -OvSOwR23, NR32COR30, NR32CSR30 30 and NR32SObbR30; and the pharmaceutically acceptable salts and trifluoroacetates thereof.
14 Particular preference is given to compounds of the formula I in which the meanings are: R1, R2, R3 and R4 5 independently of one another H, F, Cl, Br, OH, NH 2 , CaH2a+1, cycloalkyl with 3, 4, 5 or 6 C atoms, OCbH2b+1; a and b in the groups CaH2a+1 and OCbH2b+1 independently of one another 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced 10 by F atoms; or R1, R2, R3 and R4 independently of one another NR11R12; R11 and R12 15 independently of one another H, CeH2e+1, CrrH2rr-1; e 1,2, 3 or4, rr 3,4, 5or6, it being possible for one or more H atoms in the groups CeH2e+1 and CrrH2rr-1 to be replaced by F 20 atoms; or R11 and R12 together with the N atom to which they are bonded form a ring selected from the group consisting of pyrrolidine, piperidine, N 25 methylpiperazine, piperazine and morpholine; or R11 and R12 independently of one another COR14, CSR14, CONHR14, CSNHR14 or SO 2 R14; 30 R14 CgH2g+l; 15 g 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; or R1, R2, R3 and R4 5 independently of one another OSO 3 H, SO 3 H, SO 2 R15; R15 CkH2k+1 or NR17R18; k 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; R17 and R18 10 independently of one another H or CmH2m+l; m 1, 2, 3, 4 or 5, it being possible for one or more H atoms in the group CmH2m+1 to be replaced by F atoms; or 15 R17 and R18 together with the N atom to which they are bonded a 5- or 6-membered ring; but where R2 must always not be equal to H; R5 methyl or trifluoromethyl; 20 R6 H; R7, R8 and R9 independently of one another OSO 3 H, SO 3 H or SO 2 R23; R23 CnnH2nn+1 or NR25R26; nn 1,2,3, 4 or5, 25 it being possible for one or more H atoms in CnnH2nn+1 to be replaced by F atoms; R25 and R26 independently of one another H, CN or CzH2z+1, in which the first CH 2 group bonded to the nitrogen is replaced by CO or 30 CS and the second CH 2 is replaced by NR27; z 1,2,3,4, 5 or6; 16 it being possible for one or more H atoms in CzH2z+1 to be replaced by F atoms; R27 H or CaaH2aa+1; aa 1,2, 3 or 4; 5 it being possible for one or more H atoms in CaaH2aa+1 to be replaced by F atoms; or R25 and R26 together with the N atom to which they are bonded a 5- or 10 6-membered ring, or R27 and a CH 2 group of R25 or R26 together with the N atom to which they are bonded a 5- or 6-membered ring; or 15 R7, R8 and R9 independently of one another NR32COR30, NR32CSR30 or NR32SO 2 R30; R30 H, OH, CccH2cc+1, CyyH2yy- 1 , pyrrolidinyl or piperidinyl, in which rings a CH 2 group may be replaced by O or NR33; R32 and R33 H, methyl or CF 3 ; 20 cc 1,2, 3, 4, 5, 6, 7 or 8; yy 3, 4, 5 or 6; it being possible for one or more H atoms in the groups CccH2cc+1 and CyyH2yy- 1 to be replaced by F atoms and for one or more CH 2 groups to be replaced by NR31 and for a CH 2 group to be replaced by O; 25 R31 H, methyl, ethyl, CF 3 , CH 2
CF
3 , acetyl, propionyl, methanesulfonyl or ethanesulfonyl; or R31 together with a CH 2 group of R30 and the N atom to which they are jointly bonded form a 5- or 6-membered ring; 30 or 17 R30 pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl or oxazolyl, which are unsubstituted or substituted by a maximum of 3 substituents selected from the group consisting of F, CI, methyl, ethyl, trifluoromethyl, NH 2 , NHacetyl; 5 or R7, R8 and R9 independently of one another H, F, CI, OH, NH 2 , CeeH2ee+1, CwwH2ww-1, OCffH2ff+1, NR40R41, CONR40R41, COOR42 or OCOR42, ee and ff 10 independently of one another 1, 2, 3 or 4; ww 3,4, 5or6, it being possible for one or more H atoms in the groups CeeH2ee+l, CwwH 2 ww- 1 and OCffH2ff+1 to be replaced by F atoms; R40 and R41 15 H, CttH2tt+1 or C(NH)NH 2 tt 1, 2, 3 or 4; it being possible for one or more H atoms in the group CttH2tt+1 to be replaced by F atoms; or 20 R40 and R41 independently of one another hydroxyethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl; or 25 R40 and R41 together with the N atom to which they are bonded a pyrrolidine, piperidine, N-methylpiperazine, piperazine or morpholine ring; R42 H or ChhH2hh+1; hh 1, 2, 3 or 4; 30 it being possible for one or more H atoms in the group ChhH2hh+1 to be replaced by F atoms; 18 but where two substituents from the group of R7, R8 and R9 may not simultaneously be OH or OCH 3 and where at least one of the radicals R7, R8 or R9 must be selected from the group consisting of CONR40R41, -OvSOwR23, NR32COR30, NR32CSR30 and 5 NR32SObbR30; and the pharmaceutically acceptable salts and trifluoroacetates thereof. Very particular preference is given to compounds of the formula I in which the 10 meanings are: R1, R2, R3 and R4 independently of one another H, F, Cl, Br, OH, NH 2 , CaH2a+1, cycloalkyl with 3, 4, 5 or 6 C atoms, OCbH2b+1; a and b 15 in the groups CaH2a+1 and OCbH2b+1 independently of one another 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; or R1, R2, R3 and R4 20 independently of one another NR11R12; R11 and R12 independently of one another H, CeH2e+l, CrrH2rr-1; e 1,2, 3or4, rr 3,4, 5 or6, 25 it being possible for one or more H atoms in the groups CeH2e+1 and CrrH2rr-1 to be replaced by F atoms; or R11 and R12 19 together with the N atom to which they are bonded form a ring selected from the group consisting of pyrrolidine, piperidine, N methylpiperazine, piperazine and morpholine; or 5 R11 and R12 independently of one another COR14, CSR14, CONHR14, CSNHR14 or SO 2 R14; R14 CgH2g+1; g 1, 2, 3 or 4, it being possible for one or more H atoms 10 to be replaced by F atoms; or R1, R2, R3 and R4 independently of one another OSO 3 H, SO 3 H, SO 2 R15; R15 CkH2k+1 or NR17R18; 15 k 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; R17 and R18 independently of one another H or CmH2m+1; m 1, 2, 3, 4 or 5, it being possible for one or more H 20 atoms in the group CmH2m+1 to be replaced by F atoms; or R17 and R18 together with the N atom to which they are bonded a 5- or 25 6-membered ring; but where R2 must always not be equal to H; R5 methyl or trifluoromethyl; R6 H; R7, R8 and R9 30 independently of one another OSO 3 H, SO 3 H or SO 2 R23; R23 CnnH2nn+1 or NR25R26; 20 nn 1,2,3, 4 or5, it being possible for one or more H atoms in CnnH2nn+1 to be replaced by F atoms; R25 and R26 5 independently of one another H, CN or CzH2z+1, in which the first CH 2 group bonded to the nitrogen is replaced by CO or CS and the second CH 2 is replaced by NR27; z 1,2,3,4, 5 or6; it being possible for one or more H atoms in CzH2z+1 10 to be replaced by F atoms; R27 H or CaaH2aa+1; aa 1, 2, 3 or 4; it being possible for one or more H atoms in CaaH2aa+1 to be replaced by F atoms; 15 or R25 and R26 together with the N atom to which they are bonded a 5- or 6-membered ring, or 20 R27 and a CH 2 group of R25 or R26 together with the N atom to which they are bonded a 5- or 6-membered ring; or R7, R8 and R9 independently of one another NR32COR30, NR32CSR30 or NR32SO 2 R30; 25 R30 H, OH, CccH2cc+1, CyyH2yy-1, pyrrolidinyl or piperidinyl, in which rings a CH 2 group may be replaced by O or NR33; R32 and R33 H, methyl or CF 3 ; cc 1,2,3,4,5,6, 7 or8; yy 3,4,5,6; 21 it being possible for one or more H atoms in the groups CccH2cc+1 and CyyH2yy-1 to be replaced by F atoms and for one or more CH 2 groups to be replaced by NR31 and for a CH 2 group to be replaced by O; R31 H, methyl, ethyl, CF 3 , CH 2
CF
3 , acetyl, propionyl, methanesulfonyl or 5 ethanesulfonyl; or R31 together with a CH 2 group of R30 and the N atom to which they are jointly bonded form a 5- or 6-membered ring; or 10 R30 pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl or oxazolyl, which are unsubstituted or substituted by a maximum of 3 substituents selected from the group consisting of F, Cl, methyl, ethyl, trifluoromethyl, NH 2 , NHacetyl; or 15 R7, R8 and R9 independently of one another H, F, Cl, OH, NH 2 , CeeH2ee+1, CwwH2ww-l, OCffH2ff+1, NR40R41, CONR40R41, COOR42 or OCOR42, ee and ff independently of one another 1, 2, 3 or 4; 20 ww 3, 4, 5 or 6, it being possible for one or more H atoms in the groups CeeH2ee+l, CwwH2ww-1 and OCffH2ff+1 to be replaced by F atoms; R40 and R41 H, CttH2tt+1 or C(NH)NH 2 ; 25 tt 1,2, 3 or4; it being possible for one or more H atoms in the group CttH2tt+1 to be replaced by F atoms; or R40 and R41 22 independently of one another hydroxyethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl; or 5 R40 and R41 together with the N atom to which they are bonded a pyrrolidine, piperidine, N-methylpiperazine, piperazine or morpholine ring; R42 H or ChhH2hh+1; hh 1, 2, 3 or 4; 10 it being possible for one or more H atoms in the group ChhH2hh+1 to be replaced by F atoms; but where two substituents from the group of R7, R8 and R9 may not simultaneously be OH or OCH 3 and where at least one of the radicals R7, R8 or R9 must be selected from the group 15 consisting of-OvSOwR23, NR32COR30, NR32CSR30 and NR32SObbR30; and the pharmaceutically acceptable salts and trifluoroacetates thereof. Very particular specific preference is given to compounds 1) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 20 acetamide; 2) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide; 3) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide; 4) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N,N-dimethyl benzenesulfonamide; 25 5) 4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline; 6) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid; 7) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-ethyl-benzamide; 8) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-propyl-benzamide; 9) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-(2-dimethylamino 30 ethyl)-benzamide; 10) 6,8-dichloro-2-methyl-4-(4-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline; 11) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-phenyl]-diethyl-amine 23 12) 6,8-dichloro-2-methyl-4-(4-piperidin 1 -yI-phenyl)-1,2,3,4-tetrahydroisoquinoline; 13) 6,8-dichloro-2-methyl-4-(4-pyrrolidin-1-yl-phenyl)-1 ,2,3,4-tetrahydroisoquinoline; 14) 6,8-dichloro-2-methyl-4-[4-(4-methyl-piperazin-1 -yl)-phenyl]-1,2,3,4-tetrahydro isoquinoline; 5 15) 6,8-dichloro-2-cyclopropyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline; 16) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine; 17) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 propylurea; 18) 1-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoqu inolin-4-yl)-phenyl]-3-methyl 10 thiourea; 19) 1-[4-(6,8-dichloro-2-methyl-1 ,2 ,3 ,4-tetrahydro-isoquinolin-4-yi)-phenyl]-3-ethyl urea; 20) N-[4-(6-methanesulfonyl-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide; 15 21) N-[4-(2,6,8-trimethyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide; 22) N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide; 23) N-[4-(8-chloro-2-methyl-6-pyrrolidin-1 -yl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-acetamide; 20 24) N-[4-(8-chloro-2-methyl-6-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-acetamide; 25) N-{4-[8-chloro-2-methyl-6-(4-methyl-piperazin-1-yl)-1,2,3,4-tetrahydro-isoquinolin 4-yl]-phenyl}-acetamide; 26) N-{4-[8-chloro-6-(cyclopropylmethyl-amino)-2-methyl-1,2,3,4-tetrahydro 25 isoquinolin-4-yl]-phenyl}-acetamide; 27) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoic acid; 28) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-N-methyl benzamide; 30 29) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-ethyl-2-hydroxy benzamide; 24 30) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-(2-dimethylamino ethyl)-2-hydroxy-benzamide; 31) N-[5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy benzoyl]-guanidine; 5 32) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide; 33) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine; 34) 2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine; 35) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 10 propionamide; 36) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] butyramide; 37) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yI) phenyl]pentanamide; 15 38) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] isobutyramide; 39) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2 dimethyl-propionamide; 40) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 20 cyclopropanecarboxamide; 41) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclobutanecarboxamide; 42) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclopentanecarboxamide; 25 43) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2 trifluoro-acetamide; 44) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 acetylpiperidine-4-carboxamide; 45) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 30 nicotinamide; 46) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane sulfonamide; 25 47) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl] ethanesulfonamide; 48) N', N'-dimethylamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-sulfamide; 5 49) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] propionamide; 50) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] butyramide; 51) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 10 pentanamide; 52) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] isobutyramide; 53) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2 dimethyl-propionamide; 15 54) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclopropanecarboxamide; 55) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclobutanecarboxamide; 56) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 20 cyclopentanecarboxamide; 57) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2 trifluoro-acetamide; 58) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 acetylpiperidine-4-carboxamide; 25 59) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] nicotinamide; 60) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane sulfonamide; 61) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl] 30 ethanesulfonamide; 62) N', N'-dimethylamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-sulfamide; 26 63) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] propionamide; 64) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] butyramide; 5 65) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] pentanamide; 66) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] isobutyramide; 67) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2 10 dimethyl-propionamide; 68) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclopropanecarboxamide; 69) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl] cyclobutanecarboxamide; 15 70) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclopentanecarboxamide; 71) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2 trifluoro-acetamide; 72) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 20 acetylpiperidine-4-carboxamide; 73) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane sulfonamide; 74) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl] ethanesulfonamide; 25 75) N',N'-dimethylamino-N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-sulfamide; 76) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl urea; 77) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl 30 thiourea; 78) 1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl urea; 27 79) 1 -[2-(6 ,8-dichloro-2-methyl-1 ,2 ,3,4-tetrahydro-isoquinolin-4-yl)-pheny]-3-methyl thiourea; 80) N-{5-[4-(6,8-d ichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yI) phenylsulfamoyl]-4-methyl-thiazol-2-yI}-acetamide; 5 81) N-{5-[3-(6 ,8-d ichloro-2-methyl-1 ,2 ,3,4-tetrahydro-isoquinolin-4-y) phenylsulfamoyl]-4-methyl-thiazol-2-yI}-acetamide; 82) N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin4-y)-phenyl]-1 ,2 dimethyl-1 H-imidazole-4-sulfonamide; 83) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y)-phenyl]-1 ,2 10 dimethyl-1 H-imidazole-4-sulfonamide; 84) N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-5-chloro I ,3-dimethyl-1 H-pyrazole-4-sulfonamide; 85) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-5-chloro I ,3-dimethyl-1 H-pyrazole-4-sulfonamide; 15 86) N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-pheny]-5-bromo thiophene-2-sulfonamide; 87) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-5-bromo thiophene-2-sulfonamide; 88) N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoqu inolin-4-yI)-phenyl]-C,C,C 20 trifluoro-methanesulfonamide; 89) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-C,C,C trifluoro-methanesulfonamide; 90) 4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-2,2,2 trifluoroethanesulfonamide; 25 91) 3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-2,2,2 trifluoro-ethanesulfonamide; 92) N-ethyl-N'-4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y) benzenesulfonylurea; 93) 2-chloro-5-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoqu inolinA--yI) 30 benzenesulfonamide; 94) 2-methyl-4-phenyl-6,8-bis-trifluoromethyl-1 ,2 ,3,4-tetrahydro-isoquinoline; 28 95) 2-amino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide; 96) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 2-methylamino-acetamide; 5 97) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 2-dimethylamino-acetamide; 98) 2-amino-N-[4-(6 ,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] propionamide; 99) 2-amino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 10 butyramide; 100) 2,6-diamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-hexanamide; 101) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] pyrrolidine-2-carboxamide; 15 102) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] isonicotinamide; 103) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H pyrrole-3-carboxamide; 104) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1H 20 pyrrole-2-carboxamide; 105) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-methyl piperidine-4-carboxamide; 106) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 1,4-dimethyl-1 H-pyrrole-2-carboxamide; 25 107) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-nitro I H-pyrrole-2-carboxamide; 108) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,5 dimethyl-1 H-pyrrole-3-carboxamide; 109) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1H 30 imidazole-4-carboxamide; 110) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-l methanesulfonyl-piperidine-4-carboxamide; 29 111) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,5 dimethyl-1 H-pyrazole-4-carboxamide; 112) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H pyrazole-4-carboxamide; 5 113) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 3-trifluoromethyl-1 H-pyrazole-4-carboxamide; 114) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 2-methylamino-acetamide; 115) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2 10 dimethylamino-acetamide; 116) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] propionamide; 117) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] butyramide; 15 118) 2,6-diamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-hexanamide; 119) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] pyrrolidine-2-carboxamide; 120) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 20 isonicotinamide; 121) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H pyrrole-3-carboxamide; 122) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H pyrrole-2-carboxamide; 25 123) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1l-methyl piperidine-4-carboxamide; 124) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 1,4-dimethyl-1 H-pyrrole-2-carboxamide; 125) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-nitro 30 1 H-pyrrole-2-carboxamide; 126) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 2,5-dimethyl-1 H-pyrrole-3-carboxamide; 30 127) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoqu inolin-4-yI)-phenyl]-1 H imidazole-4-carboxamide: 128) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yI)-phenylj 1 -methanesulfonyl-piperidine-4-carboxamide; 5 129) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoqu inolin-4-yl)-phenylj 3,5-dimethyl-1 H-pyrazole-4-carboxamide; 130) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoqu inolin-4-yl)-phenyl-1 H pyrazole-4-carboxamide; 131) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y)-phenyl] 10 3-trifluoromethyl-1 H-pyrazole-4-carboxamide; 132) 1 -[2-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-3-ethyl thiourea; 133) 1 -[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-3-ethyl thiourea; 15 134) 1 -[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl thiourea; 135) 3-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoqu inolin-4-yI)-phenyl] I ,1 -dimethyl-urea; 136) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-4-methyl 20 piperazine-1 -carboxamide; 137) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-piperidine 1 -carboxamide; 138) N-[3-(6,8-d ichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yI)-phenyl] morpholine-4-carboxamide; 25 139) N-[3-(6,8-d ichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl] pyrrolidine-1 -carboxamide; 140) 3-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y)-phenyl] 1,1 -diethyl-urea; 141) 1 -[3-(6,8-dichloro-2-methyl-1 ,2 ,3,4-tetrahydro-isoqu inolin-4-yI)-phenyl]-3-methyl 30 urea; 142) 1 -[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y)-pheny] 3-(2-d imethylamino-ethyl )-u rea; 31 143) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 3-(tetrahydro-furan-3-yl)-urea; 144) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 3-(tetrahydro-pyran-4-yl)-urea; 5 145) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1l-methyl 1-(1 -methyl-piperidin-4-yl)-urea; 146) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 1-(3-dimethylamino-propyl)-1 -methyl-urea; 147) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 10 1-(2-dimethylamino-ethyl)-1l-methyl-urea; 148) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 (3-dimethylamino-propyl)-urea; 149) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 3-(2-methoxy-ethyl)-urea; 15 150) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin 3-yl-urea; 151) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin 4-yl-urea; 152) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl 20 piperazine-1 -carboxamide; 153) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl urea; 154) 3-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 1,1-dimethyl-urea; 25 155) 3-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 1,1-diethyl-urea; 156) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-piperidine 1-carboxamide; 157) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 30 morpholine-4-carboxamide; 158) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] pyrrolidine-1 -carboxamide; 32 159) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 3-(2-dimethylamino-ethyl)-urea; 160) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl piperazine-1 -carboxamide; 5 161) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] pyrrolidine-1 -carboxamide; 162) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl urea; 163) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 10 1,1-dimethyl-urea; 164) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 1,1-diethyl-urea; 165) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 3-(2-dimethylamino-ethyl)-urea; 15 166) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-piperidine 1-carboxamide; 167) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] morpholine-4-carboxamide; 168) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 20 formamide; 169) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl amine; 170) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 1,3-dimethyl-urea; 25 171) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl 4-methyl-piperazine-1 -carboxamide; 172) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 1,3,3-trimethyl-urea; 173) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl 30 piperidine-1 -carboxamide; 174) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl morpholine-4-carboxamide; 33 175) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl pyrrolidine-1 -carboxamide; 176) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 3-(2-dimethylamino-ethyl)-1l-methyl-urea; 5 177) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 3,3-diethyl-1 -methyl-urea; 178) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] formamide; 179) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl 10 amine; 180) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl pyrrolidine-1 -carboxamide; 181) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl piperidine-1 -carboxamide; 15 182) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 1,3,3-trimethyl-urea; 183) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 1,3-dimethyl-urea; 184) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl 20 morpholine-4-carboxamide; 185) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-4 methyl-piperazine-1 -carboxamide; 186) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 3-(2-dimethylamino-ethyl)-l -methyl-urea; 25 187) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 3,3-diethyl-1 -methyl-urea; 188) 2-dimethylamino-ethyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin 4-yl)-phenyl]-carbamate; 189) 2-dimethylamino-ethyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin 30 4-yl)-phenyl]-carbamate; 190) 2-dimethylamino-ethyl [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin 4-yl)-phenyl]-carbamate; 34 191) methyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] carbamate; 192) ethyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] carbamate; 5 193) isopropyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] carbamate; 194) 2,2-dimethyl-propyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-carbamate; 195) methyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 10 carbamate; 196) isopropyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] carbamate; 197) 2,2-dimethyl-propyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-carbamate; 15 198) ethyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] carbamate; 199) (R)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] methanesulfonamide; 200) (S)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 20 methanesulfonamide; 201) (R)-1l-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 3-ethyl-urea; 202) (S)-1l-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 3-ethyl-urea; 25 203) N-[3-(6,8-difluoro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide; 204) 4-(3-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoline; 205) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 3-(2-hydroxy-ethyl)-urea; 206) ethyl 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoate; 30 207) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid. and the pharmaceutically acceptable salts thereof.
35 Exceptionally particular preference is given to compounds from the group of 1) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide; 5 2) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide; 3) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide; 4) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl thiourea; 5) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl 10 urea; 6) N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide; 7) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide; 15 8) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] propionamide; 9) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -acetyl piperidine-4-carboxamide; 10) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane 20 sulfonamide; 11) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] ethanesulfonamide; 12) N',N'-dimethylamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin 4-yl)-phenyl]-sulfamide; 25 13) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] propionamide; 14) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] butyramide; 15) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 30 isobutyramide; 16) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclopropanecarboxamide; 36 17) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclobutanecarboxamide; 18) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2 trifluoro-acetamide; 5 19) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -acetyl piperidine-4-carboxamide; 20) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] nicotinamide; 21) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane 10 sulfonamide; 22) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] ethanesulfonamide; 23) N', N'-dimethylamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-sulfamide; 15 24) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclopropanecarboxamide; 25) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-acetyl piperidine-4-carboxamide; 26) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl 20 urea; 27) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl thiourea; 28) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl urea; 25 29) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl thiourea; 30) N-{5-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenylsulfamoyl]-4-methyl-thiazol-2-yl}-acetamide; 31) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 30 1,2-dimethyl-1 H-imidazole-4-sulfonamide; 32) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-C,C,C trifluoro-methanesulfonamide; 37 33) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-C,C,C trifluoro-methanesulfonamide; 34) N-ethyl-N'-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) benzenesulfonylurea; 5 35) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2 dimethylamino-acetamide; 36) 2,6-diamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-hexanamide; 37) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1lH 10 pyrrole-3-carboxamide; 38) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1l-methyl piperidine-4-carboxamide; 39) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 methanesulfonyl-piperidine-4-carboxamide; 15 40) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1lH pyrazole-carboxamide; 41) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2 methylamino-acetamide; 42) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2 20 dimethylamino-acetamide; 43) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl] propionamide; 44) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] butyramide; 25 45) 2,6-diamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-hexanamide; 46) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-methyl piperidine-4-carboxamide; 47) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1H 30 imidazole-4-carboxamide; 48) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 methanesulfonyl-piperidine-4-carboxamide; 38 49) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,5 dimethyl-1 H-pyrazole-4-carboxamide; 50) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1lH pyrazole-carboxamide; 5 51) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1 dimethyl-urea; 52) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl piperazine-1 -carboxamide; 53) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahyd ro-isoquinolin-4-yl)-phenyl]-piperidine 10 1-carboxamide; 54) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] morpholine-4-carboxamide; 55) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] pyrrolidine-1 -carboxamide; 15 56) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-l,1 diethyl-urea; 57) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl urea; 58) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 20 dimethylamino-ethyl)-urea; 59) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 (tetrahydro-furan-3-yl)-urea; 60) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 (tetrahyd ro-pyran-4-yl)-urea; 25 61) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-methyl 1-(1-methyl-piperidin-4-yl)-urea; 62) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1l-(3 dimethylamino-propyl)-1l-methyl-urea; 63) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1l-(2 30 dimethylamino-ethyl)-1l-methyl-urea; 64) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(3 diethylamino-propyl)-urea; 39 65) 1 -[3-(6,8-d ich lo ro-2-m ethyl- 1,2,3,4-tetra hyd ro-isoq u i nol in-4-yi)-ph enyl]-3-(2 methoxy-ethyl )-u rea; 66) 1 -[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yI)-phenyl]-3-pyridin 3-yi )-u rea; 5 67) 1 -[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoqu inolin-4-yI)-phenyl]-3-pyridin 4-yl-urea; 68) N-[2-(6,8-d ichloro-2-methyl-1 ,2 ,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-4-methyl piperazine-1 -carboxamide; 69) 1 -[2-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-3-methyl 10 urea; 70) 1 -[2-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-3-(2 dimethylamino-ethyl)-u rea; 71) N-[4-(6,8-dichloro-2-methyl-1 ,2 ,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl piperazine-1 -carboxamide; 15 72) 1 -14-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyj-3-methyl urea; 73) 3-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yl)-phenyl]-1 , 1 dimethyl-urea; 74) 3-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y)-phenyl]-1 , 1 20 diethyl-urea; 75) 1 -[4-(6,8-dichloro-2-methyl-1 ,2,3 ,4-tetrahyd ro-isoquinolin-4-yI)-phenyl]-3-(2 dimethylamino-ethyl)-urea; 76) N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y)-phenyl] morpholine-4-carboxamide; 25 77) N-4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-formamide; 78) N-[3-(6,8-dichloro-2-methyl-1 ,2 ,3,4-tetrahydro-isoquinolin-4-y)-phenyl] formamide; 79) 1 -[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoqu inolin-4-yI)-phenyl]-1 ,3,3 trimethyl-urea; 30 80) 1 -[3-(6,8-dichloro-2-methyl-1 ,2 ,3,4-tetrahydro-isoquinolin-4-y)-pheny]-1 ,3 dimethyl-urea; 40 81) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl morpholine-4-carboxamide; 82) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-4 methyl-piperazine-1 -carboxamide; 5 83) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahyd ro-isoquinolin-4-yl)-phenyl]-3-(2 dimethylamino-ethyl)-1l-methyl-urea; 84) 2-dimethylamino-ethyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-carbamate; 85) 2-dimethylamino-ethyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 10 yl)-phenyl]-carbamate; 86) 2-dimethylamino-ethyl [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-carbamate; 87) methyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] carbamate; 15 88) (R or S)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] methanesulfonamide; 89) (R or S)-1l-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 ethyl-urea; 90) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 20 hydroxy-ethyl)-urea; and the pharmaceutically acceptable salts thereof. The invention further encompasses the use of the compounds of the formula I for producing a medicament for the treatment of disorders which can be influenced by 25 inhibition of the sodium-proton exchanger of subtype III (NHE3), in which the meanings are: R1, R2, R3 and R4 independently of one another H, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , CaH2a+1, CqqH2qq- 1 , OCbH2b+1, COOR10, OCOR10, COR10 or Ox-(CH2)y-phenyl; 30 a and b 41 in the groups CaH2a+1 and OCbH2b+1 independently of one another 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms; qq 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be 5 replaced by F atoms; R10 H or CcH2c+1; c 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms, x zero or 1; 10 y zero, 1, 2, 3 or 4; where the phenyl ring in the group Ox-(CH2)y-phenyl is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, CI, Br, CN, NO 2 , OH, NH 2 or CdH2d+1; 15 d 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms, or R1, R2, R3 and R4 independently of one another heteroaryl, it being possible for zero, 1, 2, 3 or 4 20 N atoms, zero or 1 oxygen atom or zero or 1 S atom to be present as ring atoms; or R1, R2, R3 and R4 independently of one another CONRI 1 R12 or NR11 R12; 25 R11 and R12 independently of one another H, CeH2e+l, CrrH2rr-1; e 1, 2, 3,4, 5, 6, 7 or 8, rr 3, 4, 5, 6, 7, or 8, it being possible for one or more H atoms in the groups CeH2e+1 and 30 CrrH2rr-1 to be replaced by F atoms and for one or more CH 2 groups to be replaced by O or NR13; 42 R13 H or CfH 2 f+ 1 ; f 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; or 5 R13 and a CH 2 group of R 1 or R12 together with the N atom to which they are bonded a 5- or 6-membered ring; or R11 and R12 together with the N atom to which they are bonded a 5-, 6- or 10 7-membered ring; or R11 and R12 independently of one another COR14, CSR14 or SO 2 R14; R14 CgH2g+l; 15 g 1,2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms, and it being possible for one or more CH 2 groups to be replaced by O or NR13, or 20 R1, R2, R3 and R4 independently of one another -Oh-SOJ-R15, with h zero or 1; j zero, 1 or 2; R15 CkH2k+l, OH, OCIH 2 1
+
1 or NR17R18; 25 k 1,2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms; I 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms; R17 and R18 30 independently of one another H or CmH2m+l; 43 m 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms in the group CmH2m+1 to be replaced by F atoms and for one or more CH 2 groups to be replaced by O, CO, CS or NR19; 5 R19 H or CnH2n+l; n 1,2, 3 or 4; it being possible for one or more H atoms in CnH2n+1 to be replaced by F atoms; or 10 R17 and R18 together with the N atom to which they are bonded a 5-, 6- or 7-membered ring; or R19 and a CH 2 group of R17 or R18 together with the N atom 15 to which they are bonded a 5- or 6-membered ring; R5 H, CpH2p+1, CssH 2 ss-.
1 , COR20 or SO 2 R20; p 1, 2, 3, 4, 5, 6, 7 or 8, ss 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms in CpH 2 p+ 1 and CssH 2 ss- 1 to be replaced by F atoms 20 R20 CqH2q+ 1 ; q 1,2, 3,4, 5, 6, 7 or 8, it being possible for one or more H atoms in CqH2q+ 1 to be replaced by F atoms and for one or more CH 2 groups to be replaced by O or NR21; 25 R21 H or CrH2r+ 1 ; r 1, 2, 3 or 4; it being possible for one or more H atoms in CrH2r+1 to be replaced by F atoms; R6 H, F, Cl, Br, I, CsH 2 s+ 1 , CddH2dd-1, OH, OCtH2t+ 1 or OCOR22; 30 s and t 44 independently of one another 1, 2, 3, 4, 5, 6, 7 or 8; dd 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms in CsH 2 s+ 1 , CddH2dd-1 and OCtH2t+1 to be replaced by F atoms; R22 CuH2u+l; 5 u 1,2, 3 or 4; it being possible for one or more H atoms in CuH2u+1 to be replaced by F atoms; R7, R8 and R9 independently of one another -Ov-SOw-R23; 10 v zero or 1; w zero, 1 or 2; R23 CnnH2nn+1, CmmH2mm-1, OH, OCppH 2 pp+ 1 or NR25R26; nn and pp independently of one another 1, 2, 3, 4, 5, 6, 7 or 8, 15 mm 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms in CnnH2nn+l, CmmH2mm-1 and OCppH2pp+1 to be replaced by F atoms; R25 and R26 independently of one another H, CN or CzH2z+1, CzzH2zz-1; 20 z 1,2, 3, 4, 5, 6, 7 or 8; zz 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms and, in CzH2z+1, it being possible for one or more H atoms to be replaced by F atoms and it being possible for 25 one or more CH 2 groups to be replaced by O, CO, CS or NR27; R27 H or CaaH2aa+1; aa 1,2, 3 or 4; it being possible for one or more H atoms in 30 CaaH2aa+1 to be replaced by F atoms; or 45 R25 and R26 together with the N atom to which they are bonded a 5-, 6- or 7-membered ring, or 5 R27 and a CH 2 group of R25 or R26 together with the N atom to which they are bonded a 5- or 6-membered ring; or R7, R8 and R9 independently of one another NR32COR30, NR32CSR30 or NR32SObbR30; 10 R30 H, CccH2cc+1, CyyH2yy- 1 , pyrrolidinyl or piperidinyl, in which rings a
CH
2 group may be replaced by O or NR33; R32 and R33 independently of one another H or ChH2h+l; bb 2 or 3; cc 1,2,3,4,5,6, 7 or8; 15 yy 3, 4, 5, 6, 7 or 8; h 1,2,3,4,5,6, 7 or8, it being possible for one or more H atoms in ChH2h+1 to be replaced by F atoms, and it being possible for one or more H atoms in the groups CccH2cc+1 and CyyH 2 yy- 1 to be replaced by F atoms and for one or more 20 (CH 2 ) groups to be replaced by NR31 and for a (CH 2 ) group to be replaced by O; R31 H, CkkH2kk+1, COR65 or SO 2 R65; kk 1,2, 3, or 4; it being possible for one or more H atoms to be replaced by F 25 atoms, R65 H, CxxH2xx+1; xx 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; or 30 R31 forms together with a CH 2 group of R30 a 5-, 6- or 7-membered ring; or 46 R30 a 5- or 6-membered heteroaryl with 1, 2, 3 or 4 N atoms, zero or 1 S atoms and zero or 1 0 atoms, which is unsubstituted or substituted by up to three substituents selected from the group consisting of F, CI, Br, I, 5 CooH 2 oo+ 1 , NR70R71; R70 and R71 independently of one another H, CuuH2uu+1 and COR72; R72 H, CvvH2vv+ 1 ; 10 oo, uu and wvv independently of one another 1, 2, 3, 4, 5, 6, 7 or 8; it being possible for one or more H atoms in the groups CooH 2 oo+ 1 , CuuH2uu+1 or CvvH2vv+1 to be 15 replaced by F atoms; or R7, R8 and R9 independently of one another H, F, CI, Br, I, NO 2 , CN, OH, NH 2 , CeeH2ee+1, CwwH 2 ww- 1 , OCffH2ff+1, NR40R41, CONR40R41, COOR42, COR42 or 20 OCOR42, ee and ff independently of one another 1, 2, 3, 4, 5, 6, 7 or 8; ww 3, 4, 5, 6, 7 or 8; it being possible for one or more H atoms in the groups CeeH2ee+1, 25 CwwH2ww-1 and OCffH2ff+1 to be replaced by F atoms; R40 and R41 H, CttH2tt+1 or C(NH)NH 2 ; tt 1,2,3,4,5,6, 7 or8; it being possible for one or more H atoms in the group CttH2tt+lto be 30 replaced by F atoms and for one or more CH 2 groups to be replaced by O or NR44; 47 R44 H or CggH2gg+1; gg 1,2, 3, 4, 5, 6, 7 or 8; it being possible for one or more H atoms in the group CggH2gg+ 1 to be replaced by F atoms, 5 or R40 and R41 with the N atom to which they are bonded a 5- or 6-membered ring; R42 H or ChhH2hh+1; hh 1,2,3,4,5,6, 7 or8; 10 it being possible for one or more H atoms in the group ChhH2hh+1 to be replaced by F atoms; and the pharmaceutically acceptable salts thereof. 15 Preference is given to the use of compounds of the formula 1, in which the meanings are: R1, R2, R3 and R4 independently of one another, H, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , CaH2a+1, cycloalkyl with 3, 4, 5 or 6 C atoms, OCbH2b+1, COOR10; 20 a and b independently of one another 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; R10 H or CcH2c+1; c 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced 25 by F atoms; or R1, R2, R3 and R4 independently of one another 5- or 6-membered heteroaryl selected from the group consisting of pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, 30 thiazolyl and oxazolyl; or 48 R1, R2, R3 and R4 independently of one another CONR11 R12 or NR11R12; R11 and R12 independently of one another H, CeH2e+l, CrrH2rr-1; 5 e 1,2, 3 or4, rr 3,4,5or6, it being possible for one or more H atoms in the groups CeH2e+1 and CrrH2rr-1 to be replaced by F atoms or 10 Rll and R12 independently of one another hydroxyethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl; or 15 Rll and R12 together with the N atom to which they are bonded a pyrrolidine, piperidine, N-methylpiperazine, piperazine or morpholine ring; or R11 and R12 20 independently of one another COR14, CSR14, CONHR14, CSNHR14 or SO 2 R14; R14 CgH2g+l; g 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; 25 or R1, R2, R3 and R4 independently of one another OSO 3 H, SO 3 H, SO 2
R
15 , or R15 CkH2k+1, OClH 2 1
+
1 or NR17R18; k 1, 2, 3 or 4, it being possible for one or more H atoms to be 30 replaced by F atoms; 49 I 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; R17 and R18 independently of one another H, CmH2m+1, in which the first 5 CH 2 group bonded to the nitrogen is replaced by CO and the second CH 2 group is replaced by NR19; m 1, 2, 3, 4 or 5, it being possible for one or more H atoms in the group CmH2m+1 to be replaced by F atoms; 10 R19 H or CnH2n+1; n 1,2, 3 or4; it being possible for one or more H atoms in CnH2n+1 to be replaced by F atoms; or 15 R17 and R18 together with the N atom to which they are bonded a 5- or 6-membered ring; R5 H, CpH2p+ 1 , CssH 2 ss- 1 ; p 1,2, 3 or 4; 20 ss 3, 4, 5 or 6, it being possible for one or more H atoms in CpH2p+ 1 and CssH 2 ss- 1 to be replaced by F atoms; R6 H, CsH 2 s+ 1 , OCtH2t+1 or OCOR22; s and t independently of one another 1, 2, 3 or 4; 25 it being possible for one or more H atoms in CsH 2 s+ 1 and OCtH2t+1 to be replaced by F atoms; R22 CuH2u+1; u 1, 2, 3 or 4; it being possible for one or more H atoms in CuH2u+1 to be replaced 30 by F atoms; 50 R7, R8 and R9 independently of one another OSO 3 H, SO 3 H or SO 2 R23; R23 CnnH2nn+1, CmmH2mm-1, OCpH 2 pp+ 1 or NR25R26; nn and pp 5 independently of one another 1,2, 3, 4 or 5, mm 3, 4, 5 or 6, it being possible for one or more H atoms in CnnH2nn+1, CmmH2mm-1 and OCppH 2 pp+ 1 to be replaced by F atoms; R25 and R26 10 independently of one another H, CN, CzH2z+1, in which the first CH 2 group bonded to the nitrogen is replaced by CO or CS and the second CH 2 is replaced by NR27; z 1,2,3,4, 5 or6; it being possible for one or more H atoms in CzH2z+1 15 to be replaced by F atoms; R27 H or CaaH2aa+1; aa 1,2, 3 or 4; it being possible for one or more H atoms in CaaH2aa+1 to be replaced by F atoms; 20 or R25 and R26 together with the N atom to which they are bonded a 5- or 6-membered ring; or 25 R27 and a CH 2 group of R25 or R26 together with the N atom to which they are bonded a 5- or 6-membered ring; or R7, R8 and R9 independently of one another NR32COR30, NR32CSR30 or NR32SO 2 R30; 51 R30 H, OH, CccH2cc+1, CyyH 2 yy-1, pyrrolidinyl or piperidinyl, in which rings a CH 2 group may be replaced by O or NR33; R32 and R33 independently of one another H or ChH2h+l; cc 1,2,3,4,5,6, 7 or8; 5 yy 3,4, 5 or6; h 1, 2, 3or4; it being possible for one or more H atoms in ChH2h+1 to be replaced by F atoms, and it being possible for one or more H atoms in the groups CccH2cc+1 and CyyH 2 yy- 1 to be replaced by F atoms and for one or more 10 (CH 2 ) groups to be replaced by NR31 and for a (CH 2 ) group to be replaced by O; R31 H, CkkH2kk+1, COR65 or SO 2 R65; kk 1, 2, 3, or 4; it being possible for one or more H atoms to be replaced by F atoms, 15 R65 H, CxxH2xx+ 1; xx 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; or R31 together with a CH 2 group or R30 and the N atom to which they are 20 jointly bonded form a 5- or 6-membered ring; or R30 a 5- or 6-membered heteroaromatic system selected from the group consisting of pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thienyl, thiazolyl and oxazolyl, 25 which are unsubstituted or substituted by up to three substituents selected from the group consisting of F, Cl, Br, I, CooH 2 oo+ 1 , NR70R71, R70 and R71 independently of one another H, CuuH2uu+1 or 30 COR72; R72 H, CwH2vv+1; 52 oo, uu and w independently of one another 1, 2, 3 or 4; it being possible for one or more H atoms in the groups CooH 2 oo+ 1 , CuuH2uu+1 or CwH2vvw+1 to be replaced by F atoms; 5 or R7, R8 and R9 independently of one another H, F, Cl, Br, I, NO 2 , CN, OH, NH 2 , CeeH2ee+l, CwwH2ww-1, OCffH2ff+1, NR40R41, CONR40R41, COOR42, COR42 or OCOR42; 10 ee and ff independently of one another 1, 2, 3 or 4; ww 3,4, 5or6, it being possible for one or more H atoms in the groups CeeH2ee+1, CwwH2ww-1 and OCffH2ff+1 to be replaced by F atoms; 15 R40 and R41 H, CttH 2 tt+ 1 or C(NH)NH 2 ; tt 1, 2, 3, 4, 5, 6, 7 or 8; it being possible for one or more H atoms in the group CttH 2 tt+ 1 to be replaced by F atoms; 20 or R40 and R41 to be selected independently of one another hydroxyethyl,, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or 25 piperidinoethyl; or R40 and R41 together with the N atom to which they are bonded form a ring selected from the group consisting of pyrrolidine, piperidine, N-methyl 30 piperazine, piperazine and morpholine; R42 H or ChhH2hh+1; 53 hh 1,2, 3 or 4; it being possible for one or more H atoms in the group ChhH2hh+1 to be replaced by F atoms; 5 and the pharmaceutically acceptable salts thereof. Particular preference is given to the use of compounds of the formula I in which the meanings are: R1, R2, R3 and R3 10 independently of one another H, F, Cl, Br, OH, NH 2 , CaH2a+1, cycloalkyl with 3, 4, 5 or 6 C atoms, OCbH2b+1; a and b in the groups CaH2a+1 and OCbH2b+1 independently of one another 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced 15 by F atoms; or R1, R2, R3 and R4 independently of one another NR11 R12; R11 and R12 20 independently of one another H, CeH2e+l, CrrH2rr.-1; e 1, 2, 3or4, rr 3, 4, 5or6, it being possible for one or more H atoms in the groups CeH2e+1 and CrrH2rr-1 to be replaced by F 25 atoms; or R11 and R12 together with the N atom to which they are bonded form a ring selected from the group consisting of pyrrolidine, piperidine, N 30 methylpiperazine, piperazine and morpholine; or 54 R11 and R12 independently of one another COR14, CSR14, CONHR14, CSNHR14 or SO 2 R14; R14 CgH2g+1; 5 g 1,2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; or R1, R2, R3 and R4 independently of one another OSO 3 H, SO 3 H, SO 2 R15; 10 R15 CkH2k+1 or NR17R18; k 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; R17 and R18 independently of one another H or CmH2m+1; 15 m 1, 2, 3, 4 or 5, it being possible for one or more H atoms in the group CmH2m+ 1 to be replaced by F atoms; or R17 and R18 20 together with the N atom to which they are bonded a 5- or 6-membered ring; R5 H, CpH2p+1, CssH 2 ss.-1; p 1,2, 3 or 4; ss 3, 4, 5 or 6, it being possible for one or more H atoms in CpH2p+ 1 and 25 CssH 2 ss-1 to be replaced by F atoms; R6 H, CH 3 ; R7, R8 and R9 independently of one another OSO 3 H, SO 3 H or S0 2 R23; R23 CnnH2nn+ 1 or NR25R26; 30 nn 1,2,3, 4 or5, 55 it being possible for one or more H atoms in CnnH2nn+1 to be replaced by F atoms; R25 and R26 independently of one another H, CN or CzH2z+1, in which the 5 first CH 2 group bonded to the nitrogen is replaced by CO or CS and the second CH 2 is replaced by NR27; z 1,2,3,4, 5 or6; it being possible for one or more H atoms in CzH2z+1 to be replaced by F atoms; 10 R27 H or CaaH2aa+l; aa 1, 2, 3 or 4; it being possible for one or more H atoms in CaaH2aa+1 to be replaced by F atoms; or 15 R25 and R26 together with the N atom to which they are bonded a 5- or 6-membered ring, or R27 and a CH 2 group of R25 or R26 together with the N atom 20 to which they are bonded a 5- or 6-membered ring; or R7, R8 and R9 independently of one another NR32COR30, NR32CSR30 or NR32SO 2 R30; R30 H, OH, CccH2cc+1, CyyH2yy- 1 , pyrrolidinyl or piperidinyl, in which 25 rings a CH 2 group may be replaced by O or NR33; R32 and R33 H, CH 3 or CF 3 ; cc 1,2,3,4,5,6, 7 or8; yy 3,4, 5 or6; 56 it being possible for one or more H atoms in the groups CccH2cc+1 and CyyH 2 yy-1 to be replaced by F atoms and for one or more (CH 2 ) groups to be replaced by NR31 and for a (CH 2 ) group to be replaced by O; R31 H, methyl, ethyl, CF 3 , CH 2
CF
3 , acetyl, propionyl, methanesulfonyl or 5 ethanesulfonyl; or R31 together with a CH 2 group of R30 and the N atom to which they are jointly bonded form a 5- or 6-membered ring; or 10 R30 pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl or oxazolyl, which are unsubstituted or substituted by a maximum of 3 substituents selected from the group consisting of F, Cl, methyl, ethyl, trifluoromethyl, NH 2 , NHacetyl; or 15 R7, R8 and R9 independently of one another H, F, Cl, OH, NH 2 , CeeH2ee+1, CwwH2ww-1, OCffH2ff+1, NR40R41, CONR40R41, COOR42 or OCOR42, ee and ff independently of one another 1, 2, 3 or 4; 20 ww 3, 4, 5 or 6, it being possible for one or more H atoms in the groups CeeH2ee+1, CwwH2ww-1 and OCffH2ff+1 to be replaced by F atoms; R40 and R41 H, CttH2tt+1 or C(NH)NH 2 ; 25 tt 1, 2, 3 or 4; it being possible for one or more H atoms in the group CttH2tt+1 to be replaced by F atoms; or R40 and R41 57 independently of one another hydroxyethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl; or 5 R40 and R41 together with the N atom to which they are bonded a pyrrolidine, piperidine, N-methylpiperazine, piperazine or morpholine ring; R42 H or ChhH2hh+1; hh 1,2, 3 or 4; 10 it being possible for one or more H atoms in the group ChhH2hh+1 to be replaced by F atoms; and the pharmaceutically acceptable salts thereof. 15 Very particular preference is given to the use of compounds selected from the group consisting of 1) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide; 2) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide; 20 3) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide; 4) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N,N-dimethyl benzenesulfonamide; 5) 4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline; 6) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid; 25 7) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-ethyl-benzamide; 8) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-propyl-benzamide; 9) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-(2-dimethylamino ethyl)-benzamide; 10) 6,8-dichloro-2-methyl-4-(4-morpholin-4-yi-phenyl)-1,2,3,4-tetrahydroisoquinoline; 30 11) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-phenyl]-diethyl-amine 12) 6,8-dichloro-2-methyl-4-(4-piperidin-1-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline; 13) 6,8-dichloro-2-methyl-4-(4-pyrrolidin-1-yl-phenyl)-1 ,2,3,4-tetrahydroisoquinoline; 58 14) 6 ,8-dichloro-2-methyl-4-[4-(4-methyl-piperazin-1 -yI)-phenyl]-1 ,2,3 ,4-tetrahydro isoquinoline; 15) 6,8-dichloro-2-cyclopropyl-4-phenyl-1 ,2,3,4-tetrahydroisoquinoline; 16) 4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenylamine; 5 17) 1 -[4-(6 ,8-d ichloro-2-methyl-1 ,2 ,3,4-tetrahydro-isoquinolin-4-y)-phenyl]-3 propyl urea; 18) 1 -[4-(6,8-dichloro-2-methyl-1 ,2 ,3,4-tetrahydro-isoquinolin-4-y)-phenyl]-3-methyl thiourea; 19) 1 -[4-(6,8-dichloro-2-methyl-1 ,2 ,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-3-ethyl 10 urea; 20) N-[4-(6-methanesulfonyl-2-methyl-1 ,2 ,3,4-tetrahydro-isoquinoin-4-yl)-pheny] acetamide; 21) N-[4-(2,6,8-trimethyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-acetamide; 22) N-[4-(6-bromo-8-chloro-2-methyl-1 ,2 ,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 15 acetamide; 23) N-[4-(8-chloro-2-methyl-6-pyrrolidin-1 -yI-1 ,2,3,4-tetrahydro-isoquinolin-4-y) phenyll-acetamide; 24) N-[4-(8-chloro-2-methyl-6-morpholin-4-y-1 ,2,3,4-tetrahydro-isoquinolin-4-yI) phenyll-acetamide; 20 25) N-{4-[8-chloro-2-methyl-6-(4-methyl-piperazin-1 -yI)-1 ,2,3,4-tetrahydro-isoquinolin 4-yiI-phenyl}-acetamide; 26) N -{4-[8-chloro-6-(cyclo pro pyl methyl-a m ino)-2-methyl-1, ,2,3,4-tetrahyd ro isoquinolin-4-yI]-phenyl}-acetamide; 27) 5-(6,8-d ichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-2-hyd roxy-benzoic 25 acid; 28) 5-(6 ,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-2-hydroxy-N-methyl benzamide; 29) 5-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y)-N-ethyl-2-hydroxy benzamide; 30 30) 5-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yl)-N-(2-dimethylamino ethyl)-2-hyd roxy-benzamide; 59 31) N-[5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy benzoyl]-guanidine; 32) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide; 5 33) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine; 34) 2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine; 35) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] propionamide; 36) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 10 butyramide; 37) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]pentanamide; 38) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] isobutyramide; 15 39) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2 dimethyl-propionamide; 40) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclopropanecarboxamide; 41) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 20 cyclobutanecarboxamide; 42) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclopentanecarboxamide; 43) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2 trifluoro-acetamide; 25 44) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 acetylpiperidine-4-carboxamide; 45) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] nicotinamide; 46) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane 30 sulfonamide; 47) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl] ethanesulfonamide; 60 48) N', N'-d imethyl amino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinol in-4 yl)-phenyl]-sulfamide; 49) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] propionamide; 5 50) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] butyramide; 51) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] pentanamide; 52) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 10 isobutyramide; 53) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2 dimethyl-propionamide; 54) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclopropanecarboxamide; 15 55) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclobutanecarboxamide; 56) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclopentanecarboxamide; 57) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2 20 trifluoro-acetamide; 58) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 acetylpiperidine-4-carboxamide; 59) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] nicotinamide; 25 60) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl]-methane sulfonamide; 61) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl] ethanesulfonamide; 62) N', N'-dimethylamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 30 yl)-phenyl]-sulfamide; 63) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] propionamide; 61 64) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] butyramide; 65) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] pentanamide; 5 66) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] isobutyramide; 67) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2 dimethyl-propionamide; 68) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 10 cyclopropanecarboxamide; 69) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl] cyclobutanecarboxamide; 70) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclopentanecarboxamide; 15 71) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2 trifluoro-acetamide; 72) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 acetylpiperidine-4-carboxamide; 73) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane 20 sulfonamide; 74) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl] ethanesulfonamide; 75) N',N'-dimethylamino-N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-sulfamide; 25 76) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl urea; 77) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl thiourea; 78) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl]-3-ethyl 30 urea; 79) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl thiourea; 62 80) N-{5-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yI) phenylsulfamoyl]-4-methyl-thiazol-2-yl}-acetamide; 81) N-{5-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-y) phenylsulfamoyl]-4-methyl-thiazol-2-yl}-acetamide; 5 82) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,2 dimethyl-1 H-imidazole-4-sulfonamide; 83) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,2 dimethyl-1 H-imidazole-4-sulfonamide; 84) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-5-chloro 10 1,3-dimethyl-1 H-pyrazole-4-sulfonamide; 85) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-5-chloro 1,3-dimethyl-1 H-pyrazole-4-sulfonamide; 86) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-5-bromo thiophene-2-sulfonamide; 15 87) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-5-bromo thiophene-2-sulfonamide; 88) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-C,C,C trifluoro-methanesulfonamide; 89) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-C,C,C 20 trifluoro-methanesulfonamide; 90) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-2,2,2 trifluoroethanesulfonamide; 91) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2 trifluoro-ethanesulfonamide; 25 92) N-ethyl-N'-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-y) benzenesulfonylurea; 93) 2-chloro-5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-y) benzenesulfonamide; 94) 2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinolin-8-ylamine; 30 95) 6,8-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 96) 4-(8-amino-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-y)-phenol; 97) 8-methoxy-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 63 98) 2-(8-amino-2-ethyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenol; 99) 2-(8-amino-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenol; 100) 5-(8-amino-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-methoxy-phenol; 101) 2-methyl-8-nitro-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 5 102) 4-(8-amino-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene-1,2-diol; 103) 2,8-dimethyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 104) 4-(3,4-dichloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline; 105) 4-(3,4-dichloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-8-ylamine; 106) 4-(2,4-dichloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-8-ylamine; 10 107) 4-(3-chloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-8-ylamine; 108) 2,4-dimethyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 109) 2-butyl-4-phenyl-1,2,3,4-tetrahydro-isoquinolin-8-ylamine; 110) N-(2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-acetamide; 111) 7-chloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 15 112) 8-chloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 113) 2,6-dimethyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 114) 6-chloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 115) 6-methoxy-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 116) 2-ethyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 20 117) 2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 118) 6,8-dichloro-2-ethyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 119) 4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoline; 120) 2-methyl-4-phenyl-6,8-bis-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline; 121) 6,8-dichloro-2-isopropyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 25 122) 5,8-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 123) 6,8-dichloro-4-(4-fluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline; 124) 6,8-dichloro-2-methyl-4-p-tolyl-1,2,3,4-tetrahydro-isoquinoline; 125) 5,6-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 126) 6,7-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 30 127) 8-bromo-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 128) 6,8-dichloro-4-(4-chloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline; 129) 6,8-dichloro-2-cyclopropyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 64 130) 2-amino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide; 131) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2 methylamino-acetamide; 5 132) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2 dimethylamino-acetamide; 133) 2-amino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] propionamide; 134) 2-amino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 10 butyramide; 135) 2,6-diamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-hexanamide; 136) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] pyrrolidine-2-carboxamide; 15 137) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] isonicotinamide; 138) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H pyrrole-3-carboxamide; 139) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H 20 pyrrole-2-carboxamide; 140) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl]-1-methyl piperidine-4-carboxamide; 141) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,4 dimethyl-1 H-pyrrole-2-carboxamide; 25 142) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-nitro 1 H-pyrrole-2-carboxamide; 143) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,5 dimethyl-1 H-pyrrole-3-carboxamide; 144) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1H 30 imidazole-4-carboxamide; 145) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 methanesulfonyl-piperidine-4-carboxamide; 65 146) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,5 dimethyl-1 H-pyrazole-4-carboxamide; 147) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H pyrazole-4-carboxamide; 5 148) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 trifluoromethyl-1 H-pyrazole-4-carboxamide; 149) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2 methylamino-acetamide; 150) N[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2 10 dimethylamino-acetamide; 151) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] propionamide; 152) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] butyramide; 15 153) 2,6-diamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-hexanamide; 154) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] pyrrolidine-2-carboxamide; 155) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 20 isonicotinamide; 156) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H pyrrole-3-carboxamide; 157) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1H pyrrole-2-carboxamide; 25 158) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1l-methyl piperidine-4-carboxamide; 159) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,4 dimethyl-1 H-pyrrole-2-carboxamide; 160) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-nitro 30 1 H-pyrrole-2-carboxamide; 161) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,5 dimethyl-1 H-pyrrole-3-carboxamide; 66 162) N-[3-(6,8-dichloro-2-methyl-1 ,2 ,3,4-tetrahydro-isoqu inolin-4-yI)-phenyl]-1 H imidazole-4-carboxamide; 163) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yI)-phenyl]-1 methanesulfonyl-piperidine-4-carboxamide; 5 164) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-3,5 dimethyl-1 H-pyrazole-4-carboxamide; 165) N-[3-(6,8-dichloro-2-methyl-1 ,2 ,3,4-tetrahydro-isoquinolin-4-y)-phenyl]-1 H pyrazole-4-carboxam ide; 166) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoqu inolin-4-yI)-phenyl]-3 10 trifluoromethyl-1 H-pyrazole-4-carboxamide; 167) 1 -[2-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yI)-phenyl]-3-ethyl thiou rea; 168) 1 -[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-3-ethyl thiourea; 15 169) 1 -[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-3-ethyl thiourea; 170) 3-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoqu inolin-4-yI)-phenyl]-1 ,1 dimethyl-urea; 171) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yI)-phenyl]-4-methyl 20 piperazine-1 -carboxamide; 172) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-piperidine 1 -carboxamide; 173) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoqu inolin-4-yI)-phenyl] morpholine-4-carboxamide; 25 174) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoqu inolin-4-yI)-phenyl] pyrrolidine-1 -carboxamide; 175) 3-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y)-phenyl]-1 ,1 diethyl-urea; 176) 1 -[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y)-phenyl]-3-methyl 30 urea; 177) 1 -[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y)-pheny]-3-(2 dimethylamino-ethyl)-urea; 67 178) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 (tetrahydro-furan-3-yl)-urea; 179) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 (tetrahydro-pyran-4-yl)-urea; 5 180) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1l-methyl 1-(1-methyl-piperidin-4-yl)-urea; 181) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1l-(3 dimethylamino-propyl)-1l-methyl-urea; 182) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1l-(2 10 dimethylamino-ethyl)-1l-methyl-urea; 183) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(3 dimethylamino-propyl)-urea; 184) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 methoxy-ethyl)-urea; 15 185) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin 3-yl-urea; 186) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin 4-yl-urea; 187) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl 20 piperazine-1-carboxamide; 188) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl urea; 189) 3-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1, 1 dimethyl-urea; 25 190) 3-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1, 1 diethyl-urea; 191) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoq uinolin-4-yl)-phenyl]-piperidine 1-carboxamide; 192) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 30 morpholine-4-carboxamide; 193) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] pyrrolidine-1 -carboxamide; 68 194) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 dimethylamino-ethyl)-urea; 195) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl piperazine-1 -carboxamide; 5 196) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] pyrrolidine-1 -carboxamide; 197) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl urea; 198) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1, 1 10 dimethyl-urea; 199) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 ,1 diethyl-urea; 200) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 dimethylamino-ethyl)-urea; 15 201) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-piperidine 1-carboxamide; 202) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] morpholine-4-carboxamide; 203) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 20 formamide; 204) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl amine; 205) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3 dimethyl-urea; 25 206) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-4 methyl-piperazine-1 -carboxamide; 207) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3,3 trimethyl-urea; 208) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl 30 piperidine-1-carboxamide; 209) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl morpholine-4-carboxamide; 69 210) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl pyrrolidine-1l-carboxamide; 211) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 dimethylamino-ethyl)-1 -methyl-urea; 5 212) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,3 diethyl-1 -methyl-urea; 213) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] formamide; 214) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl 10 amine; 215) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl pyrrolidine-1 -carboxamide; 216) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl piperidine-1 -carboxamide; 15 217) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3,3 trimethyl-urea; 218) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3 dimethyl-urea; 219) N-[3-(6 ,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl 20 morpholine-4-carboxamide; 220) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-4 methyl-piperazine-1 -carboxamide; 221) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 dimethylamino-ethyl)-1l-methyl-urea; 25 222) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,3 diethyl-1 -methyl-urea; 223) 2-dimethylamino-ethyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-carbamate; 224) 2-dimethylamino-ethyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 30 yl)-phenyl]-carbamate; 225) 2-dimethylamino-ethyl [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-carbamate; 70 226) methyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] carbamate; 227) ethyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] carbamate; 5 228) isopropyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] carbamate; 229) 2,2-dimethyl-propyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-carbamate; 230) methyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 10 carbamate; 231) isopropyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] carbamate; 232) 2,2-dimethyl-propyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-carbamate; 15 233) ethyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] carbamate; 234) (R)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] methanesulfonamide; 235) (S)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 20 methanesulfonamide; 236) (R)-1l-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 ethyl-urea; 237) (S)-1l-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 ethyl-urea; 25 238) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide; 239) 4-(3-bromo-phenyl)-6,8-dichloro-methyl-1,2,3,4-tetrahydro-isoquinoline; 240) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 hydroxy-ethyl)-urea; 30 241) ethyl 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoate; 242) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid.
71 and the pharmaceutically acceptable salts thereof. Exceptionally particular preference is given to the use of compounds selected from the 5 group consisting of 1) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide; 2) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide; 3) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide; 10 4) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid; 5) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-ethyl-benzamide; 6) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-propyl-benzamide; 7) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-(2-dimethylamino ethyl)-benzamide; 15 8) 6,8-dichloro-2-methyl-4-(4-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline; 9) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine; 10) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl thiourea; 11) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl]-3-ethyl 20 urea; 12) N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide; 13) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoic acid; 25 14) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-y)-N-(2-dimethylamino ethyl)-2-hydroxy-benzamide; 15) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide; 16) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine; 30 17) 2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine; 18) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] propionamide; 72 19) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyi]-1 -acetyl piperidine-4-carboxamide; 20) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane sulfonamide; 5 21) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] ethanesulfonamide; 22) N',N'-dimethylamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-sulfamide; 23) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 10 propionamide; 24) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] butyramide; 25) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] isobutyramide; 15 26) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclopropanecarboxamide; 27) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclobutanecarboxamide; 28) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2 20 trifluoro-acetamide; 29) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl]-1-acetyl piperidine-4-carboxamide; 30) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] nicotinamide; 25 31) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl]-methane sulfonamide; 32) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] ethanesulfonamide; 33) N', N'-dimethylamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 30 yl)-phenyl]-sulfamide; 34) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclopropanecarboxamide; 73 35) N-[2-(6,8-d ichloro-2-methyl-1 ,2 ,3,4-tetrahydro-isoqu inolin-4-yI)-pheny]-1 -acetyl piperidine-4-carboxamide; 36) 1 -[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y)-phenyl]-3-ethyl urea; 5 37) 1 -[3-(6,8-dichloro-2-methyl-1 ,2 ,3,4-tetrahyd ro-isoquinolin-4-yI)-phenyl]-3-methyl thiourea; 38) 1 -[2-(6,8-d ichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yl)-phenyl]-3-ethyl urea; 39) 1 -[2-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yI)-phenyl]-3-methyl 10 thiourea; 40) N-{5-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yI) phenylsu Ifamoyl]-4-methyl-th iazol-2-yI-acetamide; 41) N-[3-(6,8-dichloro-2-methyl-1 ,2 ,3,4-tetrahydro-isoquinolin-4-y)-phenyl]-1 ,2 dimethyl-1 H-imidazole-4-sulfonamide; 15 42) N-[4-(6,8-d ichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-C,C,C trifluoro-methanesulfonamide; 43) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-C,C ,C trifluoro-methanesulfonamide; 44) N-ethyl-N'-4-(6,8-dichloro-2-methyl-1 ,2,3 ,4-tetrahyd ro-isoquinolin-4-yI) 20 benzenesulfonylurea; 45) N-[4-(6,8-d ichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y)-phenyl]-2 dimethylamino-acetamide; 46) 2,6-d amino N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yI) phenyl]-hexanamide; 25 47) N-[4-(6,8-dichloro-2-methyl-1 ,2 ,3,4-tetrahydro-isoquinolin-4-y)-pheny]-1 H pyrrole-3-carboxamide; 48) N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoqu inolin-4-yI)-phenyl]-1 -methyl piperidine-4-carboxamide; 49) N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yI)-phenyl]-1 30 methanesulfonyl-piperidine-4-carboxamide; 50) N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]l- H pyazole-4-carboxam ide; 74 51) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2 methylamino-acetamide; 52) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2 dimethylamino-acetamide; 5 53) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] propionamide; 54) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl] butyramide; 55) 2,6-diamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) 10 phenyl]-hexanamide; 56) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1l-methyl piperidine-4-carboxamide; 57) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1lH imidazole-4-carboxamide; 15 58) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 methanesulfonyl-piperidine-4-carboxamide; 59) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,5 dimethyl-1 H-pyrazole-4-carboxamide; 60) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1H 20 pyrazole-4-carboxamide; 61) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-l,1 dimethyl-urea; 62) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl piperazine-1 -carboxamide; 25 63) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-piperidine 1-carboxamide; 64) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] morpholine-4-carboxamide; 65) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 30 pyrrolidine-1 -carboxamide; 66) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-l,1 diethyl-urea; 75 67) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl urea; 68) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 dimethylamino-ethyl)-urea; 5 69) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 (tetrahydro-furan-3-yl)-urea; 70) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 (tetrahydro-pyran-4-yl)-urea; 71) 3-[3-(6,8-dichloro-2-methyl-1,2,3 ,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-methyl 10 1 -(1-methyl-piperidin-4-yl)-urea; 72) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -(3 dimethylamino-propyl)-1l-methyl-urea; 73) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1l-(2 dimethylamino-ethyl)-1 -methyl-urea; 15 74) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(3 dimethylamino-propyl)-urea; 75) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 methoxy-ethyl)-urea; 76) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin 20 3-yl-urea; 77) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin 4-yl-urea; 78) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl]-4-methyl piperazine-1 -carboxamide; 25 79) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl urea; 80) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 dimethylamino-ethyl)-urea; 81) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-y)-phenyl]-4-methyl 30 piperazine-1 -carboxamide; 82) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl urea; 76 83) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1, 1 dimethyl-urea; 84) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1, 1 diethyl-urea; 5 85) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 dimethylamino-ethyl)-urea; 86) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] morpholine-4-carboxamide; 87) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 10 formamide; 88) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl amine; 89) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] formamide; 15 90) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl amine; 91) 1[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3,3 trimethyl-urea; 92) 1[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3 20 dimethyl-urea; 93) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] morpholine-4-carboxamide; 94) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methy1-4 methyl-piperazine-1 -carboxamide; 25 95) 1[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 dimethylamino-ethyl)-1l-methyl-urea; 96) 2-dimethylamino-ethyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-carbamate; 97) 2-dimethylamino-ethyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 30 yl)-phenyl]-carbamate; 98) 2-dimethylamino-ethyl [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-carbamate; 77 99) methyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] carbamate; 100) (R or S)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] methanesulfonamide; 5 101) (R or S)-1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 ethyl-urea; 102) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 hydroxy-ethyl)-urea; 103) ethyl 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoate; 10 104) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid. and the pharmaceutically acceptable salts thereof. If the compounds of the formula I contain one or more centers of asymmetry, these 15 may have both the S and the R configuration. The compounds may be in the form of optical isomers, of diastereomers, of racemates or of mixtures thereof. The defined alkyl radicals and partly or completely fluorinated alkyl radicals may be both straight-chain and branched. Groups CaH2a-1 and their analogs as far as 20 CyyH2yy-1 mean either the corresponding alkenyls, cycloalkyls, cycloalkylalkyls or alkylcycloalkyls. Appropriate heteroaryls are, in particular, 2- or 3-thienyl, 2- or 3-furyl, 1-, 2- or 3 pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 1,2,3-triazol-1-, -4- or 5-yl, 25 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 1,2,3-oxadiazol-4- or 5-yl, 1,2,4-oxadiazol-3-or 5-yl, 1,3,4-oxadiazol-2-yl or -5-yl, 2-, 4 or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or 5-yl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 30 1-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl. The corresponding 78 N-oxides of these compounds are additionally encompassed, that is to say, for example, 1-oxy-2-, 3- or 4-pyridyl. Of these, the 5- or 6-membered heterocycles are preferred. The particularly preferred 5 heterocycles are imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl and oxazolyl. The terminal CH 3 groups in an alkyl chain are also regarded as CH 2 units and are in this connection viewed as CH 2 groups. 10 Methods for preparing the compounds used are also described. Thus, the substances described herein can be prepared starting from the benzylamine precursors IV. These in turn can, if not obtainable commercially, be synthesized by 15 standard processes from the corresponding benzyl chlorides or bromides 111. R1 R1 R2 R5-NH 2 R2 / X R R3 R3 R5 R4 R4 X = CI, Br III IV 20 The benzylamines IV obtained in this way are alkylated in a manner known to the skilled worker with the appropriately substituted alpha-bromoacetophenone compounds V.
79 R8 R8 R9 R7 R9 R7 R1 Br R1 R2 0 R2 I1 ~V O R3 R5 R3 N ' R5 R4 R4 IV VI The alpha-bromacetophenone compounds V can be obtained from the corresponding 5 acetophenone precursors by bromination in processes known from the literature. The desired tetrahydroisoquinolines I can be obtained by known processes by reduction of the carbonyl group in VI and subsequent acid-catalyzed cyclization of the corresponding alcohols VII (cf. Tetrahedron Lett.; 1989, 30, 5837; Org. Prep. Proced. Int.; 1995, 27, 513). 10 R8 R8 R9 R7 R9 R1IR R R1Rn NaBH 4 R R R2 _ _ _ _ _ _R2 10 OH ,4/ N, N, R3 R5 R3 R5 R4 R4 vi [H VII R8 R9 R7 R1 R2 R3 R5 R4 80 When R6 is not equal to H, the desired compounds of the formula I can be prepared for example from the iodides VIII by halogen/metal exchange and subsequent nucleophilic attack of the intermediate organolithium species on the carbonyl group (cf. Chem. Pharm. Bull.; 1995, 43,1543). 5 R8 R7 R8 a O R9 / R7 R9 1 R9 R5 R1 I NBuLi 2 OH RR2 I'R1 " N, R3 R5 R2 R4 R4 R4 R3 VIII IX The tertiary alcohols synthesized in this way can be converted by known methods into 10 other derivatives. Alkyl-branched analogs (I) are prepared by alkylating the corresponding diphenylacetic esters X in the alpha position by known methods. The desired product XI can be converted by standard processes into the corresponding amides XII, which are 15 converted into the desired tetrahydroisoquinolines I in a Pictet-Spengler-analogous reaction (cf. Tetrahedron; 1987, 43, 439; Chem. Pharm. Bull.; 1985, 33, 340).
81 R8 R8 R9 ~ R7 R9 - R7 R1 \ 1. LDA RI R2 2. R6-X R6 COOR COOR R3 R3 Z R4 R4 x XI 1. NaOH 2. SOCI 2 3. R5-NH 2 R8 R8 R9 / R7 R9 - R7 R1 R1 R2 R6 HCHO/LiAJH 4 R2 R60 \ NN HN, R3 R5 R3 R5 R4 R4 I XII Compounds of the type I are described in the published specifications WO 01 32 624 and WO 01 32 625 as norepinephrine, dopamine and serotonin reuptake inhibitors. 5 However, these patent applications protect exclusively compounds in which R1 and R2 may be exclusively H. It has emerged, however, with the compounds according to the invention that at least for R2 it is necessary that R2 is not equal to H. In addition, it was not possible to detect by means of an exemplary compound of the compounds according to the invention any inhibitory properties on the described receptors, so that 10 the described compounds differ distinctly both in structure and in their pharmacological properties from the compounds described in the patent applications mentioned. In addition, compounds of type I are described in the patent specification EP 11 13 007 as estrogen agonists and antagonists. It was possible to show that the compounds 15 according to the invention show no activity on said receptors, so that the structural differences of the compounds according to the invention result in distinctly different pharmacological properties in this regard too.
82 It was possible to show that compounds of the formula I are excellent inhibitors of the sodium-hydrogen exchanger (NHE) - especially of the sodium-hydrogen exchanger of subtype 3 (NHE3). 5 On the basis of these properties, the compounds are suitable for the treatment of disorders caused by oxygen deficiency. The compounds are, as a result of their pharmacological properties, outstandingly suitable as antiarrhythmic medicaments with a cardioprotective component for prophylaxis of infarction and for treatment of 10 infarction, and for the treatment of angina pectoris, in which connection they also inhibit or greatly reduce in a preventive manner the pathophysiological processes associated with the development of ischemia-induced damage, in particular in the induction of ischemia-induced cardiac arrhythmias. Because of their protective effects against pathological hypoxic and ischemic situations, the compounds of the formula I 15 which are used according to the invention can, as a result of inhibition of the cellular Na'/H exchange mechanism, be used as medicaments for the treatment of all acute or chronic damage induced by ischemia or disorders induced primarily or secondarily thereby. This relates to the use thereof as medicaments for surgical interventions, e.g. in organ transplantations, in which cases the compounds can be used both to protect 20 the organs in the donor before and during removal, to protect removed organs for example on treatment with or storage thereof in physiological bath fluids, as well as during the transfer into the recipient organism. The compounds are likewise valuable medicaments with a protective action during the performance of angioplastic surgical interventions, for example on the heart as well as peripheral vessels. In accordance 25 with their protective action against ischemia-induced damage, the compounds are also suitable as medicaments for the treatment of ischemias of the nervous system, especially of the CNS, in which connection they are suitable for example for the treatment of stroke or of cerebral edema. In addition, the compounds of the formula I which are used according to the invention are likewise suitable for the treatment of 30 types of shock, such as, for example, of allergic, cardiogenic, hypovolemic and bacterial shock.
83 In addition, the compounds induce an improvement in the respiratory drive and are therefore used to treat respiratory conditions associated with the following clinical conditions and diseases: disturbance of central respiratory drive (e.g. central sleep apnea, sudden infant death, postoperative hypoxia), muscle-related breathing 5 disorders, breathing disorders after long-term ventilation, breathing disorders associated with altitude adaptation, obstructive and mixed type of sleep apnea, acute and chronic pulmonary disorders with hypoxia and hypercapnia. The compounds additionally increase the tone of the muscles of the upper airways, so that snoring is suppressed. 10 A combination of an NHE inhibitor with a carbonic anhydrase inhibitor (e.g. acetazolamide), the latter inducing metabolic acidosis and thus itself increasing respiratory activity, proves to be advantageous due to an enhanced effect and reduced use of active ingredient. 15 It has emerged that the compounds used according to the invention have a mild laxative effect and accordingly can be used advantageously as laxatives or if there is a risk of constipation, in which case the prevention of the ischemic damage associated with constipation in the intestinal region is particularly advantageous. 20 It is additionally possible to prevent the formation of gall stones. The compounds of the formula I used according to the invention are furthermore distinguished by a strong inhibitory effect on the proliferation of cells, for example of 25 fibroblast cell proliferation and the proliferation of smooth muscular muscle cells. The compounds of the formula I are therefore suitable as valuable therapeutic agents for diseases in which cell proliferation represents a primary or secondary cause, and can therefore be used as antiatherosclerotic agents, agents to prevent late complications of diabetes, cancers, fibrotic disorders such as pulmonary fibrosis, hepatic fibrosis or 30 renal fibrosis, organ hypertrophies and hyperplasias, in particular for prostate hyperplasia or prostate hypertrophy.
84 The compounds used according to the invention are effective inhibitors of the cellular sodium-proton antiporter (Na/H exchanger) which is elevated in numerous disorders (essential hypertension, atherosclerosis, diabetes, etc.), also in those cells which are readily amenable to measurements, such as, for example, in erythrocytes, platelets or 5 leukocytes. The compounds used according to the invention are therefore suitable as excellent and simple scientific tools, for example in their use as diagnostic agents for determining and distinguishing different types of hypertension, but also of atherosclerosis, of diabetes, proliferative disorders etc. The compounds of the formula I are moreover suitable for preventive therapy to prevent the development of high 10 blood pressure, for example of essential hypertension. It has additionally been found that NHE inhibitors show a beneficial effect on serum lipoproteins. It is generally acknowledged that blood lipid levels which are too high, so called hyperlipoproteinemias, represent a considerable risk factor for the development 15 of arteriosclerotic vascular lesions, especially coronary heart disease. The reduction of elevated serum lipoproteins therefore has exceptional importance for the prophylaxis and regression of atherosclerotic lesions. The compounds used according to the invention can therefore be used for the prophylaxis and regression of atherosclerotic lesions by eliminating a causal risk factor. With this protection of the vessels against 20 the syndrome of endothelial dysfunction, compounds of the formula I are valuable medicaments for the prevention and treatment of coronary vasospasms, of atherogenesis and of atherosclerosis, of left-ventricular hypertrophy and of dilated cardiomyopathy, and thrombotic disorders. 25 Said compounds are therefore advantageously used for producing a medicament for the prevention and treatment of sleep apneas and muscle-related respiratory disorders; for producing a medicament for the prevention and treatment of snoring; for producing a medicament for lowering blood pressure; for producing a medicament for the prevention and treatment of disorders induced by ischemia and reperfusion of 30 central and peripheral organs, such as acute renal failure, stroke, endogenous states of shock, intestinal disorders etc.; for producing a medicament for the treatment of late damage from diabetes and chronic renal disorders, in particular of all inflammations of 85 the kidneys (nephritides) which are associated with increased protein/albumin excretion; for producing a medicament for the treatment of infection by ectoparasites in human and veterinary medicine; for producing a medicament for the treatment of said disorders in combinations with hypotensive substances, preferably with angiotensin 5 converting enzyme (ACE) inhibitors, with diuretics and saluretics such as furosemide, hydrochlorothiazide, pseudoaldosterone antagonists and aldosterone antagonists; with adenosine receptor modulators, in particular with adenosine receptor activators (A2 agonists); and with angiotensin receptor antagonists. 10 The administration of sodium-proton exchange inhibitors of the formula I as novel medicaments for lowering elevated blood lipid levels, and the combination of sodium proton exchange inhibitors with hypotensive medicaments and/or medicaments with hypolipidemic activity is claimed. 15 Medicaments which comprise a compound I can in this connection be administered orally, parenterally, intravenously, rectally, transdermally or by inhalation, the preferred administration being dependent on the particular characteristics of the disorder. The compounds I may moreover be used alone or together with pharmaceutical excipients, both in veterinary medicine and in human medicine. 20 The excipients suitable for the desired pharmaceutical formulation are familiar to the skilled worker on the basis of his expert knowledge. Besides solvents, gel formers, suppository bases, tablet excipients, and other active ingredient carriers, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavorings, 25 preservatives, solubilizers or colors. For a form for oral administration, the active compounds are mixed with additives suitable for this purpose, such as carriers, stabilizers or inert diluents, and converted by conventional methods into suitable dosage forms such as tablets, coated tablets, 30 hard gelatin capsules, aqueous, alcoholic or oily solutions. Examples of inert carriers which can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. It is moreover possible 86 for the preparation to take place both as dry granules and as wet granules. Examples of suitable oily carriers or solvents are vegetable or animal oils such as sunflower oil or fish liver oil. 5 For subcutaneous or intravenous administration, the active compounds used are converted, if desired with the substances customary for this purpose, such as solubilizers, emulsifiers or other excipients, into a solution, suspension or emulsion. Examples of suitable solvents are: water, physiological saline or alcohols, e.g. ethanol, propanol, glycerol, as well as sugar solutions such as glucose or mannitol solutions, or 10 else a mixture of the various solvents mentioned. Suitable as pharmaceutical formulation for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active ingredient of the formula I in a pharmaceutically acceptable solvent such as, in particular, ethanol or 15 water, or a mixture of such solvents. The formulation may, if required, also contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers, and a propellant gas. Such a preparation normally contains the active ingredient in a concentration of about 0.1 to 10, in 20 particular of about 0.3 to 3, % by weight. The dosage of the active ingredient of the formula I to be administered, and the frequency of administration, depend on the potency and duration of action of the compounds used; additionally also on the nature and severity of the disorder to be 25 treated and on the sex, age, weight and individual responsiveness of the mammal to be treated. On average, the daily dose of a compound of the formula I for a patient weighing about 75 kg is at least 0.001 mg/kg, preferably 0.01 mg/kg, to a maximum of 10 mg/kg, 30 preferably 1 mg/kg, of body weight. For acute episodes of the disorder, for example immediately after suffering a myocardial infarction, higher and, in particular, more frequent dosages may also be necessary, e.g. up to 4 single doses a day. Up to 87 200 mg a day may be necessary, in particular on i.v. administration, for example for a patient with infarction in the intensive care unit. Descriptions of experiments and examples: 5 List of abbreviations used: Rt retention time TFA trifluoroacetic acid HPLC high performance liquid chromatography 10 eq equivalent LCMS liquid chromatography mass spectroscopy MS mass spectroscopy Cl chemical ionization RT room temperature 15 THF tetrahydrofuran TOTU O-[(ethoxycarbonyl)-cyanomethyleneamino]-N,N,N',N' tetramethyluronium tetrafluoroborate DMSO dimethyl sulfoxide abs. absolute 20 decomp. decomposition DMF dimethylformamide General: The retention times (Rt) indicated below relate to LCMS measurements with the 25 following parameters: Method A: stationary phase: Merck Purospher 3 p/2 x 55 mm mobile phase: 95% H 2 0 (0.05% TFA)-* 95% acetonitrile; 4 min; 95% acetonitrile; 1.5 min - 5% acetonitrile; 1 min; 0.5 ml/min, 30 30 0 C. Method B: stationary phase: Merck Purospher 3p/2 x 55 mm 88 mobile Phase: 0 min 90% H 2 0 (0.05% TFA) 2.5 min-95% acetonitrile; 95% acetonitrile to 3.3 min; 10% acetonitrile 3.4 min; 1 ml/min. 5 Method BI: stationary phase: YMC, J'sphere ODS H80 41p 2 x 20 mm mobile phase 0 min 90% H 2 0 (0.05% TFA) 1.9 min-95% acetonitrile; 95% acetonitrile to 2.4 min; 10% acetonitrile 2.45 min; 1 ml/min. 10 Method C: stationary phase: Merck LiChroCart 55-2 Purospher STAR RP 18e solvent: solvent A: acetonitrile/water 90:10 + 0.5% HCOOH solvent B: acetonitrile/water 10:90 + 0.5% HCOOH 15 flow rate: 0.75 ml/min time[min] solvent B[%] 0.00 95.0 0.50 95.0 1.75 5.0 20 4.25 5.0 4.50 95.0 5.00 95.0 stop time: 6.20 min temperature: 40 0 C 25 Method D: stationary phase: Merck RP18 Purospher STAR, 55 x 2 mm, 3 p particle size. solvent: solvent A: acetonitrile + 0.08% HCOOH solvent B: water + 0.1% HCOOH 30 flow rate: 0.45 ml/min time[min] solvent B[%] 0 95 89 5 5 7 5 8 95 9 5 5 temperature: room temperature Example 1: N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide HNL C1 Nz CI " NI N 10 Intermediate 1: 2,4-Dichlorobenzyl-(methyl)-amine is prepared by methods known from the literature (J. Med. Chem.; 1984, 27, 1111). Intermediate 2: N-[4-(2-Bromo-acetyl)-phenyl]-acetamide 15 is synthesized in a manner known to the skilled worker by bromination of N-(4-acetyl phenyl)-acetamide. The starting compound (0.256 mol) is introduced into 300 ml of acetic acid and, at 60 0 C, a solution of 39.9 g of bromine (1.0 eq) in 60 ml of acetic acid is added dropwise. After 1.5 h, the reaction mixture is allowed to cool to room temperature and is added to 20 1 I of ice-water. The precipitate is filtered off with suction, washed with water and dried, with 60 g of the title compound being isolated (melting point: 192 0 C). Intermediate 3: N-{4-[2-(2,4-Dichloro-benzylamino)-acetyl]-phenyl}-acetamide; 37.1 g (0.195 mol) of intermediate 1 are introduced into 400 ml of dioxane, and a 25 solution of 60 g (0.234 mol) of intermediate 2 in 600 ml of dioxane is added. 134 ml of triethylamine are added, and the mixture is stirred at room temperature for 4 h. After standing overnight, the precipitate is filtered off and the filtrate is concentrated in 90 vacuo. The residue is taken up in ethyl acetate, washed with NaHCO 3 and H 2 0, dried with MgSO 4 and concentrated. The oily residue resulting thereby is triturated with an ethyl acetate/ether mixture, resulting in 36 g of intermediate 3 in the form of a crystalline solid (melting point: 115-1170C). 5 Intermediate 4: N-{4-[2-(2,4-Dichloro-benzylamino)-1 -hydroxy-ethyl]-phenyl}-acetamide; 36 g (0.099 mol) of intermediate 3 are dissolved in 500 ml of methanol and, at 00C, 7.8 g (2 eq) of sodium borohydride are added. The mixture is then stirred at 00C for 10 30 min and at room temperature for a further hour. For workup, the reaction mixture is concentrated and the residue is partitioned between 1 N HCI and ethyl acetate. The aqueous phase is separated off, adjusted to pH 9 and extracted twice with ethyl acetate. The combined organic phases are dried with MgSO 4 and concentrated. The crude product obtained in this way can be reacted further without further purification. 15 N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide; 20 g (0.054 mol) of intermediate 4 are dissolved in 250 ml of dichloromethane and, at 00C, 250 ml of conc. H 2
SO
4 are added dropwise. The mixture is stirred at 00C for 2 h and at room temperature for I h. For workup, the reaction mixture is added to ice 20 water, and the precipitate is filtered off with suction. The precipitate is taken up in 300 ml of 1 N NaOH and extracted three times with ethyl acetate. Drying of the organic phases and concentration affords a crude product which is triturated with diisopropyl ether, whereupon 11.7 g of the compound of the example are isolated as a crystalline solid (melting point: 205-2060C). 25 la: N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide hydrochloride; 91 HNL I CIH CI N.' An analytical sample (100 mg) of the title compound from example 1 is suspended in 10 ml of 2 N HCI, and THF is added until a clear solution is produced. It is concentrated in vacuo, and the residue is triturated with ether and filtered off with 5 suction, whereupon the title compound is obtained as a crystalline solid (Rt = 3.807 min (method A); melting point.: 125 0 C with decomposition). Example 2: 2a: (+)-4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene 10 sulfonamide hydrochloride; 2b: (+)-3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene sulfonamide hydrochloride; 2c: (-)-4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene sulfonamide acetate; 15 2d: (-)-3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene sulfonamide acetate; 0 \\ NH 2 NH2 Ci N. HCUIAcOH ci HCI/AcOH I | / Nq N N, (+ and -) (+ and -) 2a/2c 2b/2d 20 Intermediate 1: 2,4-Dichlorobenzyl-(methyl)-amine is prepared by methods known from the literature (J. Med. Chem.; 1984, 27, 1111).
92 Intermediate 2: 2-[(2,4-Dichloro-benzyl)-methyl-amino]-1l-phenyl-ethanone; Intermediate 1 is reacted with 2-bromo-1-phenyl-ethanone in the manner described in example 1, intermediate 3. Workup in an analogous manner and purification on silica gel affords the desired alkylation product in good yield as a yellowish oil (Rt = 5 4.188 min (method A); MS(CI
+
) = 308.2/310.2). Intermediate 3: 2-[(2,4-Dichloro-benzyl)-methyl-amino]-1-phenyl-ethanol; Intermediate 2 is reduced with sodium borohydride in the manner described in example 1, intermediate 4. Once monitoring of the reaction indicates complete 10 conversion, the mixture is concentrated and the residue is taken up in ethyl acetate. It is washed twice with H 2 0, dried with MgSO 4 and freed of solvent. The crude product, which is obtained in quantitative yield, can be reacted further without further purification (Rt = 4.149 min (method A); MS(Cl
+
) = 310.2/312.2). 15 Intermediate 4: 6,8-Dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 20 g (64.5 mmol) of intermediate 3 are dissolved in 55 ml of dichloromethane and cooled to 00C. This solution is added dropwise to 55 ml of precooled conc. H 2
SO
4 and then stirred at room temperature for two hours. For workup, the mixture is poured onto ice and made strongly alkaline with 6 N NaOH. Three extractions with dichloromethane 20 are carried out. The combined organic phases are dried with MgSO 4 and concentrated. The oily crude product is purified on silica gel, resulting in intermediate 4 in a yield of 53% (Rt = 4.444 min (method A); MS(CI
+
) = 292.2/294.2). 4a: (-)-6,8-Dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline trifluoroacetate; 25 4b: (+)-6,8-Dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline trifluoroacetate; Intermediate 4 is separated into the two enantiomers by HPLC on a chiral phase. chiral column: Chiralpak OD 250 x 4.6 cm; solvent: n-heptane/isopropanol 7:3 + 0.1% TFA; flow rate: 1 ml/min; 30 Rt((-)-enantiomer/4a) = 9.340 min; Rt((+)-enantiomer/4b) = 20.327 min.
93 2a: (+)-4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene sulfonamide hydrochloride; 2b: (+)-3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene 5 sulfonamide hydrochloride; A suspension of 500 mg (1.7 mmol) of intermediate 4a in 10 ml of dichloromethane is introduced at 00C into 1.2 ml of chlorosulfonic acid. The mixture is stirred at 00C for one hour and at room temperature for a further hour. A further 5 ml of chlorosulfonic acid is added and the mixture is stirred at room temperature for one hour. For workup, 10 it is poured onto ice and adjusted to pH 8 with NaHCO 3 . Three extractions with ethyl acetate are carried out. The combined organic phases are dried with Na 2
SO
4 and freed of solvent. The crude product obtained in this way is heated in 20 ml of conc.
NH
3 solution at 900C for three hours. After the conversion is complete, the reaction solution is concentrated and the residue is partitioned between H 2 0 and ethyl acetate. 15 The organic phase is separated off and the aqueous phase is extracted once more with ethyl acetate. The combined organic phases are dried with Na2SO4 and the solvent is removed in vacuo. Subsequent chromatography on silica gel affords 335 mg of a mixture of example 2a and 2b in the form of a yellow amorphous solid. Further purification on a preparative HPLC affords 212 mg of the para-substituted title 20 compound 2a, plus 58 mg of the meta isomer 2b. Conditions for the preparative HPLC. chiral column: Chiralpak AS 250 x 4.6 mm; solvents: n-heptanelethanol/methanollacetonitrile 20:1.5:0.5:0.5 flow rate: 1 ml/min; 25 Rt(main fraction) = 14.145 min (-->2a); Rt(subsidiary fraction) = 11.623 min (-+2b). Both fractions were dissolved in methanol/2 N HCI mixture and freeze dried, and it was possible to obtain the title compounds 2a and 2b in the form of crystalline solids.
94 (Rt(2a) = 3.630 min (method A); MS(2a),(ES
+
) =371.3/373.3 (M++H)/ 412.3/ 414.3
(M++CH
3 CN); Rt (2b) = 3.668 min (method A); MS(2b),(ES
+
) =371.3/373.3 (M++H)/ 412.3/ 414.3 (M++CH 3 CN). 5 2c: (-)-4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene sulfonamide acetate; 2d: (-)-3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene sulfonamide acetate; The title compound is synthesized by the method described under 2a/2b, using 10 intermediate 4b as starting compound. The purification and separation from the meta isomer which is to be expected takes place under the following conditions: chiral column: Chiralpak AS 250 x 4.6/12 mm; solvent: acetonitrile flow rate: 1 ml/min; 15 Rt(main fraction)= 4.394 min (-+2c); Rt(subsidiary fraction) = 4.130 min (-+2d). The purified products are each taken up in a 10% acetic acid solution and freeze dried, resulting in the desired acetates as slightly yellowish solids (Rt(2c) = 3.656 min (method A); MS(ES
+
) =371.1/373.1 (M++H)/412.1/414.1 (M++CH 3 CN)); (Rt(2d)= 20 1.562 min (method B); MS(ES
+
) =371.1/373.1 (M++H)/412.1/414.1 (M++CH 3 CN)). Example 3: 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N,N-dimethyl benzenesulfonamide, hydrochloride; 0\ I CIH CI CI 25 95 6,8-Dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline (intermediate 4, example 2) was introduced in portions into chlorosulfonic acid (6.6 ml). The mixture was subsequently stirred at 400C for one hour. The reaction mixture was then cooled to room temperature and an ice/water mixture was added. The precipitate which 5 separated out during this was filtered off with suction and taken up in ethyl acetate which, after washing with saturated brine was dried over magnesium sulfate. Subsequent concentration afforded 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro isoquinolin-4-yl)-benzenesulfonyl chloride as a solid crude product, a portion of which (150 mg) was directly introduced in portions into dimethylamine solution (5 ml, approx. 10 40% in water) cooled to 100C. The resulting suspension was subsequently stirred at this temperature for 1.5 h. Then ice-water was added and, after extraction three times with ethyl acetate, the combined ethyl acetate phases were washed with saturated brine and dried over magnesium sulfate. The residue was taken up with water and, after addition of 2 N HCI, freeze dried. The crude product obtained in this way was 15 then purified by preparative HPLC. Conditions: stationary phase: Merck Purospher RP18 (10pM) 250 x 25 mm mobile phase: 90% H 2 0 (0.05% TFA)-+ 90% acetonitrile; 40 min; flow rate: 20 25 ml/min The fractions containing the product were combined, the acetonitrile was stripped off in a rotary evaporator, and the aqueous phase was washed with saturated potassium carbonate solution and then extracted three times with ethyl acetate. The combined ethyl acetate phases were washed with saturated brine, dried over magnesium sulfate 25 and concentrated. The residue was taken up in water and, after addition of 2 N HCl, freeze dried. 80 mg of a pale solid were obtained. This consisted of -80% of the desired compound, in addition to -20% of a regioisomer (Rt = 4.000 min (method A); MS(ClI) = 399.1).
96 Example 4: 4a: 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide, hydrochloride; ON , NH2 0 CIH CI / N CI 5 Intermediate 1: 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl) benzenesulfonyl chloride At 0°C, 1 mmol of 6,8-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline (intermediate 4, example 2) is introduced into 1 ml of chlorosulfonic acid and stirred at 10 room temperature for 3 hours. For workup, the reaction mixture is poured onto ice, adjusted to pH 7 to 8 with 1 N NaOH and extracted twice with ethyl acetate. The combined ethyl acetate phases are dried with Na 2
SO
4 and concentrated in a rotary evaporator. The crude product obtained in this way is reacted further without further purification. 15 Intermediate 2: 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene sulfonamide 319 mg of intermediate 1 are suspended in 6 ml of 25% strength ammonia and heated to 90 0 C. After 3 h, the mixture is diluted with H 2 0 and extracted with ethyl acetate. The 20 organic phase is separated off and dried with Na 2
SO
4 , resulting in 165 mg of the title compound. 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide, hydrochloride; 25 145 mg of intermediate 2 are suspended in 15 ml of diethyl ether, and 1 ml of ethereal HCI is added. After stirring at room temperature for 30 minutes, the precipitate is 97 filtered off with suction and dried, resulting in 136 mg of the hydrochloride in the form of a yellowish solid. 4b: 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide, 5 acetate; ON
,NH
2 0 AcOH CI N cl 255 mg of intermediate 2, example 8, are mixed with 5 ml of glacial acetic acid, and 50 ml of H 2 0 is added. Filtration of sparingly soluble constituents is followed by freeze drying, resulting in 250 mg of the title compound. 10 Example 5: 4-(4-Bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline, hydrochloride; r C1 CH ci N Cl Intermediate 1: 15 1-(4-Bromo-phenyl)-2-[(2,4-dichloro-benzyl)-methyl-amino]-ethanone; (2,4-Dichloro-benzyl)-methyl-amine (see example 1, intermediate 1) and 2-bromo-1l-(4 bromo-phenyl)-ethanone are reacted in analogy to the method described in example 1, intermediate 3. After analogous workup and chromatography on silica gel, the alkylation product can be isolated in a yield of 69%. 20 98 Intermediate 2: 1-(4-Bromo-phenyl)-2-[(2,4-dichloro-benzyl)-methyl-amino]-ethanol; Intermediate 1 is reduced to the corresponding alcohol with 2 equivalents of NaBH4 in analogy to the manner described for intermediate 4, example 1, and the alcohol can be isolated in a yield of 86%. 5 Intermediate 3: 4-(4-Bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydro isoquinoline; 5.45 g (14.0 mmol) of 1-(4-bromo-phenyl)-2-[(2,4-dichloro-benzyl)-methyl-amino] ethanol are introduced into 15 ml of dichloromethane and, at 0 0 C, 15 ml of conc. 10 H 2
SO
4 are added. After stirring at room temperature for 2 hours, the reaction mixture is poured onto ice and made alkaline with 6 N NaOH. Three extractions with dichloromethane are carried out. The combined organic phases are dried with MgSO 4 and concentrated. For further purification, the residue is chromatographed on silica gel, resulting in 2.6 g of the title compound as a yellowish oil. 15 4-(4-Bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline, hydrochloride; r Ci CIH CI 300 mg of 4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline are 20 stirred in 2 N HCI at room temperature. The resulting precipitate is filtered off with suction and dried. Example 6: 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid; OOH C CIH CII C I N 11 99 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid; 5.57 g (15 mmol) of 4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4 tetrahydroisoquinoline (example 5, intermediate 3) are dissolved in 150 ml of abs. DMF/benzene (1:1). After the solution has been degassed, under argon 1.18 g 5 (4.5 mmol) of triphenylphosphine and 1.17 g (9 mmol) of Ca(HCO2)2 are added. After renewed flushing with argon, 867 mg (0.75 mmol) of Pd(PPh 3
)
4 are added and carbon monoxide is passed into the solution. The mixture is stirred at 1200C. After six hours at 1200C and standing overnight under argon, a further 867 mg (0.75 mmol) of Pd(PPh 3
)
4 were added and stirring at 120 0 C and passing carbon monoxide into the 10 solution were continued for eight hours. After again standing overnight, 135 mg of PdCI 2 were added and reaction was allowed to take place under the same conditions. For workup, the solvent is removed in vacuo and the residue is taken up in ethyl acetate. Three extractions with 2 N NaOH are carried out. The combined aqueous phases are adjusted to pH 6 with 6 N HCI and extracted three times with ethyl acetate. 15 The organic phases are dried with MgSO 4 and freed of solvent. The residue is purified on silica gel using a dichloromethane/methanol mixture, resulting in 420 mg of the title compound (Rt = 4.025 min (method A); MS(CI
+
) = 336.1/338.1). Example 7: 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-ethyl 20 benzamide, trifluoroacetate; TFA CI N 146 mg (0.43 mmol) of 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) benzoic acid (see example 6) are dissolved in 5 ml of DMF, and 1.0 equivalent of triethylamine is added. At 00C, a solution of 141 mg (0.43 mmol) TOTU in 3 ml of DMF 25 is added. The mixture is stirred at 0OC for 30 min and at room temperature for 30 min. This solution is then added at 00C to a solution of 0.28 ml of 2 M ethylamine solution and 0.06 ml (0.043 mmol) of triethylamine in 5 ml of DMF, and the reaction mixture is 100 stirred at room temperature for three hours. For workup, the solvent is distilled off in vacuo, and the residue is taken up in ethyl acetate and washed twice with 1 N KOH and once with H 2 0. The organic phase is dried with Na 2
SO
4 and concentrated. Chromatography on silica gel (dichloromethane/methanol 95:5) is used for further 5 purification. Further purification on a preparative HPLC (acetonitrile/H20/trifluoroacetic acid) affords the desired carboxamide as trifluoroacetate (Rt = 4.169 min (method A); MS(ClI
+
) = 363.3/365.3). Example 8: 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-propyl 10 benzamide, trifluoroacetate; o
I
TFA cl CII ci The title compound can be prepared by the method described in example 7 starting from n-propylamine and 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) benzoic acid (see example 6). 15 (Rt = 1.881 min (method B); MS(CI+) = 377.3/379.3). Example 9: 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-(2 dimethylamino-ethyl)-benzamide, trifluoroacetate; o TFA CI c N CI 20 was prepared in analogy to example 7 starting from example 6 and N1,N1 dimethylethane-1,2-diamine by a TOTU-mediated coupling reaction (Rt = 1.449 min (method B); MS(CIl) = 406.3/408.3).
101 Example 10: 6,8-Dichloro-2-methyl-4-(4-morpholin-4-yl-phenyl)-1,2,3,4 tetrahydroisoquinoline, trifluoroacetate; 0 N TFA CI 5 456 mg (1.4 mmol) of Cs2CO3, 6.75 mg (0.03 mmol) of palladium acetate and 28 mg (0.045 mmol) of 2,2-bis-(diphenylphosphino)-1,1-binaphthyl are introduced into 5 ml of abs. toluene. Under argon, a solution of 0.104 ml (1.2 mmol) of morpholine in 2.5 ml of abs. DMF, and a solution of 371 mg (1.0 mmol) of 4-(4-bromo-phenyl)-6,8-dichloro-2 methyl-1,2,3,4-tetrahydroisoquinoline in 2.5 ml of abs. toluene are added, and the 10 mixture is stirred at 100C for a total of 9 hours. For workup, the solvent is removed, the residue is taken up in dichloromethane, and insoluble constituents are filtered off. After concentration of the filtrate, the residue is chromatographed on silica gel (CH 2
CI
2 /methanol 95:5), resulting in 350 mg of the desired morpholine derivative. After a further purification on a preparative HPLC it is possible to isolate 160 mg of the 15 corresponding trifluoroacetate in the form of a colorless solid. Example 11: [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-phenyl] diethyl-amine, trifluoroacetate; N TFA cl CI 20 The procedure is analogous to the method described in example 10 starting from diethylamine and 4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydro isoquinoline (example 5, intermediate 3). Reaction time: 2 days at 100 0 C; three times 102 the amount of Pd catalyst and phosphine ligand. The desired trifluoroacetate can be isolated as a colorless solid after preparative HPLC. Example 12: 6,8-Dichloro-2-methyl-4-(4-piperidin-1 -yl-phenyl)-1,2,3,4-tetrahydro 5 isoquinoline, trifluoroacetate; N TFA
CI
/Nq CI The desired piperidine derivative can be obtained starting from piperidine and 4-(4 bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline (example 5, intermediate 3) in analogy to the method described in example 10. 10 Example 13: 6,8-Dichloro-2-methyl-4-(4-pyrrolidin-1-yl-phenyl)-1,2,3,4 tetrahydroisoquinoline, hydrochloride; N ClH C I Cl The reaction is carried out in analogy to the method described in example 10, starting 15 from pyrrolidine and 4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4 tetrahydroisoquinoline (example 5, intermediate 3). The product obtained after purification by chromatography is taken up in the DMSO/acetonitrile mixture, whereupon a precipitate separates out. This is filtered off, dissolved in 2 N HCI and freeze dried, resulting in the title compound of a colorless solid. 20 Example 14: 6,8-Dichloro-2-methyl-4-[4-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4 tetrahydro-isoquinoline, trifluoroacetate; 103 N N TFA CI N CI Reaction of N-methyl-piperazine and 4-(4-bromo-phenyl)-6,8-dichloro-2-methyl 1,2,3,4-tetrahydroisoquinoline (example 5, intermediate 3) by the method described in example 10 affords the title compound in the form of a colorless solid. 5 Example 15: 6,8-Dichloro-2-cyclopropyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline, trifluoroacetate; I TFA CI /N cl Intermediate 1: 10 Cyclopropyl-(2,4-dichloro-benzyl)-amine; 5.25 g (30 mmol) of 2,4-dichlorobenzaldehyde are introduced into 140 ml of methanol and, at room temperature, a solution of 1.71 g (30 mmol) of cyclopropylamine is added. The mixture is stirred at room temperature for 40 min and then 1.42 g (37.5 mmol) of NaBH 4 are added in portions. After standing overnight, the solvent is 15 removed and the residue is taken up in 2 N HCI. Two extractions with ethyl acetate are carried out. The aqueous phase is made alkaline with NaOH and again extracted twice with ethyl acetate. The organic phases are dried with MgSO 4 and concentrated. The crude product obtained in this way, in the form of a slightly yellowish oil, can be reacted further without further purification. 20 Intermediate 2: 2-[Cyclopropyl-(2,4-dichloro-benzyl)-amino]-1l-phenyl-ethanone; 104 Intermediate 1 is reacted with alpha-bromoacetophenone in the presence of triethylamine in dioxane by the method described in example 1, intermediate 3. For workup, the solvent is distilled off, and the residue is taken up in ethyl acetate. It is washed twice with H 2 0 and twice with 2 N HCI, dried with MgSO 4 and concentrated. 5 The crude product obtained in this way can be reacted further without further purification. Intermediate 3: 2-[Cyclopropyl-(2,4-dichloro-benzyl)-amino]-1l-phenyl-ethanol; Intermediate 2 is reduced with NaBH 4 in analogy to the method described in 10 example 1, intermediate 4. For workup, the mixture is concentrated, and the residue is partitioned between 1 N HCI and ethyl acetate. The aqueous phase is separated off and extracted once more with ethyl acetate. The combined organic phases are dried with MgSO 4 and the solvent is removed in vacuo. 15 6,8-Dichloro-2-cyclopropyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline, trifluoroacetate; Intermediate 3 (1.9 g) is dissolved without further purification in 10 ml of dichloromethane and cyclized with conc. H 2
SO
4 by the method described in example 1. For workup, the reaction mixture is poured onto ice. The organic phase is separated off, and the aqueous phase is extracted once more with dichloromethane. 20 The combined organic phases are dried with MgSO 4 and freed of solvent. Chromatography on silica gel (n-heptane/ethyl acetate 5:1 - 3:1) affords 200 mg of a yellowish oil, which is subjected to further purification on a preparative HPLC. This results in 184 mg of the title compound as trifluoroacetate. 25 Example 16: 16a: (-)-N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-acetamide; 16b: (+)-N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide; 105 o N~k (+ and-) Cl /N Cl 500 mg of the title compound from example 1 are separated on a chiral phase, resulting in about 250 mg of the two enantiomeric acetamides 16a and 16b. chiral column: Chiralpak OD 250 x 4.6 mm; 5 solvent: acetonitrile; flow rate: 1 mI/min; Rt((-)-enantiomer/16a) = 5.856 min; Rt((+)-enantiomer/16b) = 8.613 min. 10 Example 17: 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine, hydrochloride;
NH
2 cl x HCI N111 Cl Intermediate 1: 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine; 15 3.0 g (8.6 mmol) of N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-acetamide (example 1) are dissolved in 100 ml of 20% strength sodium ethanolate solution and heated under reflux for four hours. A further 2.0 g (29.4 mmol) of solid sodium ethanolate are added, and the mixture is heated under reflux for three more hours. For workup, the solvent is removed in vacuo, and the residue is taken up 20 in 200 ml of H 2 0 and extracted twice with dichloromethane. The combined organic phases are dried with MgSO 4 and concentrated. Further purification by 106 chromatography on silica gel (ethyl acetate/heptane 1:1) results in the aniline as a yellowish oil in quantitative yield. 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine, 5 hydrochloride; 200 mg (0.65 mmol) of 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenylamine are dissolved in 30 ml of ethanolic HCI. The clear solution is concentrated in vacuo. The residue is triturated in ether, filtered off with suction and dried, whereupon it was possible to isolate 208 mg of the desired hydrochloride. 10 Example 18: N-Ethyl-N'-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) benzenesulfonylurea, hydrochloride HN IS, HN Cl N CIH 1.0 mmol of 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene 15 sulfonamide (example 4, intermediate 2) is mixed with 350 mg (2.5 eq) of K 2
CO
3 in 15 ml of dry acetone and stirred at room temperature for 1.5 hours. A solution of 2.5 eq of ethyl isocyanate in acetone is added dropwise at room temperature, and the solution is heated to reflux. For workup, the mixture is concentrated in vacuo, and the residue is taken up in H 2 0 and extracted twice with ethyl acetate. The aqueous phase is acidified 20 with 6 N HCI, and the resulting precipitate is filtered off with suction. Washing with ethyl acetate and drying in vacuo affords the title compound in good yield. Example 19: 1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 propylurea; 107 o HN N CI CI A solution of 0.17 g (2.0 mmol) of n-propyl isocyanate in toluene is added dropwise to a stirred solution of 500 mg (1.63 mmol) of 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro isoquinolin-4-yl)-phenylamine (see example 17) in 15 ml of toluene. After one hour at 5 400C, a further 0.17 g of n-propyl isocyanate is added, and the mixture is stirred at 800C for one hour. For workup, the solvent is removed and the residue is triturated with
H
2 0 and ether. Drying affords 503 mg of the desired n-propylurea. 19a: 1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-propyl 10 urea, hydrochloride; HN N-N CI CIH CI 450 mg of 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 propyl-urea are dissolved in a mixture of 2 N HCI and THF. The clear solution is concentrated in vacuo, and the residue is triturated with ether and filtered off with 15 suction. Drying affords 473 mg of the desired hydrochloride. Example 20: 1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 methyl- thiourea; HN N CI k
CI
108 Proceeding in analogy to the method described in example 19 and starting from 500 mg (1.63 mmol) of 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenylamine (see example 17) and 220 mg (3.0 mmol) of methyl isothiocyanate allows 245 mg of the desired thiourea to be isolated. 5 Example 21: 1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 ethylurea; HN N-' CI N I /Nq CI Preparation takes place in analogy to a method described in example 19, starting from 10 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (500 mg; 1.63 mmol) and ethyl isocyanate (284 mg/4 mmol). 21 a: 1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl urea, hydrochloride; HN N~N HN S CIH 15 CI Conversion into the corresponding hydrochloride takes place in analogy to the method described in example 19a. Example 22: N-[4-(6-Methanesulfonyl-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) 20 phenyl]-acetamide; o HN,
N
109 Intermediate 1: (4-Methanesulfonyl-benzyl)-methyl-amine is synthesized starting from 1-bromomethyl-4-methanesulfonylbenzene and methylamine in a manner known to the skilled worker. 5 The title compound is prepared in analogy to the synthetic route indicated in example 1, starting from (4-methanesulfonyl-benzyl)-methyl-amine (intermediate 1) and N-[4-(2-bromo-acetyl)-phenyl]-acetamide (example 1, intermediate 2). Example 23: N-[4-(2,6,8-Trimethyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 10 acetamide; HNL I
I
I N The synthetic route detailed in example 1 is followed, starting from (2,4-dimethyl benzyl)-methyl-amine, which can be prepared from 1-bromomethyl-2,4-dimethyl benzene and methylamine in a manner known to the skilled worker, and N-[4-(2 15 bromo-acetyl)-phenyl]-acetamide (example 1, intermediate 2). Example 24: N-[4-(6-Bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-acetamide; HN /N Br N 20 The synthetic route detailed in example 1 is followed, starting from (4-bromo-2-chloro benzyl)-methyl-amine, which can be prepared from 4-bromo-1-bromomethyl-2-chloro benzene and methylamine in a manner known to the skilled worker, and N-[4-(2 bromo-acetyl)-phenyl]-acetamide (example 1, intermediate 2).
110 Example 25: N-[4-(8-Chloro-2-methyl-6-pyrrolidin-1-yl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-acetamide; HN ON N CI 1.02 g (3.12 mmol) of Cs2CO 3 , 8.8 mg (0.04 mmol) of palladium acetate and 36.1 mg 5 (0.06 mmol) of 2,2-bis-diphenylphosphino-1,1-binaphthyl are introduced into 6.5 ml of abs. toluene under argon. At room temperature, a solution of 512 mg (1.3 mmol) of N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide (example 24) in 4 ml of abs. DMF, and a solution of 111 mg (1.56 mmol) of pyrrolidine in 4 ml of DMF are added, and the mixture is heated at 1000C for 7 hours. For workup, 10 the solvent is removed in vacuo, and the residue is taken up in dichloromethane. Insoluble constituents are filtered off, and the filtrate is concentrated. The residue is chromatographed on silica gel with a dichloromethane/methanol mixture, and it is possible to isolate 360 mg of the compound of the example. 15 25a: N-[4-(8-Chloro-2-methyl-6-pyrrolidin-1-yl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-acetamide, hydrochloride; HNL CN CiH I CI 320 mg of N-[4-(8-chloro-2-methyl-6-pyrrolidin-1-yl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-acetamide are dissolved in 20 ml of ethanolic HCI, stirred at room temperature 20 for 30 min and concentrated. The residue is taken up in H 2 0 and freeze dried. Example 26: N-[4-(8-Chloro-2-methyl-6-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-acetamide, trifluoroacetate; 111 o HNk Nx TFA Preparation takes place in analogy to the method described in example 25, starting from N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide (example 24) and morpholine. The chromatography on silica gel was 5 followed by a further purification on a preparative HPLC. Example 27: N-{4-[8-Chloro-2-methyl-6-(4-methyl-piperazin-1-yl)-1,2,3,4-tetrahydro isoquinolin-4-yl]-phenyl}-acetamide; HNL N / Nq CI 10 Preparation takes place in analogy to the method described in example 25, starting from N-[4-(6-Bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide (example 24) and N-methyl-piperazine. 27a: N-{4-[8-Chloro-2-methyl-6-(4-methyl-piperazin-1-yl)-1,2,3,4-tetrahydro-isoquinolin 15 4-yl]-phenyl}-acetamide, hydrochloride; HNL. NN N x HCI I /Nq 220 mg of N-{4-[8-Chloro-2-methyl-6-(4-methyl-piperazin-1-yl)-1,2,3,4-tetrahydro isoquinolin-4-yl]-phenyl}-acetamide are dissolved in a little methanol, diluted with 2 N HCI and freeze dried, resulting in 226 mg of the desired hydrochloride.
112 Example 28: N-{4-[8-Chloro-6-(cyclopropylmethyl-amino)-2-methyl-1,2,3,4-tetrahydro isoquinolin-4-yl]-phenyl}-acetamide, hydrochloride; 0 HN. N x HC N N " CI Preparation takes place in analogy to the method described in example 25, starting 5 from N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide (example 24) and C-cyclopropyl-methylamine. The chromatography on silica gel was followed by a further purification on a preparative HPLC. The purified compound was dissolved in 1 N HCI, diluted with H 2 0 and freeze dried. 10 Example 29: 5-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy benzoic acid; H OH CI 1N CI Intermediate 1: Ethyl 5-acetyl-2-hydroxy-benzoate is prepared from 5-acetyl-2-hydroxy-benzoic acid by acid-catalyzed esterification in a 15 manner known to the skilled worker. Intermediate 2: Ethyl 5-(2-bromo-acetyl)-2-hydroxy-benzoate is prepared from ethyl 5-acetyl-2-hydroxy-benzoate by a known method in analogy to the process described in example 1, intermediate 2. 20 Intermediate 3: Ethyl 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2 hydroxy-benzoate The title compound is synthesized by the synthetic route described in example 1, starting from ethyl 5-(2-bromo-acetyl)-2-hydroxy-benzoate and 2,4-dichlorobenzyl 25 (methyl)-amine (see example 1, intermediate 1).
113 5-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoic acid; 6.8 g (18 mmol) of ethyl 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2 hydroxy-benzoate are hydrolyzed in an ethanol/2 N KOH mixture in a manner known to 5 the skilled worker, resulting in 5.4 g of the free acid. 29a: 5-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoic acid, sodium salt; H I ONa c C F CI 10 352 mg (1 mmol) of the free acid 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro isoquinolin-4-yl)-2-hydroxy-benzoic acid are dissolved in 10 ml of 0.1 M NaOH, diluted with H 2 0 and freeze dried, resulting in 375 mg of the title compound. Example 30: 5-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-N 15 methyl-benzamide, trifluoroacetate; H CI
N
, TFA CI The title compound can be prepared starting from 5-(6,8-dichloro-2-methyl-1,2,3,4 tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoic acid in a TOTU-mediated reaction with methylamine in analogy to the method described in example 7. 20 Example 31: 5-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-ethyl-2 hydroxy-benzamide, trifluoroacetate; 114 H C TFA CI The title compound can be prepared starting from 5-(6,8-dichloro-2-methyl-1,2,3,4 tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoic acid in a TOTU-mediated reaction with ethylamine in analogy to the method described in example 7. 5 Example 32: 5-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-(2 dimethylamino-ethyl)- 2-hydroxy-benzamide, trifluoroacetate; H Nq I4 x TFA CI The title compound can be prepared starting from 5-(6,8-dichloro-2-methyl-1,2,3,4 10 tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoic acid in a TOTU-mediated reaction with N1,N1-dimethyl-ethane-1,2-diamine in analogy to the method described in example 7. Example 33: N-[5-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2 hydroxy-benzoyl]-guanidine; H NH z -N NH 2 15 cI 2.52 g of potassium tert-butoxide are added to a solution of 2.39 g (25 mmol) of guanidine hydrochloride in 15 ml of abs. DMF and stirred at room temperature for 45 min. A solution of 950 mg (2.5 mmol) of ethyl 5-(6,8-dichloro-2-methyl-1,2,3,4 tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoate (example 29, intermediate 3) in 10 ml 20 of abs. DMF is added, and the mixture is stirred at room temperature for four hours. After no further increase in conversion is detectable, the precipitate is removed by filtration with suction and the solvent is removed in vacuo. The residue is taken up in 115 2 N HCI and extracted twice with dichloromethane. The aqueous phase is adjusted to a pH of about 10 with KOH, whereupon the desired acylguanidine separates out as a colorless precipitate. Filtration with suction and drying affords 793 mg of the title compound. 5 Example 34: N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide; lo Cl cN CI 10 N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide; The desired meta-acetanilide is prepared in analogy to the synthetic route indicated for example 1, starting from N-(3-acetyl-phenyl)-acetamide and 2,4-dichlorobenzyl (methyl)-amine (example 1, intermediate 1) in four analogous stages. 15 Example 35: 3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine;
NH
2 CI /N, CI Acetyl is eliminated from N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-acetamide (example 34) by the method described in example 17, intermediate 1, in the presence of sodium ethanolate. 20 Example 36: 2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine;
NH
2 CI n ItaNy Intermediate: N-[2-(2-Bromo-acetyl)-phenyl]-acetamide; 116 31 g (0.175 mol) of N-(2-Acetylphenyl)-acetamide (prepared by acylation of 2-aminoacetophenone with acetyl chloride as described by Fuerstner, Alois; Jumbam, Denis N.; Tetrahedron; 48; 29; 5991-6010, (1992)) are dissolved in 200 ml of glacial acetic acid. 127 ml of 33% strength HBr in glacial acetic acid are added and then, at 5 room temperature, 8.75 ml (0.175 mol) of bromine are slowly run in. The mixture is stirred at room temperature overnight. The mixture is stirred into 1.5 I of ice-water, and the precipitated product is filtered off with suction, thoroughly washed with ice-water and dried in vacuo. The crude product contains, according to HPLC and NMR, some precursor and dibrominated product, but is pure enough (about 85% strength) for 10 further reaction. Yield: 43 g Intermediate 2: N-(2-{2-[(2,4-Dichloro-benzyl)-methyl-amino]-acetyl}-phenyl) acetamide; 15 12.4 g (65.24 mmol) of 2,4-dichloro-N-methylbenzylamine (example 1, intermediate 1) are dissolved in 200 ml of dioxane. To this are added 19.96 g of the crude product from the preceding bromination, likewise dissolved in 200 ml of dioxane, and 45 ml of triethylamine. The mixture is stirred at room temperature overnight and then filtered. The filtrate is evaporated, and the residue is taken up in ethyl acetate and washed with 20 saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated in a rotary evaporator. The crude product (20.4 g) is pure enough according to NMR for further reaction. Intermediate 3: N-(2-{2-[(2,4-Dichloro-benzyl)-methyl-amino]-1-hydroxy-ethyl}-phenyl) 25 acetamide; 20 g of the crude product from the preceding stage (about 50 mmol) are dissolved in 200 ml of methanol and cooled to < 5 0 C in an icebath. To this are added, while stirring vigorously, 4.3 g (109 mmol) of sodium borohydride in portions so that the internal temperature does not exceed 10 0 C. The mixture is then stirred in the icebath for 30 30 min and at RT for 1 h. After standing overnight, the mixture is evaporated, and the residue is taken up in ethyl acetate, washed 3x with water and 1 x with brine, dried 117 over sodium sulfate and concentrated in a rotary evaporator. The crude product (19.4 g) is reacted further without purification. Intermediate 4: 1-(2-Amino-phenyl)-2-[(2,4-dichloro-benzyl)-methyl-amino]-ethanol; 5 10Og of the crude product from the preceding stage are dissolved in 300 ml of methanol. 200 ml of conc. hydrochloric acid are added, and the mixture is stirred at 500C for 10 h. The mixture is allowed to cool and is poured into water, and the pH is adjusted to 10-12 with 20% strength NaOH. The product is extracted with ethyl acetate, and the combined extracts are washed with brine, dried over sodium sulfate and evaporated. 10 The crude product (9.9 g) contains some sodium chloride, but this does not interfere with further reaction. 2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine; 9.9 g of the crude product from the preceding stage are dissolved in 350 ml of 15 chloroform. While cooling in an icebath, 123 ml of conc. sulfuric acid are added dropwise. The mixture is stirred in the icebath for 2 h and is then allowed slowly to reach RT and is finally heated at 500C overnight. The cooled mixture is poured onto ice and made alkaline (pH > 10) with sodium hydroxide solution. The organic phase is separated off, the aqueous phase is back-extracted 2x with methylene chloride, and 20 the combined organic phases are washed with water and NaCI, dried over sodium sulfate and evaporated. General method for preparing the compounds of examples 37 to 77: 154 mg (0.5 mmol) of the title compounds from example 35, example 36 or 25 example 17, intermediate 1, are introduced into 5 ml of dichloromethane, and 0.076 ml (0.55 mmol) of triethylamine is added. At 00C, a solution of 1.1 equivalents (0.55 mmol) of an acid chloride in 5 ml of dichloromethane is added, and the mixture is stirred overnight while warming up. For workup, it is filtered and freed of solvent. The residue is dissolved in 20 ml of ethyl acetate and washed once each with 5% strength 30 NaHCO 3 solution and 5% strength NaCI solution, and dried. Evaporation of the solvent is followed by final purification on a preparative HPLC.
118 Table 1: Precursor 1/ Precursor 2/ Example Product aniline acid chloride
NH
2 NH 37 ciiNciN 37 N Cl TFA O I 0/ N Ex. 17, Int. 1
NH
2 38 CI ,N, V~ Ci , 38 N ci TFA 0 N Ex. 17, Int. 1 NH HN 3c9 ci 39 N C TFA o Ex. 17, Int. 1
NH
2 4 0 N -- y Cl c, N "rFA HN NH 400 ci, . HN 41 cNI cl a1 I m O Ex. 17, Int. 1 119 NH, 0 1HN 42 c I , cI cl Cl TFA o Ex. 17, Int. 1 c NH, HN II NH , 43 cl N l Cl Cl TFA o NN O / Ex. 17, Int. 1
NH
2 I HN 44 N N' 44 cc N cl TFA O Ex. 17, Int. 1 NHo HN F c F 45 IN F NF CC cl TFA EN Ex. 17, Int. 1 NH2 N o HN 4 6 * C N )'Nr NI 0 Ex. 17, Int. 1 0 NH, HN N ca 47 NCI Cl TFA N" Ex. 17, Int. 1 120
NH
2 0 ,O HN c 48 No c N T " N S.'C I 1 -" ' " c NT Ex. 17, Int. 1
NH
2 O, 0 /HNN 49 Cl N 0 0 IS cl N Cl TFA Ex. 17, Int. 1
NH
2 0 0 HN N
,,
c l I'S TFA 50 N \N I Cl TFA Ex. 17, Int. 1 NH2 II CI N 51 I l Cl / NN 52 " Ex. 17, mt-,I NH2 53l C TFA 0 CI N o 1 Ex. 35 NH, N NHN 52I NNC 54 1 , " cl c0\ F I NIT 0 N Ex. 35 ~. NH 2 54N.lc TFA Ex. 35 121 - NH, Ex. 35 cI . NH 2 N 56l 0~C E 5 6~ N,, NlT Ex. 35 .NH, NN TO~ 57 N 0lTF 0 Ex. 35 ~. NH, NI N 58 ,- NN I CI N - TEA Ex. 350 '' NH2 Nl F N' 0 59 NI - NN Fy F
-
,F CI N TE 0 Ex. 35
NH
2 N, 60l N NN 6 1 Nl cl CATFA CI I- "-' Ex. 350 122 ~. NH 2 N. N , 62 - N ~ 0 ,O N Ex. 35 SNH, 63 N.- 0 1 0 N.TF Ex. 35 . NH 2 64 N Nc yTF E. 005N 64c NH C N CC 0 Ex. 35 cl NH, Ex. 36 cl ~ NH, 67 N~ O N T 0 Ex. 36 I NH, 67I N~ a1 N N 0 Ex. 36 123 Q-NH, 69 cI l 0 Ex. 36 70 NN ci 11- N-, TFA 0 Ex. 36 CIl Ex. 36 2 N QlN , F I N. 72NH, ci c A F .- N, TFA Ex. 360 N,. F4 No y TF Ex. 360 CiY IIH NoN S N, 0 AT TFA I >"CI Ex. 360 124 NH, OO CI N. S.. 76 N 0 , C o cSC N TFA Ex. 36 O'NH O ,, O~ N. NN 77 NO o I N 'CI N. TFA Ex. 36 *) Product precipitates from the reaction solution and requires no further purification Example 78: 1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 ethyl-urea, trifluoroacetate; \ N ON CI SN TFA 5 0.355 mmol of the compound of example 35 is dissolved in 5 ml of dry acetonitrile, and 0.39 mmol of ethyl isocyanate is added. After standing overnight with exclusion of moisture, the solvent is removed and the crude product is purified on a preparative HPLC, resulting in the title compound as a colorless solid. 10 Example 79: 1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 methyl-thiourea, trifluoroacetate; \ N Nq - S CI N C N TFA The title compound is synthesized starting from the compound of example 35 and 15 methyl isothiocyanate by the method described in example 78.
125 Example 80: 1-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 ethyl-urea; 0 CI Nz The process is analogous to example 78, starting from the compound of example 36 5 and ethyl isocyanate. For workup, the resulting precipitate is filtered off with suction and washed with acetonitrile, resulting in the desired ethylurea as a colorless solid. Example 81: 1-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 methyl-thiourea, trifluoroacetate; S CI TFA /Nq 10 The compound of example 36 and methyl isothiocyanate are reacted in analogy to the method described in example 78. Example 82: N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 15 ethanesulfonamide, hydrochloride; CI CIH 307.1 mg (1 mmol) of the compound of example 35 are dissolved in 10 ml of pyridine and at 0oC, 0.19 g (1.5 mmol) of ethanesulfonyl chloride, and a catalytic amount of DMAP are added. The mixture is stirred at room temperature. 20 For workup, the solvent is removed in vacuo, the residue is taken up in ethyl acetate and washed with H 2 0. The organic phase is dried with MgSO 4 and concentrated. The 126 crude product is chromatographed on silica gel. The sulfonamide obtained in this way is dissolved in a THF/2 N HCI mixture and again concentrated in vacuo, resulting in 208 mg of the desired hydrochloride. 5 Example 83: N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] methanesulfonamide, hydrochloride; I 00 C N CIH /N, CI The process is analogous to the method described in example 82, starting from the compound of example 35 and methanesulfonyl chloride. 10 Example 84: N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl] ethanesulfonamide, hydrochloride; 0,o HNS Cl ClH N C The process is analogous to the method described in example 82, starting from the 15 compound of example 17, intermediate 1, and ethanesulfonyl chloride. Example 85: N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] methanesulfonamide, hydrochloride; HN
I
CI CIH 127 The process is analogous to the method described in example 82, starting from the compound of example 17, intermediate 1, and methanesulfonyl chloride. Example 86: 86a: (-)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) 5 phenyl]-acetamide; 86b: (+)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide; -- 0 (+ and-) Cl N, CI 2.0 g of the title compound from example 34 are separated on a chiral phase, resulting 10 in about 1.0 g of the two enantiomeric acetamides 86a and 86b. chiral column: Chiralpak ADH/31 250 x 4.6 mm; solvent: acetonitrile; flow rate: 1 ml/min; Rt((-)-enantiomer/86a) = 5.541 min; 15 Rt((+)-enantiomer/86b) = 7.033 min. General method for preparing the compounds of examples 87 to 98 1.0 mmol of 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (example 17, intermediate 1) or 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin 20 4-yl)-phenylamine (example 35) is introduced into 10 ml of pyridine and, at 0 0 C, a solution of 1.2 equivalents of the appropriate sulfonyl chloride (see table 2) in 5 ml of dichloromethane is added dropwise. The mixture is stirred at room temperature. A catalytic amount of DMAP is added depending on the progress of the reaction and, where appropriate, the reaction temperature is increased to 50 0 C until no further 25 increase in conversion can be detected. For workup, the mixture is concentrated and the residue is partitioned between ethyl acetate and saturated NaHCO 3 solution. The 128 organic phase is separated off and washed once more with saturated NaHCO 3 solution and H 2 0, dried with Na 2
SO
4 and concentrated. For further purification, the crude product obtained in this way is chromatographed on silica gel. The products obtained in this way are converted into the corresponding hydrochlorides by dissolving 5 the substances in 2 N HCI or ethanolic HCI and freeing off solvent, resulting in the desired HCI salts. Purification in a preparative HPLC system results in the corresponding products as trifluoroacetates. 10 Table 2: Precursor 1/ Precursor 2/ Example Product Example aniline acid chloride Product
NH
2 O 0 HNS F N/ F N1 0 0 1 87 ca N F OSO 87N" " ' F %%.CI Cl TFA F 7N Ex. 17, Int. 1 NH, HO F INN 88 N
F
0 / NN Ex. 17, Int. 1
NH
2 F HIS F 88a N F 0 0 H Cl N Fx 17, Int.I1 /NN Ex. 17, Int. 1
NH
2 O O NHN N 89 N N Bar S=o ci / NN Ex. 17, Int. 1 129
NH
2 0 O HN 89a c N Br O cI rCl CIH CI /NN Ex. 17, Int. 1 NH, // I2N o s' 90 ck, a N =0-a o Cl Cl N . Ex. 17, Int. 1 c
NH
2 0 O / 2 HN N\IN Nl 0 N- 0 90a - N, N C =0 I o cI CIH /NN Ex. 17, Int. 1 c NH, 0 0 HNSN NN N 91 oN oP// N 91 N N CC/ c N N NN Ex. 17, Int. 1
NH
2 00 N HN S N NN ol N 91a 0,// N 91a N C I N Ex. 17, Int. 1 N H 2 o -'S0 NHN
H',ON
O N Cl O |/ 92 N c / N N NL 0 CI /N Ex. 17, Int. 1 130
NH
2 0..0 c
-
HN N Nl 0U// 92a -N~ N N-l clC Ex. 17, Int. 1 . NH, F Nr 00 0 93F A FITF Ex. 35 clscIN S NH 2 F cl~N 0 1 0 F NN Ex. 35 cI N NH 2 9 4 a .- N F 0 0 N, Il CIH Ex. 35 CI NH 95 N" Br -S=O NHN I CI Ex. 35 ~. NH 2 N 96 l" N NN~K NN cI c' NI Ex. 35 - NN 131 S NH, N |4 97Co' ' N " Ex. 35 N OI / Cl 97a N 0 NN N CN CI Ex. 35 C NH, N NN CII C I N I/ Ex. 35 General method for synthesizing the compounds of examples 99 to 110 Preparation of the amine component 4.0 mmol of the aromatic aldehyde (see table 3) are stirred with 8.0 mmol of the 5 aliphatic amine (see table 3) in methanol at room temperature for 2 hours and then, depending on the progress of the reaction, 0.67 to 2.0 eq of NaBH 4 are added in portions. After standing at room temperature overnight, the solvent is removed and the residue is taken up in 1 N HCI. It is extracted with dichloromethane. The aqueous phase is adjusted to a pH of 11 to 12 with NaOH and again extracted with 10 dichloromethane. The organic phases are dried with MgSO 4 and concentrated in a rotary evaporator. Further purification takes place by chromatography on silica gel or on a preparative HPLC. Preparation of the bromo ketone component 15 The bromo ketone building blocks are synthesized by methods known from the literature, starting from commercial acetophenones by treatment with bromine in glacial acetic acid in analogy to example 1, intermediate 2. NH, "N N 0 98 N N N1 Ex. 351 General method for synthesizing the compounds of examples 99 to 110 Preparation of the amine component 4.0 mmol of the aromatic aldehyde (see table 3) are stirred with 8.0 mmol of the 5 aliphatic amine (see table 3) in methanol at room temperature for 2 hours and then, depending on the progress of the reaction, 0.67 to 2.0 eq of NaBH 4 are added in portions. After standing at room temperature overnight, the solvent is removed and the residue is taken up in 1 N HCI. It is extracted with dichloromethane. The aqueous phase is adjusted to a pH of 11 to 12 with NaOH and again extracted with 10 dichloromethane. The organic phases are dried with MgSO 4 and concentrated in a rotary evaporator. Further purification takes place by chromatography on silica gel or on a preparative H PLC. Preparation of the bromo ketone component 15 The bromo ketone building blocks are synthesized by methods known from the literature, starting from commercial acetophenones by treatment with bromine in glacial acetic acid in analogy to example 1, intermediate 2.
132 The compounds of examples 100 to 111 can be prepared starting from the amine and bromo ketone components shown in table 3 in analogy to the synthetic route shown in example 1 (alkylation of the amine component by the bromo ketone component, subsequent reduction with NaBH 4 and final H 2
SO
4 -mediated cyclization). 5 The resulting tetrahydroisoquinolines can be converted into the corresponding salts in a manner known to the skilled worker. Table 3: Bromo Example Aromatic Aliphatic Amine ketone Compound of ketone Copudf No. aldehyde amine component component example component exml C NH, NH, 99 CHO NH2 O . Br a-' Cl *) 101 CI N CHO 2CI CH CH Br 100 CHO -NH 2 Br N , 0 H( 102 c CHO -NH 2 CI H CII C0 Br 102 C" CHO \-NH 2 c, , { B r c,. CI Br N F F F 103 CHO -NH 2 FBr 0 F FF F F F F 133 CI CI NN - O 105 No C CHO -NH2 O Br N N N N I 105 HO -NH 2 0 C1 CO2O,, Br N F F 10CCiO__ HCcI 106 CHO NH 2 CI aCIH Cl Br N 107 cHO cuC,2O 0
CI
108 -I& CO -NH2 \ 9 B CI NrJ O CliOBr Lo 109 c CHO -NH 2 Br CI CIH CII 110 CHO NH 2 CIH 109-NHH 2 Br i Br Br N . *) Synthesis described in: Lang et al., DE-A 24 36 263 General method for preparing the compounds of examples 111 to 124 0.358 mmol of the acids indicated in table 4 are dissolved in 1 ml of DMF, and 5 0.221 ml (1.30 mmol) of diisopropylethylamine is added. At 0 0 C, a solution of 128 mg (0.390 mmol) of TOTU in 1 ml of DMF is added dropwise. After addition of a solution of 100 mg (0.325 mmol) of the amine component indicated in table 4, in 2 ml of DMF, the mixture is stirred at room temperature overnight. For workup, insoluble constituents are filtered off and washed with 20 ml of ethyl acetate. The filtrate is washed twice with 134 saturated NaHCO 3 solution and once with 5% strength NaCI solution, dried and concentrated. The crude products which still contain Boc protective groups are deprotected without 5 further purification (see below: general method for eliminating the Boc protective groups). Workup of building blocks without Boc protection is followed by purification by preparative HPLC, with the desired compounds of the examples being obtained as trifluoroacetates. 10 General method for preparing the compounds of examples 124 to 147 0.358 mmol of the acids indicated in table 4 are dissolved in 1 ml of DMF, and 0.221 ml (1.30 mmol) of diisopropylethylamine is added. At 00C, 151 mg (0.975 mmol) of diethylcarbodiimide, a solution of 132 mg (0.975 mmol) of HOBt in 1 ml of DMF, and 20 mg (0.162 mmol) of DMAP are added. After addition of a solution of the amine 15 component indicated in table 4, in 2 ml of DMF, the mixture is stirred at room temperature overnight. For workup, insoluble constituents are filtered off and washed with 20 ml of ethyl acetate. The filtrate is washed twice with saturated NaHCO 3 solution and once with 5% strength NaCl solution, dried and concentrated. 20 The crude products which still contain Boc protective groups.are deprotected without further purification (see below: general method for eliminating the Boc protective groups). Workup of building blocks without Boc protection is followed by purification by preparative HPLC, with the desired compounds of the examples being obtained as trifluoroacetates. 25 General method for eliminating Boc protective groups The resulting crude products are stirred in 5 ml of a 10% strength solution of trifluoroacetic acid in dichloromethane at room temperature for one hour. The residue from evaporation in vacuo is purified on a preparative HPLC, with the desired 30 compounds of the examples being obtained as trifluoroacetates. Table 4: 135 Example No. Acid component Amine component Compound of example 0111 NHH N \ \ N TFA CI a Ex.17, int. 1 HO ' N HN N I " N\ N TFA CI a 113 HO0 H N CN N N, W Cl aI 136 114
H,~
0 C14 N NN 115 H N 1 H HO 0 HN N N N TFA 11 -HNH, 0 H N NM HO yo N ol N H
NH
2 N N N. TPA C4 ci 117 0 0 NH, 0a o HN a TWA N NN 0 2 HO NNM NN CI TFA N"N a al 119 NH., 0 HO~>~'NH N NNrIN NO Nc NH cl cl
TN
137 120 NNH2 H HOHNN HN N HO L cs cl TWA N N 121 0 NH 2 0 HO NN 12 NK HN N. 122 NHNH AF 123 -H NH2 HH HOO, 0A NO, NO, C A' TFA CA S124 NH, HO ~NH H Cl A'a W 125NH H O N NN IAH N N C s ci 138 126 NH,0 0 alc N NN N.. TFA 127 HY NNH. K 0 N *A H A A 128 0 NH, H H H CI a3 TFA 129 F F 129 F0 F F , NHN- l4 . HOI J, II N N H *N TN 130 0 1NH HA 0 Ex. 35 131 NNH, > y~ I'NNN N,,, TFA al 139 132 NH '. NN . TFA 133 H NH, HO Ny ,. N NF 0 0 134 0 H NH, NH, HO NKo".
1 N HO NN0 1H6 0 N JN NNW 1357%"~ NH, H HO H~ y 0 A0 cl i a WFA ci
C
140 138
HNH
2 ~ " Ho H a .a T. A NlN. 139 qNH 2 H N 0N N N, NH 140 1 NII-H
NH
2 N NN ci F A 141 01 H NH 2 NO, N H HO H NO, CIA lW NN ci 142 0" Z H H NH -0 NN Clcl TFA 143 0N'N H H _N. H c N H Cl.
CI
141 144 NH, HO H fQc, o 0 cI - 0 N N "I NNN CI C ' cl as 145 NH 2 I wo H - Z L CI O C / TFA N NN" Cl C CA 146NH, H H C1 C N NN TFA H / F 5\ N CI CCI Eap4:-2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]- 5rg 0 147 FNH 2 H 3-ethl-torehydrhochlote rie; dd fe tadn tro emeauefr1 H N HO \ NNN7 _'N 0 N NTF /S. C1 Example 148: 1-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-y)-phenyl] 3-ethyl-thiourea, hydrochorides; ci N N,,,. 5 2-(6,8-d ichloro-2-methyl-1 ,2,3,4-tetrahydro-isoqu inolin-4-yl)-phenylamine (95 mg, compound of example 36) is introduced into 4 ml of acetonitrile and, while stirring, 27 mg of ethyl isothiocyanate are added. After standing at room temperature for 15 hours, the solvent is removed in vacuo, and the residue is purified on a preparative 142 HPLC. The trifluoroacetate obtained in this way is taken up in water and made alkaline with K 2
CO
3 .The aqueous phase is extracted with ethyl acetate. The organic phase is separated off, dried with MgSO 4 and concentrated. The residue is taken up in dilute HCI and freeze dried, resulting in 36 mg of the title compound. 5 Example 149: 1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 3-ethyl-thiourea, hydrochlorides; Cl N1 N CI N C l N 10 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (50 mg, compound of example 17, intermediate 1) are introduced into 4 ml of THF, and ethyl isothiocyanate (14 mg) is added. After heating to reflux for 2 hours, the reaction solution is concentrated and heated at 85 0 C to 2 hours. The crude product obtained in this way is purified on a preparative HPLC. Further treatment of the trifluoroacetate 15 obtained in this way as described in example 148 affords 33 mg of the desired hydrochloride after freeze drying. Example 150: 1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 3-ethyl-thiourea, trifluoroacetate; Cl / /S Cl N N N TFA 20 143 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (50 mg, compound of example 35) are dissolved in 3 ml of THF and, while stirring, 14 mg of ethyl isothiocyanate are added. After heating to reflux for 2 hours, the reaction solution is concentrated and heated at 850C for 2 hours. The crude product obtained in this way 5 is purified on a preparative HPLC, becoming 66 mg of the title compound. Example 151: 3-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 1,1-dimethyl-urea, hydrochloride; ~NirN1 O 0 Cl Cl 10 Intermediate 1: 4-nitrophenyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]carbamate, hydrochlorides; 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (350 mg, compound of example 35) are dissolved in 17.5 ml of dichloromethane and, while 15 stirring, 230 mg of 4-ntirophenyl chloroformate are added. After 4.5 hours, a further 0.1 equivalent (23 mg) of 4-nitrophenyl chloroformate were added, and the solution was stirred overnight. For workup, the resulting precipitate is filtered off and washed with dichloromethane. The title compound obtained in this way can be reacted further without further purification. 20 3-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1, 1-dimethyl urea, hydrochloride; 35 mg of 4-nitrophenyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]carbamate hydrochlorides (intermediate 1) are suspended in 3.5 ml of 25 dichloromethane and, while stirring, a solution of 3.7 mg of dimethylamine in 1 ml of dichloromethane is added dropwise. After 1 hours, the mixture is diluted with 144 dichloromethane and washed with aqueous K 2
CO
3 solution. The organic phase is separated and washed twice with saturated K 2
CO
3 solution, dried with MgSO 4 and concentrated. The residue is taken up in dilute HCI and freeze dried, resulting in 29 mg of the title compound. 5 The following examples are prepared in analogy to the method described in example 151, starting from intermediate 1 and the appropriate amine components: 145 Table 5: Example No.: Structure 152 153 K N yW .- 0 C l C 154 r - 0 CA 155 N NO - 0 N 156 N 0 C1 C1 Ci 157 yNYNN, I c0 ____ ____ ____ ___ C 146 158. N N -. C I CCI ci The following examples were prepared in analogy to the method described in example 151. THF was used as solvent, and the reactions were carried out in a closed reaction vessel. Reaction temperatures of 85°C were necessary for examples 159 to 5 166. Compound of example 167 was purified by preparative HPLC.
147 Table 6: Example No.: Structure 159 N o Chiral No CI Cl Cl 160 y /No A0 CI 1601 /N 1 cl a CI A Cl Cl 162 1 o " AN C CI A-- N C N Cl 148 163 N- SN I 164NQ cl 'CI NN cCi 165 Ns~ KNN 166 NN 167 IN N y 0 *l . l N N K-N NNCl 149 Example 168: N-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 4-methylpiperazine-1l-carboxamide, hydrochloride; 0 " N N Cl Cl Intermediate 1: 4-Nitrophenyl [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin 5 4-yl)-phenyl]carbamate, hydrochlorides; [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (200 mg, comparative example 36) are dissolved in 10 ml of dichloromethane and, while stirring, 131 mg of 4-nitrophenyl chloroformate are added. After 3.5 hours, the resulting precipitate is filtered off with suction and washed with dichloromethane. The crude 10 product obtained in this way is recrystallized from dichloromethane, resulting in 159 mg of the title compound. N-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4 methylpiperazine-1-carboxamide, hydrochloride; 15 15 mg of 4-nitrophenyl [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]carbamate hydrochlorides are suspended in 2 ml of dichloromethane, and a solution of 3.2 mg of 1-methylpiperazine in 1 ml of dichloromethane is added. After 1 hours, the mixture is diluted with dichloromethane and washed with aqueous K 2
CO
3 solution. The organic phase is separated and washed twice with saturated K 2
CO
3 20 solution, dried with MgSO 4 and concentrated. The residue is taken up in dilute HCI and freeze dried, resulting in 13 mg of the title compound. The following examples are prepared in analogy to the method described for example 168. 25 150 Table 7: Example No.: Structure 169 I 0 N N N,, C1 C1 170 0 NN Cci C1 171 N N' CI-1 NQ C 1 173 N.0 CI NA CI1 174 N.0 CI1 NN NCC 175 i? ~~N N, Ci 0I 151 Example 176: N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 4-methyl-piperazine-1l-carboxamide, hydrochlorides; 0 N N Cl Cl 105 N.. Cl CI Intermediate 1: 4-Nitrophenyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin 5 4-yl)-phenyl]carbamate, hydrochlorides; 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (200 mg, compound of example 17, intermediate 1) are dissolved in 10 ml of dichloromethane and, while stirring, 131 mg of 4-nitrophenyl chloroformate are added. After 4.5 hours, the resulting precipitate is filtered off with suction and washed with dichloromethane. 10 The crude product obtained in this way is recrystallized twice from dichloromethane, resulting in 254 mg of the title compound. N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl piperazine-1-carboxamide, hydrochlorides; 15 15 mg of 4-nitrophenyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]carbamate hydrochloride are suspended in 2 ml of dichloromethane, and a solution of 3.2 mg of 1-methylpiperazine in 1 ml of dichloromethane is added. After stirring for 5 hours and standing overnight, the mixture is diluted with dichloromethane and washed with aqueous K 2
CO
3 solution. The organic phase is separated and 20 washed twice with saturated K 2
CO
3 solution, dried with MgSO 4 and concentrated. The residue is taken up in dilute HCI and freeze dried, resulting in 13 mg of the title compound. The following examples are prepared in analogy to the method described for 25 example 176.
152 Table 8: Example No.: Structure 177 0 SN CI C CI 178 o N N Cl Cl
CI
153 179 0 N N II ci1 CI 180 0 Cl CI CI 181 N N *, CI Cl a cI N, CI 182 0 NN 'O Ct /N CI 183 0 NN I) Example 184: N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]formamide, hydrochloride; 154 N^O N'- C Cl 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (200 mg, compound of example 17, intermediate 1) is dissolved in 1 ml of formic acid and 5 heated to reflux for 15 min. After standing overnight, the mixture is added to an ice/water mixture and extracted twice with ethyl acetate. The combined organic phases are dried with MgSO 4 and concentrated. The residue is taken up in dichloromethane and washed with saturated NaHCO 3 solution. The phases are separated and the aqueous are extracted three times more with dichloromethane. Drying of the organic 10 phases (MgSO 4 ) and removal of the solvent by distillation afford 167 mg of crude product. 10 mg are dissolved in dilute HCI and freeze dried, resulting in 11 mg of the title compound. Example 185: [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) 15 phenyl]methyl-amine, hydrochloride N Cl .; Cl CI I N Cl N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]formamide (150 mg, compound of example 184) are dissolved in 2.5 ml of THF and, at 50*C 20 under argon, added dropwise to a solution of 0.45 ml of a 1 M solution of lithium 155 aluminum hydride/THF in 2.5 ml of THF. The mixture is heated to reflux for 1 hour. After standing overnight, a further 0.22 ml of a 1 M lithium aluminum hydride solution are added at 50 0 C, and the mixture is heated to reflux for a further hour. For workup, the solvent is removed and the residue is partitioned between dichloromethane and 5 aqueous HCL The phases are separated and the aqueous are extracted three times with dichloromethane, The combined organic phases are dried with with MgSO 4 and concentrated. Further purification takes place on a preparative HPLC. The product obtained in this way is taken up in an NaHCO 3 solution and extracted with dichloromethane. Drying of the organic phase with MgSO 4 affords 80 mg of the free 10 base. 10 mg are taken up in diluted HCI and freeze dried, resulting in 10 mg of the title compound. Example 186: 1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 1,3-dimethyl-urea, hydrochlorides; O N N Cl CCI C1 15 The title compound is prepared by the method described for example 151, starting from [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]methyl-amine (example 185), 4-nitrophenyl chloroformate and methylamine (20 pl, 2 M in THF) 20 resulting in 9 mg of the desired hydrochloride.
156 The following compounds are prepared in analogy to example 186 starting from [4 (6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]methyl-amine (example 185), 4-nitrophenyl chloroformate and the appropriate amine components: 5 Table 9: Example No.: Structure 157 1870 N N 1880 N )lN CN N13 ci CI N 00 190 cl N l clo 158 192 N N ClH N. CH Cl 1930 CI 193 0. c,.. N N. c, K Cl Example 194: N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]formamide N~O CI CI 5 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (600 mg, compound of example 35) is dissolved in 2.4 ml of formic acid and heated to reflux for 15 min. After standing overnight, the mixture is added to a mixture of ice/water and 159 saturated NaHCO3 solution and extracted three times with dichloromethane. The combined organic phases are dried with MgSO 4 and concentrated, resulting in 588 mg of the title compound. 5 Example 195: [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] methyl-amine, hydrochloride; N Cl CI CI N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]formamide 10 (588 mg, compound of example 194) is dissolved in 10 ml of THF and, at 50 0 C under argon, added to a solution of 1.8 ml of a 1 M solution of lithium aluminum hydride in THF. The mixture is heated to reflux for 1 hour. After standing overnight, a further 2 ml of a 1 M lithium aluminum hydride solution are added at 50 0 C, and heated to reflux for a further 30 min. For workup, ice is added and the aqueous phase is extracted four 15 times with ethyl acetate. The combined organic phases are dried with MgSO 4 and concentrated. Further purification takes place on a preparative HPLC. The product obtained in this way is taken up in NaHCO 3 solution and extracted with ethyl acetate. Drying of the organic phase with MgSO 4 affords 270 mg of the free base. 45 mg are taken up in diluted HCI and freeze dried, resulting in 45 mg of the title compound. 20 The compounds of the following examples can be prepared starting from [3-(6,8 dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]methylamine 160 (example 195), 4-nitrochloroformate and the appropriate amine components by the method described for example 151: Table 10: Example No.: Structure 196 ci cl 161 197 ~~~I N, 198 I I - 0 CA 199 - 0 S Nl 200 r N N - 0 N, 201. - 0 Nlclc 162 202 N 0 CI CI CI 203 r 0 CI C1 ci Example 204: 2-Dimethylaminoethyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro isoquinolin-4-yl)-phenyl]-carbamate, hydrochloride; N oH CI CI 5 15 mg of 4-nitrophenyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]carbamate hydrochloride (see example 151, intermediate 1) are suspended in 1.5 ml of dichloromethane while stirring under an argon atmosphere, and a solution of 163 3 mg of 2-dimethylaminoethanol in 0.5 ml of dichloromethane is added, and the mixture is stirred for 6 hours. After standing overnight, water, dichloromethane and saturated NaHCO 3 solution are added, and the organic phase is separated. The dichloromethane phase is washed three times with saturated NaHCO 3 and dried with 5 MgSO4, and the solvent is removed in vacuo. The crude product obtained in this way is purified on a preparative HPLC. The product fractions are concentrated and partitioned between ethyl acetate and saturated NaHCO 3 solution. The organic phase is separated off, dried with MgSO 4 and concentrated. The residue is taken up in dilute HCI and freeze dried, resulting in 5 mg of the title compound. 10 In an analogous manner, the corresponding isomers 2-dimethylaminoethyl [4-(6,8 dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]carbamate hydrochloride and 2-dimethylaminoethyl [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-carbamate hydrochloride are prepared starting from 4-nitrophenyl [4-(6,8 15 dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate hydrochloride and 4-nitrophenyl [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] carbamate hydrochloride.
164 Table 11: Example No.: Sfructure Nt N CI C 1 C 1 CC1 2056 N OpN'--,
I
Ct l Cl N, C1 206 \. .0 o ,C \ CI Cl Example 207: Methyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-carbamate, hydrochloride; N ON O CI C Cl 5 15 mg of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (example 35) are introduced under an argon atmosphere into 1.5 ml of dichloromethane while stirring, and a solution of 4.6 mg of methyl chloroformate in 0.5 ml of dichloromethane is added. After stirring for 6 hours and standing overnight, a 165 further 2.3 mg of methyl chloroformate are added, and the mixture is stirred for 5 hours. For workup, the solvent is removed, and the residue is taken up in dilute HCI and freeze dried, resulting in 20 mg of the title compound. 5 The following carbamates can be prepared in an analogous manner starting from the appropriate anilines 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenylamine and 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenylamine. Table 12: Example No.: Structure 208 o 0 CT
.
CI 209 o N 0 ci 210 1 y 0 cl Cl 10 166 211 0 N 0O N, CI 212 C N, 213 0 NO0 cl NO ;CI
CI%
167 Example 215a: (+)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] methanesulfonamide, hydrochloride; 215b: : (-)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 5 methanesulfonamide, hydrochloride; 0N,0 N0 00 0 CI - CI Cl Cl , N N Cl Cl 96 mg of racemic N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]methanesulfonamide (see example 83) are separated into the enantiomers on a chiral preparative HPLC. 10 chiral column: Chiralpak AD 250 x 50 mm; 20 p; solvent: heptane:ethanol:methanol: 10:1:1; flow rate: 50 ml/min; the resulting enantiomers are dissolved in dilute HCI and freeze dried, resulting in 37 mg of each of the title compounds 215a and 215b. The enantiomeric purity is 15 determined on a chiral HPLC. chiral column: Chiralpak AD-H/31 250 x 4.6 mm; solvent: heptane:ethanol:methanol: 10:1:1; flow rate: 1 ml/min; Rt (enantiomer eluting first) = 6.84 min; 100% ee; 20 Rt (enantiomer eluting second) = 8.02 min, 100% ee. Example 216a: (+)-1l-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 ethylurea, hydrochloride; 25 216b: (-)-1l-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 ethylurea, hydrochloride; 168 O' O N N - N N CI Cl Cl Cl CI Cl 316 mg of racemic 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-3-ethylurea (compound of example 80) are separated into the enantiomers on a chiral preparative HPLC. 5 chiral column: Chiralpak OD 250 x 50 mm, 20 1; solvent: heptane:ethanol:isopropanol: 50:2:1; 0.3% diethylamin flow rate: 50 ml/min; The enantiomers are subjected separately to further purification on a preparative 10 HPLC. The resulting products are partitioned between saturated NaHCO 3 solution and ethyl acetate, and the organic phase is separated off, dried with MgSO 4 and freed of solvent. Dissolving the residue in dilute HCI and freeze drying affords 37 mg of the enantiomer eluting first and 58 mg of that eluting second. The enantiomeric purity is determined by analytical HPLC. 15 chiral column: Chiralpak OD 250 x 4.6 mm; solvent: heptane:ethanol:isopropanol: 50:2:1; (0.3% diethylamine); flow rate: 10 ml/min; Rt (enantiomer eluting first) = 9.22 min; 100% ee; Rt (enantiomer eluting second) = 9.96 min, 98% ee. 20 Example 217: N-[3-(6,8-Difluoro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide, hydrochloride; 169 N 0 F Cl F Intermediate 1: 2,4-Difluorobenzylmethylamine 2,4-Difluorobenzylmethylamine can be prepared in a manner known to the skilled 5 worker starting from 2,4-difluorobenzaldehyde (cf. example 1, intermediate 1). N-[3-(6,8-Difluoro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]acetamide, hydrochloride; The title compound can be prepared by the synthetic route described in example 1 10 starting from N-(3-acetylphenyl)acetamide and 2,4-difluorobenzylmethylamine (intermediate 1). Example 218: 4-(3-Bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydro isoquinoline, hydrochloride; Br CIl CI
CI
170 The title compound can be prepared by the synthetic route described in example 1 starting from 2,4-dichlorobenzylmethylamine (see example 1) and 2-bromo-1-(3 bromophenyl)ethanone as alkylating agent. 5 Example 219: 1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl-3 (2-hydroxyethyl)urea H H N N -OH 7- 0 CI CI 509 mg (1 mmol) of 4-nitrophenyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroiso 10 quinolin-4-yl)-phenyl]carbamate hydrochlorides (compound of example 151, intermediate 1) are dissolved in 15 ml of absolute DMF and, at 0 0 C, a solution of 67.2 mg (1.1 mmol) of 2-aminoethanol in 10 ml of DMF is added. The mixture is stirred at room temperature for three hours and then the solvent is removed in vacuo. The residue is partitioned between ethyl acetate and saturated NaHCO 3 solution. The 15 organic phase is separated off and the aqueous is extracted twice more with ethyl acetate. The combined organic phases are washed with saturated NaCI solution, dried with MgSO 4 and concentrated. Chromatography on silica gel (dichloromethane/methanol) affords 265 mg of the title compound. 20 Example 220: Ethyl 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) benzoate 171 0 Cl Intermediate 1: 3-Acetylbenzoic acid is prepared in a manner known to the skilled worker from 3-acetylbenzonitrile by hydrolysis of the nitrile group. 5 Intermediate 2: Ethyl 3-acetylbenzoate is prepared from intermediate 1 in a manner known to the skilled worker. Intermediate 3: Ethyl 3-(2-bromoacetyl)benzoate is synthesized in analogy to the 10 method described in example 1, intermediate 2, from ethyl 3-acetylbenzoate (intermediate 2). Ethyl 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoate, Starting from ethyl 3-(2-bromoacetyl)benzoate (intermediate 3) and 2,4-dichlorobenzyl 15 methylamine (example 1, intermediate 1) it is possible to proceed further in analogy to the synthetic route described in example 1, resulting in ethyl 3-(6,8-dichloro-2-methyl 1,2,3,4-tetrahydroisoquinolin-4-yl)benzoate after alkylation reaction, reduction and ring closure reaction. 20 Example 221: 3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzoic acid; 172 0 N OH Cl 500 mg of ethyl 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoate (compound of example 220) are dissolved in 15 ml of methanol, and 10 ml of 2 N of 5 KOH are added. After one hour at 50°C, the mixture is concentrated in vacuo and the residue is partitioned between water and ether. The aqueous phase is adjusted to a pH of about 6 with 2 N HCI, and the resulting precipitate is filtered off with suction. Drying affords 304 mg of the title compound as a colorless solid. 10 Analytical data for the compounds of examples 1 to 221: 173 Table 13:
MS
Rt Remarks Ex. Structure [min] Method MS, MM+H*] Method O. HN 1 O 349,1/350,1/ S m.p.: a 1,60 B 349,1/350,1/ ESI 351,0 205-206 °C - . HN la cmp. la a 1,60 B 349,2/351,2 ESI m.p.: 125 0 C (decomp.) N I 371,3/373,3 2a CH (+) 2 3,63 A ESI enantiomer - N412,3/414,3 C1 0_0 I S N H , 371,3/373,3 2b a C (+)S I3,67 A .ES enantiomer N 412,3/414,3 0 NH 371,1/373,1 2c a 3,66 A ESI enantiomer 0412,1/414,1 Ca 174 - . 371,1/373,1 (-) 2d a O 1,56 B ESI enantiomer a 412,1/414,1 o' 0 a N 4,00 A 399,1/401,1 CI I /N 1 371,2/373,2 4a OH S4a 3,59 A ESI lN 412,2/414,2 NH o 4b 1,58 B 371,0/372,0/ ESI c .1,58 B ESI - , 373,0/373,9 5 H 369,9/371,9/ S 4,57 A Cl ~373,9 OOH 6 a 4,03 A 336,1/338,1 CI a 175 o 7 - WA c 4,17 A 363,3/365,3 Cl /N o 8 TFA c. Ns l 1,88 B 377,3/379,3 CI c l cII a 1,45 B 406,3/408,3 Cl N, N a " A 4,37 A 377.1/379,1 Cl I aJ N. 10. K- J. 11 / TFA CA TFA 4,05 A 363,2/365,2 ESI 12 T) TA 3,79 A 375,2/377,2 ESI ci / Nq CI TA 405 A 33216, S 176 13 C . 4,92 A 361,2/363,2 ESI I / Nq N 14 TFA 4,08 A 390,2/392,2 ESI aTPA N. Q TFA 15 a - 4,80 A 318,2/320,2 CI N 16a 349,1/350,1/ () 1,61 B ESI enantiomer 351,1 a Ni 16b 6 349,1/350,1/ (+) a 1,61 B ESI enantiomer N 351,1 NH,
N
17 0 x H CI 17 C x HCI 0,91 B 307,1/309,0 ESI K-N" 0 177 N N,_%A 18 C CI 1,63 B 442,01444,0 ESI cI Cl HN c19 4,00 A 392,2/394,2 ESI I N I 1 9a 19a a ac 1,80 B 392,1/394,1 ESI HN, N 20A a 1,67 B 380,1/382,2 ESI 21 1,68 B 378,3/380,2 ESI m.p.: 218-220 "C N 21a .
378,1/379,1/ a CN 1,68 B ES I H. 380,1 178 HN 359,1 22 2 so 0,32 B ESI ,ss 717,3/718,3/ ' 719,3 N 23 N 1,60 B 309,2/310,1 ESI HN 24 167 B 393,0/394,0/3 ESI 1,67 B ES1 96,0/397,0 0 Nq O 25 O 1,85 B 384,1/386,1 ESI - N Nq 25a cH 1,78 B 384,1/385,1/ ESI I '386,2 NN HN 26 T 400,1/401,2/ N xTPA. 1,46 B ESI I N- 401,2 / NSI 179 HN 27 2'7 413,2/414,2/ ESI tON 0.27 B ES1 &,N I -- 415,2 / N" HN 27a 0,25 413,2/414,2/ x~. iHC B i 415,2 cl HN" HN 2I 384,21385,2 28 xC 1,65 B ESI N 1 386,2 / N cl CI -- * H N OH 29 1,67 B 352,0/353,0/ ESI a9 a 1,67 B ESI, N , 354,0 HO N .ONa 29a 1,68 B 352,0/353,0/ ESI a9 a 1 .. 1,68 B E54, I NN 354,0 Cl HO 30 TFA 68 B 365,1/366,1/ ESI 30 \ TFA. 1468 B ES,036, N1 MN 367,0/368,0 cl 180 180 H 3 es379,1/380,1/ 31 cl TFA 1,79 B 379,1/3 ESI 381,1 OH 32 c TFA 1,47 B 422,1/423,1/ cJ xT'FA 1,47 BES • ESI . N. 424,1/425,1 S NH N NH 1 33 ,46 B 393,1/394,1/ ESI 1-,46 B ESI N - 395,1 To 34 a 6 349,0/350,1/ 1,63 B ESI 351,0 CI 35 ~clJ .NH, 35 C 1,1'7 307,0/308,1/ ESI N 1,1'7 B 391 ES1 309,1 cI
NH
2 36 C I307,0/308,0/ | 1,66 B ESI 309,1 Cl 181 HNf 37 TFA 2,35 C 363,3/365,3 ESI HN 38 , TFA 2,43 C 377,3379,3 ESI 39 STFA 2,49 C 391,3/393,3 ESI / N 0 HNy 40 c TFA 2,43 C 377,3/379,3 ESI * ~ -I 41. a TWA 2,48 C 391,3/393,3 ES! Cl 42 a WsA 2,40 C 375,3/377,3 ESI
CI
182 43 ' /N N "- A 2,45 C 389,31391,3 ES! o 44 N. a A 2,52 C 403,41405,4 ESI I F 45 cl TFA 2,49 C 403,2/404,2 ESI I S N HN Q 46 4 2,36 C 460,4/462,4 ESI II 47 ' 4 TFA 2,35 C 412,2/414,3 ESI - I N /N" co 0_00 HN 48 N' N TFA 2,29 C 385,3/387,3 ESI 1 183 103 HN ' c49 e TFA 2,37 C 399,3/401,3 ESI CI HN -N 50 cl TFA 2,42 C 414,4/416,4 ESI 51 C N A 2,37 C 363,3/365,3 ESI - NN / 0 52 c N TFA 2,44 C 377,3/379,3 ESI cl N 5 2,51 C 391,3/393,3 ESI CI N N1 0 54 c TFA 2,44 C 377,3/379,3 ESI N
CI
184 184 /N 5 0 TFA 2,49 C 391,3/393,3 ESI 7,N 56a 56.TFA 2,41 C 375,3/377,3 ESI / -N cl 57 I TFA 2,47 C 389,3/391,3 ESI /Nq /N 58 c N TFA 2,52 C 403,4/405,4 ESI / Nq N, N F 59 c' I TFA 2,48 C 403,2/404,2 ESI 60 , STFA 2,34 C 460,4/462,4 ESI 185 -~ 0 61 1TFA 2,36 C 412,2/414,3 ESI N, 62 c TFA 2,32 C 385,3/387,3 ESI cI /- Nq CI N' I o''" 63 cl \ TFA 2,38 C 399,3/401,3 ESI Cl CII 64No 64 c TFA 2,41 C 414,4/416,4 ESI 6C5 65 aA 2,30 C 363,3/365,3 ESI N CI 67 a TFA 2,52 C 391,3/393,3 ESI - N 186 - 0 68 0 x I . v " 2,41 C 377,3/379,3 ESI / N TFA cl 0 69 CI N 69 N TFA 2,45 C 391,3/393,3 ESI cI N TF 70 aI S N A 2,36 C 375,3/377,3 ESI CI 71 a - N N TFA 2,44 C 389,3/391,3 ESI a 72 a N 7 2,51 C 403,4/405,4 ESI / Nc TPA 0 F 73 a I/ N TFA 2,70 C' 403,21404,2 ESI a 74 o9 I TEA 2,30 C 460,4/462,4 ESI ci 187 75 al N FA 2,41 C 385,3/387,3 ESI CI ~I.,,o0 76 a N 2,49 C 399,3/401,3 ESI (o,-,o .,S N 77 c 2,55 C 414,41416,4 ESI N, TFA N N,_,, 78 alES 78 al 1,72 B 378,3/380,3 ESI . N N " 79 O", N \ 79 l TFA 1,74 B -'380,31382,3 ESI /N 80 cI N /NN 1,75 B 378,3/380,3 ESI a 81 c TFA 1,68 B 380,3/382,3 ESI
NN
188 82 399,0/400,01 82 ci 1,71 B 401,0/402,01 ESI a 403,0 (I 83 ci CIH 1,66 B 385,0/386,0/ 1,66 B ESI N 387.0 Ci 84 399,0/400,0/ a . as 1,69 B ESI - 401,0/402,0 I HN 85 B 385,0/386,0/ ESI 0 GH 1,64 B ESI K. '387,0/388,0 N /O 86a a() I N 1,64 B 349,3/351,3 ESI Enantiomer - N CI 86b a., 6,E I'1:63 B 349,3/351,3 ESI Enantiomer 189 00 87 cl TFA 1,97 B 439,0/441,1 ES! / N CI O,1 10 F F 88 a 1,83 B 453,0/455,0 ESI /NN CI N0F 88a l 88a H 1,83 B 453,0/455,0 ESI / N O,,0 0 'IS"0 Br 89 531,0/533,0/ C 2,01 B ESI 534,9 a 0,, Br 89a 2,02 B 531,0/533,01 ESI c. c 2,02 B ESI, 1534,9 / N
CI
190 A S HN Y /-N \ N 90 S1,78 B 525,1/527,1 ESI I HN S SN \ N 90a 9a H 1,79 B 525,1/527,1 ESI a O CIH N N C SN 91 c 1,63 B 465,1/467,1 ESI 91a a,5 ESI al 1,64 B 465,1/467,1 ES I / N I4 91a a~ ~ 'N N- 16 6,/6, S 92 N 1,81 B 499,1/501,1/ ESI I503,1 - Nl cI 191 191 o, o0 C, os 00 N ___ 92a 1,82 B 499,1/501,1/ ESI 9 a c N cJ 1,82 B ESI, C!H 503,1 /Nq. F CI I , o,s'o 93 e TFA 1,99 B 439,0/441,1 ESI /N 95 ~ ~~CI N ,tB. 3, cl S N/ F 94 a 1,87 B 453,0/455,0 ESI ci 94N lH 1,87 B 453,0/455,0 ESI 94a al CIII 1,87 B 453,0/455,0 ESI / N Cl Br N 95 531,0/533,0/ a 2,01 B ESI * ' 535,0 NS I, o 96 1 1,75 B 525,0/527,0 ESI
CI
192 , d,,' o 96a . 96a 1,75 B 525,0/527,0 ESI /- N/ N 1 SN I , . o 97 a 1,66 B 465,0/467,0 ESI 97a 00 9N 1,66 B 465,0/467,0 ES1 aa cl N 98 499,1/501,1/ a 1,81 B ESi 1 503,1 CN 99 a 405,1/407,1 ESI m.p.: N .122 °C a N see Ex. 2; 100 cI intermediate CIH 4,'44 A 292,2/294,2 Cl i N 4 al 193 see Ex. 2; 100a cI intermediate 1.1 TFA .- ) 4a CI cI see Ex. 2; 100b c intermediate () ITA 4b Cl CI 101 aH 4,43 A 326,0/328,0 ES1 102 a a 102 4,23 A 306,1/308,0 ESI cN FF 103 -ozo 2,84 C 360,0 ESI F 104 a o..o I N 2,79 C 320,0/322,0 ESI /N 105 N 105 I 2,64 C 291,9/293,9 ESI
//N.
194 F 106 C 4,26 A 310,0/312,0 ESI C N 107 a . S107 c 4,43 A 306,1/308,1 ESI a 108 108 CIH 4,11 A 292,0/294,0 ESI N 109 N caH 4,28 A 292,0/294,0 ESI I ' 110 CI 110 I 4,05 A 302,0/304 ESI Br 0 111, I 1,37 D 364,4/366,4 ESI I TFA t 195 112 N N 1,44 D 378,4/380,4 ESI a, N TFA Cl cI 113 HN N 1,51 D 392,4/394,4 ESI a S N* TFA a 114 oN0 HN 1,51 D 378,3/380,3 ESI 0, N TFA 11.5 0 . 1,58 D 392,4/394,4 ESI S N, TFA C J 0 '" 116 o HN NH, 1 1,04 D 435,5/437,5 ESI I Nl TFA.. cl a ,N 117 HN SN 1,67 D 404,4/406,4 ESI O I TFA
SWA
196 2,08 D 412,3/414,3 ESI a TFA 10 119 .0 HN >NH 1 2,27 D 400,4/402,4 ESI Ca TFA N 120 HNI N 2,37 D 400,4/402,4 ESI 0 / WA N a 121 NN a 1,7054 D 432,5/434,5 ESI C0 TFA N " 1",70 D 428,5/430,5 ESI C-r FA I a 123 I O 2,55 D 445,4/447,4 ESI 197 124 HNI) NH 1 2,43 D 428,51430,5 ESI C'/ TFA I N cI 125 0 HN N .1,88 D 401,4/403,4 ESI ci TFA N ci 0 126 0 HN KQ S2,31 D 496,5/498,5 ESI ci / TFA 127 0 HN I 2 2,14 D 429,4/431,4 ESI C', TFA \ N 128 N. H - 2,07 D 401,4/403,4 ESI CI TFA ciN 129 o F F HN S. 2,44 D 469,4/471,4 ESI C3 TFA Il 198 130 1 0 a N 1,55 D 378,4/380,4 ESI N TFA " a 131 H a A 1.52 D 392,4/394,4 ESI \i N TFA a 132 0 0 a N A 1,63 D 378,3/380,3 ES1 C. I \ N1 TFA 133 H H 0 N O N z aA 1,64 D 392,4/394,4 ESI \ N TFA a 134 NHz I 0NH 1,14 0 "435,5/437,5 ESI \ N TFA a 135 H a A 1,62 D 404,4/406,4 ESI /. N A 199 136 H I a 2,16 D 412,3/414,3 ESI C / TFA \N CI 137" H -0 A 2,31 D 400,4/402,4 ESI C3 138N 0 0 Cl WA 2,41 D 400,4/402,4 ESI N N.. Cl I -I N 139 1,62 D 432,5/434,5 ES! STFA 140 N N o \ .o1,76 D 428,5/430,5 ESI TFA N" 141 NO, ~I . 0 2,54 D 445,4/447,4 ESI 0 TFA C3 W \N a 200 142 H NH 0 2,50 D 428,5/430,5 ESI _, TFA NN 143 N. 70 1,95 D 401,4/403,4 ES1 ci TFA \N a 144 H. N 0 2,34 D 496,5/498,5 ESI a TFA ci 145 H HI !N N 70 2,31 D 429,4/431,4 ESI S"TFA \N 146 H " /O 146 /I N - 0 2,11 D 401,4/403,4 ESI 0 / TFA \ N ci H N I / N /O 147 F F 2,48 D 469,4/471,4 ESI / TFA \ N 201 CI \Nl 148 c 2,36 B 394,2 ESI N Ng / S s 149 P 2,35 B 394,2 ESI N m 150 : N- 2,35 B 394,2 ESI N TFA I \N N W - 0 151 a 2,15 B 378,2 ESI C3 N N N 152 a 1,64 B J 433,3 ESI a N NyN 153 cl 0 c 2,56 B 418,3 ESI CI ; CI CI r~o N <) 154 C 2,16 B 420,2 ESI
CI
202 r O 0 155 ca cl 2,34 B 404,2 ESI cN CI 156 ci ca 2,43 B 406,2 ESI I N., I /N cl T 0 157 a s2,12 B 364,2 ESI c I a N N a0 158 a. a 1,65 B 421,2 ESI C Cie
O
hW N 159 N2,23 B 420,3 ESI Cl CI 160 2,25 B 434,3 ESI 161 Ca C N 1,72 B 461,4 ESI
CI
203 N o 162 ci cl 1,68 B 449,4 ESI cl - N Cl CI 163 cl cl N. 1,62 B 435,3 ESI /N C I CI .N N a 164 c 1,71 B 435,3 ESI Cl NO / N 165 Cl 2,21 B 408,3 ESI /N CI NO /.N 166 cl c N 1,88 B J 427,3 ESI 167 cI a N 1,80 B 427,3 ESI - N~ CI Cll CI 168 -. 1,59 B 433,3 ESI cl cl 204 0 N N 169 cl . c 2,12 B 364,2 ESI Cl CI N N 170 cl I 2,12 B 378,2 ESI - N~ Cl CI 171 a 2,34 B 406,3 ESI 172 a 2,44 B 418,3 ESI ca 173 a ,'N-Zc 2,11 B 420,3 ESI / N a >174 a s N 2,25 B 404,3 ESI /N,_ C 175 . 0,90 B' 421,5 ESI ~cl 17 c~ lh t ,5 B 43,3 ES aa - N- CI
CI
205 N INo 177 - l 2,34 B 404,3 ESI N, 0 * N N 178 2,11 B 364,2 ESI 0 N N 17 - 2,17 B 378,3 ESI 79 NN~ 180 cl2,51 B 406,3 ESI cI - N CI N N 181 - l 1,59 B 421,2 ESI 182 1 2 . 47 B 418,2 ESI C3- N ci C3 206 O 183 o 2,16 B 420,2 ESI a a I N K-N.Oa NO CI /I N 185 Cl 1,92 B 321,2 ESI c! N" CI N cI 0 Nh N 186 CI 1,05 C 378,4 ESI I N . CI 187 a 0,92 C 447,5 ES O C N, 0 N N 188 cl 1,10 C 392,5 ESI cl CI N Cl 207 o 'N l N) 189 c1 1,24 C 432,5 ESI Cl Cl O 0 ~N JNh Lo 190 cl 1,10 C 434,5 ESI Cl I N, Cl 0 191 - l 1,15 C 418A4 ESI CI CI 0 N N CIH 192 c CIH 0,93 C 435,4 ESI CI N, 0 LK, CIH Cl CCl 193 1,22 C 420,5 -ES!
CI
208 II 194 Ci 2,04 C 3354 ESI /o! N, cl Cl N 195 c 0,90 C 321,3 ESI /N, ci I'ys \N yN 0 196 cl 2,48 B 418,3 ESI CC NI" y ( 197 cl 2,62 B 432,3 ESI C C cI N N C"I I • - 0 198 cl 2,32 B 392,3 ESI cl N 0 199 c 2,19 B 378,2 ESI .. CI 209 \N yNJ 200 2,16 B 434,3 ESI CI CCl cl N N 201 C 1,61 B 447,4 ESI cl N N 0 0 202 C 1,59 B 435,3 ESI aa \N yN,-, cO - 0 . 203 2,57 B 420,3 ESI cCI Cl o~0a 204 a - 1,71 B 422,2 ESI I a a 210 N. I oC) N-- ... 205 1,70 B 422,3 ESI t o I N. 1 , 0 206 a 1,68 B 422,3 ESI NO cl - 0 207 CI Cl 2,34 B 365,1 ESI 9N CI N O - 0 208 a ". C1,18 C 379,4 ESI 209 a a 1,24 C 393,4 ESI \N a N O 0 210 a. a 1,38 C 421,5 ESI S N al 211 0 NO Cl 211 1,13 C 365,4 ESI Cl CI NO CI \ 212 ' 1,26 C 393,4 ESI CI I N, Cl 0 NO 213 1,40 C- 421,5 ESI CI ~ CI CI 0 CI 214 I 1,20 C 379,4 ESI C l N 215a 9< 385,2 ESI 216ab 216a 378,1 ESI 216b N 0 217 F 1,86 B 317,2 ESI
CI
212 CI Br 218 c. 1,27 C 370,2 ESI C1 H H NN,_,-OH 0 219 CI n 0,99 B1 394,1/396,2 ESI cN CI 0 O 220 ca1,24 B1 364,1/366,1 ESI N OH 221 1,02 B1 336,1/338,1 ESI N1 C I Pharmacological data: Description of test: 5 In this test, the recovery in the intracellular pH (pHi) after an acidification is ascertained, which is initiated if the NHE is capable of functioning, even under bicarbonate-free conditions. For this purpose, the pH i was determined using the pH sensitive fluorescent dye BCECF (Calbiochem, the precursor BCECF-AM is employed). The cells were initially loaded with BCECF. The BCECF fluorescence was 10 determined in a "Ratio Fluorescence Spectrometer" (Photon Technology International, South Brunswick, N.J., USA) at excitation wavelengths of 505 and 440 nm and an emission wavelength of 535 nm and converted into the pHi using calibration curves. The cells were incubated in NH 4 CI buffer (pH 7.4) (NH 4 CI buffer: 115 mM NaCI, 20 mM NH 4 CI, 5 mM KCI, 1 mM CaCl2, 1 mM MgSO4, 20 mM Hepes, 5 mM glucose, 15 1 mg/ml BSA; a pH of 7.4 is adjusted with 1 M NaOH) even during the BCECF loading.
213 The intracellular acidification was induced by adding 975 pl of an NH 4 CI-free buffer (see below) to 25 pl1 aliquots of the cells incubated in NH 4 CI buffer. The subsequent rate of pH recovery was recorded for two minutes with NHE1, five minutes with NHE2 and three minutes with NHE3. To calculate the inhibitory potency of the tested 5 substances, the cells were initially investigated in buffers with which a complete or absolutely no pH recovery took place. For complete pH recovery (100%), the cells were incubated in Na+-containing buffer (133.8 mM NaCI, 4.7 mM KCI, 1.25 mM CaCI2, 1.25 mM MgCI 2 , 0.97 mM Na 2
HPO
4 , 0.23 mM NaH 2
PO
4 , 5 mM Hepes, 5 mM glucose, a pH of 7.0 is adjusted with 1 M NaOH). To determine the 0% value, the cells 10 were incubated in an Na+-free buffer (133.8 mM choline chloride, 4.7 mM KCI, 1.25 mM CaCI 2 , 1.25 mM MgCI 2 , 0.97 mM K 2
HPO
4 , 0.23 mM KH 2
PO
4 , 5 mM Hepes, 5 mM glucose, a pH of 7.0 is adjusted with 1 M NaOH). The substances to be tested were made up in the Na+-containing buffer. The recovery of the intracellular pH at each test concentration of a substance was expressed as a percentage of the 15 maximum recovery. The IC 50 value for the particular substance for the individual NHE subtypes was calculated from the pH recovery percentages using the Sigma-Plot program.
214 Results: Table 14: Example IC 5 0 [pM], Example IC50 [pM], Example Example (rNHE3) (rNHE3) la 0.075 119 0.0682 2a 0.082 144 0.695 2b 0.026 146 0.024 6 0.670 153 0.602 7 0.250 183 0.597 10 1.000 199 0.252 17 0.049 207 0.186 21 0.814 23 1.507 24 0.340 29 0.318 36 0.274 48 0.349 51 0.215 60 0.202 64 0.507 81 0.730 87 0.418 97 0.308 113 0.279

Claims (16)

1. A 4-phenyltetrahydroisoquinoline of the formula I R8 R9 R7 R1 I R6 R2 /N R R3 R5 R4 5 in which the meanings are: R1, R2, R3 and R4 independently of one another H, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , CaH2a+1, CqqH2qq-1, OCbH2b+1, COOR10, OCOR10, COR10 or Ox-(CH2)y-phenyl; a and b 10 in the groups CaH2a+1 and OCbH2b+1 independently of one another 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms; qq 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms; 15 R10 H or CcH2c+l; c 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms, x zero or 1; y zero, 1,2, 3 or 4; 20 where the phenyl ring in the group Ox-(CH2)y-phenyl is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, Br, CN, NO 2 , OH, NH 2 or CdH2d+l; d 1, 2, 3 or 4, it being possible for one or more H atoms 25 to be replaced by F atoms, or 216 R1, R2, R3 and R4 independently of one another heteroaryl, it being possible for zero, 1, 2, 3 or 4 N atoms, zero or 1 oxygen atom or zero or 1 S atom to be present as ring atoms; 5 or R1, R2, R3 and R4 independently of one another CONR11R12 or NR11R12; R11 and R12 independently of one another H, CeH2e+l, CrrH2rr-1; 10 e 1,2,3,4,5,6, 7 or8, rr 3, 4, 5, 6, 7, or 8, it being possible for one or more H atoms in the groups CeH2e+1 and CrrH2rr-1 to be replaced by F atoms and for one or more CH 2 groups to be replaced by O or NR13; 15 R13 H or CfH2f+ 1 ; f 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; or R13 and a CH 2 group of R11 or R12 together with the N atom 20 to which they are bonded a 5- or 6-membered ring; or R11 and R12 together with the N atom to which they are bonded a 5-, 6- or
7-membered ring; 25 or R11 and R12 independently of one another COR14, CSR14 or SO 2 R14; R14 CgH2g+1; g 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or 30 more H atoms to be replaced by F atoms, and it being 217 possible for one or more CH 2 groups to be replaced by O or NR13, or R1, R2, R3 and R4 5 independently of one another -Oh-SOj-R15, with h zero or 1; j zero, 1 or 2; R15 CkH2k+1, OH, OCIH 2 1 + 1 or NR17R18; k 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H 10 atoms to be replaced by F atoms; I 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms; R17 and R18 independently of one another H or CmH2m+1; 15 m 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms in the group CmH2m+1 to be replaced by F atoms and for one or more CH 2 groups to be replaced by O, CO, CS or NR19; R19 H or CnH2n+l; 20 n 1,2, 3 or 4; it being possible for one or more H atoms in CnH2n+1 to be replaced by F atoms; or R17 and R18 25 together with the N atom to which they are bonded a 5-, 6- or 7-membered ring; or R19 and a CH 2 group with R17 or R18 together with the N atom to which they are bonded a 5- or 6-membered 30 ring; but where R2 must always not be equal to H, 218 R5 H, CpH2p+l, CssH 2 ss-1, COR20 or SO 2 R20; p 1, 2, 3, 4, 5, 6, 7 or 8, ss 3, 4, 5, 6, 7 or 8, R20 CqH2q+1; 5 q 1,2, 3, 4, 5, 6, 7 or8, it being possible for one or more H atoms in the groups CpH2p+1, CssH 2 ss- 1 and CqH2q+1 to be replaced by F atoms and for one or more CH 2 groups to be replaced by O or NR21; R21 H orCrH2r+1; 10 r 1,2, 3 or4; it being possible for one or more H atoms in CrH2r+1 to be replaced by F atoms; R6 H, F, Cl, Br, I, CsH 2 s+ 1 , CddH2dd-1, OH, OCtH2t+1 or OCOR22; s and t 15 independently of one another 1, 2, 3, 4, 5, 6, 7 or 8; dd 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms in CsH 2 s+ 1 , CddH2dd-1 and OCtH2t+1 to be replaced by F atoms; R22 CuH2u+1; u 1, 2, 3 or 4; 20 it being possible for one or more H atoms in CuH2u+1 to be replaced by F atoms; R7, R8 and R9 independently of one another -Ov-SOw-R23; v zero or 1; 25 w zero, 1 or 2; R23 CnnH2nn+1, CmmH2mm-1, OH, OCppH2pp+1 or NR25R26; nn and pp independently of one another 1, 2, 3, 4, 5, 6, 7 or 8, mm 3, 4, 5, 6, 7 or 8, 219 it being possible for one or more H atoms in CnnH2nn+1, CmmH2mm-1 and OCppH 2 pp+ 1 to be replaced by F atoms; R25 and R26 independently of one another H, CN or CzH2z+1, CzzH2zz-1; 5 z 1, 2, 3, 4, 5, 6, 7 or8; zz 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms and, in CzH2z+1, it being possible for one or more H atoms to be replaced by F atoms and it being possible for 10 one or more CH 2 groups to be replaced by O, CO, CS or NR27; R27 H or CaaH2aa+1; aa 1, 2, 3 or 4; it being possible for one or more H atoms in 15 CaaH2aa+1 to be replaced by F atoms; or R25 and R26 together with the N atom to which they are bonded a 5-, 6- or 7-membered ring, 20 or R27 and a CH 2 group of R25 or R26 together with the N atom to which they are bonded a 5- or 6-membered ring; or R7, R8 and R9 25 independently of one another NR32COR30, NR32CSR30 or NR32SObbR30; R30 H, CccH2cc+1, CyyH 2 yy- 1 , pyrrolidinyl or piperidinyl, in which rings a CH 2 group may be replaced by O or NR33; R32 and R33 independently of one another H or ChH2h+1; bb 2 or 3; 30 cc 1,2,3,4,5,6, 7 or8; yy 3, 4, 5, 6, 7 or 8; 220 h 1,2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms in ChH2h+1 to be replaced by F atoms, and it being possible for one or more H atoms in the groups CccH2cc+1 and CyyH 2 yy- 1 to be replaced by F atoms and for one or more 5 CH 2 groups to be replaced by NR31 and for a CH 2 group to be replaced by O R31 H, CkkH2kk+1, COR65 or SO 2 R65 kk 1, 2, 3, or 4; it being possible for one or more H atoms to be replaced by F atoms, 10 R65 H, CxxH 2 xx+l; xx 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; or R31 forms together with a CH 2 group of R30 a 5-, 6- or 7-membered ring; 15 or R30 a 5- or 6-membered heteroaryl with 1, 2, 3 or 4 N atoms, zero or 1 S atoms and zero or 1 0 atoms, which is unsubstituted or substituted by up to three substituents selected from the group consisting of F, Cl, Br, I, 20 CooH 2 oo+ 1 , NR70R71; R70 and R71 independently of one another H, CuuH2uu+1 and COR72; R72 H, CvvH2vv+1; 25 oo, uu and wvv independently of one another 1, 2, 3, 4, 5, 6, 7 or 8; it being possible for one or more H atoms in the groups CooH 2 oo+ 1 , CuuH2uu+1 or CwH2vv+1 to be 30 replaced by F atoms; or 221 R7, R8 and R9 independently of one another H, F, CI, Br, I, NO 2 , CN, OH, NH 2 , CeeH2ee+1, CwwH2ww- 1 , OCffH2ff+1, NR40R41, CONR40R41, COOR42, COR42 or OCOR42, 5 ee and ff independently of one another 1, 2, 3, 4, 5, 6, 7 or 8; ww 3, 4, 5, 6, 7 or 8; it being possible for one or more H atoms in the groups CeeH2ee+1, CwwH2ww-1 and OCffH2ff+1 to be replaced by F atoms; 10 R40 and R41 H, CttH2tt+1 or C(NH)NH 2 ; ft 1,2,3,4,5,6, 7 or8; it being possible for one or more H atoms in the group CttH2tt+1 to be replaced by F atoms and for one or more CH 2 groups to be replaced 15 by O or NR44; R44 H or CggH2gg+1; gg 1,2,3,4,5,6, 7 or8; it being possible for one or more H atoms in the group CggH2gg+1 to be replaced by F atoms, and it being possible 20 for R44 together with a (CH 2 ) group of R40 or R41 and the N atom to which they are jointly bonded to form a 5- or 6 membered ring; or R40 and R41 25 with the N atom to which they are bonded a 5- or 6-membered ring; R42 H or ChhH2hh+1; hh 1,2,3,4,5,6, 7 or8; it being possible for one or more H atoms in the group ChhH2hh+1 to be replaced by F atoms; 30 but where two substituents from the group of R7, R8 and R9 may not simultaneously be OH or OCH 3 222 and where at least one of the radicals R7, R8 or R9 must be selected from the group consisting of CONR40R41, -OvSOwR23, NR32COR30, NR32CSR30 and NR32SObbR30; and the pharmaceutically acceptable salts and trifluoroacetates 5 thereof. 2. A compound of the formula I as claimed in claim 1, in which the meanings are: R1, R2, R3 and R4 independently of one another, H, F, CI, Br, I, CN, NO 2 , OH, NH 2 , CaH2a+1, 10 cycloalkyl with 3, 4, 5 or 6 C atoms, OCbH2b+1, COOR10; a and b independently of one another 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; R10 H or CcH2c+1; 15 c 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; or R1, R2, R3 and R4 independently of one another 5- or 6-membered heteroaryl selected from the 20 group consisting of pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl and oxazolyl; or R1, R2, R3 and R4 independently of one another CONR11R12 or NR11R12; 25 R11 and R12 independently of one another H, CeH2e+l, CrrH2rr-1; e 1,2, 3 or4, rr 3,4, 5or6, it being possible for one or more H atoms in the groups 30 CeH2e+ 1 and CrrH2rr-1 to be replaced by F atoms or 223 R11 and R12 independently of one another hydroxyethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl; 5 or R11 and R12 together with the N atom to which they are bonded a pyrrolidine, piperidine, N-methylpiperazine, piperazine or morpholine ring; or 10 Rll and R12 independently of one another COR14, CSR14, CONHR14, CSNHR14 or SO 2 R14; R14 CgH2g+1 ; g 1, 2, 3 or 4, it being possible for one or more H atoms 15 to be replaced by F atoms; or R1, R2, R3 and R4 independently of one another OSO 3 H, SO 3 H, SO 2 R 15 , with R15 CkH2k+1, OClH 2 1 + 1 or NR17R18; 20 k 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; I 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; R17 and R18 25 independently of one another H, CmH2m+l, in which the first CH 2 group bonded to the nitrogen is replaced by CO and the second CH 2 group is replaced by NR19; m 1, 2, 3, 4 or 5, it being possible for one or more H atoms in the group CmH2m+1 to be replaced by F 30 atoms; R19 H or CnH2n+l; 224 n 1,2, 3 or4; it being possible for one or more H atoms in CnH2n+1 to be replaced by F atoms; or 5 R17 and R18 together with the N atom to which they are bonded a 5- or 6-membered ring; but where R2 must always not be equal to H, R5 H, CpH2p+1 ; 10 p 1,2, 3 or 4; it being possible for one or more H atoms in CpH2p+1 to be replaced by F atoms; R6 H, CsH 2 s+ 1 , OCtH2t+1 or OCOR22; s and t 15 independently of one another 1, 2, 3 or 4; it being possible for one or more H atoms in CsH 2 s+ 1 and OCtH2t+1 to be replaced by F atoms; R22 CuH2u+1; u 1,2, 3 or 4; 20 it being possible for one or more H atoms in CuH2u+1 to be replaced by F atoms; R7, R8 and R9 independently of one another OSO 3 H, SO 3 H or SO 2 R23; R23 CnnH2nn+1, CmmH2mm-.1, OCppH2pp+1 or NR25R26; 25 nn and pp independently of one another 1, 2, 3, 4 or 5, mm 3,4, 5 or6, it being possible for one or more H atoms in CnnH2nn+1, CmmH2mm- 1 and OCppH 2 pp+ 1 to be replaced by F atoms; 225 R25 and R26 independently of one another H, CN or CzH2z+1, in which the first CH 2 group bonded to the nitrogen is replaced by CO or CS and the second CH 2 is replaced by NR27; 5 z 1,2,3,4, 5 or6; it being possible for one or more H atoms in CzH2z+1 to be replaced by F atoms; R27 H or CaaH2aa+1; aa 1,2, 3 or 4; 10 it being possible for one or more H atoms in CaaH2aa+1 to be replaced by F atoms; or R25 and R26 together with the N atom to which they are bonded a 5- or 15 6-membered ring; or R27 and a CH 2 group of R25 or R26 together with the N atom to which they are bonded a 5- or 6-membered ring; or 20 R7, R8 and R9 independently of one another NR32COR30, NR32CSR30 or NR32SO 2 R30; R30 H, OH, CccH2cc+1, CyyH 2 yy- 1 , pyrrolidinyl or piperidinyl, in which rings a CH 2 group may be replaced by O or NR33; R32 and R33 independently of one another H or ChH2h+1; 25 cc 1,2, 3, 4, 5, 6, 7 or 8; yy 3,4,5,6; h 1,2, 3 or 4; it being possible for one or more H atoms in ChH2h+1 to be replaced by F atoms, and it being possible for one or more H atoms in the groups 226 CccH2cc+1 and CyyH2yy-1 to be replaced by F atoms and for one or more CH 2 groups to be replaced by NR31 and for a CH 2 group to be replaced by O; R31 H, CkkH2kk+1, COR65 or SO 2 R65; kk 1, 2, 3, or 4; 5 it being possible for one or more H atoms to be replaced by F atoms, R65 H, CxxH2xx+ 1 ; xx 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; or 10 R31 together with a CH 2 group of R30 and the N atom to which they are jointly bonded form a 5- or 6-membered ring; or R30 a 5- or 6-membered heteroaromatic system selected from the group consisting of pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, 15 thienyl, thiazolyl and oxazolyl, which are unsubstituted or substituted by up to three substituents selected from the group consisting of F, Cl, Br, I, CooH 2 oo+ 1 , NR70R71, R70 and R71 20 independently of one another H, CuuH2uu+1 or COR72; R72 H, CwH2vv+1;; oo, uu and w independently of one another 1, 2, 3 or 4; it being possible for one or more H atoms in the groups 25 CooH 2 oo+ 1 , CuuH2uu+1 or CvvH2vvw+1 to be replaced by F atoms; or R7, R8 and R9 independently of one another H, F, Cl, Br, I, NO 2 , CN, OH, NH 2 , CeeH2ee+1, 30 CwwH 2 ww-1, OCffH2ff+1, NR40R41, CONR40R41, COOR42, COR42 or OCOR42; 227 ee and ff independently of one another 1, 2, 3 or 4; ww 3,4, 5or6, it being possible for one or more H atoms in the groups CeeH2ee+1, 5 CwwH2ww-1 and OCffH2ff+1 to be replaced by F atoms; R40 and R41 H, CttH2tt+1 or C(NH)NH 2 ; tt 1,2, 3, 4, 5, 6, 7 or 8; it being possible for one or more H atoms in the group CttH2tt+1 to be 10 replaced by F atoms; or R40 and R41 to be selected independently of one another hydroxyethyl,, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, 15 N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl; or R40 and R41 together with the N atom to which they are bonded form a ring selected 20 from the group consisting of pyrrolidine, piperidine, N-methyl piperazine, piperazine and morpholine; R42 H or ChhH2hh+1; hh 1,2, 3 or 4; it being possible for one or more H atoms in the group ChhH2hh+1 to 25 be replaced by F atoms; but where two substituents from the group of R7, R8 and R9 may not simultaneously be OH or OCH 3 and where at least one of the radicals R7, R8 or R9 must be selected from the group consisting of CONR40R41, -OvSOwR 2 3, NR32COR30, NR32CSR30 and 30 NR32SObbR30; and the pharmaceutically acceptable salts and trifluoroacetates thereof. 228 3. A compound of the formula I as claimed in claims 1 or 2, in which the meanings are: R1, R2, R3 and R4 independently of one another H, F, Cl, Br, OH, NH 2 , CaH2a+1, cycloalkyl with 5 3, 4, 5 or 6 C atoms, OCbH2b+1; a and b in the groups CaH2a+ 1 and OCbH2b+ 1 independently of one another 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; 10 or R1, R2, R3 and R4 independently of one another NR1 1 R12; R11 and R12 independently of one another H, CeH2e+l, CrrH2rr-1; 15 e 1,2, 3 or4, rr 3,4, 5or6, it being possible for one or more H atoms in the groups CeH2e+1 and CrrH2rr-1 to be replaced by F atoms; 20 or R11 and R12 together with the N atom to which they are bonded form a ring selected from the group consisting of pyrrolidine, piperidine, N methylpiperazine, piperazine and morpholine; 25 or R11 and R12 independently of one another COR14, CSR14, CONHR14, CSNHR14 or SO 2 R14; R14 CgH2g+ 1 ; 30 g 1,2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; 229 or R1, R2, R3 and R4 independently of one another OSO 3 H, SO 3 H, SO 2 R15; R15 CkH2k+1 or NR17R18; 5 k 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; R17 and R18 independently of one another H or CmH2m+1; m 1, 2, 3, 4 or 5, it being possible for one or more H 10 atoms in the group CmH2m+1 to be replaced by F atoms; or R17 and R18 together with the N atom to which they are bonded a 5- or 15 6-membered ring; but where R2 must always not be equal to H; R5 methyl or trifluoromethyl; R6 H; R7, R8 and R9 20 independently of one another OSO 3 H, SO 3 H or SO 2 R23; R23 CnnH2nn+1 or NR25R26; nn 1, 2, 3, 4 or5, it being possible for one or more H atoms in CnnH2nn+1 to be replaced by F atoms; 25 R25 and R26 independently of one another H, CN or CzH2z+1, in which the first CH 2 group bonded to the nitrogen is replaced by CO or CS and the second CH 2 is replaced by NR27; z 1, 2, 3,4, 5 or6; 30 it being possible for one or more H atoms in CzH2z+1 to be replaced by F atoms; 230 R27 H or CaaH2aa+ 1; aa 1,2, 3 or 4; it being possible for one or more H atoms in CaaH2aa+1 to be replaced by F atoms; 5 or R25 and R26 together with the N atom to which they are bonded a 5- or 6-membered ring, or 10 R27 and a CH 2 group of R25 or R26 together with the N atom to which they are bonded a 5- or 6-membered ring; or R7, R8 and R9 independently of one another NR32COR30, NR32CSR30 or NR32SO 2 R30; 15 R30 H, OH, CccH2cc+1, CyyH 2 yy- 1 , pyrrolidinyl or piperidinyl, in which rings a CH 2 group may be replaced by O or NR33; R32 and R33 H, methyl or CF 3 ; cc 1,2,3,4,5,6, 7 or8; yy 3,4,5,6; 20 it being possible for one or more H atoms in the groups CccH2cc+1 and CyyH2yy-1 to be replaced by F atoms and for one or more CH 2 groups to be replaced by NR31 and for a CH 2 group to be replaced by O; R31 H, methyl, ethyl, CF 3 , CH 2 CF 3 , acetyl, propionyl, methanesulfonyl or ethanesulfonyl; 25 or R31 together with a CH 2 group of R30 and the N atom to which they are jointly bonded form a 5- or 6-membered ring; or R30 pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl or 30 oxazolyl, which are unsubstituted or substituted by a maximum of 3 231 substituents selected from the group consisting of F, CI, methyl, ethyl, trifluoromethyl, NH 2 , NHacetyl; or R7, R8 and R9 5 independently of one another H, F, Cl, OH, NH 2 , CeeH2ee+1, CwwH2ww-1, OCffH2ff+1, NR40R41, CONR40R41, COOR42 or OCOR42, ee and ff independently of one another 1, 2, 3 or 4; ww 3, 4, 5or6, 10 it being possible for one or more H atoms in the groups CeeH2ee+1, CwwH2ww-1 and OCffH2ff+1 to be replaced by F atoms; R40 and R41 H, CttH2tt+ 1 or C(NH)NH 2 ; tt 1,2, 3 or 4; 15 it being possible for one or more H atoms in the group CttH2tt+1 to be replaced by F atoms; or R40 and R41 independently of one another hydroxyethyl, N,N-dimethylaminoethyl, 20 N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl; or R40 and R41 together with the N atom to which they are bonded a pyrrolidine, 25 piperidine, N-methylpiperazine, piperazine or morpholine ring; R42 H or ChhH2hh+1; hh 1,2, 3 or 4; it being possible for one or more H atoms in the group ChhH2hh+1 to be replaced by F atoms; 30 but where two substituents from the group of R7, R8 and R9 may not simultaneously be OH or OCH 3 , 232 and where at least one of the radicals R7, R8 or R9 must be selected from the group consisting of CONR40R41, -OvSOwR 2 3, NR32COR30, NR32CSR30 and NR32SObbR30; and the pharmaceutically acceptable salts and trifluoroacetates thereof. 5 4. A compound of the formula I as claimed in claims 1-3 in which the meanings are: R1, R2, R3 and R4 independently of one another H, F, Cl, Br, OH, NH 2 , CaH2a+1, cycloalkyl with 3, 4, 5 or 6 C atoms, OCbH2b+1; 10 a and b in the groups CaH2a+1 and OCbH2b+1 independently of one another 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; or 15 R1, R2, R3 and R4 independently of one another NR11R12; R11 and R12 independently of one another H, CeH2e+l, CrrH2rr-1; e 1,2, 3 or4, 20 rr 3, 4, 5 or 6, it being possible for one or more H atoms in the groups CeH2e+1 and CrrH2rr-1 to be replaced by F atoms; or 25 R11 and R12 together with the N atom to which they are bonded form a ring selected from the group consisting of pyrrolidine, piperidine, N methylpiperazine, piperazine and morpholine; or 30 R11 and R12 233 independently of one another COR14, CSR14, CONHR14, CSNHR14 or SO 2 R14; R14 CgH2g+l; g 1, 2, 3 or 4, it being possible for one or more H atoms 5 to be replaced by F atoms; or R1, R2, R3 and R4 independently of one another OSO 3 H, SO 3 H, SO 2 R15; R15 CkH2k+1 or NR17R18; 10 k 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; R17 and R18 independently of one another H or CmH2m+1 ; m 1, 2, 3, 4 or 5, it being possible for one or more H 15 atoms in the group CmH2m+1 to be replaced by F atoms; or R17 and R18 together with the N atom to which they are bonded a 5- or 20 6-membered ring; but where R2 must always not be equal to H; R5 methyl or trifluoromethyl; R6 H; R7, R8 and R9 25 independently of one another OSO 3 H, SO 3 H or SO 2 R23; R23 CnnH2nn+1 or NR25R26; nn 1,2,3,4or5, it being possible for one or more H atoms in CnnH2nn+1 to be replaced by F atoms; 30 R25 and R26 234 independently of one another H, CN or CzH2z+1, in which the first CH 2 group bonded to the nitrogen is replaced by CO or CS and the second CH 2 is replaced by NR27; z 1, 2, 3, 4, 5 or6; 5 it being possible for one or more H atoms in CzH2z+1 to be replaced by F atoms; R27 H or CaaH2aa+ 1 ; aa 1, 2, 3 or 4; it being possible for one or more H atoms in 10 CaaH2aa+1 to be replaced by F atoms; or R25 and R26 together with the N atom to which they are bonded a 5- or 6-membered ring, 15 or R27 and a CH 2 group of R25 or R26 together with the N atom to which they are bonded a 5- or 6-membered ring; or R7, R8 and R9 20 independently of one another NR32COR30, NR32CSR30 or NR32SO 2 R30; R30 H, OH, CccH2cc+1, CyyH 2 yy- 1 , pyrrolidinyl or piperidinyl, in which rings a CH 2 group may be replaced by O or NR33; R32 and R33 H, methyl or CF 3 ; cc 1,2, 3,4, 5, 6, 7 or8; 25 yy 3, 4, 5 or 6; it being possible for one or more H atoms in the groups CccH2cc+ 1 and CyyH2yy-1 to be replaced by F atoms and for one or more CH 2 groups to be replaced by NR31 and for a CH 2 group to be replaced by O; R31 H, methyl, ethyl, CF 3 , CH 2 CF 3 , acetyl, propionyl, methanesulfonyl or 30 ethanesulfonyl; 235 or R31 together with a CH 2 group of R30 and the N atom to which they are jointly bonded form a 5- or 6-membered ring; or 5 R30 pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl or oxazolyl, which are unsubstituted or substituted by a maximum of 3 substituents selected from the group consisting of F, Cl, methyl, ethyl, trifluoromethyl, NH 2 , NHacetyl; or 10 R7, R8 and R9 independently of one another H, F, Cl, OH, NH 2 , CeeH2ee+1, CwwH2ww-1, OCffH2ff+1, NR40R41, CONR40R41, COOR42 or OCOR42, ee and ff independently of one another 1, 2, 3 or 4; 15 ww 3, 4, 5or6, it being possible for one or more H atoms in the groups CeeH2ee+l, CwwH2ww-1 and OCffH2ff+1 to be replaced by F atoms; R40 and R41 H, CttH2tt+ 1 , or C(NH)NH 2 ; 20 tt 1,2, 3 or 4; it being possible for one or more H atoms in the group CttH2tt+ 1 to be replaced by F atoms; or R40 and R41 25 independently of one another hydroxyethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl; or R40 and R41 30 together with the N atom to which they are bonded a pyrrolidine, piperidine, N-methylpiperazine, piperazine or morpholine ring; 236 R42 H or ChhH2hh+l; hh 1, 2, 3 or 4; it being possible for one or more H atoms in the group ChhH2hh+1 to be replaced by F atoms; 5 but where two substituents from the group of R7, R8 and R9 may not simultaneously .be OH or OCH 3 , and where at least one of the radicals R7, R8 or R9 must be selected from the group consisting of -OvSOwR23, NR32COR30, NR32CSR30 and NR32SObbR30; and the pharmaceutically acceptable salts and trifluoroacetates thereof. 10 5. A compound of the formula I characterized in that it is selected from the group consisting of: 1) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide; 15 2) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide; 3) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide; 4) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N,N-dimethyl benzenesulfonamide; 5) 4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline; 20 6) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid; 7) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-ethyl-benzamide; 8) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-propyl-benzamide; 9) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-(2-dimethylamino ethyl)-benzamide; 25 10) 6,8-dichloro-2-methyl-4-(4-morpholin-4-yl-phenyl)-1 ,2,3,4-tetrahydroisoquinoline; 11) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-phenyl]-diethyl-amine 12) 6,8-dichloro-2-methyl-4-(4-piperidin-1-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline; 13) 6,8-dichloro-2-methyl-4-(4-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline; 14) 6,8-dichloro-2-methyl-4-[4-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro 30 isoquinoline; 15) 6,8-dichloro-2-cyclopropyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline; 16) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine; 237 17) 1 -[4-(6,8-d ich lo ro-2-m ethyl-1, ,2,3,4-tetra hyd ro-isoq u i nol in-4-yI)-p he nyl]-3 propylurea; 18) 1 -[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoqu inolin-4-yI)-phenyll-3-methyl th iou rea; 5 19) 1 -[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-3-ethyl urea; 20) N-[4-(6-methanesulfonyl-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl] acetamide; 21) N-[4-(2,6,8-trimethyl-1 ,2 ,3,4-tetrahydro-isoqu inolin-4-yi)-phenyl]-acetamide; 10 22) N-[4-(6-bromo-8-chloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl] acetamide; 23) N-[4-(8-chloro-2-methyl-6-pyrrolidin-1 -yI-1 ,2 ,3,4-tetrahydro-isoquinolin-4-yi) phenyl]-acetamide; 24) N-14-(8-chloro-2-methyl-6-morpholin-4-yI-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yI) 15 phenyl]-acetamide; 25) N-{4-[8-chloro-2-methyl-6-(4-methyl-piperazin-1 -yl)-l ,2,3,4-tetrahydro-isoquinolin 4-yi]-phenyl}-acetamide; 26) N-{4-[8-chloro-6-(cyclopropylmethyl-amino)-2-methyl-1 ,2,3,4-tetrahyd ro isoquinolin-4-yI]-phenyl}-acetamide; 20 27) 5-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yI)-2-hydroxy-benzoic acid; 28) 5-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoqu inolin-4-yI)-2-hyd roxy-N-methyl benzamide; 29) 5-(6,8-dichloro-2-methyl-1 ,2 ,3,4-tetrahydro-isoqu inolin-4-yI)-N-ethyl-2-hydroxy 25 benzamide; 30) 5-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y)-N-(2-dimethylamino ethyl)-2-hyd roxy-benzamide; 31) N-[5-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y)-2-hydroxy benzoyl]-guanidine; 30 32) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y)-phenyl] acetamide; 33) 3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenylamine; 238 34) 2-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yl)-phenylamine; 35) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] propionamide; 36) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 5 butyramide; 37) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]pentanamide; 38) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] isobutyramide; 10 39) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2 dimethyl-propionamide; 40) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclopropanecarboxamide; 41) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 15 cyclobutanecarboxamide; 42) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclopentanecarboxamide; 43) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2 trifluoro-acetamide; 20 44) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 acetylpiperidine-4-carboxamide; 45) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] nicotinamide; 46) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl]-methane 25 sulfonamide; 47) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl] ethanesulfonamide; 48) N',N'-dimethylamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-sulfamide; 30 49) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] propionamide; 239 50) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] butyramide; 51) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] pentanamide; 5 52) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] isobutyramide; 53) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2 dimethyl-propionamide; 54) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 10 cyclopropanecarboxamide; 55) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclobutanecarboxamide; 56) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclopentanecarboxamide; 15 57) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2 trifluoro-acetamide; 58) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 acetylpiperidine-4-carboxamide; 59) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 20 nicotinamide; 60) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl]-methane sulfonamide; 61) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl] ethanesulfonamide; 25 62) N',N'-dimethylamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-sulfamide; 63) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] propionamide; 64) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 30 butyramide; 65) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] pentanamide; 240 66) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] isobutyramide; 67) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2 dimethyl-propionamide; 5 68) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]cyclopropanecarbox-amide; 69) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl] cyclobutanecarboxamide; 70) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 10 cyclopentanecarboxamide; 71) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2 trifluoro-acetamide; 72) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-l acetylpiperidine-4-carboxamide; 15 73) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane sulfonamide; 74) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl] ethanesulfonamide; 75) N',N'-dimethylamino-N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 20 yl)-phenyl]-sulfamide; 76) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl urea; 77) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl thiourea; 25 78) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl urea; 79) 1-[2-(6 ,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl thiourea; 80) N-{5-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) 30 phenylsulfamoyl]-4-methyl-thiazol-2-yl}-acetamide; 81) N-{5-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenylsulfamoyl]-4-methyl-thiazol-2-yl}-acetamide; 241 82) N-[4-(6,8-d ichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y )-phenyl]-1 ,2 dimethyl-1 H-imidazole-4-sulfonamide; 83) N-[3-(6,8-d ichloro-2-methyl-1 ,2 ,3,4-tetrahydro-isoquinolin-4-y)-phenyl]-1 ,2 dimethyl-1 H-imidazole-4-sulfonamide; 5 84) N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-5-chloro 1 ,3-dimethyl-1 H-pyrazole-4-sulfonamide; 85) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-5-chloro 1 ,3-d imethyl-1 H-pyrazole-4-sulfonamide; 86) N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoqu inolin-4-yI)-phenyl]-5-bromo 10 thiophene-2-sulfonamide; 87) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoqu inolin-4-yI)-phenyl]-5-bromo thiophene-2-sulfonamide; 88) N-[4-(6,8-d ichloro-2-methyl-1 ,2,3,4-tetrahydro-isoqu inolin-4-yI)-phenyl]-C,C,C trifluoro-methanesulfonamide; 15 89) N-[3-(6,8-d ichloro-2-methyl-1 ,2 ,3,4-tetrahydro-isoqu inolin-4-yI)-phenyl]-C,C,C trifluoro-methanesulfonamide; 90) 4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-2,2 ,2 trifluoroethanesulfonamide; 91) 3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-2,2,2 20 trifluoro-ethanesulfonamide; 92) N-ethyl-N'-4-(6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoqu inolin-4-yI) benzenesulfonylurea; 93) 2-chloro-5-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yI) benzenesulfonamide; 25 94) 2-methyl-4-phenyl-6,8-bis-trifluoromethyl-1 ,2,3,4-tetrahydro-isoquinoline; 95) 2-amino-N-[4-(6,8-dichloro-2-methyl-1 ,2 ,3,4-tetrahydro-isoquinolin-4-y)-phenyl] acetamide; 96) N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl] 2-methylamino-acetamide; 30 97) N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yI)-phenyl] 2-dimethylamino-acetamide; 242 98) 2-amino-N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoqu inolin-4-yI)-phenyl] propionamide; 99) 2-amino-N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y)-phenyl] butyra mide; 5 100) 2,6-diamino-N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y) phenyl]-hexanamide; 101) N-[4-(6,8-d ichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl] pyrrolidine-2-carboxamide; 102) N-[4-(6,8-d ichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 10 isonicotinamide; 103) N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-1 H pyrrole-3-carboxamide; 104) N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-1 H pyrrole-2-carboxamide; 15 105) N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y)-phenyl]l--methyl piperid ine-4-carboxamide; 106) N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl] I ,4-dimethyl-1 H-pyrrole-2-carboxamide; 107) N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoqu inolin-4-yl)-phenyl]-4-nitro 20 1 H-pyrrole-2-carb oxamide; 108) N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoqu inolin-4-yl)-phenyl]-2,5 dimethyl-1 H-pyrrole-3-carboxamide; 109) N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H imidazole-4-carboxamide; 25 110) N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y)-phenyl]-1 methanesulfonyl-piperidine-4-carboxamide; 111) N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 ,5 dimethyl-1 H-pyrazole-4-carboxamide; 112) N-[4-(6,8-d ichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y )-phenyl]-1 H 30 pyrazole-4-carboxamide; 113) N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yI)-pheny] 3-trifluoromethyl-1 H-pyrazole-4-carboxamide; 243 114) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 2-methylamino-acetamide; 115) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2 dimethylamino-acetamide; 5. 116) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] propionamide; 117) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] butyramide; 118) 2,6-diamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) 10 phenyl]-hexanamide; 119) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] pyrrolidine-2-carboxamide; 120) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] isonicotinamide; 15 121) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H pyrrole-3-carboxamide; 122) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H pyrrole-2-carboxamide; 123) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl]-1-methyl 20 piperidine-4-carboxamide; 124) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 1,4-dimethyl-1 H-pyrrole-2-carboxamide; 125) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-nitro 1 H-pyrrole-2-carboxamide; 25 126) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 2,5-dimethyl-1 H-pyrrole-3-carboxamide; 127) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H imidazole-4-carboxamide; 128) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 30 1-methanesulfonyl-piperidine-4-carboxamide; 129) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 3,5-dimethyl-1 H-pyrazole-4-carboxamide; 244 130) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H pyrazole-4-carboxamide; 131) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 3-trifluoromethyl-1 H-pyrazole-4-carboxamide; 5 132) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-pheny]-3-ethyl thiourea; 133) 1-[4-(6,8-dichloro-2-methyl-1,2,3 ,4-tetrahydro-isoquinolin-4-yi)-phenylj]-3-ethyl thiourea; 134) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl 10 thiourea; 135) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 1,1-dimethyl-urea; 136) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl piperazine-1 -carboxamide; 15 137) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-piperidine 1-carboxamide; 138) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] morpholine-4-carboxamide; 139) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 20 pyrrolidine-1-carboxamide; 140) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 1,1-diethyl-urea; 141) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl urea; 25 142) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 3-(2-dimethylamino-ethyl)-urea; 143) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 3-(tetrahydro-furan-3-yl)-urea; 144) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 30 3-(tetrahydro-pyran-4-yl)-urea; 145) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1l-methyl 1-(1-methyl-piperidin-4-yl)-urea; 245 146) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 1-(3-dimethylamino-propyl)-1l-methyl-urea; 147) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 1-(2-dimethylamino-ethyl)-1l-methyl-urea; 5 148) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 (3-dimethylamino-propyl)-urea; 149) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 3-(2-methoxy-ethyl)-urea; 150) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin 10 3-yl-urea; 151) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin 4-yl-urea; 152) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl piperazine-1 -carboxamide; 15 153) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl urea; 154) 3-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 1,1-dimethyl-urea; 155) 3-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 20 1,1-diethyl-urea; 156) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-piperidine 1-carboxamide; 157) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] morpholine-4-carboxamide; 25 158) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] pyrrolidine-1l-carboxamide; 159) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 3-(2-dimethylamino-ethyl)-urea; 160) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl 30 piperazine-1 -carboxamide; 161) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] pyrrolidine-1 -carboxamide; 246 162) 1-[4-(6,8-dichloro-2-methyl-1 2,3,4-tetrahydro-isoquinoli n-4-yl)-phenyl]-3-methyl urea; 163) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 1,1-dimethyl-urea; 5 164) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 1,1-diethyl-urea; 165) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 3-(2-dimethylamino-ethyl)-urea; 166) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-piperidine 10 1-carboxamide; 167) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] morpholine-4-carboxamide; 168) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] formamide; 15 169) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl amine; 170) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 1,3-dimethyl-urea; 171) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl 20 4-methyl-piperazine-1 -carboxamide; 172) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 1,3,3-trimethyl-urea; 173) N-[4-(6 ,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl piperidine-1 -carboxamide; 25 174) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl morpholine-4-carboxamide; 175) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl pyrrolidine-1l-carboxamide; 176) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 30 3-(2-dimethylamino-ethyl)-1l-methyl-urea; 177) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 3,3-diethyl-1 -methyl-urea; 247 178) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] formamide; 179) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl amine; 5 180) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl pyrrolidine-1 -carboxamide; 181) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl piperidine-1 -carboxamide; 182) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 10 1,3,3-trimethyl-urea; 183) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 1,3-dimethyl-urea; 184) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl morpholine-4-carboxamide; 15 185) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-4 methyl-piperazine-1 -carboxamide; 186) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 3-(2-dimethylamino-ethyl)-l1-methyl-urea; 187) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 20 3,3-diethyl-1 -methyl-urea; 188) 2-dimethylamino-ethyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin 4-yl)-phenyl]-carbamate; 189) 2-dimethylamino-ethyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin 4-yl)-phenyl]-carbamate; 25 190) 2-dimethylamino-ethyl [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin 4-yl)-phenyl]-carbamate; 191) methyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] carbamate; 192) ethyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 30 carbamate; 193) isopropyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] carbamate; 248 194) 2,2-dimethyl-propyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-carbamate; 195) methyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] carbamate; 5 196) isopropyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] carbamate; 197) 2,2-dimethyl-propyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-carbamate; 198) ethyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 10 carbamate; 199) (R)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] methanesulfonamide; 200) (S)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] methanesulfonamide; 15 201) (R)-1l-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 3-ethyl-urea; 202) (S)-1l-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 3-ethyl-urea; 203) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 20 acetamide; 204) 4-(3-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoline; 205) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 3-(2-hydroxy-ethyl)-urea; 206) ethyl 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoate; 25 207) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid. and the pharmaceutically acceptable salts thereof. and from the pharmaceutically acceptable salts thereof. 6. A compound of the formula I as claimed in claim 1, selected from the group 30 consisting of: 1) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide; 249 2) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide; 3) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide; 4) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoqu inolin-4-yl)-phenyl]-3-methyl thiourea; 5 5) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl urea; 6) N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide; 7) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 10 acetamide; 8) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] propionamide; 9) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -acetyl piperidine-4-carboxamide; 15 10) N-[4-(6 ,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane sulfonamide; 11) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] ethanesulfonamide; 12) N', N'-dimethylamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 20 yl)-phenyl]-sulfamide; 13) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] propionamide; 14) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] butyramide; 25 15) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] isobutyramide; 16) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclopropanecarboxamide; 17) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 30 cyclobutanecarboxamide; 18) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2 trifluoro-acetamide; 250 19) N-[3-(6,8-dichloro-2-methyl-1,2,3 ,4-tetrahydro-isoquinolin-4-yi)-phenyl]-1-acetyl piperidine-4-carboxamide; 20) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] nicotinamide; 5 21) N-[3-(6,8-dichloro-2-methyl-1,2,3 ,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane sulfonamide; 22) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] ethanesulfonamide; 23) N',N'-dimethylamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 10 yl)-phenyl]-sulfamide; 24) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclopropanecarboxamide; 25) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -acetyl piperidine-4-carboxamide; 15 26) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl]-3-ethyl urea; 27) 1-[3-(6 ,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl thiourea; 28) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl 20 urea; 29) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl]-3-methyl thiourea; 30) N-{5-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenylsulfamoyl]-4-methyl-thiazol-2-yl}-acetamide; 25 31) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,2 dimethyl-1 H-imidazole-4-sulfonamide; 32) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-C,C,C trifluoro-methanesulfonamide; 33) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-C,C,C 30 trifluoro-methanesulfonamide; 34) N-ethyl-N'-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) benzenesulfonylurea; 251 35) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2 dimethylamino-acetamide; 36) 2,6-diamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-hexanamide; 5 37) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H pyrrole-3-carboxamide; 38) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1l-methyl piperidine-4-carboxamide; 39) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 10 methanesulfonyl-piperidine-4-carboxamide; 40) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1lH pyrazole-carboxamide; 41) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2 methylamino-acetamide; 15 42) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2 dimethylamino-acetamide; 43) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl] propionamide; 44) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl] 20 butyramide; 45) 2,6-diamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-hexanamide; 46) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-methyl piperidine-4-carboxamide; 25 47) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1lH imidazole-4-carboxamide; 48) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 methanesulfonyl-piperidine-4-carboxamide; 49) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,5 30 dimethyl-1 H-pyrazole-4-carboxamide; 50) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1lH pyrazole-carboxamide; 252 51) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1 dimethyl-urea; 52) N-[3-(6,8-dichloro-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl piperazine-1 -carboxamide; 5 53) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahyd ro-isoquinolin-4-yl)-phenyl]-piperidine 1-carboxamide; 54) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] morpholine-4-carboxamide; 55) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 10 pyrrolidine-1-carboxamide; 56) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1 diethyl-urea; 57) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-3-methyl urea; 15 58) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 dimethylamino-ethyl)-urea; 59) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 (tetrahydro-furan-3-yl)-urea; 60) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 20 (tetrahyd ro-pyran-4-yl)-urea; 61) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -methyl 1-(l -methyl-piperidin-4-yl)-urea; 62) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1l-(3 dimethylamino-propyl)-1l-methyl-urea; 25 63) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1l-(2 dimethylamino-ethyl)-1l-methyl-urea; 64) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(3 diethylamino-propyl)-urea; 65) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 30 methoxy-ethyl)-urea; 66) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin 3-yl)-urea; 253 67) 1 -[3-(6,8-d ichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yI)-phenyl]-3-pyrid in 4-yI-urea; 68) N-[2-(6,8-d ichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yI)-phenyl]-4-methyl piperazine-1 -carboxamide; 5 69) 1 -[2-(6,8-d ichloro-2-methyl-1 ,2,3 ,4-tetrahydro-isoqu inolin-4-yI)-phenyl]-3-methyl urea; 70) 1 -[2-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI )-phenyl]-3-(2 d imethylamino-ethyl)-urea; 71) N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y)-phenyl]-4-methyl 10 piperazine-1 -carboxamide; 72) 1 -[4-(6,8-d ich loro-2-m ethyl- 1,2,3,4-tetra hyd ro-isoq u inol in-4-y)-p he nyl]-3-methyl urea; 73) 3-14-(6,5-d ichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yI)-phenyl]-1 , 1 dimethyl-urea; 15 74) 3-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin4-y)-phenyl]-1 , 1 d iethyl-u rea; 75) 1 -[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y)-phenyl]-3-(2 dimethylamino-ethyl)-urea; 76) N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y)-phenyl] 20 morpholine-4-carboxamide; 77) N-4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoqu inolin-4-yI)-phenyll-formamide; 78) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl] formamide; 79) 1 -[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y)-phenyl]-1 ,3,3 25 trimethyl-urea; 80) 1 -[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y)-phenyl]-1 ,3 d imethyl-urea; 81) N-[3-(6,8-d ichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y)-phenyl]-methyl morpholine-4-carboxamide; 30 82) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y)-phenyl]-methy-4 methyl-piperazine-1 -carboxamide; 254 83) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 dimethylamino-ethyl)-1 -methyl-urea; 84) 2-dimethylamine-ethyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-carbamate; 5 85) 2-dimethylamino-ethyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-carbamate; 86) 2-dimethylamino-ethyl [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-carbamate; 87) methyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 10 carbamate; 88) (R or S)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] methanesulfonamide; 89) (R or S)-1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 ethyl-urea; 15 90) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 hydroxy-ethyl)-urea; and from the pharmaceutically acceptable salts thereof. 7. The use of a compound of the formula I and of the pharmaceutically acceptable 20 salts thereof for producing a medicament for the treatment of disorders which can be influenced by inhibition of the sodium-proton exchanger of subtype Ill (NHE3), in which the meanings are: R1, R2, R3 and R4 independently of one another H, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , CaH2a+1, 25 CqqH2qq- 1 , OCbH2b+1, COOR10, OCOR10, COR10 or Ox-(CH2)y-phenyl; a and b in the groups CaH2a+1 and OCbH2b+1 independently of one another 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms; 30 qq 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms; R10 H or CcH2c+1; 255 c 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms, x zero or 1; y zero, 1,2, 3 or 4; 5 where the phenyl ring in the group Ox-(CH2)y-phenyl is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, CI, Br, CN, NO 2 , OH, NH 2 or CdH2d+l; d 1, 2, 3 or 4, it being possible for one or more H atoms 10 to be replaced by F atoms, or R1, R2, R3 and R4 independently of one another heteroaryl, it being possible for zero, 1, 2, 3 or 4 N atoms, zero or 1 oxygen atom or zero or 1 S atom to be present as ring 15 atoms; or R1, R2, R3 and R4 independently of one another CONR 11R12 or NR11R12; R11 and R12 20 independently of one another H, CeH2e+l, CrrH2rr.-1; e 1,2, 3, 4, 5, 6, 7 or 8, rr 3, 4, 5, 6, 7, or 8, it being possible for one or more H atoms in the groups CeH2e+1 and CrrH2rr-1 to be replaced by F atoms and for one or more CH 2 25 groups to be replaced by O or NR13; R13 H or CfH2f+ 1 ; f 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; or 30 R13 and a CH 2 group of R11 or R12 together with the N atom to which they are bonded a 5- or 6-membered ring; 256 or R11 and R12 together with the N atom to which they are bonded a 5-, 6- or 7-membered ring; 5 or R11 and R12 independently of one another COR14, CSR14 or SO 2 R14; R14 CgH2g+l; g 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or 10 more H atoms to be replaced by F atoms, and it being possible for one or more CH 2 groups to be replaced by O or NR13, or R1, R2, R3 and R4 15 independently of one another -Oh-SOj-R15, with h zero or 1; j zero, 1 or 2; R15 CkH2k+l, OH, OClH 2 1 + 1 or NR17R18; k 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H 20 atoms to be replaced by F atoms; I 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms; R17 and R18 independently of one another H or CmH2m+1 ; 25 m 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms in the group CmH2m+1 to be replaced by F atoms and for one or more CH 2 groups to be replaced by O, CO, CS or NR19; R19 H or CnH2n+1; 30 n 1, 2, 3 or 4; 257 it being possible for one or more H atoms in CnH2n+1 to be replaced by F atoms; or R17 and R18 5 together with the N atom to which they are bonded a 5-, 6- or 7-membered ring; or R19 and a CH 2 group of R17 or R18 together with the N atom to which they are bonded a 5- or 6-membered ring; 10 R5 H, CpH2p+l, CssH 2 ss-1, COR20 or SO 2 R20; p 1,2, 3, 4, 5, 6, 7 or 8, ss 3, 4, 5, 6, 7 or 8, is being possible for one or more H atoms in CpH2p+1 and CssH2ss-1 to be replaced by F atoms, R20 CqH2q+1; 15 q 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms in CqH2q+1 to be replaced by F atoms and for one or more CH 2 groups to be replaced by O or NR21; R21 H or CrH2r+1; 20 r 1,2, 3 or 4; it being possible for one or more H atoms in CrH2r+1 to be replaced by F atoms; R6 H, F, Cl, Br, I, CsH 2 s+ 1 , CddH2dd-1, OH, OCtH2t+1 or OCOR22; s and t 25 independently of one another 1, 2, 3, 4, 5, 6, 7 or 8; dd 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms in CsH 2 s+ 1 , CddH2dd-1 and OCtH2t+1 to be replaced by F atoms; R22 CuH2u+1; u 1,2, 3 or4; 258 it being possible for one or more H atoms in CuH2u+1 to be replaced by F atoms; R7, R8 and R9 independently of one another -Ov-SOw-R23; 5 v zero or 1; w zero, 1 or 2; R23 CnnH2nn+1, CmmH2mm-1, OH, OCppH 2 pp+ 1 or NR25R26; nn and pp independently of one another 1, 2, 3, 4, 5, 6, 7 or 8, 10 mm 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms in CnnH2nn+1, CmmH2mm-1 and OCppH2pp+1 to be replaced by F atoms; R25 and R26 independently of one another H, CN or CzH2z+1, CzzH 2 zz- 1 ; 15 z 1,2,3,4,5,6, 7 or8; zz 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms and, in CzH2z+1, it being possible for one or more H atoms to be replaced by F atoms and it being possible for 20 one or more CH 2 groups to be replaced by O, CO, CS or NR27; R27 H or CaaH2aa+1; aa 1,2, 3 or 4; it being possible for one or more H atoms in 25 CaaH2aa+1 to be replaced by F atoms; or R25 and R26 together with the N atom to which they are bonded a 5-, 6- or 7-membered ring, 30 or 259 R27 and a CH 2 group of R25 or R26 together with the N atom to which they are bonded a 5- or 6-membered ring; or R7, R8 and R9 5 independently of one another NR32COR30, NR32CSR30 or NR32SObbR30; R30 H, CccH2cc+1, CyyH 2 yy- 1 , pyrrolidinyl or piperidinyl, in which rings a CH 2 group may be replaced by O or NR33; R32 and R33 independently of one another H or ChH2h+1; bb 2 or 3; 10 cc 1,2,3,4,5,6, 7 or8; yy 3, 4, 5, 6, 7 or 8; h 1,2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms in ChH2h+1 to be replaced by F atoms, and it being possible for one or more H atoms in the groups 15 CccH2cc+1 and CyyH2yy-1 to be replaced by F atoms and for one or more CH 2 groups to be replaced by NR31 and for a (CH 2 ) group to be replaced by O; R31 H, CkkH2kk+1, COR65 or SO 2 R65; kk 1,2, 3, or 4; 20 it being possible for one or more H atoms to be replaced by F atoms, R65 H, CxxH2xx+l; xx 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; 25 or R31 forms together with a CH 2 group of R30 a 5-, 6- or 7-membered ring; or R30 a 5- or 6-membered heteroaryl with 1, 2, 3 or 4 N atoms, zero or 1 S atoms and zero or 1 0 atoms, 260 which is unsubstituted or substituted by up to three substituents selected from the group consisting of F, CI, Br, I, CooH 2 oo+ 1 , NR70R71; R70 and R71 5 independently of one another H, CuuH2uu+1 and COR72; R72 H, CwH2wvv+1 ; oo, uu and w independently of one another 1, 2, 3, 4, 5, 6, 7 10 or 8; it being possible for one or more H atoms in the groups CooH 2 oo+ 1 , CuuH2uu+1 or CwH2wvv+1 to be replaced by F atoms; or 15 R7, R8 and R9 independently of one another H, F, Cl, Br, I, NO 2 , CN, OH, NH 2 , CeeH2ee+l, CwwH2ww- 1 , OCffH2ff+1, NR40R41, CONR40R41, COOR42, COR42 or OCOR42, ee and ff 20 independently of one another 1, 2, 3, 4, 5, 6, 7 or 8; ww 3, 4, 5, 6, 7 or 8; it being possible for one or more H atoms in the groups CeeH2ee+1, CwwH2ww-1 and OCffH2ff+1 to be replaced by F atoms; R40 and R41 25 H, CttH2tt+1 or C(NH)NH 2 ; tt 1,2,3,4,5,6, 7 or8; it being possible for one or more H atoms in the group CttH2tt+lto be replaced by F atoms and for one or more CH 2 groups to be replaced by O or NR44; 30 R44 H or CggH2gg+1; gg 1,2,3,4,5,6, 7 or8; 261 it being possible for one or more H atoms in the group CggH2gg+1 to be replaced by F atoms, and it being possible for R44 together with a (CH 2 ) group of R40 or R41 and the N atom to which they are jointly bonded to form a 5- or 6 5 membered ring, or R40 and R41 with the N atom to which they are bonded a 5- or 6-membered ring; R42 H or ChhH2hh+1; 10 hh 1,2,3,4,5,6, 7 or8; it being possible for one or more H atoms in the group ChhH2hh+l to be replaced by F atoms.
8. The use as claimed in claim 7, characterized in that compounds of the formula I are 15 used, in which the meanings are: R1, R2, R3 and R4 independently of one another, H, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , CaH2a+1, cycloalkyl with 3, 4, 5 or 6 C atoms, OCbH2b+1, COOR10; a and b 20 independently of one another 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; R10 H or CcH2c+1; c 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; 25 or R1, R2, R3 and R4 independently of one another 5- or 6-membered heteroaryl selected from the group consisting of pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl and oxazolyl; 30 or R1, R2, R3 and R4 262 independently of one another CONR11 R12 or NR 11 R12; R11 and R12 independently of one another H, CeH2e+l, CrrH2rr-1; e 1,2, 3 or4, 5 rr 3, 4, 5or6, it being possible for one or more H atoms in the groups CeH2e+ 1 and CrrH2rr-1 to be replaced by F atoms or R11 and R12 10 independently of one another hydroxyethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl; or R11 and R12 15 together with the N atom to which they are bonded a pyrrolidine, piperidine, N-methylpiperazine, piperazine or morpholine ring; or R11 and R12 independently of one another COR14, CSR14, CONHR14, CSNHR14 20 or SO 2 R14; R14 CgH2g+1; g 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; or 25 R1, R2, R3 and R4 independently of one another OSO 3 H, SO 3 H, SO2R 1 5 , or R15 CkH2k+1, OClH 21 + 1 or NR17R18; k 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; 30 I 1,2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; 263 R17 and R18 independently of one another H, CmH2m+l, in which the first CH 2 group bonded to the nitrogen is replaced by CO and the second CH 2 group is replaced by NR19; 5 m 1, 2, 3, 4 or 5, it being possible for one or more H atoms in the group CmH2m+1 to be replaced by F atoms; R19 H or CnH2n+l; n 1,2, 3 or 4; 10 it being possible for one or more H atoms in CnH2n+1 to be replaced by F atoms; or R17 and R18 together with the N atom to which they are bonded a 5- or 15 6-membered ring; R5 H, CpH2p+ 1 ; CssH 2 ss- 1 ; p 1,2, 3 or 4; ss 3, 4, 5 or 6, it being possible for one or more H atoms in CpH2p+1 and CssH 2 ss- 1 to be replaced by F atoms; 20 R6 H, CsH 2 s+ 1 , OCtH2t+1 or OCOR22; s and t independently of one another 1, 2, 3 or 4; it being possible for one or more H atoms in CsH 2 s+ 1 and OCtH2t+1 to be replaced by F atoms; 25 R22 CuH2u+1; u 1,2, 3 or 4; it being possible for one or more H atoms in CuH2u+1 to be replaced by F atoms; R7, R8 and R9 30 independently of one another OSO 3 H, SO 3 H or SO 2 R23; 264 R23 CnnH2nn+1, CmmH2mm-1, OCppH2pp+ 1 or NR25R26; nn and pp independently of one another 1, 2, 3, 4 or 5, mm 3, 4, 5 or 6, 5 it being possible for one or more H atoms in CnnH2nn+l, CmmH2mm-1 and OCppH 2 pp+ 1 to be replaced by F atoms; R25 and R26 independently of one another H, CN or CzH2z+1, in which the first CH 2 group bonded to the nitrogen is replaced by CO or 10 CS and the second CH 2 is replaced by NR27; z 1,2,3,4, 5 or6; it being possible for one or more H atoms in CzH2z+1 to be replaced by F atoms; R27 H or CaaH2aa+ 1 ; 15 aa 1,2, 3 or 4; it being possible for one or more H atoms in CaaH2aa+1 to be replaced by F atoms; or R25 and R26 20 together with the N atom to which they are bonded a 5- or 6-membered ring; or R27 and a CH 2 group of R25 or R26 together with the N atom to which they are bonded a 5- or 6-membered ring; 25 or R7, R8 and R9 independently of one another NR32COR30, NR32CSR30 or NR32SO 2 R30; R30 H, OH, CccH2cc+1, CyyH 2 yy- 1 , pyrrolidinyl or piperidinyl, in which rings a CH 2 group may be replaced by O or NR33; 30 R32 and R33 independently of one another H or ChH2h+1; 265 cc 1,2, 3, 4, 5, 6, 7 or8; yy 3,4,5or6; h 1,2, 3 or 4; it being possible for one or more H atoms in ChH2h+1 to be replaced by F 5 atoms, and it being possible for one or more H atoms in the groups CccH2cc+1 and CyyH2yy-1 to be replaced by F atoms and for one or more (CH 2 ) groups to be replaced by NR31 and for a (CH 2 ) group to be replaced by O; R31 H, CkkH2kk+1 ,COR65 or SO 2 R65; 10 kk 1,2,3,or4; it being possible for one or more H atoms to be replaced by F atoms, R65 H, CxxH2xx+1; xx 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; 15 or R31 together with a CH 2 group or R30 and the N atom to which they are jointly bonded form a 5- or 6-membered ring; or R30 a 5- or 6-membered heteroaromatic system selected from the group 20 consisting of pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thienyl, thiazolyl and oxazolyl, which are unsubstituted or substituted by up to three substituents selected from the group consisting of F, Cl, Br, I, CooH 2 oo+ 1 , NR70R71, 25 R70 and R71 independently of one another H, CuuH2uu+1 or COR72; R72 H, CwH2vv+1; oo, uu and w independently of one another 1, 2, 3 or 4; 266 it being possible for one or more H atoms in the groups CooH 2 oo+ 1 , CuuH2uu+1 or CwvH 2 vv+ 1 to be replaced by F atoms; or 5 R7, R8 and R9 independently of one another H, F, Cl, Br, I, NO 2 , CN, OH, NH 2 , CeeH2ee+1, CwwH 2 ww- 1 , OCffH2ff+1, NR40R41, CONR40R41, COOR42, COR42 or OCOR42; ee and ff 10 independently of one another 1, 2, 3 or 4; ww 3,4, 5or6, it being possible for one or more H atoms in the groups CeeH2ee+1, CwwH2ww-1 and OCffH2ff+1 to be replaced by F atoms; R40 and R41 15 H, CttH2tt+1 or C(NH)NH 2 ; tt 1,2,3,4,5,6, 7 or8; it being possible for one or more H atoms in the group CttH2tt+1 to be replaced by F atoms; or 20 R40 and R41 to be selected independently of one another hydroxyethyl,, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl; 25 or R40 and R41 together with the N atom to which they are bonded form a ring selected from the group consisting of pyrrolidine, piperidine, N-methyl piperazine, piperazine and morpholine; 30 R42 H or ChhH2hh+1; hh 1, 2, 3 or 4; 267 it being possible for one or more H atoms in the group ChhH2hh+1 to be replaced by F atoms.
9. The use as claimed in claim 7, characterized in that the meanings in formula I are: 5 R1, R2, R3 and R4 independently of one another H, F, Cl, Br, OH, NH 2 , CaH2a+1, cycloalkyl with 3, 4, 5 or 6 C atoms, OCbH2b+1; a and b in the groups CaH2a+1 and OCbH2b+1 independently of one another 10 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; or R1, R2, R3 and R4 independently of one another NR11 R12; 15 R11 and R12 independently of one another H, CeH2e+l, CrrH2rr-1; e 1, 2, 3 or4, rr 3, 4, 5or6, it being possible for one or more H atoms in the 20 groups CeH2e+1 and CrrH2rr-1 to be replaced by F atoms; or R11 and R12 together with the N atom to which they are bonded form a ring selected 25 from the group consisting of pyrrolidine, piperidine, N methylpiperazine, piperazine and morpholine; or R11 and R12 independently of one another COR14, CSR14, CONHR14, CSNHR14 30 or SO 2 R14; R14 CgH2g+l; 268 g 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; or R1, R2, R3 and R4 5 independently of one another OSO 3 H, SO 3 H, SO 2 R15; R15 CkH2k+1 or NR17R18; k 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; R17 and R18 10 independently of one another H or CmH2m+1; m 1, 2, 3, 4 or 5, it being possible for one or more H atoms in the group CmH2m+1 to be replaced by F atoms; or 15 R17 and R18 together with the N atom to which they are bonded a 5- or 6-membered ring; R5 H, CpH2p+1 , CssH 2 ss.-1; p 1, 2, 3 or 4; 20 ss 3, 4, 5 or 6, it being possible for one or more H atoms in CpH2p+ 1 and CssH 2 ss- 1 to be replaced by F atoms; R6 H, CH 3 ; R7, R8 and R9 independently of one another OSO 3 H, SO 3 H or SO 2 R23; 25 R23 CnnH2nn+1 or NR25R26; nn 1,2,3,4or5, it being possible for one or more H atoms in CnnH2nn+1 to be replaced by F atoms; R25 and R26 269 independently of one another H, CN or CzH2z+1, in which the first CH 2 group bonded to the nitrogen is replaced by CO or CS and the second CH 2 is replaced by NR27; z 1,2, 3, 4, 5 or 6; 5 it being possible for one or more H atoms in CzH2z+1 to be replaced by F atoms; R27 H or CaaH2aa+1 ; aa 1,2, 3 or 4; it being possible for one or more H atoms in 10 CaaH2aa+1 to be replaced by F atoms; or R25 and R26 together with the N atom to which they are bonded a 5- or 6-membered ring, 15 or R27 and a CH 2 group of R25 or R26 together with the N atom to which they are bonded a 5- or 6-membered ring; or R7, R8 and R9 20 independently of one another NR32COR30, NR32CSR30 or NR32SO 2 R30; R30 H, OH, CccH2cc+1, CyyH2yy.-1, pyrrolidinyl or piperidinyl, in which rings a CH 2 group may be replaced by O or NR33; R32 and R33 H, CH 3 or CF 3 ; cc 1, 2, 3, 4, 5 or 6; 25 yy 3, 4, 5, 6, 7 or 8; it being possible for one or more H atoms in the groups CccH2cc+1 and CyyH2yy-1 to be replaced by F atoms and for one or more (CH 2 ) groups to be replaced by NR31 and for a (CH 2 ) group to be replaced by O; R31 H, methyl, ethyl, CF 3 , CH 2 CF 3 , acetyl, propionyl, methanesulfonyl or 30 ethanesulfonyl; 270 or R31 together with a CH 2 group of R30 and the N atom to which they are jointly bonded form a 5- or 6-membered ring; or 5 R30 pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl or oxazolyl, which are unsubstituted or substituted by a maximum of 3 substituents selected from the group consisting of F, CI, methyl, ethyl, trifluoromethyl, NH 2 , NHacetyl; or 10 R7, R8 and R9 independently of one another H, F, CI, OH, NH 2 , CeeH2ee+1, CwwH2ww-1, OCffH2ff+1, NR40R41, CONR40R41, COOR42 or OCOR42, ee and ff independently of one another 1, 2, 3 or 4; 15 ww 3,4, 5or6, it being possible for one or more H atoms in the groups CeeH2ee+1, CwwH2ww-1 and OCffH2ff+1 to be replaced by F atoms; R40 and R41 H, CttH2tt+1 or C(NH)NH 2 ; 20 tt 1, 2, 3 or 4; it being possible for one or more H atoms in the group CttH 2 tt+ 1 to be replaced by F atoms; or R40 and R41 25 independently of one another hydroxyethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl; or R40 and R41 30 together with the N atom to which they are bonded a pyrrolidine, piperidine, N-methylpiperazine, piperazine or morpholine ring; 271 R42 H or ChhH2hh+1; hh 1, 2, 3 or 4; it being possible for one or more H atoms in the group ChhH2hh+1 to be replaced by F atoms. 5
10. The use as claimed in claim 7, characterized in that the compounds of the formula I are selected from the group consisting of: 1) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide; 10 2) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide; 3) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide; 4) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N,N-dimethyl benzenesulfonamide; 5) 4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline; 15 6) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid; 7) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-ethyl-benzamide; 8) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-propyl-benzamide; 9) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-(2-dimethylamino ethyl)-benzamide; 20 10) 6,8-dichloro-2-methyl-4-(4-morpholin-4-yi-phenyl)-1,2,3,4-tetrahydroisoquinoline; 11) [4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yi)-phenyl]-diethyl-amine 12) 6,8-dichloro-2-methyl-4-(4-piperidin-1-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline; 13) 6,8-dichloro-2-methyl-4-(4-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline; 14) 6,8-dichloro-2-methyl-4-[4-(4-methyl-piperazin-1 -yl)-phenyl]-1,2,3,4-tetrahydro 25 isoquinoline; 15) 6,8-dichloro-2-cyclopropyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline; 16) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine; 17) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 propylurea; 30 18) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl thiourea; 272 19) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl urea; 20) N-[4-(6-methanesulfonyl-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide; 5 21) N-[4-(2,6,8-trimethyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide; 22) N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide; 23) N-[4-(8-chloro-2-methyl-6-pyrrolidin-1 -yl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-acetamide; 10 24) N-[4-(8-chloro-2-methyl-6-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-acetamide; 25) N-{4-[8-chloro-2-methyl-6-(4-methyl-piperazin-1 -yl)-1,2,3,4-tetrahydro-isoquinolin 4-yl]-phenyl}-acetamide; 26) N-{4-[8-chloro-6-(cyclopropylmethyl-amino)-2-methyl-1,2,3,4-tetrahydro 15 isoquinolin-4-yl]-phenyl}-acetamide; 27) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoic acid; 28) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-2-hydroxy-N-methyl benzamide; 20 29) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-ethyl-2-hydroxy benzamide; 30) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-N-(2-dimethylamino ethyl)-2-hydroxy-benzamide; 31) N-[5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy 25 benzoyl]-guanidine; 32) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide; 33) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine; 34) 2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine; 30 35) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] propionamide; 273 36) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] butyramide; 37) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-y) phenyl]pentanamide; 5 38) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] isobutyramide; 39) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2 dimethyl-propionamide; 40) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 10 cyclopropanecarboxamide; 41) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclobutanecarboxamide; 42) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclopentanecarboxamide; 15 43) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2 trifluoro-acetamide; 44) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 acetylpiperidine-4-carboxamide; 45) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 20 nicotinamide; 46) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane sulfonamide; 47) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl] ethanesulfonamide; 25 48) N',N'-dimethylamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-sulfamide; 49) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] propionamide; 50) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 30 butyramide; 51) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] pentanamide; 274 52) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] isobutyramide; 53) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2 dimethyl-propionamide; 5 54) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclopropanecarboxamide; 55) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclobutanecarboxamide; 56) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 10 cyclopentanecarboxamide; 57) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2 trifluoro-acetamide; 58) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 acetylpiperidine-4-carboxamide; 15 59) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] nicotinamide; 60) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane sulfonamide; 61) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl] 20 ethanesulfonamide; 62) N',N'-dimethylamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-sulfamide; 63) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] propionamide; 25 64) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] butyramide; 65) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] pentanamide; 66) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 30 isobutyramide; 67) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2 dimethyl-propionamide; 275 68) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclopropanecarboxamide; 69) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl] cyclobutanecarboxamide; 5 70) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclopentanecarboxamide; 71) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2 trifluoro-acetamide; 72) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 10 acetylpiperidine-4-carboxamide; 73) N-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane sulfonamide; 74) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl] ethanesulfonamide; 15 75) N', N'-dimethylamino-N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-sulfamide; 76) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl urea; 77) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl]-3-methyl 20 thiourea; 78) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl]-3-ethyl urea; 79) 1-[2-(6 ,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl thiourea; 25 80) N-{5-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenylsulfamoyl]-4-methyl-thiazol-2-yl}-acetamide; 81) N-{5-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenylsulfamoyl]-4-methyl-thiazol-2-yl}-acetamide; 82) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,2 30 dimethyl-1 H-imidazole-4-sulfonamide; 83) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1l,2 dimethyl-1 H-imidazole-4-sulfonamide; 276 84) N-[4-(6,8-d ichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoqu inolin-4-yI )-phenyl]-5-chloro 1 ,3-dimethyl-1 H-pyrazole-4-sulfonamide; 85) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-5-chloro I ,3-dimethyl-1 H-pyrazole-4-sulfonamide; 5 86) N-[4-(6,8-dichloro-2-methyl-1 ,2 ,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-5-bromo thiophene-2-sulfonamide; 87) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-5-bromo thiophene-2-sulfonamide; 88) N-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yI)-phenyl]-C,C,C 10 trifluoro-methanesulfonamide; 89) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-C,C,C trifluoro-methanesulfonamide; 90) 4-(6,8-dichloro-2-methyl-1 ,2 ,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-2,2,2 trifluoroethanesulfonamide; 15 91) 3-(6,8-dichloro-2-methyl-1 ,2 ,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-2,2,2 trifluoro-ethanesulfonamide; 92) N-ethyl-N'-4-(6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yI) benzenesulfonylurea; 93) 2-chloro-5-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y) 20 benzenesulfonamide; 94) 2-methyl-4-phenyl-1 ,2,3,4-tetrahydro-isoquinolin-8-ylamine; 95) 6 ,8-dichloro-2-methyl-4-phenyl-1 ,2,3,4-tetrahydro-isoquinoline; 96) 4-(8-amino-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenol; 97) 8-methoxy-2-methyl-4-phenyl-1 ,2,3,4-tetrahydro-isoqu inoline; 25 98) 2-(8-amino-2-ethyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenol; 99) 2-(8-amino-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenol; 100) 5-(8-a m ino-2-methyl- 1,2,3,4-tetrahyd ro-isoq u inol in-4-yi)-2-methoxy- phenol; 101) 2-methyl-8-nitro-4-phenyl-1 ,2,3,4-tetrahydro-isoquinoline; 102) 4-(8-amino-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-benzene-1 ,2-diol; 30 103) 2,8-dimethyl-4-phenyl-1 ,2,3,4-tetrahydro-isoquinoline; 104) 4-(3,4-dichloro-phenyl)-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinoline; 105) 4-(3,4-dichloro-phenyl)-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-8-ylamine; 277 106) 4-(2,4-dichloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-8-ylamine; 107) 4-(3-chloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-8-ylamine; 108) 2,4-dimethyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 109) 2-butyl-4-phenyl-1,2,3,4-tetrahydro-isoquinolin-8-ylamine; 5 110) N-(2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-acetamide; 111) 7-chloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 112) 8-chloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 113) 2,6-dimethyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 114) 6-chloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 10 115) 6-methoxy-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 116) 2-ethyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 117) 2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 118) 6,8-dichloro-2-ethyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 119) 4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoline; 15 120) 2-methyl-4-phenyl-6,8-bis-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline; 121) 6,8-dichloro-2-isopropyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 122) 5,8-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 123) 6,8-dichloro-4-(4-fluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline; 124) 6,8-dichloro-2-methyl-4-p-tolyl-1,2,3,4-tetrahydro-isoquinoline; 20 125) 5,6-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 126) 6,7-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 127) 8-bromo-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 128) 6,8-dichloro-4-(4-chloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline; 129) 6,8-dichloro-2-cyclopropyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 25 130) 2-amino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide; 131) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2 methylamino-acetamide; 132) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2 30 dimethylamino-acetamide; 133) 2-amino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] propionamide; 278 134) 2-amino-N-[6-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] butyramide; 135) 2,6-diamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-hexanamide; 5 136) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] pyrrolidine-2-carboxamide; 137) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] isonicotinamide; 138) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H 10 pyrrole-3-carboxamide; 139) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H pyrrole-2-carboxamide; 140) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1l-methyl piperidine-4-carboxamide; 15 141) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,4 dimethyl-1 H-pyrrole-2-carboxamide; 142) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-nitro 1 H-pyrrole-2-carboxamide; 143) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,5 20 dimethyl-1 H-pyrrole-3-carboxamide; 144) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1H imidazole-4-carboxamide; 145) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-l methanesulfonyl-piperidine-4-carboxamide; 25 146) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,5 dimethyl-1 H-pyrazole-4-carboxamide; 147) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1H pyrazole-4-carboxamide; 148) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 30 trifluoromethyl-1 H-pyrazole-4-carboxamide; 149) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2 methylamino-acetamide; 279 150) N[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2 dimethylamino-acetamide; 151) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] propionamide; 5 152) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] butyramide; 153) 2,6-diamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-hexanamide; 154) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 10 pyrrolidine-2-carboxamide; 155) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] isonicotinamide; 156) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H pyrrole-3-carboxamide; 15 157) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H pyrrole-2-carboxamide; 158) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-methyl piperidine-4-carboxamide; 159) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,4 20 dimethyl-1 H-pyrrole-2-carboxamide; 160) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-nitro 1 H-pyrrole-2-carboxamide; 161) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,5 dimethyl-1 H-pyrrole-3-carboxamide; 25 162) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H imidazole-4-carboxamide; 163) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-l methanesulfonyl-piperidine-4-carboxamide; 164) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,5 30 dimethyl-1 H-pyrazole-4-carboxamide; 165) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H pyrazole-4-carboxamide; 280 166) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 trifluoromethyl-1 H-pyrazole-4-carboxamide; 167) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl thiourea; 5 168) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl thiourea; 169) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl]-3-ethyl thiourea; 170) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 ,1 10 dimethyl-urea; 171) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl piperazine-1 -carboxamide; 172) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-piperidine 1-carboxamide; 15 173) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] morpholine-4-carboxamide; 174) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] pyrrolidine-1 -carboxamide; 175) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 ,1 20 diethyl-urea; 176) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl urea; 177) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 dimethylamino-ethyl)-urea; 25 178) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 (tetrahydro-furan-3-yl)-urea; 179) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 (tetrahydro-pyran-4-yl)-urea; 180) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1l-methyl 30 1-(1-methyl-piperidin-4-yl)-urea; 181) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1l-(3 dimethylamino-propyl)-1l-methyl-urea; 281 182) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -(2 dimethylamino-ethyl)-1-methyl-urea; 183) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(3 dimethylamino-propyl)-urea; 5 184) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 methoxy-ethyl)-urea; 185) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin 3-yl-urea; 186) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin 10 4-yl-urea; 187) N-[2-(6,8-dichloro-2-methyl-1 2,3,4-tetrahydro-isoquinol in-4-yl)-phenyl]-4-methyl piperazine-1 -carboxamide; 188) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl urea; 15 189) 3-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1, 1 dimethyl-urea; 190) 3-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 ,1 diethyl-urea; 191) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-piperidine 20 1-carboxamide; 192) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] morpholine-4-carboxamide; 193) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] pyrrolidine-1 -carboxamide; 25 194) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 dimethylamino-ethyl)-urea; 195) N-[4-(6,8-dichloro-2-methyl-1,2,3 ,4-tetrahydro-isoquinolin-4-yi)-pheny]-4-methyl piperazine-1 -carboxamide; 196) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 30 pyrrolidine-1 -carboxamide; 197) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl]-3-methyl urea; 282 198) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1, 1 dimethyl-urea; 199) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 ,1 diethyl-urea; 5 200) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 dimethylamino-ethyl)-urea; 201) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-piperidine 1-carboxamide; 202) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 10 morpholine-4-carboxamide; 203) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] formamide; 204) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl amine; 15 205) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3 dimethyl-urea; 206) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-4 methyl-piperazine-1 -carboxamide; 207) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3,3 20 trimethyl-urea; 208) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl piperidine-1 -carboxamide; 209) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] morpholine-4-carboxamide; 25 210) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl pyrrolidine-1 -carboxamide; 211) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 dimethylamino-ethyl)-1 -methyl-urea; 212) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,3 30 diethyl-1 -methyl-urea; 213) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] formamide; 283 214) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl amine; 215) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl pyrrolidine-1 -carboxamide; 5 216) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl piperidine-1 -carboxamide; 217) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3,3 trimethyl-urea; 218) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3 10 dimethyl-urea; 219) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl morpholine-4-carboxamide; 220) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-4 methyl-piperazine-1l-carboxamide; 15 221) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 dimethylamino-ethyl)-1 -methyl-urea; 222) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,3 diethyl-1 -methyl-urea; 223) 2-dimethylamino-ethyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 20 yl)-phenyl]-carbamate; 224) 2-dimethylamino-ethyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-carbamate; 225) 2-dimethylamino-ethyl [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-carbamate; 25 226) methyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] carbamate; 227) ethyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] carbamate; 228) isopropyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 30 carbamate; 229) 2,2-dimethyl-propyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-carbamate; 284 230) methyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] carbamate; 231) isopropyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] carbamate; 5 232) 2,2-dimethyl-propyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-carbamate; 233) ethyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] carbamate; 234) (R)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 10 methanesulfonamide; 235) (S)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] methanesulfonamide; 236) (R)-1l-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 ethyl-urea; 15 237) (S)-1l-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 ethyl-urea; 238) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide; 239) 4-(3-bromo-phenyl)-6,8-dichloro-methyl-1,2,3,4-tetrahydro-isoquinoline; 20 240) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 hydroxy-ethyl)-urea; 241) ethyl 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoate; 242) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid. 25 and from the pharmaceutically acceptable salts thereof.
11. The use as claimed in claim 7, characterized in that the compounds of the formula I are selected from the group consisting of: 1) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 30 acetamide; 2) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide; 3) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide; 285 4) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid; 5) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-ethyl-benzamide; 6) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-propyl-benzamide; 7) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-(2-dimethylamino 5 ethyl)-benzamide; 8) 6,8-dichloro-2-methyl-4-(4-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline; 9) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine; 10) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinol in-4-yi)-phenyl]-3-methyl thiourea; 10 11) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl urea; 12) N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide; 13) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoic 15 acid; 14) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-N-(2-dimethylamino ethyl)-2-hyd roxy-benzamide; 15) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] acetamide; 20 16) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine; 17) 2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine; 18) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] propionamide; 19) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-acetyl 25 piperidine-4-carboxamide; 20) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane sulfonamide; 21) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] ethanesulfonamide; 30 22) N',N'-dimethylamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-sulfamide; 286 23) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] propionamide; 24) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] butyramide; 5 25) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] isobutyramide; 26) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclopropanecarboxamide; 27) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 10 cyclobutanecarboxamide; 28) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2 trifluoro-acetamide; 29) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-acetyl piperidine-4-carboxamide; 15 30) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] nicotinamide; 31) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane sulfonamide; 32) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 20 ethanesulfonamide; 33) N', N'-dimethylamino-N-[3-(6,8-dichloro-2-methyl-1,2,3 ,4-tetrahydro-isoquinolin-4 yl)-phenyl]-sulfamide; 34) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] cyclopropanecarboxamide; 25 35) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-pheny]-1-acetyl piperidine-4-carboxamide; 36) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl]-3-ethyl urea; 37) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl]-3-methyl 30 thiourea; 38) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl]-3-ethyl urea; 287 39) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl]-3-methyl thiourea; 40) N-{5-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenylsulfamoyl]-4-methyl-thiazol-2-yl}-acetamide; 5 41) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,2 dimethyl-1 H-imidazole-4-sulfonamide; 42) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-C,C,C trifluoro-methanesulfonamide; 43) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-C,C,C 10 trifluoro-methanesulfonamide; 44) N-ethyl-N'-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) benzenesulfonylurea; 45) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2 dimethylamino-acetamide; 15 46) 2,6-diamino N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl) phenyl]-hexanamide; 47) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1lH pyrrole-3-carboxamide; 48) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-methyl 20 piperidine-4-carboxamide; 49) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 methanesulfonyl-piperidine-4-carboxamide; 50) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1lH pyrazole-4-carboxamide; 25 51) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2 methylamino-acetamide; 52) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2 dimethylamino-acetamide; 53) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 30 propionamide; 54) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] butyramide; 288 55) 2 ,6-d iamino-N-[3-(6 ,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinoin-4-yi) phepiyll-hexanamide; 56) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yI)-phenyl]-1 -methyl piperidine-4-carboxamide; 5 57) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-y )-phenyl]-1 H imidazole-4-carboxamide; 58) N-[3-(6,8-dichloro-2-methyl-1 ,2,3 ,4-tetrahydro-isoquinolin-4-y)-phenyl]-1 methanesulfonyl-piperidine-4-carboxamide; 59) N-[3-(6,8-dichloro-2-methyl-1 ,2 ,3,4-tetrahyd ro-isoquinolin-4-yI)-phenyl]-3 ,5 10 dimethyl H-pyrazole-4-carboxamide; 60) N-[3-(6,8-d ichloro-2-methyl-1 ,2 ,3,4-tetrahyd ro-isoqu inolin-4-yI)-phenyl]-1 H pyrazole-4-carboxamide; 61) 3-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yI)-phenyl]- , 1 d imethyl-u rea; 15 62) N-13-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoqu inolin-4-yI)-phenyl]-4-methyl piperazine-1 -carboxamide; 63) N-[3-(6,8-d ich lo ro-2-methyl- 1 ,2,3,4-tetra hyd ro-isoq u inol in-4-yI)-p henyl]-p ipe rid ine 1 -carboxamide; 64) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] 20 morpholine-4-carboxamide; 65) N-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yI)-phenyl] pyrrolidine-1 -carboxamide; 66) 3-[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y)-phenyl]-1, 1 diethyl-urea; 25 67) 1 -[3-(6,8-d ichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yI)-phenylj-3-methyl urea; 68) 1 -[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahyd ro-isoquinolin-4-yI)-phenyl]-3-(2 d imethylamino-ethyl)-urea; 69) 1 -[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-y)-phenyl]-3 30 (tetra hyd ro-fu ra n-3-y)-u rea; 70) 1 -[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 (tetra hyd ro-pyra n-4-yl)-u rea; 289 71) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-methyl 1-(1-methyl-piperidin-4-yl)-urea; 72) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -(3 dimethylamino-propyl)-1l-methyl-urea; 5 73) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -(2 dimethylamino-ethyl)-1l-methyl-urea; 74) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(3 dimethylamino-propyl)-urea; 75) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 10 methoxy-ethyl)-urea; 76) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin 3-yl-urea; 77) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl]-3-pyridin 4-yl-urea; 15 78) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-pheny]-4-methyl piperazine-1 -carboxamide; 79) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl]-3-methyl urea; 80) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 20 dimethylamino-ethyl)-urea; 81) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl piperazine-1 -carboxamide; 82) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl urea; 25 83) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1, 1 dimethyl-urea; 84) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahyd ro-isoquinolin-4-yl)-phenyl]-l,1 diethyl-urea; 85) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 30 dimethylamino-ethyl)-urea; 86) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] morpholine-4-carboxamide; 290 87) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] formamide; 88) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl amine; 5 89) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] formamide; 90) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahyd ro-isoquinolin-4-yl)-phenyl]-methyl amine; 91) 1[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3,3 10 trimethyl-urea; 92) 1[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3 dimethyl-urea; 93) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] morpholine-4-carboxamide; 15 94) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methy1-4 methyl-piperazine-1 -carboxamide; 95) 1[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 dimethylamino-ethyl)-1 -methyl-urea; 96) 2-dimethylamino-ethyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 20 yl)-phenyl]-carbamate; 97) 2-dimethylamino-ethyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-carbamate; 98) 2-dimethylamino-ethyl [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-carbamate; 25 99) methyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] carbamate; 100) (R or S)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] methanesulfonamide; 101) (R or S)-1l-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3 30 ethyl-urea; 102) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2 hydroxy-ethyl)-urea; 291 103) ethyl 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoate; 104) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid. and from the pharmaceutically acceptable salts thereof. 5 12. The use of a compound I as claimed in claim 7 for producing a medicament for the treatment or prophylaxis of disorders of respiratory drive.
13. The use of a compound I as claimed in claim 7 for producing a medicament for the treatment or prophylaxis of respiratory disorders, in particular sleep-related respiratory 10 disorders such as sleep apneas.
14. The use of a compound I as claimed in claim 7 for producing a medicament for the treatment or prophylaxis of snoring. 15 15. The use of a compound I as claimed in claim 7 for producing a medicament for the treatment or prophylaxis of acute and chronic renal disorders, particularly of acute renal failure and of chronic renal failure.
16. The use of a compound I as claimed in claim 7 for producing a medicament for the 20 treatment or prophylaxis of disorders of intestinal function.
17. The use of a compound I as claimed in claim 7 for producing a medicament for the treatment or prophylaxis of disorders of biliary function. 25 18. The use of a compound I as claimed in claim 7 for producing a medicament for the treatment or prophylaxis of ischemic states of the peripheral and central nervous system and of stroke.
19. The use of a compound I as claimed in claim 7 for producing a medicament for the 30 treatment or prophylaxis of ischemic states of peripheral organs and limbs. 292
20. The use of a compound I as claimed in claim 7 for producing a medicament for the treatment of states of shock.
21. The use of a compound I as claimed in claim 7 for producing a medicament for use 5 in surgical operations and organ transplantations.
22. The use of a compound I as claimed in claim 7 for producing a medicament for the preservation and storage of transplants for surgical procedures. 10 23. The use of a compound I as claimed in claim 7 for producing a medicament for the treatment of disorders in which cell proliferation represents a primary or secondary cause.
24. The use of a compound I as claimed in claim 7 for producing a medicament for the 15 treatment or prophylaxis of disorders of lipid metabolism.
25. The use of a compound I as claimed in claim 7 for producing a medicament for the treatment or prophylaxis of infestation by ectoparasites. 20 26. A medicine comprising an effective amount of a compound I as claimed in claim 1.
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