OA12740A - Substituted 4-phenyltetrahydroisoquinolines, method for the production thereof, the use thereof as medicaments, in addition to a medicament containingsame. - Google Patents

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

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OA12740A
OA12740A OA1200400166A OA1200400166A OA12740A OA 12740 A OA12740 A OA 12740A OA 1200400166 A OA1200400166 A OA 1200400166A OA 1200400166 A OA1200400166 A OA 1200400166A OA 12740 A OA12740 A OA 12740A
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methyl
dichloro
tetrahydro
isoquinolin
phenyl
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OA1200400166A
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Armin Hofmeister
Uwe Heinelt
Hans-Jochen Lang
Markus Bleich
Klaus Wirth
Michael Gekle
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Aventis Pharma Gmbh
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    • 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
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    • C07—ORGANIC CHEMISTRY
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    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
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    • 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
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    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
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    • 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
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    • 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
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    • 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
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    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • 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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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
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Abstract

The invention relates to compounds of formula (I), wherein R1 - R9 which have the meaning as cited in the claims, are extremely suitable as antihypertensives for reducing or preventing ischemically induced injuries, as medicaments for operative intervention for the treatment of ischemics of the nervous system, strokes and swelling of the brain, shocks, disturbed respiratory functions, for the treatment of snorers, as a laxative, as agents against ectopic parasites, for the prevention of gallstones, as antiatherosclerotic agents, agents against diabetic late complications, cancer, fibrotic diseases, endothelial dysfunctions, organ hypertrophia and hyperplasia. Said compounds are also inhibitors of the cellular sodium-proton-antiporters, they influence serum lipoproteins and can be used in the prophylaxis of and for the regression of atherosclerotic alterations.

Description

012740
The invention relates to compounds of the formula I
in which the meanings are: R1, R2, R3 and R4 independently of one another H, F, Cl, Br, I, CN, NO2, OH, NH2, CaH2a+l.CqqH2qq-1> æbH2b+1> OOOR10, OCOR10, COR10 or Ox-(CH2)y-phenyl;a and b in the groups CaH2a+i and OC^^b+l independently of one another1,2,3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to bereplaced by F atoms; qq 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to bereplaced by F atoms; ; R10 HorCcH2c+i; c 1,2, 3, 4, 5, 6, 7 or 8, it being possible for one or more Hatoms to be replaced by F atoms, x zéro or 1 ;y zéro, 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, Cl, Br, CN, NO2, OH, NH2 or
CdH2d+i; 2 012740 d 1,2, 3 or 4, it being possible for one or more H atomsto be replaced by F atoms, or R1, R2, R3 and R4 5 independently of one another heteroaryl, it being possible for zeroA 1,2, 3 or 4 N atoms, zéro or 1 oxygen atorn or zéro or 1 S atom to be présent as ring " atoms; or R1, R2, R3andR4 10 independently of one another GONR11R12 or NR11R12; R11 and R12 independently of one another H, CeH2e+i , 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+i and crrH2rr-1to replaced by F atoms and for one or more CH2groups to be replaced by O or NR13; R13 H or CfH2f+i ;
f 1,2,3 or 4, it being possible for one or more H 20 atoms to be replaced by F atoms; or RI 3 and a CH2 group of R11 or R12 together with the N atom to which they are bonded a 5- or 6-membered ring;or λ Ί·% 25 R11andR12 together with the N atom to which they are bonded a 5-, 6- or 7-membered ring; or R11andR12 30 independently of one another COR14, CSR14 or SÛ2R14; R14 CgH2g+i; 3 012740 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 beingpossible for one or more CH2 groups to be replaced byOorNR13, or R1, R2, R3 and R4 independently of one another -Oh-SOj-R15, withh zéro or 1 ; j zéro, 1 or 2; R15 C|<H2k+l, OH, OC|H2|+1 or NR17R18; k 1,2, 3, 4, 5, 6, 7 or 8, it being possible for one or more Hatoms to be replaced by F atoms; I 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more Hatoms to be replaced by F atoms; R17andR18 independently of one another H or CmH2m+i ;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 Fatoms and for one or more CH2 groups to be replacedby O, CO, CS or NR19; R19 HorCnH2n+i;n 1,2,3qr4; it being possible for one or more H atoms inθη^2η+1 to be replaced by F atoms; or R17 and R18 together with the N atom to which they are bonded a 5-, 6- or 7-membered ring;or R19 and a CH2 group of R17 or R18 together with the N atom to which they are bonded a 5- or 6-membered ring; 4 012740 10 15 20 25 but where R2 must always not be equal to H, R5 H, CpH2p+i ; Css^2ss-1, COR20 or SO2R2O; p 1, 2, 3, 4, 5, 6, 7 or 8, ss 3, 4, 5, 6, 7 or 8, R20 CqH2q+i; q 1,2, 3, 4, 5, 6, 7 or up to 8, it being possible for one or more H atoms in the groups CpH2p+-|,CSsH2ss-1 ancl CqH2q+11° be replaced by F atoms and for ooe ormore CH2 groups to be replaced by O or NR21 ; R21 HorCrH2r+i; r 1,2, 3 or up to 4; it being possible for one or more H atoms in CrH2r+i to bereplaced by F atoms; R6 H, F, Cl, Br, I, CgH2s+-|, ^ddR2dd-1> θθί^2ί+1 orOCOR22;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
Cs^2s+1 > CddH2dd-1 anc* θθί^2ί+1b® replaced by F atoms;R22 cuh2u+i; u 1,2, 3 or 4; it being possible for one or more H atoms in CUH2U+-| to bereplaced by F atoms; R7, R8 and R9 independently of one another -OV-SOW-R23;v zéro or 1; w zéro, 1 or 2; R23 0ηη^2ηη+1» CmmH2mrn-1< θΗ, OCppH2pp+i 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, 30 5 012740 it being possible for one or more H atoms in CnnH2nn+1 >Cmm^2mm-1 and OûppH2pp+i to be replaced by F atoms; R25 and R26 independently of one another H, CN or CZH2Z+1, CZZH2ZZ-1 ;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 > R being possible for one or more H atomsto be replaced by F atoms and it being possible forone or more CH2 groups to be replaced by O, CO, CSor NR27; R27 H or CaaH2aa+1 !aa 1, 2, 3 or 4; it being possible for one or more H atoms inCaaH2aa+i to be replaced by F atoms; or R25 and R26 together with the N atom to which they are bonded a 5-, 6- or7-membered ring,or R27 and a CR2 group of R25 or R26 together with the N atom to which they are bonded a 5- or 6-membered ring;or i R7, R8 and R9 independently of one another NR32COR30, NR32CSR30 or NR32SObbR30;R30 H, CccH2cc+1 . Cyy^2yy-1, pyrrolidinyl or piperidinyl, in which rings a CH2 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 or 8; yy 3, 4, 5, 6, 7 or 8; 012740 6 10 15 20 25 h 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms in ChH2h+l to be replaced by Fatoms, and it being possible for one or more H atoms in the groupeCCcH2cc+1 anc* CyyH2yy-1 1° be replaced by F atoms and for one or moreCH2 groups to be replaced by NR31 and for one CH2 group to be replaced byO; R31 H, Cj<i<H2kk+1 > COR65 or SO2 R65 ;kk 1,2, 3, or 4; it being possible for one or more H atoms to be replaced by Fatoms, R65 H, ΟχχΗ^χχ+ι ; xx 1,2, 3 or 4, it being possible for one or more H atomsto be replaced by F atoms; or R31 forms together with a CH2 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, zéro or 1 Satoms and zéro or 1 O atoms, which is unsubstituted or substituted by up to threesubstituents selected from the group consisting of F, Cl, Br, I,C00H200+I. NR70R71; R70andR71 independently of one another H, CuuH2uu+1 andCOR72; R72 H, CvyH2w+1 ! 00, uu and w independently of one another 1,2,3, 4, 5, 6,7or 8; it being possible for one or more H atoms in the groups CqqH2oo+1 » ^uu^2uu+1 or θνν^2νν+1 to be replaced by F atoms; 30 012740 7 R7, R8 and R9 independently of one another H, F, Cl, Br, I, NO2, CN, OH, NHg, CeeH2ee+i>
Cww^ww-I- °CffH2ff+l, NR40R41, CONR40R41, COOR42, COR42 or 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 CeeH2©e+l »CwwH2ww-1 anc· 0CffH2ff+1 to be replaced by F atoms; R40 and R41 H, CttH2tt+1 orC(NH)NH2;tt 1,2, 3, 4, 5, 6, 7 or 8; it being possible for one or more H atoms in the group OttH2tt+1 t0 bereplaced by F atoms and for one or more CH2 groups to be replacedby O or NR44; R44 H0rCggH2gg+1; gg 1,2, 3, 4, 5, 6, 7 or 8;it being possible for one or more H atoms in the groupCggH2gg+i to be replaced by F atoms and it being possiblefor R44 to form a 5- or 6-membered ring together with a (CH2)group of R40 or R41 and the n-atom to which they are bound; or R40 and R41 with the N atom to which they are bonded a 5- or 6-membered ring;R42 HorChhH2hh+i; hh 1,2, 3, 4, 5, 6, 7 or 8; it being possible for one or more H atoms in the group ChhH2hh+1 tobe replaced by F atoms; 8 012740 with the proviso that not two substituents from the group R7, R8 and R9 can simultaneously be OH and OCH3 and that at least one of the substituents R7, R8 and R9 must be seiected from the group consisting of CONR40R41, -OV_SOW'R23, NR32COR30, NR32CSR30 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 independently of one another, H, F, Cl, Br, I, CN, NOg, OH, NH2, CaH2a+i»cycloalkyl with 3, 4, 5 or 6 C atoms, OCbH2b+l. COOR10;a and b independently of one another 1,2, 3 or 4,4 being possible for one ormore H atoms to be replaced by F atoms; R10 HorCcH2c+1; c 1,2, 3 or 4, it being possible for one or more H atoms to be replacedby F atoms; or R1, R2, R3 and R4 independently of one another 5- or 6-membered heteroaryl seiected from thegroup consisting of pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl,thiazolyl and oxazolyl; or R1, R2, R3 and R4 independently of one another CONR11R12 or NR11R12; R11 and R12 independently of one another H, CeH2e+i, CrrH2rr-1 ;e 1,2, 3 or 4, rr 3, 4, 5 or 6, it being possible for one or more H atoms in the groupsCeH2e+i and CrrH2rr-1 to be replaced by F atoms 012740 9 R11andR12 independently of one another hydroxyethyl, N.N-dimethylaminoethyl, Ν,Ν-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl; or R11andR12 together with the N atom to which they are bonded a pyrrolidine,piperidine, N-methylpiperazine, piperazine or morpholine ring; or R11andR12 independently of one another COR14, CSR14, CONHR14, CSNHR14orSÛ2R14; R14 CgH2g+i; g 1, 2, 3 or 4, it being possible for one or more H atomsto be replaced by F atoms; or R1, R2, R3 and R4 independently of one another OSO3H, SO3H, SO2R15, withR15 CkH2k+1, °C|H2|+1 orNR17R18; k 1,2, 3 or 4, it being possible for one or more H atoms to bereplaced by F atoms; I 1,2, 3 or 4, it being possible for one or more H atoms to bereplaced by F atoms; R17andR18 independently of one another H, CmH2m+i, in which the firstCH2 group bonded to the nitrogen is replaced by CO and thesecond CH2 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 βθ replaced by F atoms; 012740 10 R19 H or CnH2n+l î n 1,2, 3 or 4; it being possible for one or more H atoms in CnH2n+l to bereplaced by F atoms; or R17andR18 together with the N atom to which they are bonded a 5- or6-membered ring; but where R2 must always not be equal to H, R5 H,CpH2p+i; p 1,2, 3 or 4; it being possible for one or more H atoms in CpH2p+i to be replacedby F atoms; R6 H, CsH2s+1 , OCtH2t+l or OCOR22; s and t . independently of one another 1,2, 3 or 4; it being possible for one or more H atoms in CsH2s+1 and OCtH2t+ito be replaced by F atoms; R22 Cu^2u+1 î u 1,2,3 or 4; it being possible for one or more H atoms in CuH2u+1 to be replacedby F atoms; R7, R8 and R9 independently of one another OSO3H, SO3H or SO2R23; R23 CnnH2nn+1> Cmm^mm-I» θθρρ^2ρρ+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+1 »CmmR2mm-1 and θθρρΗ2ρρ+1 to be replaced by F atoms; 012740 11 R25 and R26 independently of one another H, CN, or CZH2Z+1, in which the first CHg group bonded to the nitrogen is replaced by CO or CS and the second CHg is replaced by NR27; z 1,2, 3, 4, 5 or 6; it being possible for one or more H atoms in CZH2Z+1to 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 incaaH2aa+1 to be replaced by F atoms; or R25 and R26 together with the N atom to which they are bonded a 5- or6-membered ring;or R27 and a CH2 group of R25 or R26 together with the N atomto which they are bonded a 5- or 6-membered ring; or R7, R8 and R9 independently of one anothej' NR32COR30, NR32CSR30 or NR_32SC>2R30;R30 H, OH, CccH2cc+1 > CyyH2yy-1 > pyrrolidinyl or piperidinyl, in which rings a CH2 group may be replaced by O or NR33; R32 and R33 independently of one another H or ChH2h+i; cc 1,2, 3, 4, 5, 6, 7 or 8;yy 3, 4, 5 or 6; h 1,2, 3 or 4;
it being possible for one or more H atoms in ChH2h+l to be replaced by F atoms, and it being possible for one or more H atoms in the groupeCCcH2cc+1 and CyyH2yy-1 to be replaced by F atoms and for one or more 12 012740 CH2 groups to be replaced by NR31 and for one CHg group to be replaced by O; R31 H, Ckk^2kk+1 > COR65 or SO2 R65;kk 1,2, 3, or 4; it being possible for one or more H atoms to be replaced by F atoms,R65 H, CxxH2xx+i; 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 CH2 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 groupconsisting of pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl,thienyl, thiazolyl and oxazolyl, which is unsubstituted or substituted by up to threesubstituents selected from the group consisting of F, Cl, Br, I,C00H200+I. NR70R71, R70 and R71 independently of one another H, CuuH2uu+1 orCOR72; R72 H, CwH2w+i: 00, uu and w independently of one another 1,2,3 or 4;it being possible for one or more H atoms in the groupsθοοΗ2οο+1 > CuuH2uu+1 or cvvH2w+1t0 be replaced by Fatoms; R8 and R9 independently of one another H, F, Cl, Br, I, NO2, CN, OH, NH2, CeeH2ee+1 »CwwH2ww-1 > OCffH2ff+i, NR40R41, CONR40R41, COOR42, COR42 orOCOR42; 012740 13 ee and ff independently of one another 1,2,3 or 4; ww 3, 4, 5 or 6, it being possible for one or more H atoms in the groups CeeH2ee+1>
Cww^2ww-1 and 0CffH2ff+i to be replaced by F atoms; R40 and R41 H, CttH2tt+i i or C(NH)NH2;tt 1,-2,3,4,5, 6, 7 or 8; it being possible for one or more H atoms in the group CttH2tt+l to bereplaced by F atoms; or R40 and R41 to be selected independently of one another hydroxyethyl,,Ν,Ν-dimethylaminoethyl, Ν,Ν-diethylaminoethyl, pyrrolidinoethyl,N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl orpiperidinoethyl; or R40 and R41 together with the N atom to which they are bonded form a ring selectedfrom the group consisting of pyrrolidine, piperidine, N-methyl-piperazine, piperazine and morpholine; R42 H or ChhH2hh+1 îhh 1,2, 3 or 4; it being possible for one or more H atoms in the group CbhH2hh+1 tobe replaced by F atoms; with the proviso that not two substituents from the group R7, R8 and R9 cansimultaneously be OH and OCH3; and that at least one of the substituents R7, R8 and R9 must be selected from thegroup consisting of CONR40R41, -OV_SOW“R23, NR32COR30, NR32CSR30 andNR32SObbR30; and the pharmaceutically acceptable salts and trifluoroacetates thereof. 14 012740
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, NH2, CaH2a+1 > cycloalkyl with 3, 4, 5 or 6 G atoms, OCbH2b+l ;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+i t CrrH2rr-i ; e 1,2, 3 or 4, rr 3, 4, 5 or 6,
it being possible for one or more H atoms in thegroups CeH2e+i and CrrH2rr-1 to be replaced by F 20 atoms; or R11andR12 together with the N atom to which they are bonded form a ring selectedfrom the group consisting of pyrrolidine, piperidine, N- 25 methylpiperazine, piperazine and morpholine; or R11andR12 independently of one another COR14, CSR14, CONHR14, CSNHR14 or SO2R14; 30 R14 CgH2g+i; 012740 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 OSO3H, SO3H, SO£R15; R15 CkH2k+1 orNR17R18; k 1,2, 3 or 4, it being possible for one or more H atoms to bereplaced by F atoms; R17andR18
. 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 1° be replaced by Fatoms; or R17andR18 together with the N atom to which they are bonded a 5- or6-membered ring; but where R2 must always not be equal to H; R5 methyl or trifluoromethyl; R6 H; R7, R8 and R9 - independently of one another OSO3H, SO3H or SO2R23; R23 CnnH2nn+1 or NR25R26; nn 1,2, 3, 4 or 5, it being possible for one or more H atoms in CnnH2nn+1 to bereplaced by F atoms; R25 and R26 independently of one another H, CN or CZH2Z+-| in which thefirst CH2 group bonded to the nitrogen is replaced by CO orCS and the second CK2 is replaced by NR27;z 1,2, 3, 4, 5 or 6; 012740 16 it being possible for one or more H atoms in CzH2z+ito 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 incaaH2aa+1 t0 b® replaced by F atoms; or R25 and R26 ** together with the N atom to which they are bonded a 5- or6-membered ring, or R27 and a CH2 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 NR32SO2R30;R30 H, OH, CccH2cc+1 » CyyH2yy-1 > pyrrolidinyl or piperidinyl, in which rings a CH2 group may be replaced by O or NR33; R32 and R33 H, methyl or CF3;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 groupe CccH2cc+1 ar,dCyyH2yy-i to be replaced by F atoms and for one or more CH2 groups to bereplaced by NR31 and for one CH2 group to be replaced by O; R31 H, methyl, ethyl, CF3, CH2CF3, acetyl or propionyl, methanesulfonylor ethanesulfonyl; or R31 together with a CH2 group of R30 and the N atom to which they are jointlybonded form a 5- or 6-membered ring; or 012740 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, Cl, methyl, ethyl, j
trifluoromethyl, NH2, NHacetyl; I or R7, R8 and R9 independently of one another H, F, Cl, OH, NH2, CeeH2ee+i, Cww^2ww-1 » 0CffH2ff+1. NR40R41, CONR40R41, COOR42 or OCOR42,eeandff independently of one another 1,2,3 or 4;ww 3,4, 5 or 6, it being possible for one or more H atoms in the groups CeeH2ee+i.CwwH2ww-1 ar,d 0CffH2ff+1 to be replaced by F atoms; R40 and R41 H, CttH2tt+i or C(NH)NH2;tt 1,2, 3 or 4; it being possible for one or more H atoms in the group CttH2tt+i to bereplaced by F atoms; or R40andR41 independently of one another hydroxyethyl, N,N-dimethylaminoethyl,*Ν,Ν-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl,piperazinoethyl, morpholinoethyl or piperidinoethyl; or R40 and R41 together with the N atom to which they are bonded a pyrrolidine,piperidine, N-methylpiperazine, piperazine or morpholine ring; R42 HorChhH2hh+i;hh 1,2, 3 or 4; it being possible for one or more H atoms in the group ChhH2hh+1 tobe replaced by F atoms; 012740 18 witb the provîso that not two substituents from the group R7, R8 and R9 cansimultaneously be OH and OCH3; and that at least one of the substituents R7, R8 and R9 must be selected from thegroup consisting of CONR40R41, -OV-SOW"R23, NR32COR30, NR32CSR30 and 5 NR32SOfc,bR30; and the pharmaceutically acceptable salts and trifluoroacetates thereof.
Very partiçular preference is given to compounds of the formula I in which the-meanings are: 10 R1, R2, R3 and R4 independently of one another H, F, Cl, Br, OH, NH2, CaH2a+1> cycloalkyl with3, 4, 5 or 6 C atoms, OCbH2b+l ;a and b in the groups CaH2a+l ancUOCb^b+l independently of one another15 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 NR11R12; 20 R11andR12 independently of one another H, CeH2e+i, Crr^2rr-1 ;e 1,2, 3 or 4, rr 3, 4, 5 or 6,
it being possible for one or more H atoms in the25 groups CeH2e+i and CrrH2rr-1 to be replaced by F atoms; or R11andR12 together with the N atôm to which they are bonded form a ring selected30 from the group consisting of pyrrolidine, piperidine, N- methylpiperazine, piperazine and morpholine; 012740 19 or R11andR12 independently of one another COR14, CSR14, CONHR14, CSNHR14 orSO2R14; 5 R14 CgHgg+i; g 1,2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms;or R1,R2, R3and R4 10 independently of one another OSO3H, SO3H, SO2R15; R15 CkH2k+i orNR17R18; k 1,2,3 or 4, it being possible for one or more H atoms to be replaced by F atoms; R17andR18 15 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 Fatoms; or 20 R17and R18 together with the N atom to which they are bonded a 5- or6-membered ring; but where R2 must always not be equal to H; R5 methyl or trifluoromethyl; 25 R6 H; R7, R8 and R9 independently of one another OSO3H, SO3H or SO2R23; R23 CnnH2nn+1 or NR25R26; nn 1,2, 3, 4 or 5, 30 it being possible for one or more H atoms in CnnH2nn+1 to be replaced by F atoms; 012740 20 R25 and R26 independently of one another H, CN or CzH2z+1 >n which the first CH2 group bonded to the nitrogen is replaced by CO or CS and the second CH2 is replaced by NR27; 5 z 1,2,3,4,5 or 6; it being possible for one or more H atoms in CzH2z+ito 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
Caa^teaa+It0 be replaced by F atoms; or R25 and R26 together with the N atom to which they are bonded a 5- or15 6-membered ring, or R27 and a CH2 group of R25 or R26 together with the N atom to which they are bonded a 5- or 6-membered ring;or 20 R7, R8andR9 independently of one another NR32COR30, NR32CSR30 or NR32SÛ2R30;R30 H, OH, CccH2cc+1 » CyyH2yy-1 » pyrrolidinyl or piperidinyl, in which rings a CH2 group may be replaced by O or NR33; R32 and R33 H, methyl or CF3; 25 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-ito be replaced by F atoms and for one or more CH2 groups to be replaced by NR31 and for one CH2 group to be replaced by O; 012740 21 R31 H, methyl, ethyl, CF3, CH2CF3, acetyl or propionyl, methanesulfonyl or ethanesulfonyl; or R31 together with a CH2 group of R30 and the N atom to which they are jointly5 bonded form a 5- or 6-membered ring; or R30 pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl oroxazolyl, which are unsubstituted or substituted by a maximum of 3substituents selected from the group consisting of F, Cl, methyl, ethyl, 10 trifluoromethyl, NH2, NHacetyl; or R7, R8 and R9 independently of one another H, F, Cl, OH, NH2, ΟθθΗ2θθ+ι, Cww^2ww-1 »0CffH2ff+1. NR40R41, CONR40R41 ,COOR42 or OCOR42, 15 eeandff independently of one another 1,2, 3 or 4; ww 3, 4, 5 or 6, it being possible for one or more H atoms in the groups CeeH2ee+l.CWwH2ww-1 ancl 0CffH2ff+1 to βθ replaced by F atoms; 20 R40 and R41 H, CttH2tt+l or C(NH)NH2;tt 1,2, 3 or 4; it being possible for one or more H atoms in the group CftH2tt+l to bereplaced by F atoms; 25 or R40 and R41 independently of one another hydroxyethyl, Ν,Ν-dimethylaminoethyl, Ν,Ν-diethylaminoethyl, pyrrolidinoethyl, N-méthylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl; 30 or R40 and R41 012740 22 together with the N atom to which they are bonded a pyrrolidine,piperidine, N-methylpiperazine, piperazine or morpholine ring; R42 HorChhH2hh+l!hh 1,2, 3 or 4; it being possible for one or more H atoms in the group ChhH2hh+1 tobe replaced by F atoms; with the proviso that not two substituents from the group R7, R8 and R9 cansimultaneously be OH and OCH3; and that at least one of the substituents R7, R8 and R9 must be selected from thegroup consisting of -Ov-SOW'R23, NR32COR30, NR32CSR30 and NR32SObbR30;and the pharmaceutically acceptable salts and trifluoroacetates thereof.
Very especially particular preference is given to compounds from the group of I ) 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)-benzenesuifonamide; 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; 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-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline; II ) [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-isoquinoline; 15) 6,8-dichloro-2-cyciopropyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline; 23 012740 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)-phenyI]-3-propylurea; 18) 1 -[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea; 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; 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-isoquinolïn-4-yl)-phenyl]-acetamide; 23) N-(4-(8-chloro-2-methyl-6-pyrrolidin-1 -y 1-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylj-acetamide; 24) N-[4-(8-chloro-2-methyl-6-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylj-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-(cyclopropylméthyl-amino)-2-methyl-1,2,3,4-tetrahydro-ïsoquinolin-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-methyI-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-N-methyl-benzamide; 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-yl)-N-(2-dimethylamino-ethyl)-2-hydroxy-benzamide; 31 ) N-[5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yI)-2-hydroxy-benzoyl]-guanidine; 32) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide; 012740 24 33) 3-(6,8-dichloro-2-methyi-1,2,3,4-îetrahydro-isoquinolin-4-yl)-phenylamine; 34) 2-(6,8-dichloro-2-methyl-1,2^4-tetrahydro4soquinolin-4-yl)-phenylamine; 35) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide; 5 36) N-[4-(6,8-dichloro-2-methyl-1I2A4-tetrahydro4soquinolin-4-yl)-phenyll- 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]- 10 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-tetrahydrci-isoqiiinolin-4-yl)-phenyl]-cyclopropanecarboxamide; 15 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; 43) N-[4-(6,8-dichloro-2-methyl-1,2,3,4"tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2- 20 trifluoro-acetamide; 44) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquindlin-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; 25 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; 48) N',N'-dimethylamino-N-[4-(6,8-dichloro-2-methyl-1)2,3,4-tetrahydro-isoquinolin-4 30 yl)-phenyl]-sulfamide; 49) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide; 012740 25 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-teirahydro-Îsoquinolin-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-teti'ahydro-isoquinolin-4-yl)-phenyl3-cyclopropanecarboxamide; 55) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-îetrahydro-isoquinolin-4-yl)-phenyl]-cyclobutanecarboxamide; 56) N-[3-(6,8-dichloro-2-methyl-1,2,3Atetrahydro4soquinolin-4-yl)-phenyl]-cyclopentanecarboxamide; 57) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolÎn-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]-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)- phenylj-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; 64) N-[2-(6,8-dichIoro-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; 012740 26 66) N-[2-(6,8-dichloro-2-methyI-1,2,3,4-teti'ahydro-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]-cyclopropanecarboxamide; 69) N-[2-(6,8-dichloro-2-methyl-1,2A44etrahydro-isoquinolîn-4-yl)- phenyl]-cyclobutanecarboxamide; 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 -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; 75) N'.N'-dimethylamino-N-p-Ce.S-dichloro^-methyl-l ,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-thiourea; 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-îsoquinolin-4-yl)-phenyl]-3-methyl-thiourea; 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; 012740 27 82) N-[4-(6,8-dichloro-2-methyl-1,2,3Atetrahydro-isoquinolin-4-yl)-phenyl]-1,2-dimethyl-1H-imidazole-4-sulfonamide; 83) N-[3-(6,8-dichlora-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-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-yl)-phenyl]-5-bromo··thiophene-2-sulfonamide; 87) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoIin-4-yl)-phenyl]-5-bromo-thiophene-2-suifonamide; 88) N-[4-(6,8<lichloro-2-methyl-1,2,3Atetrahydro-isoquinolin-4-yl)-phenyl]-C,C,C-trifluoro-methanesulfonamide; 89) N-[3-(6,8“dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-C,C,C-trifluoro-methanesulfonamide; 90) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoroethanesulfonamide; 91) 3-(6,8-dichloro-2-methyi-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylî-2,2,2-trifluoro-ethanesulfonamide; 92) N-ethyl-N’-4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonylurea; 93) 2-chloro-5-(6.8-dichIoro-2-methyl’1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide; 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-yl)-phenyl]-acetamide; 96) N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinorm-4-yl)-phenyl]-2-methylamino- acetamide; 97) N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-dimethylamino-acetamide; 28 012740 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]-butyramide; 5 100) 2,6-Diamino-hexanoic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)- phenylj-amide; 101) Pyrrolidine-2-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydiO-isoquinolin-4- yl)-phenyl]-amide; 102) N-[4-{6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]- 10 isonicotinamide; 103) 1 H-Pyrrole-3-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 104) 1 H-Pyrrole-2-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 15 105) 1 -Methyl-piperidine-4-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 106) 1,4-Dimethyl-1 H-pyrrole-2-carboxylic acid [4-(6,8-dicbloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 107) 4-Nitro-1 H-pyrrole-2-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- 20 isoquinolin-4-yl)-phenyl]-amide; 108) 2,5-Dimethyl-1H-pyrrole-3-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide; 109) 1 H-lmidazole-4-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin- 4-yl)-phenyl]-amide; 25 110) 1 -Methanesulfonyl-piperidine-4-carboxylic acid [4-(6,8-dichloro-2-methyI-1,2,3,4- tetrahydro-isoquinolin-4-yl)-phenyl]-amide; 111) 3,5-Dimethyl-1H-pyrazole-4-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 112) 1 H-Pyrazole-4-carboxyIic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- 30 isoquinolin- 4-yl)-phenyl]-amide; 113) 3-Trifluoromethyl-1H-pyrazole-4-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolîn-4-yl)-phenyi]-amide; 012740 29 114) 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-yi)-phenyl3-butyramide; 118) 2,6-Diamino-hexanoic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- 10 isoquinolin-4-yl)- phenyl]-amide; 119) Pyrrolidine-2-carboxyiic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 120) N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isomcotinamide; 15 121)1 H-Pyrrole-3-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4- yl)-phenyl]-amide; 122) 1 H-Pyrrole-2-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl3-amide; 123) 1-Methyl-piperidine-4-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro 20 isoquinolin-4-yl)-phenyl]-amide; 124) 1,4-Dimethyl-1 H-pyrrole-2-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 125) 4-Nitro-1 H-pyrrole-2-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide; 25 126) 2,5-Dimethyl-1 H-pyrrole-3-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4- tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 127) 1 H-lmidazole-4-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin- 4-yl)-phenyl]-amide; 128) 1-Methanesulfonyl-piperidine-4-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4- 30 tetrahydro-isoquinolin-4-yl)-phenyl3-amide; 129) 3,5-Dimethyl-1H-pyrazole-4-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoiin-4-yl)-phenyl]-amide; 30 012740 130) 1 H-Pyrazole-4-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin- 4-yl)-phenyl]-amide; 131) 3-TrifIuoromethyl-1 H-pyrazole-4-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl)-amide; 5 132) 1-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl- thiourea; 133) 1 -(4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoiin-4-yl)-phenyl]-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) 4-Methyl-piperazine-1-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 15 137) Piperidine-1 -carboxÿlic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4- yl)-phenyl]-amide; 138) Morpholine-4-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 139) Pyrrolidine-1 -carboxÿlic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- 20 isoquinolin-4- yl)-phenyl]-amide; 140) 3-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinol1n-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-DichIoro-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- 30 (tetrahydro- pyran-4-yl)-urea; 145) 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; 012740 31 146) 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]-1 -(2-dimethylamino-ethyl)-1 -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; 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) 4-Methyl-piperazine-1-carboxylic acid (2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 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)-phenyiJ-1,1 -dimethyl- urea; 155) 3-(2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1 -diethyl- urea; 156) Piperîdine-1-carboxylic acid [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 157) Morpholine-4-carboxylic acid (2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 158) Pyrrolidine-1-carboxylic acid (2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 159) 1 -(2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea; 160) 4-Methyl-piperazine-1-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 161) Pyrrolidine-1-carboxylic acid [4-(6,8-dichloro-2-methyJ-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 012740 32 162) 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]-1,1 -dimethyUurea; 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-dimethyiamino-ethyl)-urea; 166) Piperidine-1 -carboxylic acid (4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 167) Morpholine-4-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 168) N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-formamide; 169) [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyll-methyl-amine; 170) 1 -(4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3-dimethyl- urea; 171) 4-Methyl-piperazine-1-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-methyl-amide; 172) 1 -(4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3,3-trimethyl- urea; 173) Piperidine-1 -carboxylic acid (4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- y,)-phenyl]-methyl-amide; 174) Morpholine-4-carboxylic acid (4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenylj-methyl-amide; 175) Pyrrolidine-1-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-methyl-amide; 176) 1 -(4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-1 -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; 012740 33 178) N-(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquino!in-4-y!)-phenyl]-formamide; 179) (3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amine; 180) Pyrrolidine-1-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-methyl-amide; 181) Piperidine-1 -carboxyiic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-methyl-amide; 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) Morpholine-4-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-methyl-amide; 185) .4-Methyl-piperazine-1 -carboxyiic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-methyl-amide; 186) 1 -(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-1-methyl-urea; 187) 1 -(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,3-diethyl-1 - methyl-urea; 188) [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid 2- dimetfiylamino-ethyl ester; 189) (4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid 2- dimethylamino-ethyl ester; 190) (2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid 2- dimethylamino-ethyl ester; 191) (3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid methyl ester; 192) [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid ethyl ester; 193) [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyI]-carbamicacid isopropyl ester; 012740 34 194) [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoiin-4-yl)-phenyl]-carbamicacid 2,2- dimethyl-propyl ester; 195) [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl3-carbamicacid methyl ester; 5 196) [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic acid isopropyl ester; 197) [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid 2,2- dimethyl-propyl ester; 198) [4-(6;8-Dichloro-2-methyl-1,2,3,4-tëtrahydro-isoquinolin-4-yl)-phenyl]-carbamic 10 acid ethyl ester; 199) (+)-N-[3-(6,8-bichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide; 200) (-)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide; 15 201) (+)-1-(2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3- ethyl-urea; 202) (-)-1 -[2-(6,8-DichlorO-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea; 203) N-[3-(6,8-Difluoro-2-rnethyl-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) 3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid ethyl 25 ester; 207) 3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid. and the pharmaceutically acceptable salts thereof. 30
Exceptionally particular preference is given to compounds from the group of 012740 35 1 ) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquino!in-4-yl)-phenyl]-acetamide; 2) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-Îsoquinolin-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-urea; 6) N-(4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylJ-acetamide; 7) N-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylJ-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; 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-y0-phenyl]-ethanesulfonamide; 12) N,,N'-dimethylamino-N-[4-(6,8-diçhloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-_ 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; 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-methyI-1,2,3,4-tetrahydro-isoquinoHn-4-yl)-phenyl]-cyclobutanecarboxamide; 36 012740 18) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoro-acetamide; 19) N-(3-(6,8-dichloro-2-methyl-1,2,3,4-îetrahydro-isoquinolin-4-yl)-phenyl]-1 -acetyl-piperidine-4-carboxamide; 5 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-îsoquinolin-4-yl)-phenyl]-methane-sulfonamide; 22) N-[3-(6!8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]- 10 ethanesulfonamide; 23) N',N'-dimethylamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-sulfamide; Λ 24) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopropanecarboxamide; 15 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-yI)-phenyl]-3-ethyl-urea; 27) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl- * 20 thiourea; 28) 1-(2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea; 29) 1 -(2-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea; 25 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]-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- 30 trifluoro-methanesulfonamide; 33) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-C,C,C-trifluoro-methanesulfonamide; 012740 37 34) N-ethyi-N'-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonylurea; 35) N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-dimethylamino-acetamide; 5 36) 2,6-Diamîno-hexanoic acid [4-(6,8-dichloro-2-methyi-1,2,3,4-tetrahydro- isoquinolin-4-yl)- phenyl]-amide; 37) 1 H-Pyrrole-3-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 38) 1 -Methyl-piperidine-4-carboxyIic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- 10 isoquinolin-4-yl)-phenyl]-amide; 39) 1-Methanesulfonyl-piperidine-4-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide; 40) 1 H-Pyrazole-4-carboxylic acid [4-(6,8-dichloro-2-methyi-1,2,3,4-tetrahydro-isoquinolin- 4-yl)-phenyl]-amide; 15 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-dimethyiamino-acetamide; 43) 2-Amîno-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylJ- 20 propionamide; 44) 2-Amino-N-[3-(6,8-dichloro-2-methyi-1,2,3,4-tetrahydro-isoqtiinolin-4-yl)-phenylj- butyramide; _ 45) 2,6-Diamino-hexanoic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl]-amide; 25 46) 1-Methyl-piperidine-4-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 47) 1 H-lmidazole-4-carboxyiic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-ietrahydro-isoquinolin- 4-yl)-phenyl]-amide; 48) 1 -Methanesulfonyl-piperidine-4-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4- 30 tetrahydro-isoquinolin-4-yl)-phenyl]-amide; 49) 3,5-Dimethyl-1 H-pyrazole-4-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 012740 38 50) 1 H-Pyrazole-4-carboxylic acid (3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin- 4-yl)-phenyl]-amide; 51) 3-(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-dimethyl- urea; 5 52) 4-Methyl-piperazine-1-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4- tetrahydro- isoquinoiin-4-yl)-phenyI3-amide; 53) Piperidine-1 -carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide; 54) Morpholine-4-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- 10 isoquinolin-4- yl)-phenyl]-amide; 55) Pyrrolidine-1-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide; 56) 3-(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1 -diethyl- urea; 15 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-dimethylamino-ethyl)-urea; 59) 1 -(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3- 20 (tetrahydro- furan-3-yl)-urea; 60) 1 -(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(tetrahydro- pyran-4-yl)-urea; 61 ) 3-(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -methyl1-(1 - methyl-piperidin-4-yl)-urea; 25 62) 3-(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -(3- dimethylamino-propyl)-1-methyl-urea; 63) 3-(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -(2-dimethylamino-ethyl)-1-methyl-urea; 64) 1 -(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(3- 30 dimethylamino-propyl)-urea; 65) 1 -(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-methoxy- ethyl)-urea; 012740 39 66) 1 -(3-(6,8-Dichloro-2-methy,-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin- 3- yl- urea; 67) 1 -(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin- 4- yl- urea; 68) 4-Methyl-piperazine-1 -carboxylic acid [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl3-amide; 69) 1 -[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoiin-4-yl)-phenyl]-3-methyl-urea; 70) 1 -(2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-îsoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea; 71 ) 4-Methyt-piperazine-1 -carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 72) 1 -[4-(6,8-Dichloro-2-methyi-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea; 73) . 3-(4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1 - dimethyl- urea; 74) 3-(4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1 -diethyl- urea; 75) 1-(4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea; 76) Morpholine-4-carboxylic acid (4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 77) N-(4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl3-fomnamide; 78) N-(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl3-formamide; 79) 1-(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3,3-trimethyl- urea; 80) 1 -(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3-dimethyl- urea; 81 ) Morpholine-4-carboxylic acid (3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4- yl)-phenyl]-methyl-amide; 012740 40 82) 4-Methyl-piperazine-1 -carboxylic acid (3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amide; 83) 1-(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-1-methyl-urea; 5 84) [3-(6,3-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic acid 2- dimethylamino-ethyl ester; 85) [4-(6,8-DichIoro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid 2- dimethylamino-ethyl ester; 86) (2-(6^-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic 10 acid 2-dimethylamino-ethyl ester; 87) [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid methyl ester; 88) (R oder S)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]- methanesulfonamide; 15 89) (R oder S)-1 -(2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl]-3-ethyl-urea; K. 90) 1-(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-hydroxy- ethyl)-urea; and the pharmaceutically acceptable salts thereof. 20
The invention further encompasses the use of the compounds of the formula I forproducing a médicament for the treatment of disorders which can be influenced byinhibition of the sodium-proton exchange of subtype III (NHE3), in which the meaningsare: 25 R1, R2, R3 and R4 independently of one another H, F, Cl, Br, I, CN, NOg, OH, NHg, CaH2a+i,CqqH2qq-1, OCj^Hgb+l» COOR10, OCOR10, COR10 or Ox_(CH2)y*phenyl;a and b in the groups CaH2a+i and OCbH2b+i independently of one another30 1,2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms; 41 012740 qq 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms; R10 HorCcH2C+i; c 1,2, 3,4, 5, 6, 7 or 8, it being possible for one or more Hatoms to be replaced by F atoms, x zéro or 1 ;y zéro, 1, 2, 3 or 4; where tbe phenyl ring in the group Ox-(CH2)y-phenyl isunsubstituted or substituted by 1-3 substituents selected fromthe group consisting of F, Cl, Br, CN, NO2, OH, NH2 orcdH2d+1 ! d 1,2, 3 or 4, it being possible for one or rriore H atomsto be replaced by F atoms, or R1, R2, R3andR4 independently of one another heteroaryl, it being possible for zéro, 1,2, 3 or 4N atoms, zéro or 1 oxygen atom or zéro or 1 S atom to be présent as ringatoms; or R1, R2, R3 and R4 independently of one another CONR11R12 or NR11R12; - R11andR12 independently of one another H, CeH2e+i, 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+l andCrrH2rr-1 to be replaced by F atoms and for one or more CH2groups to be replaced by O or NR13; R13 HorCfH2f+-|;
f 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; 012740 42 or R13 and a CH2 group of R11 or R12 together with the N atom to which they are bonded a 5- or 6-membered ring; R11andR12 together with the N atom to which they are bonded a 5-, 6- or7-membered ring; or RÎ1 and R12 " independently of one another COR14, CSR14 or SÛ2R14; R14 CgH2g+i; 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 beingpossible for one or more CH2 groups to be replaced byOorNR13, or R1, R2, R3 and R4 independently of one another -Oh-SOj-R15, with h j R15 zéro or 1 ; zéro, 1 or 2;
CkH2k+ii OH, OC1H21+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; R17andR18 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 CH2 groups to be replaced by O, CO, CS or NR19; 012740 43 R19 HorCnH2n+i; η 1,2,3 or 4; it being possible for one or more H atoms in
CnH2n+l to be replaced by F atoms; or R17andR18 together with the N atom to which they are bonded a 5-, 6- or7-membered ring;or R19 and a CH2 group of R17 or R18 together with the N atomto which they are bonded a 5- or 6-membered ring; R5 H, θρΗ2ρ+1, CssH2ss-1, COR20 or SO2R2O;p 1, 2, 3, 4, 5, 6, 7or 8, ss 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms in CpH2p+i and CssH2ss-1 t0 βθ replaced by F atoms R20 CqH2q+i ; q 1,2,3,4, 5, 6, 7 or up to 8, it being possible for one or more H atoms in CqH2q+-| to be replacedby F atoms and for one or more CH2 groups to be replaced by O orNR21; - R21 H orCrH2r+i; r 1, 2, 3 or up to 4; it being possible for one or more H atoms in CrH2r+l to bereplaced by F atoms; R6 H, F, Cl, Br, I, CgH2s+i, Cdd^2dd-1’ θΗ> θθΐ^2ί+1 ®r OCOR22;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
CsH2s+1 > Cdd^2dd-1 and θθί^2Ι+1 to βθ replaced by F atoms; R22 CuH2u+i; 012740 44 u 1,2, 3 or 4; it being possible for one or more H atoms in CuH2u+1 to bereplaced by F atoms; R7, R8 and R9 independently of one another -OV-SOW-R23; v zéro or 1 ; w zéro, 1 or 2; R23 Cnn^2nn+1 > CmmH2mm-1 » θΗ, OCppH2pp+i 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, it being possible for one or more H atoms in CnnH2nn+1.Cmm^2mm-1 and OCppH2pp+1 be replaced by F atoms; R25 and R26 independently of one another H, CN or CzH2z+1, θζζ^2ζζ-1 '>z zz i, à, a, 4, o, e, / or b; 3, 4, 5, 6, 7 or 8, it being possible for one or more Hatoms to be replaced by F atoms and,in CzH2z+i , it being possible for one or more H atomsto bé replaced by F atoms and it being possible forone or more CH2 groups to be replaced by O, CO, CSorNR27; H or CaaH2aa+1 îaa 1, 2, 3 or 4; it being possible for one or more H atoms inCaaH2aa+1 to be replaced by F atoms; R27 or R25 and R26 together with the N atom to which they are bonded a 5-, 6- or7-membered ring, or 012740 45 R27 and a CH2 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; Ί • 1 R30 H, CccH2cc+1 > CyyH2yy-1 > pyrrolidinyl or piperidinyl, in which rings aCH2 group may be replaced by OorNR33; R32 and R33 independently of one another H or ChH2h+1 ;bb 2 or 3; cc 1,2,3,4,5,6, 7 or 8; 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+i to be replaced by Fatoms, and it being possible for one or more H atoms in the groupsCCcH2cc+1 anc! CyyH2yy-1 to be replaced by F atoms and for one or moreCH2 groups to be replaced by NR31 and for one CH2 group to be replaced byO; R31 H, Ckk^2kk+1 » COR65 or SO2R65;kk 1,2, 3, or 4; it being possible for one or more H atoms to be replaced by Fatoms, R65 H, Cxx^xx+i ; xx 1,2, 3 or 4, it being possible for one or more H atomsto be replaced by F atoms; or R31 forms together with a CH2 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, zéro or 1 S atoms and zéro or 1 O atoms, 46 012740 which is unsubstituted or substituted by up to three subsiituents selected from the group consisting of F, Cl, Br, I, θοο^2οο+1 > NR70R71 ; R70andR71 independently of one another H, CuuH2uu+1 ar>dCOR72; R72 H, Cvv^2vv+1 >oo, uu and w independently of one another 1,2,3, 4, 5, 6, 7or 8; it being possible for one or more H atoms in the groups CooH2oo+1 > Cuu^2uu+1 orCwH2w+1 t° bereplaced by F atoms; or R7, R8 and R9 independently of one another H, F, Cl, Br, I, NO2, CN, OH, NH2, CeeH2ee+1>Cww^2ww-1> 0CffH2ff+i, NR40R41, CONR40R41, COOR42, COR42 orOCOR42, 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 0CffH2ff+i to be replaced by F atoms; R40 and R41 H, CttH2tt+1 or C(NH)NH2;tt 1,2, 3,4, 5, 6, 7 or 8; it being possible for one or more H atoms in the group CttH2tt+1to bereplaced by F atoms and for one or more CH2 groups to be replacedbyOorNR44; R44 H or CggH2gg+-| ; gg 1,2, 3,4, 5, 6, 7 or 8; 47 012740 it being possible for one or more H atoms in the groupCggH2gg+i to be replaced by F atoms, 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 or 8; it being possible for one or more H atoms in the group ChhH2hh+1tobe replaced by F atoms; and the pharmaceutically acceptable salts thereof.
Preference is given to the use of compounds of the formula I, in which the meaningsare: R1, R2, R3 and R4 independently of one another, H, F, Cl, Br, I, CN, NO2, OH, NH2, CaH2a+i,cycloalkyl with 3, 4, 5 or 6 C atoms, OCfc>H2b+l. COOR10;a and b independently of one another 1,2, 3 or 4, it being possible for one ormore H atoms to be replaced by F atoms; R10 HorCcH2c+1; c 1, 2, 3 or 4, it being possible for one or more H atoms to be replacedby F atoms; or R1, R2, R3 and R4 independently of one another 5- or 6-membered heteroaryl selected from thegroup consisting of pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl,thiazolyl and oxazolyl; or R1, R2, R3 and R4 independently of one another CONR11R12 or NR11R12; 012740 48 R11andR12 independently of one another H, CeH2e+i t Crr^2rr-1 ; e 1,2, 3 or 4, rr 3, 4, 5 or 6, 5 it being possible for one or more H atoms in the groups
CeH2e+i and CrrH2rr-1 to be replaced by F atoms or R11andR12 independently of one another hydroxyethyl, N,N-dimethylaminoethyl,10 Ν,Ν-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl;or . ' . R11 and R12 together with the N atom to which they are bonded a pyrrolidine, 15 piperidine, N-methylpiperazine, piperazine or morpholine ring; or R11andR12 independently of one another COR14, CSR14, CONHR14, CSNHR14orSO2R14; 20 R14 CgH2g+1; g 1, 2, 3 or 4, it being possible for one or more H atomsto be replaced by F atoms; or R1, R2, R3 and R4 25 independently of one another OSO3H, SO3H, SO2Rj5, or R15 CkH2k+l,OC|H2|+1 orNR17R18; k 1, 2,3 or 4, it being possible for one or more H atoms to bereplaced by F atoms; I 1, 2, 3 or 4, it being possible for one or more H atoms to bereplaced by F atoms; R17andR18 30 012740 49 independently of one another H or CmH2m+i, in which the first CH2 group bonded to the nitrogen is replaced by CO and the second CH2 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+1to be replaced by Fatoms; R19 H or CnH2n+1 ; n 1,2, 3 or 4; it being possible for one or more H atoms in CnH2n+i to bereplaced by F atoms; or R17 and R18 together with the N atom to which they are bonded a 5- or6-membered ring; R5 H, CpH2p+i, CssH2ss-i:p 1,2, 3 or 4; ss 3, 4, 5 or 6, it being possible for one or more H atoms in CpH2p+i andCSsH2ss-1 to be replaced by F atoms; R6 H, CsH2s+i, OCtH2t+l orOCOR22;s and t independently of one another 1,2, 3 or 4; it being possible for one ôr more H atoms in CsH2s+1 and OCtH2t+ito be replaced by F atoms; R22 Cu^2u+1 ! u 1,2, 3 or 4; it being possible for one or more H atoms in CuH2u+i to be replacedby F atoms; R7, R8 and R9 independently of one another OSO3H, SO3H or SO2R23; R23 θηηΗ2ηη+1 > ^mm^mm-l > θ^ρρΗ2ρρ+ι or NR25R26; 50 012740 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 Cnn^2nn+1 · cmmH2mm-1 and 0CppH2pp+1 t0 b® replaced by F atoms; R25 and R26 independently of one another H, CN or CzH2z+1 , in which thefirst CH2 group bonded to the nitrogen is replaced by CO or __ •T î_ CS and the second CH2 is replaced by NR27;z 1,2, 3, 4, 5 or 6; it being possible for one or more H atoms in CzH2z+1to 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; or R25 and R26 together with the N atom to which they are bonded a 5- or6-membered ring;or R27 and a CH2 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 NR32SO2R30; R30 H, OH, CccH2cc+1 » cyyH2yy-1 » pyrrolidinyl or piperidinyl, in which rings a CH2 group may be replaced by O or NR33; R32 and R33 independently of one another H or CftH2h+i ; cc 1,2, 3, 4, 5, 6, 7 or 8; 012740 51 yy 3,4,5 or 6; h 1,2,3 or 4; it being possible for one or more H atoms in ChH2h+i to be replaced by F atoms, and it being possible for one or more H atoms in the groups CccH2ce+1 and GyyH2yy-1t0 be replaced by F atoms and for one or more CH2 groups to be replaced by NR31 and for one CH2 group to be replaced by O; R31 H, Gkk^2kk+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,R65 H, Οχχ^χχ+ι ; xx 1,2, 3 or 4, it being possible for one or more H atomsto be replaced by F atoms; or R31 together with a CH2 group or R30 and the N atom to which they arejointly bonded form a 5- or 6-membered ring; or R30 a 5- or 6-membered heteroaromatic System selected from the groupconsisting of pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl,thienyl, thiazolyl and oxazolyl, which is unsubstituted or substituted by up to threesubstituents selected from the group consisting of F, Cl, Br, I,C00H200+I. NR70R71, R70 and R71 independently of one another H, CuuH2uu+1 orCOR72; R72 H, CyyH2w+1> 00, uu and vv independently of one another 1,2, 3 or 4; it being possible for one or more H atoms in the groups
θοο^2οο+1> Cuu^2uu+1 °r GwH2vv+1 1° b® replaced by F atoms; 012740 52 R7, R8 and R9 independently of one another H, F, Cl, Br, I, NO2, CN, OH, NH2, CeeH2ee+i,
CwwH2ww-1 . OCffH2ff+i, NR40R41, CONR40R41, COOR42, COR42 or OCOR42; ee and ff independently of one another 1,2, 3 or 4;ww 3, 4, 5 or 6, it being possible for one or more H atoms in the groups CeeH2ee+-|,Cwwh2ww-1 and °CffH2ff+1 t0 be replaced by F atoms; R40 and R41 H, CttH2tt+1 or C(NH)NH2!tt 1,2, 3, 4,5, 6, 7 or 8; it being possible for one or more H atoms in the group CttH2tt+i to bereplaced by F atoms; or R40 and R41 to be selected independently of one another hydroxyethyl,,N,N-dimethylaminoethyl, Ν,Ν-diethylaminoethyl, pyrrolidinoethyl,N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl orpiperidinoethyl; or R40 and R41 together with the N atom to which they are bonded form a ring selectedfrom the group consisting of pyrrolidine, piperidine, N-methyl-piperazine, piperazine and morpholine; R42 HorChhH2hh+i;hh 1,2, 3 or 4; it being possible for one or more H atoms in the group ChhH2hh+1tobe replaced by F atoms; 53 0127 4 0 and the pharmaceutically acceptable salts thereof.
Particular preference is given to the use of compounds of the formula I in which themeanings are: R1, R2, R3 and R3 independently of one another H, F, Cl, Br, OH, NHg, CaH2a+l » cycloalkyl with3, 4, 5 or 6 C atoms, OCpHgb+i ;a and b in the groups CaH2a+1 and æbH2b+1 independently of one another1,2, 3 or 4, it being possible for one or more H atoms to be replacedby F atoms; or R1, R2, R3 and R4 independently of one another NR11R12; R11andR12 independently of one another H, CeH2e+-|, CrrH2rr-1 ;e 1,2, 3 or 4, rr 3, 4, 5 or 6, it being possible for one or more H atoms in thegroups CeH2e+-| and CrrH2rr-1 to be replaced by Fatoms; or R11andR12 together with the N atom to which they are bonded form a ring selectedfrom the group consisting of pyrrolidine, piperidine, N-methylpiperazine, piperazine and morpholine; or R11andR12 independently of one another COR14, CSR14, CONHR14, CSNHR14orSO2R14; R14 CgH2g+i; 012740 54 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 OSO3H, SO3H, SO2RI5; R15 CkH2k+l orNR17R18; k 1, 2, 3 or 4, it being possible for one or more H atoms to bereplaced by F atoms; R17andR18
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 Fatoms; or R17andR18 together with the N atom to which they are bonded a 5- or6-membered ring; R5 H, CpH2p+-)( CssH2ss_i;p 1, 2, 3 or 4; ss 3,4, 5 or 6, it being possible for one or more H atoms in CpH2p+i andcssh2ss-1 to be replaced by F atoms; R6 H, CH3; R7, R8 and R9 independently of one another OSO3H, SO3H or SO2R23; R23 θηη^2ηη+1 or NR25R26; nn 1,2,3,4 or 5, it being possible for one or more H atoms in CnnH2nn+l to bereplaced by F atoms; R25 and R26 55 independently of one another H, CN or CzH2z+1 in which the first CH2 group bonded to the nitrogen is replaced by CO or CS and the second CH2 is replaced by NR27; z 1,2, 3, 4, 5 or 6; it being possible for one or more H atoms in CZH2Z+1to 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 inCaaH2aa+1to b® replaced by F atoms; or R25 and R26 together with the N atom to which they are bonded a 5- or6-membered ring,or R27 and a CH2 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 NR32SO2R30; -, R30 H, OH, CccH2cc+1 > cÿyH2yy-1 > pyrrolidinyl or piperidinyi, in which rings a CH2 group may be replaced by O or NR33; R32 and R33 H, CH3 or CF3;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+1and CyyH2yy-i to be replaced by F atoms and for one or more CH2groups to be replaced by NR31 and for one CH2 group to be replacedbyO; 012740 56 R31 H, methyl, ethyl, CF3, CH2CF3, acetyl, propionyl, methanesulfonyl or ethanesulfonyl; or R31 together with a CH2 group of R30 and the N atom to which they are jointlybonded form a 5- or 6-membered ring; or R30 pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl oroxazolyl, which are unsubstituted or substituted by a maximum of 3substituents selected from the group consisting of F, Cl, methyl, ethyl,trifluoromethyl, NH2, NHacetyl; or R7, R8 and R9 independently of one another H, F, Cl, OH, NH2, CeeH2ee+i, CwwH2ww-1»0CffH2ff+1, NR40R41, CONR40R41, COOR42 or OCOR42,ee and ff independently of one another 1,2, 3 or 4;ww 3, 4, 5 or 6, it being possible for one or more H atoms in the groups CeeH2ee+i,Cwwh2ww-1 and 0CffH2ff+1to be replaced by F atoms; R40 and R41 H,CttH2tt+i orC(NH)NH2;tt 1,2, 3 or 4; it being possible for one or more H atoms in the group CttH2tt+i to bereplaced by F atoms; °r R40andR41 independently of one another hydroxyethyl, N.N-dimethylaminoethyl,Ν,Ν-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl,piperazinoethyl, morpholinoethyl or piperidinoethyl; or R40 and R41 57 012740 together with the N atom to which they are bonded a pyrrolidine, piperidine, N-methylpiperazine, piperazine or morpholine ring; R42 HorChhH2hh+1î hh 1,2, 3 or 4; it being possible for one or more H atoms in the group Chh^2hh+1 tobe replaced by F atoms; and the pharmaceutically acceptable salts thereof.
Very particular preference is given to the use of compounds selected from the groupconsisting of I ) 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; 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; 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-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline; II ) [4-(6,8-dichloro-2-methy!-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-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; 012740 58 17) 1 -(4-(6,8-dichloro-2-methyl-1,2,3^-tetrahydro-isoquinolin-4-yl)-phenyl]-3-propylurea; 18) 1 -(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea; 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; 21 ) N-[4-(2,6,8-trimethyl-1,2,3,4-tetrahÿdro-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 -yI-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide; 24) N-(4-(8-chloro-2-methyl-6-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylj-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-isoquinolin-4-yl]-phenyl}-acetamide; 27) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoicacid; 28) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-N-methyl-benzamide; 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-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; 32) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl3-acetamide; 33) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine; 59 012740 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-tetrahydiO-isoquinolin-4-yl)-phenyl]-butyramide; 37) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyljpentanamide; 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]-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-yI)-phenyl]-cyclopentanecarboxamide; 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)-phanyl]- 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; 48) N',N'-dimethylamino-N-[4-(6,8-dichioro-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; 012740 60 50) N-[3-(6,8-dichloro-2-methyl-1,2^4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide; 51 ) N-[3-(6,8-dichloro-2-metbyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pentanamide; 52) N-[3-(6,8-dichloro-2-methyI-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-[3r(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]-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; 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-isoquino1in-4-yi)-phenyl]-methane-sulfonamide; 61) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl]-ethanesu Ifonamide; 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-tatrahydro-isoquinolin-4-yl)-phenyl]-propionamide; 64) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylJ-butyramide; 65) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pentanamide; 012740 61 66) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquÎnolin-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]-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; 71 ) N-[2-(6,8-dichIoro-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-sulfonamide; 74) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenylj-ethanesulfonamide; 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-etbyl-urea; 77) 1 -[3-(6,8-dichioro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea; 78) 1-[2-(6l8-dichloro-2-methyl-1,2,3,4-teti'ahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea; 79) 1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinofin-4-yl)-phenyl]-3-methyl-thiourea; 80) N-{5-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylsulfamoyl3-4-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; 62 012740 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-1H-imidazole-4-suIfonamide; 84) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-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-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-yl)-phenyl]-54)romo-thiophene-2-sulfonamide; 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-yl)-phenyl]-C,C,C-trifluoro-methanesulfonamide; 90) 4-(6,8-dichloro-2-methyl-1,2)3,4-tetrahydro-isoquinolin-4-yl)-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; 92) N-ethyl-N'-4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonylurea; 93) 2-chloro-5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-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-yl)-phenol; 97) 8-methoxy-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 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; 63 102) 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; 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-ÿlamine; 110) N-(2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinolÎn-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; 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; 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; 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; 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; 012740 64 132) 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]-butyramide; 135) 2,6-Diamino-hexanoic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl]-amide; 136) Pyrrolidine-2-carboxylic acid [4-(6,8-dichloro-2-methyi-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 137) N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isonicotinamide; 138) 1 H-Pyrrole-3-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 139) 1 H-Pyrrole-2-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 140) 1-Methyl-piperidine-4-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide; 141) 1,4-Dimethyl-1 H-pyrrole-2-carboxylic acid [4-(6,8-dichloro-2-methyi-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 142) 4-Nitro-1 H-pyrrole-2-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide; 143) 2,5-Dimethyl-1H-pyrrole-3-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 144) 1 H-lmidazole-4-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin- 4-yl)-phenyl]-amide; 145) 1-Methanesulfonyl-piperidine-4-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide; 146) 3,5-Dimethyl-1H-pyrazole-4-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 147) 1 H-Pyrazole-4-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide; 65 148) 3-Trifiuoromethyl-1H-pyrazo,e-4-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide; 149) N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl]-2-methylamino- acetamide; 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-methyi-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyi]-propionamide; 152) 2-Amino-N-[3-(6,8-dichloro-2-methyi-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide; 153) 2,6-Diamino-hexanôîc acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyi]-amide; 154) Pyrrolidine-2-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yi)-phenyi]-amide; 155) N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isonicotinamide; 156) 1 H-Pyrrole-3-carboxylic acid [3-(6,8-dichloro-2-methyi-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 157) 1 H-Pyrrole-2-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyi]-amide; 158) 1-Methyl-piperidine-4-carboxylic acid [3-(6,8-dichloro-2-methyi-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide; 159) 1,4-Dimethyl-1H-pyrrole-2-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 160) 4-Nitro-1H-pyrrole-2-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-teîrahydro-isoquinolin-4-yl)-phenyl]-amide; 161) 2,5-Dimethyl-1H-pyrrole-3-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinoIin-4-yl)-phenyl]-amide; 162) 1 H-lmidazole-4-carboxy!ic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin- 4-yl)-phenyl]-amide; 163) 1-Methanesulfonyl-piperidine-4-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide; 012740 66 164) 3,5-Dimethyl-1H-pyrazoie-4-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 165) 1 H-Pyrazole-4-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoiin-4-yl)-phenyl]-amide; 166) 3-Trifluoromethyl-1H-pyrazole-4-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide; 167) 1 -[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-thiourea; 168) 1 -[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylJ-3-ethyl-thiourea; 169) 1 -(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-thiourea; 170) 3-(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1 -dimethyl- urea; 171) 4-Methyl-piperazine-1-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 172) Piperidine-1-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 173) Morpholine-4-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 174) Pyrrolidine-1-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 175) 3-(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1 -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; 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; 0/2740 67 180) 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; 181 ) 3-(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl)-1 -(3-dimethylamino-propyl)-1-rnethyl-urea; 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-dîmethylamino-propyl)-urea; 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)-phenyl3-3-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) . 4-Methyl-piperazine-1-carboxylic acid (2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yi)-phenyl]-amide; 188) 1 -(2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl3-3-methyl-urea; 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) Piperidine-1-carboxylic acid [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenylj-amide; 192) Morpholine-4-çarboxylic acid (2-(6,8-diçhloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 193) Pyrrolidine-1-carboxylic acid (2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 194) 1 -(2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea; 195) 4-Methyl-piperazine-1 -carboxylic acid (4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 68
0Î274O 196) Pyrrolidine-1-carboxylic acid (4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenylj-amide; 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 -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; 201) Piperidine-1-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 202) Morphoiine-4-carboxylic acid (4-(6,8-dichioro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 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; 205) 1 -(4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3-dimethyl- urea; 206) 4-Methyl-piperazine-1-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-methyl-amide; 207) 1-(4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylJ-1,3,3-trimethyl- urea; 208) Piperidine-1 -carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-methyl-amide; 209) Morpholine-4-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-methyl-amide; 210) Pyrrolidine-1 -carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-methyl-amide; 211) 1 -(4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-1-methyl-urea; 69 0127 40 212) 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-amine; 215) Pyrrolidine-1-carboxylic acid [3-(6,8-dîchloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amide; 216) Piperidine-1-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoiin-4- yl)-phenyl]-methyl-amide; 217) 1 -(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-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) .Morpholine-4-carboxylic acid (3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-methyl-amide; 220) 4-Methyl-piperazine-1-carboxylic acid (3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolîn-4-yl)-phenyl]-methyl-amide; 221 ) 1 -(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-1 -methyl-u rea; 222) 1 -(3-(6,8-Dich!oro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,3-diethyl-1-methyl-urea; 223) [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl3-carbamicacid 2- dimethylamino-ethyl ester; 224) [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid 2- dimethylamino-ethyl ester; 225) (2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid 2- dimethylamino-ethyl ester; 226) [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid methyl ester; 227) [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid ethyl ester; 012740 70 228) [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid isopropyl ester; 229) [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid 2,2- dimethyl-propyl ester; 230) [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid methyl ester; 231 ) [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl3-carbamicacid isopropyl ester; 232) [4-(6,B-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid 2,2- dimethyl-propyl ester; 233) [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid ethyl ester; 234) (+)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide; 235) (-)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide; 236) (+)-1 -[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea; 237H-)-1-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl urea; 238) N-[3-(6,8-Difluoro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide; 239) 4-(3-Bromo-phenyt)-6,8-dichloro-2-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; 241) 3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid ethylester; 242) 3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid. and the pharmaceutically acceptable salts thereof. 012740 71
Exceptionally particular preference is given to the use of compounds selected from thegroup 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; 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-t©trahydroisoquinolin-4-yl)-N-ethyl-benzamide; 6) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoiin-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; 8) 6,8-dichIoro-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-Jhiourea; 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-benzoicacid; 14) __ 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-(2-dirnethylamino- ethyl)-2-hydroxy-benzamide; 15) N-[3-(6,8-dichloro-2-methyi-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; 17) 2-(6)8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine; 18) N-[4-(6,8-dichloro-2-methyi-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-piperidine-4-carboxamide; 72 012740 20) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-teti'ahyclro-isoquinolin-4-yi)-phenyl]-methane-sulfonamide; 21 ) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-Îetrahydro-isoquinolin-4-yl)-phenyl]-ethanesulfonamide; 22) N',N'-dimeîhylamino-N-[4-(6,8-dichîoro-2-methyl-1,2,3(4-tetrahydro-isoquinolin-4-yl)-phenyl3-sulfamide; 23) N-[3-(6,8<lichloro-2-methyl-l,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; 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]-cyclobutanecarboxamide; 28) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-Îsoquinolin-4-yl)-phenyl]-2,2,2-triiluoro-acetamide; 29) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -acetyl-piperidine-4-carboxamide; 30) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-teti'ahydro-isoquinoHn-4-yl)-phenyl]-nicotinamide; 31 ) N-[3-(6,8-dichloro-2-methyI-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-yl)-phenyl]-sulfamide; 34) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopropanecarboxamide; 35) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -acetyl-piperidine-4-carboxamide; 73 36) 1 -[3-(6,8-dichloro-2-methyi-1,2,3,4-tetrahydro-isoquino!in-4-yl)-phenyl]-3-ethyl-urea; 37) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyi-thiourea; 38) 1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea; 39) 1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-nnethyl-thiourea; 40) N-{5-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylsulfamoylJ-4-methyl-thiazol-2-yl)-acetamide; 41 ) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoiin-4-yl)-phenyl]-1,2-dimethyl-1 H-îmidazole-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-methyi-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-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; 46) 2,6-Diamino-hexanoic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-_ isoquinolin-4-yl)- phenyl]-amide; " 47) 1 H-Pyrrole-3-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 48) 1 -Methyl-piperidine-4-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylJ-amide; 49) 1 -Methanesulfonyl-piperidine-4-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide; 50) 1 H-Pyrazole-4-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin- 4-yl)-phenylj-amide; 51) N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-methylamino- acetamide; 012740 74 52) N-[3-(6,8-DichIoro-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]-propionamide; 54) 2-Amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl}-butyramide; 55) 2,6-Diamino-hexanoic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl]-amide; 56) 1-Methyl-piperidine-4-carboxyiic acid (3-(6,8-dichloro-2-methyl-1,2,3,4-tefrahydro-isoquinolin-4-yl)-phenyl]-amide; 57) 1 H-lmidazole-4-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin- 4-yl)-phenyl]-amide; 58) 1 -Methanesulfonyl-piperidine-4-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide; 59) 3,5-Dimethyl-1 H-pyrazole-4-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yi)-phenyl]-amide; 60) 1 H-Pyrazole-4-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- »isoquinolin- 4-yl)-phenyl]-amide; 61 ) 3-(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1 -dimethyl- urea; 62) 4-Methyl-piperazine-1-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 63) Piperidine-1 -carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 64) Morpholine-4-carboxylic acid (3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 65) Pyrrolidine-1 -carboxylic acid (3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 66) 3-(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-diethyl- urea; 67) 1 -(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea; 012740 75 68) 1 -(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea; 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-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)-1-methyl-urea; 73) 3-(3-(6,8-DichIoro-2-methyl-1,2,3,4-tetrahydro-isoquînolin-4-yl)-phenyl]-1 -(2-dimethylamino-ethyl)-1-methyl-urea; 74) 1 -(3-(6,8-Dichloro-2-metbyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(3-dimethylamino-propyl)-urea; 75) J -(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- 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) 4-Methyl-piperazine-1 -carboxylic acid [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 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-dimethyiamino-ethyl)-urea; 81) 4-Methyl-piperazine-1 -carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 82) 1 -(4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea; 83) 3-(4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1 -dimethyl- urea; 012740 76 84) 3-(4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1 -diethyl- urea; 85) 1 -(4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea; 5 86) Morpholine-4-carboxylic acid (4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4- y,)-phenyl]-amide; 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- 10 amine; 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-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amine; 15 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-dimethyl- urea; 93) Morpholine-4-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- 20 isoquinolin-4- yl)-phenyl]-methyl-amide; 94) 4-Methyl-piperazine-1-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-methyl-amide; 95) 1 -(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-1-methyl-urea; 25 96) [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic acid 2- dimethylamino-ethyl ester; 97) [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid 2- dimethylamino-ethyl ester; 98) (2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic 30 acid 2- dimethylamino-ethyl ester; 99) [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid methyl ester; 012740 77 100) (R oder S)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]- methanesulfonamide; 101) (R oder S)-1-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yI)-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) 3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid etbyl- | ester; 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, thesemay hâve both the S and the R configuration. The compounds may be in the form ofoptical isomers, of diastereomers, of racemates or of mixtures thereof.
The defined alkyl radicale and partly or completely fluorinated alkyl radicals may beboth straight-chain and branched. Groups CaH2a-l and their analogs as far asCyyH2yy-i niean either the corresponding âlkenyls, cycloalkyls, cycloalkylalkyls oralkylcycloalkyls.
Apprppriate 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, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 2-, 4- or 5-oxazoiyl, 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- pyridazinyi, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or8-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 012740 78 N-oxides of these compounds are additionally encompassed, that is to say, forexample, 1 -oxy-2-, 3- or 4-pyridyI.
Of these, the 5- or 6-membered heterocycles are preferred. The particularly preferred5 heterocycles are imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl and oxazolyl.
The terminal CH3 groups in an alkyl Chain are also regarded as CH2 units and are inthis connection viewed as CH2 groups. 10
Methods for preparing the compounds used are also described.
Thus, the substances described herein can be prepared starting from the benzylamineprecursors IV. These in turn can, if not obtainable commercially, be synthesized by 15 standard processes from the corresponding benzyl chlorides or bromides III.
X = Cl, Br
III IV 20 The benzylamines IV obtained in this way are alkylated in a manner known to theskilled worker with the appropriately substituted alpha-bromoacetophenonecompounds V. 012740
The alpha-bromacetophenone compounds V can be obtaïned from the correspondingacetophenone precursors by bromination in processes known from the literature. Thedesired tetrahydroisoquinolines I can be obtaïned by known processes by réduction ofthe carbonyl group in VI and subséquent acid-catalyzed cyclization of thecorresponding alcohols VII (cf. Tetrahedron Lett.; 1989, 30, 5837; Org. Prep. Proced.Int.; 1995,27,513). 10
NaBH4
I 012740 80
When R6 is not equal to H, the desired compounds of the formula I can be preparedfor example from the iodides VIII by halogen/metal exchange and subséquentnucleophilic attack of the intermediate organolithium species on the carbonyl group (cf.Chem. Pharm. Bull.; 1995,43,1543). 5
The tertiary alcohols synthesized in this way can be converted by known methods into10 other dérivatives.
Alkyl-branched analogs (I) are prepared by alkylating the corresponding diphenylaceticesters X in the alpha position by known methods. The desired product XI can beconverted by standard processes into the corresponding amides XII, which are 15 converted into the desired tetrahydroisoquinolines I in a Pictet-Spengler-analogousreaction (cf. Tetrahedron; 1987, 43, 439; Chem. Pharm. Bull.; 1985, 33, 340). 012740 81
1. LDA
2. R6-X
HCHO/L1AIH4
XII
Compounds of the type I are described in the published spécifications WO 01 32 624and WO 01 32 625 as norepinephrine, dopamine and serotonin reuptake inhibitors. 5 However, these patent applications protect exclusively compounds in which R1 and R2may be exclusively H, It has emerged, however, with the compounds according to theinvention that at least for R2 it is necessary that R2 is not equal to H. In addition, it wasnot possible to detect by means of an exemplary compound of the compoundsaccording to the invention any inhibitory properties on the described receptors, so that 10 the described compounds differ distinctly both in structure and in their pharmacologicalproperties from the compounds described in the patent applications mentioned. AlsoUS 3 666 763 discloses related compounds.
In addition, compounds of type I are described in the patent spécification EP 11 13 007 as estrogen agonists and antagoniste. It was possible to show that the compounds 15 according to the invention show no activity on said receptors, so that the structural différences of the compounds according to the invention resuit in distinctly different pharmacological properties in this regard too. 012740 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).
On the basis of these properties, the compounds are suitable for the treatment ofdisorders caused by oxygen deficiency. The compounds are, as a resuit of theirpharmacological properties, outstandingly suitable as antiarrhythmic médicaments witha cardioprotective component for prophylaxie of infarction and for treatment ofinfarction, and for the treatment of angina pectoris, in which connection they alsoinhibit or greatly reduce in a préventive manner the pathophysiological processesassociated with the development of ischemia-induced damage, in particular in theinduction of ischemia-induced cardiac arrhythmias. Because of their protective effectsagainst pathological hypoxie and ischémie situations, the compounds of the formula Iwhich are used according to the invention can, as a resuit of inhibition of the cellularNa+/H+ exchange mechanism, be used as médicaments for the treatment of ail acuteor chronic damage induced by ischemia or disorders induced primarily or secondarilythereby. This relates to the use thereof as médicaments for surgical interventions, e.g.in organ transplantations, in which cases the compounds can be used both to protectthe organs in the donor before and during removal, to protect removed organs forexample on treatment with or stôrage thereof in physiological bath fluids, as well asduring the transfer into the récipient organism. The compounds are likewise valuablemédicaments with a protective action during the performance of angioplastie surgicalinterventions, for example on the heart as well as peripheral vessels. In accordancewith their protective action against ischemia-induced damage, the compounds are alsosuitable as médicaments for the treatment of ischemias of the nervous System,especially of the CNS, in which connection they are suitable for example for thetreatment of stroke or of cérébral edema. In addition, the compounds of the formula Iwhich are used according to the invention are likewise suitable for the treatment oftypes of shock, such as, for example, of allergie, cardiogenic, hypovolémie andbacterial shock. 012740 83
In addition, the compounds induce an improvement in the respiratory drive and aretherefore used to treat respiratory conditions associated with the following clinicalconditions and diseases: disturbance of central respiratory drive (e.g. central sleepapnea, sudden infant death, postoperative hypoxia), muscle-related breathingdisorders, breathing disorders after long-term ventilation, breathing disordersassociated with altitude adaptation, obstructive and mixed type of sleep apnea, acuteand chronic pulmonary disorders with hypoxia and hypercapnia.
The compounds additionally increase the tone of the muscles of the upper airways, sothat snoring is suppressed. A combination of an NHE inhibitor with a carbonic anhydrase inhibitor (e.g.acetazolamide), the latter inducing metabolic acidosis and thus itself increasingrespiratory activity, proves to be advantageous due to an enhanced effect and reduceduse of active ingrédient.
It has emerged that the compounds used according to the invention hâve a mildlaxative effect and accordingly can be used advantageously as laxatives or if there is arisk of constipation, in which case the prévention of the ischémie damage associatedwith constipation in the intestinal région is particularly advantageous. it is additionally possible to prevent the formation of gall stones.
The compounds of the formula I used according to the invention are furthermoredistinguished by a strong inhibitory effect on the prolifération of cells, for example offibroblast cell prolifération and the prolifération of smooth muscular muscle cells. Thecompounds of the formula I are therefore suitable as valuable therapeutic agents fordiseases in which cell prolifération represents a primary or secondary cause, and cantherefore be used as antiatherosclerotic agents, agents to prevent late complications ofdiabètes, cancers, fibrotic disorders such as pulmonary fibrosis, hepatic fibrosis orrénal fibrosis, organ hypertrophies and hyperplasias, in particular for prostatehyperplasia or prostate hypertrophy. 012740 84
The compounds used according to the invention are effective inhibitors of the cellularsodium-proton antiporter (Na/H exchanger) which is elevated in numerous disorders(essential hypertension, atherosclerosis, diabètes, etc.), also in those cells which arereadily amenable to measurements, such as, for example, in érythrocytes, platelets orleukocytes. The compounds used according to the invention are therefore suitable asexcellent and simple scientific tools, for example in their use as diagnostic agents fordetermining and distinguishing different types of hypertension, but also ofatherosclerosis, of diabètes, proliférative disorders etc. The compounds of the formulaI are moreover suitable for préventive therapy to prevent the development of highblood pressure, for example of essential hypertension.
It has additionally been found that NHE inhibitors show a bénéficiai effect on sérumlipoprotéine. It is generally acknowledged that blood lipid levels which are too high, so-called hyperlipoproteinemias, represent a considérable risk factor for the developmentof arteriosclerotic vascular lésions, especially coronary heart disease. The réduction ofelevated sérum lipoproteins therefore has exceptional importance for the prophylaxieand régression of atherosclerotic lésions. The compounds used according to theinvention can therefore be used for the prophylaxie and régression of atheroscleroticlésions by eliminating a causal risk factor. With this protection of the vessels againstthe syndrome of endothélial dysfunction, compounds of the formula I are valuablemédicaments for the prévention and treatment of coronary vasospasms, ofatherogenesis and of atherosclerosis, of left-ventricular hypertrophy and of dilatedcardiomyopathy, and thrombotic disorders.
Said compounds are therefore advantâgeously used for producing a médicament forthe prévention and treatment of sleep apneas and muscle-related respiratorydisorders; for producing a médicament for the prévention and treatment of snoring; forproducing a médicament for lowering blood pressure; for producing a médicament forthe prévention and treatment of disorders induced by ischemia and reperfusion ofcentral and peripheral organs, such as acute rénal failure, stroke, endogenous Statesof shock, intestinal disorders etc.; for producing a médicament for the treatment of latedamage from diabètes and chronic rénal disorders, in particular of ail inflammations of 012740 85 the kidneys (nephritides) which are associated with increased protein/albuminexcrétion; for producing a médicament for the treatment of infection by ectoparasites inhuman and veterinary medicine; for producing a médicament for the treatment of saiddisorders in combinations with hypotensive substances, preferably with angiotensinconverting enzyme (ACE) inhibitors, with diuretics and saluretics such as furosemide,hydrochlorothiazide, pseudoaidosterone antagoniste and aldostérone antagoniste; withadenosine receptor modulators, in particular with adenosine receptor activators (A2agonists); and with angiotensin receptor antagonists.
The administration of sodium-proton exchange inhibitors of the formula I as novelmédicaments for lowering elevated blood lipid levels, and the combination of sodium-proton exchange inhibitors with hypotensive médicaments and/or médicaments withhypolipidémie activity is claimed. Médicaments which comprise a compound I can in this connection be administeredorally, parenterally, intravenously, rectally, transdermally or by inhalation, the preferredadministration being dépendent on the particular characteristics of the disorder. Thecompounds I may moreover be used alone or together with pharmaceutical excipients,both in veterinary medicine and in human medicine.
The excipients suitable for the desired pharmaceutical formulation are familiar to theskilled worker on the basis of his expert knowledge. Besides solvents, gel formers,suppository bases, tablet excipients, and other active ingrédient carriers, it is possibleto use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavorings,preservatives, solubilizers or colors.
For a form for oral administration, the active compounds are mixed with additivessuitable for this purpose, such as carriers, stabilizers or inert diluents, and convertedby conventional methods into suitable dosage forms such as tablets, coated tablets,hard gelatin capsules, aqueous, alcoholic or oily solutions. Examples of inert carrierswhich can be used are gum arabic, magnesia, magnésium carbonate, potassiumphosphate, lactose, glucose or starch, especially corn starch. It is moreover possible 012740 86 for the préparation to take place both as dry granules and as wet granules. Examplesof suitable oily carriers or solvents are vegetable or animal oils such as sunflower oil orfish liver oil.
For subcutaneous or intravenous administration, the active compounds used areconverted, if desired with the substances customary for this purpose, such assolubilizers, emulsifiers or other excipients, into a solution, suspension or émulsion.Examples of suitable solvents are: water, physiological saline or alcohols, e.g. éthanol,propanol, glycerol, as well as sugar solutions such as glucose or mannitol solutions, orelse a mixture of the various solvents mentioned.
Suitable as pharmaceutical formulation for administration in the form of aérosols orsprays are, for example, solutions, suspensions or émulsions of the active ingrédient ofthe formula I in a pharmaceutically acceptable solvent such as, in particular, éthanol orwater, or a mixture of such solvents.
The formulation may, if required, also contain other pharmaceutical excipients such assurfactants, emulsifiers and stabilizers, and a propellant gas. Such a préparationnormally contains the active ingrédient in a concentration of about 0.1 to 10, inparticular of about 0.3 to 3, % by weight.
The dosage of the active ingrédient of the formula I to be administered, and thefrequency of administration, dépend on the potency and duration of action of thecompounds used; additionally also on the nature and severity of the disorder to betreated and on the sex, âge, weight and individual responsiveness of the mammal tobe treated.
On average, the daily dose of a compound of the formula I for a patient weighing about75 kg is at least 0.001 mg/kg, preferably 0.01 mg/kg, to a maximum of 10 mg/kg,preferably 1 mg/kg, of body weight. For acute épisodes of the disorder, for exampleimmediately after suffering a myocardial infarction, higher and, in particular, morefrequent 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 apatient with infarction in the intensive care unit.
Descriptions of experiments and examples:
List of abbreviations used:
Rt rétention time TFA trifluoroacetic acid HPLC high performance liquid chromatography eq équivalent LCMS liquid chromatography mass spectroscopy MS mass spectroscopy
Cl Chemical ionizalion RT room température THF tetrahydrofuran TOTU O-KethoxycarbonyO-cyanomethyleneaminoJ-N.N.N'.N'- tetramethyluronium tetrafluoroborate DMSO dimethyl sulfoxide abs. absolute decomp. Décomposition DMF dimethylformamid
General:
The rétention times (Rj) indicated below relate to LCMS measurements with the following parameters:Method A:stationary phase:mobile phase:
Merck Purospher 3μ2 x 55 mm 95% H2O (0.05% TFA)-> 95% acetonitrile; 4 min; 95% acetonitrile; 1.5 min -> 5% acetonitrile; 1 min; 0.5 ml/min, 30°C.
Merck Purospher 3μ2 x 55 mm
Method B: stationary phase: 012740 88 mobile Phase:
MethodBI: 5 stationary phase mobile phase:
Method C: 10 stationary phase:solvent: flow rate: 15 0 min 90% H2O (0.05% TFA) 2.5 min-95% acetonitrile; 95% acetonitrile to 3.3 min; 10% acetonitrile 3.4 min; 1 ml/min. YMC, J’sphere ODS H80 4μ 2 x 20 mm 0 min 90% H2O (0.05% TFA) 1,9 min-95 % acetonitrile; 95 % acetonitrile bis 2,4 min; 10 % acetonitrile 2,45 min; 1ml/min.
Merck LiChroCart 55-2 Purospher STAR RP 18esolvent A: acetonitrile/water 90:10 + 0.5% HCOOH
solvent B: acetonitrile/water 10:90 + 0.5% HCOOH 20 stop time:température:Method D:stationary phase: 25 solvent:
Flow ratetime [min] 0.75 ml/mintime[min]0.000.501.754.254.505.006.20 min solvent B[%] 95.0 95.0 5.0 5.0 95.0 95.0
40°C
Merck RP18 Purospher Star, 55 x 2 mm, 3 μ KomgrôBeSolvent A: acetonitrile + 0,08% HCOOHSolvent B: water + 0,1% HCOOH0,45 ml/min solvent B[%] 0 95 5 5 7 5 8 95 30 012740 89 9 5 room température température:
Example 1 : N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide
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 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, at60°C, a solution of 39.9 g of bromine (1.0 eq) in 60 ml of acetic acid is added dropwise.Afteî 1.5 h, the reaction mixture is allowed to cool to room température and is added to1 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°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 asolution of 60 g (0.234 mol) of intermediate 2 in 600 ml of dioxane is added. 134 ml oftriethylamine are added, and the mixture is stirred at room température for 4 h. Afterstanding overnight, the preqipitate is filtered off and the filtrate is concentrated invacuo. The residue is taken up in ethyl acetate, washed with NaHCO3 and H2O, dried 012740 90 with MgSO4 and concentrated. The oily residue resulting thereby is triturated with anethyl acetate/ether mixture, resulting in 36 g of intermediate 3 in the form of acrystalline solid (melting point: 115-117°C).
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 0°C, 7.8 g (2 eq) of sodium borohydride are added. The mixture is then stirred at 0°C for30 min and at room température for a further hour. For workup, the reaction mixture isconcentrated and the residue is partitioned between 1 N HCl and ethyl acetate. Theaqueous phase is separated off, adjusted to pH 9 and extracted twice with ethylacetate. The combined organic phases are dried with MgSC>4 and concentrated. Thecrude product obtained in this way can be reacted further without further purification. 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 dichloromethanè and, at0°C, 250 ml of conc. H2SO4 are added dropwise. The mixture is stirred at 0°C for 2 hand at room température for 1 h. For workup, the reaction mixture is added to ice-water, and the precipitate is filtered off with suction. The precipitate is taken up in300 ml of 1 N NaOH and extracted three times with ethyl acetate. Drying of the organicphases and concentration affords a crude product which is triturated with diisopropylether, whereupon 11.7 g of the compound of the example are isolated as a crystallinesolid (melting point: 205-206°C). 1 a: N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl3-acetamide-hydrochloride;
y cih ci^ 012740 91
An analytical sample (100 mg) of the title compound from example 1 is suspended in10 ml of 2 N HCl, and THF is added until a clear solution is produced. It isconcentrated in vacuo, and the residue is triturated with ether and filtered off withsuction, whereupon the title compound is obtained as a crystalline solid (Rt = 5 3.807 min (method A); melting point.: 125°C with décomposition). 10 15
Example 2: 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-sulfonamide hydrochloride; 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;
(+ and -) 2a/2c (+ and -) 2b/2d 20 Intermediate 1: 2,4-Dichlorobenzyl-(methyl)-amine is prepared by methods known fromthe literature (J. Med. Chem.; 1984, 27, 1111).
Intermediate 2: 2-[(2,4-Dichloro-benzyl)-methyl-amino]-1-phenyl-ethanone;
Intermediate 1 is reacted with 2-bromo-1-phenyl-ethanone in the manner described in 25 example 1, intermediate 3. Workup in an analogous manner and purification on silica 012740 92 gel affords the desired alkylation product in good yield as a yellowish oil (Rf = 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 inexample 1, intermediate 4. Once monitoring of the reaction indicates complétéconversion, the mixture is concentrated and the residue is taken up in ethyl acetate. Itis washed twice with H2O, dried with MgSO4 and freed of solvent. The crude product,which is obtained in quantitative yield, can be reacted further without furtherpurification (R| = 4.149 min (method A); MS(CI+) = 310.2/312.2).
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 andcooled to 0°C. This solution is added dropwise to 55 ml of precooled conc. H2SO4 andthen stirred at room température for two hours. For workup, the mixture is poured ontoice and made strongly alkaline with 6 N NaOH. Three extractions with dichloromethaneare carried out. The combined organic phases are dried with MgSÛ4 andconcentrated. The oily crude product is purified on silica gel, resulting in intermediate 4in 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;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;
Rt((-)-enantiomer/4a) = 9.340 min;
Rt((+)-enantiomer/4b) = 20.327 min. 2a: (+)-4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene- sulfonamide hydrochloride; 012740 93 2b: (+)-3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene-sulfonamide hydrochloride; A suspension of 500 mg (1.7 mmol) of intermediate 4a in 10 ml of dichloromethane isintroduced at 0°C into 1.2 ml of chlorosulfonic acid. The mixture is stirred at 0°C forone hour and at room température for a further hour. A further 5 ml of chlorosulfonicacid is added and the mixture is stirred at room température for one hour. For workup,it is poured onto ice and adjusted to pH 8 with NaHCO3. Three extractions with ethylacetate are carried out. The combined organic phases are dried with Na2SO4 andfreed of solvent. The crude product obtained in this way is heated in 20 ml of conc. NH3 solution at 90°C for three hours. After the conversion is complété, the reactionsolution is concentrated and the residue is partitioned between K2O and ethyl acetate.The organic phase is separated off and the aqueous phase is extracted once morewith ethyl acetate. The combined organic phases are dried with Na2SÛ4 and thesolvent is removed in vacuo. Subséquent chromatography on silica gel affords 335 mgof a mixture of example 2a and 2b in the form of a yellow amorphous solid. Furtherpurification on a préparative HPLC affords 212 mg of the para-substituted titlecompound 2a, plus 58 mg of the meta isomer 2b.
Conditions for the préparative HPLC. chiral column: Chiralpak AS 250 x 4.6 mm; solvents: n-heptane/ethanol/methanol/acetonitrile 20:1.5:0.5:0.5 flow rate: 1 ml/min;
Romain fraction) = 14.145 min (~+2a);
Rt(subsidiary fraction) = 11.623 min (->2b).
Both fractions were dissolved in methanol/2 N HCl mixture and freeze dried, and it waspossible to obtain the title compounds 2a and 2b in the form of crystalline solids. (Rt(2a) = 3.630 min (method A); MS(2a),(ES+) =371.3/373.3 (M++H)/ 412.3/ 414.3(M++CH3CN); Rt (2b) = 3.668 min (method A); MS(2b),(ES+) =371.3/373.3 (M++H)/412.3/414.3 (M++CH3CN). 012740 94 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, usingintermediate 4b as starting compound. The purification and séparation from the metaisomer 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;
Romain 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 acétates as slightly yellowish solids (Rt(2c) = 3.656 min(method A); MS(ES+) =371.1/373.1 (M++H)/ 412.1/414.1 (M++CH3CN)); (Rt(2d) =1.562 min (method B); MS(ES+) =371.1/373.1 (M++H)/ 412.1/414.1 (M++CH3CN)).
Example 3: 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N,N-dimethyl-benzenesulfonamide, hydrochloride;
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 mixturewas subsequently stirred at 40°C for one hour. The reaction mixture was then cooledto room température and an ice/water mixture was added. The précipitais which 95 separated oui during this was filtered off with suction and taken up in ethyl acetatewhich, after washing with saturated brine was dried over magnésium sulfate.Subséquent 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.40% in water) cooled to 10°C. The resulting suspension was subsequently stirred atthis température for 1.5 h. Then ice-water was added and, after extraction three timeswith ethyl acetate, the combined ethyl acetate phases were washed with saturatedbrine and dried over magnésium sulfate. The residue was taken up with water and,after addition of 2 N HCI, freeze dried. The crude product obtained in this way wasthen purified by préparative HPLC.
Conditions: stationary phase: Merck Purospher RP18 (10μΜ) 250 x 25 mm mobile phase: 90% H2O (0.05% TFA)-> 90% acetonitrile; 40 min; flow rate: 25ml/min
The fractions containing the product were combined, the acetonitrile was stripped off ina rotary evaporator, and the aqueous phase was washed with saturated potassiumcarbonate solution and then extracted three times with ethyl acetate. The combinedethyl acetate phases were washed with saturated brine, dried over magnésium sulfateand 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 thedesired compound, in addition to -20% of a regioisomer (Rj = 4.000 min (method A);MS(CI+) = 399.1).
Example 4: 4a: 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide,hydrochloride; 012740 96
Intermediate 1:4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-benzenesulfonyl chloride 5 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 atroom température 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. Thecombined ethyl acetate phases are dried with NagSC^ and concentrated in a rotary 10 evaporator. The crude product obtained in this way is reacted further without furtherpurification.
Intermediate 2: 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene-sulfonamide 15 319 mg of intermediate 1 are suspended in 6 ml of 25% strength ammonia and heated to 90°C. After 3 h, the mixture is diluted with H2O and extracted with ethyl acetate. Theorganic phase is separated off and dried with Na2SO4, resulting in 165 mg of the titlecompound. 20 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide,hydrochloride; 145 mg of intermediate 2 are suspended in 15 ml of diethyl ether, and 1 ml of etherealHCl is added. After stirring at room température for 30 minutes, the precipitate isfiltered off with suction and dried, resulting in 136 mg of the hydrochloride in the form 25 of a yellowish solid. 4b: 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide,acetate; 012740 97
255 mg of intermediate 2, example 8, are mixed with 5 ml of glacial acetic acid, and50 ml of H2O is added. Filtration of sparingly soluble constituents is followed by freezedrying, resulting in 250 mg of the title compound.
Example 5:4-(4-Bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline,hydrochloride;
10 15 20
Intermediate 1 : 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-1 -(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, thealkylation product can be isolated in a yield of 69%.
Intermediate 2:1 -(4-Bromo-phenyl)-2-[(2,4-dichloro-benzyl)-methyl-amino]-ethanol;Intermediate 1 is reduced to the corresponding alcohol with 2 équivalents of NaBH4 inanalogy to the manner described for intermediate 4, example 1, and the alcohol can beisolated in a yield of 86%.
Intermediate 3: 4-(4-Bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinoline; 012740 98 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°C, 15 ml of conc.H2SO4 are added. After stirring at room température for 2 hours, the reaction mixtureis poured onto ice and made alkaline with 6 N NaOH. Three extractions with 5 dichloromethane are carried out. The combined organic phases are dried with MgSO4and concentrated. For further purification, the residue is chromatographed on silica gel,resulting in 2.6 g of the title compound as a yellowish oil. 4-(4-Bromo-phenyl)-6,8-dichloro-2-methyl-T,2,3,4-tetrahydroisoquinoline, 10 hydrochloride;
300 mg of 4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline arestirred in 2 N HCl at room température. The resulting precipitate is filtered off withsuction and dried. 15
Example 6: 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid;
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- 20 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 (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(PPh3)4 are added and carbon 012740 99 monoxide is passed into the solution. The mixture is stirred at 120°C. After six hours at120°C and standing ovemight under argon, a further 867 mg (0.75 mmol) ofPd(PPh3)4 were added and stirring at 120°C and passing carbon monoxide into thesolution were continued for eight hours. After again standing overnight, 135 mg of 5 PdCl2 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 ethylacetate. Three extractions with 2 N NaOH are carried out. The combined aqueousphases are adjusted to pH 6 with 6 N HCl and extracted three times with ethyl acetate.The organic phases are dried with MgSÛ4 and freed of solvent. The residue is purified 10 on silica gel using a dichloromethane/methanol mixture, resulting in 420 mg of the titlecompound (R| = 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-benzamide, trifluoroacetate; o
J
Cl
IM 15 146 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 équivalent oftriethylamine is added. At 0°C, a solution of 141 mg (0.43 mmol) TOTU in 3 ml of DMFis added. The mixture is stirred at 0°C for 30 min and at room température for 30 min. 20 This solution is then added at 0°C to a solution of 0.28 ml of 2 M ethylamine solutionand 0.06 ml (0.043 mmol) of triethylamine in 5 ml of DMF, and the reaction mixture isstirred at room température for three hours. For workup, the solvent is distilled off invacuo, and the residue is taken up in ethyl acetate and washed twice with 1 N KOHand once with H2O. The organic phase is dried with Na2SO4 and concentrated. 25 Chromatography on silica gel (dichloromethane/methanol 95:5) is used for further purification. Further purification on a préparative HPLC (acetonitrile/H2O/trifluoroacetic 012740 100 acid) affords the desired carboxamide as trifluoroacetate (Rt = 4.169 min (method A);MS(CI+) = 363.3/365.3).
Example 8: 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-propyl-5 benzamide, trifluoroacetate;
The title compound can be prepared by the method described in example 7 startingfrom n-propylamine and 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid (see example 6). 10 (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;
15 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(CI+) = 406.3/408.3).
Example 10: 6,8-Dichloro-2-methyl-4-(4-morpholin-4-yl-phenyl)-1,2,3,4- 20 tetrahydroisoquinoline, trifluoroacetate; 012740 101
TFA 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 m, ofabs. toluene. Under argon, a solution of 0.104 ml (1.2 mmol) of morpholine in 2.5 ml of 5 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 themixture is stirred at 100°C 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 (CH2CI2 10 /methanol 95:5), resulting in 350 mg of the desired morpholine dérivative. After afurthër purification on a préparative HPLC it is possible to isolate 160 mg of thecorresponding trifluoroacetate in the form of a colorless solid.
Example 11 : [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-phenyl]- 15 diethyl-amine, trifluoroacetate;
U
Cl
TFA
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°C; three times 20 the amount of Pd cataiyst and phosphine ligand. The desired trifluoroacetate can be isolated as a colorless solid after préparative HPLC. 012740 102
Example 12: 6,8-Dichloro-2-methyl-4-(4-piperidin-1-yl-phenyl)-1,2,3,4-tetrahydro-isoquinoline, trifluoroacetate;
5 The desired piperidine dérivative 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.
Example 13: 6,8-Dichloro-2-methyl-4-(4-pyrrolidin-1-yl-phenyl)-1,2,3,4- 10 tetrahydroisoquinoline, hydrochloride;
The reaction is carried out in analogy to the method described in example 10, startingfrom pyrrolidine and 4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline (example 5, intermediate 3). The product obtained after 15 purification by chromatography is taken up in the DMSO/acetonitrile mixture, whereupon a precipitate séparâtes out. This is filtered off, dissolved in 2 N HCl andfreeze dried, resulting in the title compound of a colorless solid. 012740 103
Example 14: 6,8-Dichloro-2-methyl-4-[4-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-isoquinoline, trifluoroacetate;
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 inexample 10 affords the title compound in the form of a colorless solid.
Example 15:6,8-Dichloro-2-cyclopropyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline,trifluoroacetate;
Intermediate 1 :
Cyclopropyl-(2,4-dichloro-benzyl)-âmïne; 5.25 g (30 mmol) of 2,4-dichlorobenzaldehyde are introduced into 140 ml of methanoland, at room température, a solution of 1.71 g (30 mmol) of cyclopropylamine is 15 added. The mixture is stirred at room température for 40 min and then 1.42 g (37.5 mmol) of NaBffy are added in portions. After standing overnight, the solvent is 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 MgSC>4 and concentrated. The 012740 104 crude product obtained in this way, in the form of a slightly yellowish oil, can bereacted further without further purification.
Intermediate 2: 2-[Cyclopropyl-(2,4-dichloro-benzyl)-amino]-1 -phenyl-ethanone; 5 intermediate 1 is reacted with alpha-bromoacetophenone in the presence of triethylamine in dioxane by the method described in example 1, intermediate 3. Forworkup, the solvent is distilled off, and the residue is taken up in ethyl acetate. It iswashed twice with H2O and twice with 2 N HCl, dried with MgSÜ4 and concentrated.
The crude product obtained in this way can be reacted further without further 10 purification.
Intermediate 3: 2-[Cyclopropyl-(2,4-dichloro-benzyl)-amino]-1 -phenyl-ethanol;Intermediate 2 is reduced with NaBH4 in analogy to the method described inexample 1, intermediate 4. For workup, the mixture is concentrated, and the residue is 15 partitioned between 1 N HCl and ethyl acetate. The aqueous phase is separated offand extracted once more with ethyl acetate. The combined organic phases are driedwith MgSO4 and the solvent is removed in vacuo. 6,8-Dichloro-2-cyclopropyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline, trifluoroacetate; 20 Intermediate 3 (1.9 g) is dissolved without further purification in 10 ml of dichloromethane and cyclized with conc. H2SO4 by the method described inexample 1. For workup, the reaction mixture is poured onto ice. The organic phase isseparated off, and the aqueous phase is extracted once more with dichloromethane.The combined organic phases are dried with MgSO4 and freed of solvent. 25 Chromatography on silica gel (n-heptane/ethyl acetate 5:1 -» 3:1) affords 200 mg of ayellowish oil, which is subjected to further purification on a préparative HPLC. Thisrésulta in 184 mg of the title compound as trifluoroacetate.
Example 16:16a: (-)-N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- 30 phenylj-acetamide; 16b: (+)-N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide; 012740 105
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 ml/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;
Intermediatel: 4-(6l8-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)- phenylj-acetamide (example 1 ) are dissolved in 100 ml of 20% strength sodiumethanolate 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 threemore hours. For workup, the solvent is removed in vacuo, and the residue is taken up 20 in 200 ml of H2O and extracted twice with dichloromethanë. The combined organicphases are dried with MgSO4 and concentrated. Further purification by 072740 106 chromatography on silica gel (ethyl acetate/heptane 1:1) results in the aniline as ayellowish 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 HCl. The clear solution is concentratedin 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 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 K2CO3 in 15 ml of dry acetone and stirred at room température for 1.5 hours. A solution of 2.5 eqof ethyl isocyanate in acetone is added dropwise at room température, and the solutionis heated to reflux. For workup, the mixture is concentrated in vacuo, and the residue istaken up in H2O and extracted twice with ethyl acetate. The aqueous phase is acidified 20 with 6 N HCl, and the resulting precipitate is filtered off with suction. Washing with ethylacetate 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; 012740 107
A solution of 0.17 g (2.0 mmol) of n-propyl isocyanate in toluene is added dropwise toa 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 40°C, a further 0.17 g of n-propyl isocyanate is added, and the mixture is stirred at 80°C for one hour. For workup, the solvent is removed and the residue is triturated withHgO 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;
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 HCl and THF. The clear solution isconcentrated 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; 012740 108
Cl
Proceeding in analogy to the method described in example 19 and starting from500 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 5 245 mg of the desired thiourea to be isolated.
Example 21: 1 -[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethylurea; ci
ci
HN 10 Préparation takes place in analogy to a method described in example 19, starting from4-(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- 15 urea, hydrochloride; 012740 109
Conversion into the corresponding hydrochloride takes place in analogy to the methoddescribed in example 19a. 5 Example 22: N-[4-(6-Methanesulfonyl-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylj-acetamide;
Intermediate 1 : (4-Methanesulfonyl-benzyl)-methyl-amine is synthesized starting from 1-bromomethyl-4-methanesulfonylbenzene and 10 methylamine in a manner known to the skilled worker.
The title compound is prepared in analogy to the synthetic route indicated inexample 1, starting from (4-methanesulfonyl-benzyl)-methyl-arnine (intermediate 1 )and N-[4-(2-bromo-acetyl)-phenyl]-acetamide (example 1, intermediate 2). 15
Example 23: N-[4-(2,6,8-Trimethyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide; 012740 110
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 meibylamine in a manner known to the skilled worker, and N-[4-(2- 5 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)-phenylj-acetamide;
10 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-ch,orO“benzene and methylamine in a manner known to the skilled worker, and N-[4-(2-bromo-acetyl)-phenyl]-acetamide (example 1, intermediate 2). 15 Example 25: N-[4-(8-Chloro-2-methyl-6-pyrrolidin-1 -yl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenylj-acetamide; 012740 111
Cl 1.02 g (3.12 mmol) of CS2CO3, 8.8 mg (0.04 mmol) of palladium acétate and 36.1 mg(0.06 mmol) of 2,2-bis-diphenyIphosphino-1,1-binaphthyl are introduced into 6.5 ml ofabs. toluene under argon. At room température, a solution of 512 mg (1.3 mmol) of 5 N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquino|in-4-yl)-phenyl]-acetamide(example 24) in 4 ml of abs. DMF, and a solution of 111 mg (1.56 mmol) of pyrrolidinein 4 ml of DMF are added, and the mixture is heated at 100°C for 7 hours. For workup,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 10 chromatographed on silica gel with a dichloromethane/methanol mixture, and it ispossible to isolate 360 mg of the compound of the example. 25a: N-[4-(8-Chloro-2-methyl-6-pyrrolidin-1 -yl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylj-acetamide, hydrochloride;
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 HCl, stirred at room température for 30 min and concentrated. The residue is taken up in H2O and freeze dried. 012740 112
Example 26: N-[4-(8-Chloro-2-methyl-6-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinolin-4 yl)-phenyl]-acetamide, trifluoroacetate;
Préparation takes place in analogy to the method described in example 25, starting5 from N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]- acetamide (example 24) and morpholirie. The chromatography on silica gel wasfollowed by a further purification on a préparative HPLC.
Example 27: N-{4-[8-Chloro-2-methyl-6-(4-methyl-piperazin-1-yl)-1,2,3,4-tetrahydro-
Preparation takes place in analogy to the method described in example 25, startingfrom N-[4-(6-Bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide (example 24) and N-methyl-piperazine. 15 27a: N-{4-[8-Chloro-2-methyl-6-(4-methyl-piperazin-1 -yl)-1,2,3,4-tetrahydro-isoquinolin 4-yl]-phenyl}-acetamide, hydrochloride; 012740 113
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 lîttle methanol, diluted with 2 NHCl and freeze dried, resulting in 226 mg of the desired hydrochloride. 5 Example 28: N-{4-[8-Chloro-6-(cyclopropylmethyl-amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl]-phenyl}-acetamide, hydrochloride;
a
Préparation takes place in analogy to the method described in example 25, startingfrom N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]- 10 acetamide (example 24) and C-cyclopropyl-methylamine. The chromatography onsilica gel was followed by a further purification on a préparative HPLC. The purifiedcompound was dissolved in 1 N HCl, diluted with H2O and freeze dried.
Example 29: 5-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy- 15 benzoicacid; 012740 114
Intermediate 1 : Ethyl 5-acetyl-2-hydroxy-benzoate is prepared from 5-acetyl-2-hydroxy-benzoic acid by acid-catalyzed estérification in amanner known to the skilled worker. 5
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. 10 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-(methyl)-amine (see example 1, intermediate 1). 15 5-(6,8-Diehloro-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 tothe skilled worker, resulting in 5.4 g of the free acid. 20 012740 115 29a: 5-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoicacid, sodium sait;
OH O
a 352 mg (1 mmol) of the free acid 5-(6,8-dichloro-2-rnethyl-1,2,3,4-tetrahydro-5 isoquinolin-4-yl)-2-hydroxy-benzoic acid are dissolved in 10 ml of 0.1 M NaOH, diluted with H2O 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-Nmethyl-benzamide, trifluoroacetate; 10
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 withmethylamine in analogy to the method described in example 7. 15
Example 31: 5-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-ethyl-2- hydroxy-benzamide, trifluoroacetate; 012740 116
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 withethylamine in analogy to the method described in example 7.
Example 32: 5-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-(2-dimethylamino-ethyl)- 2-hydroxy-benzamide, trifluoroacetate;
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 réaction 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-benzoylj-guanidine;
2.52 g of potassium tert-butoxide are added to a solution of 2.39 g (25 mmol) ofguanidine hydrochloride in 15 ml of abs. DMF and stirred at room température for 117 0127 4 Ο 45 min. A solution of 950 mg (2.5 mmol) of ethyl 5-(6,8-dichlorô-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoate (example 29, intermediate 3) in 10 mlof abs. DMF is added, and the mixture is stirred at room température for four hours.After no further increase in conversion is détectable, the precipitate is removed by 5 filtration with suction and the solvent is removed in vacuo. The residue is taken up in2 N HCl and extracted twice with dichloromethane. The aqueous phase is adjusted toa pH of about 10 with KOH, whereupon the desired acylguanidîne séparâtes out as acolorless precipitate. Filtration with suction and drying affords 793 mg of the titlecompound. 10
Example 34: N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;
15 N-[3-(6I8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;
The desired meta-substituted acetanilide is prepared in analogy to the synthetic routeindicated for example 1, starting from N-(3-acetyl-phenyl)-acetamide and 2,4-dichlorobenzyl-(methy1)-amine (example 1, intermediate 1 ) in four analogous stages. 20 Example 35: 3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine;
Cl 012740 118
Acetyl is elimînated 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.
Example 36: 2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoIin-4-yl)-phenylamine;
Cl
Intermediate 1 : N-[2-(2-Bromo-acetyl)-phenyl]-acetamide; 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 glacialacetic acid. 127 ml of 33% strength HBr in glacial acetic acid are added and then, atroom température, 8.75 ml (0.175 mol) of bromine are slowly run in. The mixture isstirred at room température overnight. The mixture is stirred into 1.51 of ice-water, andthe precipitated product is filtered off with suction, thoroughly washed with ice-waterand dried in vacuo. The crude product contains, according to.HPLC and NMR, someprecursor and dibrominated product, but is pure enough (about 85% strength) forfurther reaction.
Yield:43g
Intermediate 2: N-(2-{2-[(2,4-Dichloro-benzyl)-methyl-amino]-acetyl}-phenyl)-acetamide; 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 productfrom the preceding bromination, likewise dissolved in 200 ml of dioxane, and 45 ml oftriethylamine. The mixture is stirred at room température overnight and then filtered.The filtrate is evaporated, and the residue is taken up in ethylacetate and washed withsaturated sodium bicarbonate solution and brine, dried over sodium sulfate and 012740 119 concentrated in a rotary evaporator. The crude product (20.4 g) is pure enoughaccording to NMR for further reaction.
Intermediate 3: N-(2-{2-[(2,4-Dichloro-benzyl)-methyl-amino]-1 -hydroxy-ethylj-phenyl)-acetamide; 20 g of the crude product from the preceding stage (about 50 mmol) are dissolved in200 ml of methanol and cooled to < 5°C in an icebath. To this are added, while stirringvigorously, 4.3 g (109 mmol) of sodium borohydride in portions so that the internaitempérature does not exceed 10°C. The mixture is then stirred in the icebath for30 min and at RT for 1 h. After standing overnight, the mixture is evaporated, and theresidue is taken up in ethyl acetate, washed 3x with water and 1x with brine, driedover 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)-methy,-amino]-ethanol; 10g 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 50°C for 10 h.The mixture is allowed to cool and is poured into water, and the pH is adjusted to10-12 with 20% strength NaOH. The product is extracted with ethyl acetate, and thecombined extracts are washed with brine, dried over sodium sulfate and evaporated.The crude product (9.9 g) contains some sodium chloride, but this does not interfèrewitb 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 ofchlorofomn. While cooling in an icebath, 123 ml of conc. sulfuric acid are addeddropwise. The mixture is stirred in the icebath for 2 h and is then allowed slowly toreach RT and is finally heated at 50°C overnight. The cooled mixture is poured onto iceand made alkaline (pH >10) with sodium hydroxide solution. The organic phase isseparated off, the aqueous phase is back-extracted 2x with methylene chloride, andthe combined organic phases are washed with water and NaCI, dried over sodiumsulfate and evaporated. 012740 120
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 orexample 17, intermediate 1, are introduced into 5 ml of dichloromethane, and 0.076 ml 5 (0.55 mmol) of triethylamine is added. At 0°C, a solution of 1.1 équivalents (0.55 mmol,) of an acid chloride in 5 ml of dichloromethane is added, and the mixtureis stirred overnight while warming up. For workup, it is filtered and freed of solvent. Theresidue is dissolved in 20 ml of ethyl acetate and washed once each with 5% strengthNaHCC>3 Solution and 5% strength NaCI solution, and dried. Evaporation of the solvent 10 is followed by final purification on a préparative HPLC.
Table 1:
012740 121
012740 122
012740 123
012740 124
012740 125
012740 126 62 Cl·^ Cl Ex. 35 X .N. „nh2 0, ,0" ς /'Cl Ck y a Cl s. /''k / IJ 0 0 'η TFA 63 Cl\ OC Cl Ex. 35 X ,N ^nh2 °s z° Cl Cl\ 0- œ Cl JJ Θ 0 S TFA zNH2 64 Cl\ çX Cl Ex. 35 JJ ,N Os z°s'e'' ''TjT 'Cl Cl\ si? O- Çk Cl J).o""o TFA 65 Cl\ ÇC Cl ,N ^nh2 Ύ O Clx a V- TFA Ex. 36 X ''nh2 yx Ί IFA NX 66 Cl\ oc ,N ^Ύα 0 (X Cl a 012740 127
Ex. 36 Cl\ ç 'NH2 û 67 oi Cl Ex. 36 À 0 Ck ÇÛ a TFA 68 C|\ çc Cl Ex. 36 -N, 'nh2 V 0 Clx çî Cl Vr ,Νχ TFA . 69 Cl\ Γ^ι' ,N„ 'nh2 >k/CI Clx ιΓύ > O X Cl Ex. 36 T O UL Cl TFA 70 Cl\ OC ,hk 'nh2 Clx Y O X Cl Ex. 36 ¥ 0 IX Cl „Νχ TFA 012740 128 71 Cl^ OC Cl Ex. 36 x 'NH2 °y0' 0 Ck 9 çô Cl 4χ TFA 11 A 9 Cl^ 'nk2 i----, yl Xn 72 nr X Vx/I Q\ iCVi T 0 CXa Cl à Ex. 36 c H Il o "nh2 X CXxf c|-\ ^x^ X''. F H r-F 73 Î xX X X Clx ιΓί F 5 ex. A TFA Cl Cl Ex. 36 Ai 'nh2 UL 74 c,\ Ce ,N, Ce CL A TR\ 0 \Λλ Cl δ a Ex. 36 x^ T 'nh2 x 1 v5r 75 Cl\ Οχ z° "e" Ck B 31 X /-Cl IX Ά TFA Cl Cl 012740 129
Ex. 36 Tl Cl\ nh2 H 76 cd 'N\ O, z° Cl Cl\ Π ζΝχ TFA Cl Cl Ex. 36 Tl zO ^nh2 <5s •l XVZ 'Sx Cl\ H 7 77 Cl Οχ ζθ'e' '"ijl" "Cl Cl\ ç Π | ZC tfa Cl Ex. 36 *) Product précipitâtes 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;
0.355 mmol of the compound of example 35 is dissolved in 5 ml of dry acetonitrile, and0.39 mmol of ethyl isocyanate is added. After standing overnight with exclusion ofmoisture, the solvent is removed and the crude product is purified on a préparativeHPLC, resulting in the title compound as a colorless solid. 5 012740 130
Example 79:1-(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea, trifluoroacetate;
The title compound is synthesized starting from the compound of example 35 and5 methyl isothiocyanate by the method described in example 78.
Example 80:1-(2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;
10 The process is analogous to example 78, starting from the compound of example 36and ethyl isocyanate. For workup, the resulting precipitate is filtered off with suctionand washed with acetonitrile, resulting in the desired ethyluréa as a colorless solid.
Example 81:1-(2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3- 15 methyl-thiourea, trifluoroacetate;
The compound of example 36 and methyl isothiocyanate are reacted in analogy to themethod described in example 78. 012740 131
Example 82: N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-ethanesulfonamide, hydrochloride;
307.1 mg (1 mmol) of the compound of example 35 are dissolved in 10 ml of pyridine 5 and at 0°C, 0.19 g (1.5 mmol) of ethanesulfonyl chloride, and a catalytic amount of DMAP are added. The mixture is stirred at room température.
For workup, the solvent is removed in vacuo, the residue is taken up in ethyl acetateand washed with H2O. The organic phase is dried with MgSC>4 and concentrated. The 10 crude product is chromatographed on silica gel. The sulfonamide obtained in this wayis dissolved in a THF/2 N HCl mixture and again concentrated in vacuo, resulting in208 mg of the desired hydrochloride.
Example 83: N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]- 15 methanesulfonamide, hydrochloride;
The process is analogous to the method described in example 82, starting from thecompound of example 35 and methanesulfonyl chloride. 20 Example 84: N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenylp ethanesulfonamide, hydrochloride; 012740 132
The process is analogous to the method described in example 82, starting from thecompound 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;
The process is analogous to the method described in example 82, starting from thecompound of example 17, intermediate 1, and methanesulfonyl chloride. 10
Example 86: 86a: (-)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide; 86b: (+)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;
15 2.0 g of the title compound from example 34 are separated on a chiral phase, resultingin about 1.0 g of the two enantiomeric acetamides 86a and 86b. 012740 133 chiral column: Chiralpak ADH/31 250 x 4.6 mm; solvent: acetonitrile; flow rate: 1 ml/min;
Rt((-)-enantiomer/86a) = 5.541 min;
Rt((+)-enantiomer/86b) = 7.033 min.
General method for preparing the compound 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-4-yi)-phenylamine (example 35) is introduced into 10 ml of pyridine and, at 0°C, asolution of 1.2 équivalents of the appropriate sulfony, chloride (see table 2) in 5 ml ofdichloromethane is added dropwise. The mixture is stirred at room température. Acatalytic amount of DMAP is added depending on the progress of the reaction and,where appropriate, the reaction température is increased to 50°C until no furtherincreàse in conversion can be detected. For workup, the mixture is concentrated andthe residue is partitioned between ethyl acetate and saturated NaHCC>3 solution. Theorganic phase is separated off and washed once more with saturated NaHCC>3solution and H2O, dried with Na2SC>4 and concentrated. For further purification, thecrude product obtained in this way is chromatographed on silica gel. The productsobtained in this way are converted into the corresponding hydrochlorides by dissolvingthe substances in 2 N HCl or ethanolic HCl and freeing off solvent, resulting in thedesired HCl salts.
Purification in a préparative HPLC System résulte in the corresponding products astrifluoroacetates.
Table 2:
Example Precursor 1/ aniline Precursor 2/ acid chloride Product 012740 134
012740 135
012740 136
012740 137 94 Cl^ OC Cl Ex. 35 . /NH, χ/ Λ jf Ό 4v cix ÇT oAo b Œ Cl JK <5^ ΊΓ .NH, Ά^·' J o' "o P Cl\ I jj c> 94a oc O - F-^^^CI cix Pï J CW Cl CO Cl Ex. 35 Cl\ O jf ,NH, t O Y«O 95 O ΟΠΟ Br^o/^S==0 JJ o" "o Cl Cl\ Cl OO Cl Ex. 35 c y ,NH. /C ci^ p H JO 96 OC O O j U N-^Xg-^-^O CK Q o' *o Cl OC Ex. 35 012740 138
General method for synthesizing the compounds of examples 99 to 110
Préparation of the amine component 012740 139 4.0 mmol of the aromatic amine (see table 3) are stirred with 8.0 mmol of the aliphaticaldéhyde (see table 3) in methanol at room température for 2 hours and then,depending on the progress of the reaction, 0.67 to 2.0 eq of NaBffy are added inportions. After standing at room température overnight, the solvent is removed and theresidue is taken up in 1 N HCl. It is extracted with dichloromethane. The aqueousphase is adjusted to a pH of 11 to 12 with NaOH and again extracted withdichloromethane. The organic phases are dried with MgSC>4 and concentrated in arotary evaporator. Further purification takes place by chromatography on silica gel oron a préparative HPLC.
Préparation of the bromo ketone component
The bromo ketone building blocks are synthesized by methods known from theliterature, starting from commercial acetophenones by treatment with bromine in glacialacetic acid in analogy to example 1, intermediate 2.
The compounds of examples 100 to 111 can be prepared starting from the amine andbromo ketone components shown in table 3 in analogy to the synthetic route shown inexample 1 (alkylation of the amine component by the bromo ketone component,subséquent réduction with NaBH4 and final H2SO4-mediated cyclization).
The resulting tetrahydroisoquinolines can be converted into the corresponding salts ina manner known to the skilled worker. 012740
Table 3:
01274C Ο C,H Cl V / o~o (Λ-Λ IL LL O^O ΛΛ-Ζ" o H -2 A -- k. Cû k. CO k. m AJ aJ A —> ο \=/ o o . J —C—σ o~r u. -σ Ό u_~V U- U. O -- « X 2 J CM X 2 1 CM X 2 A O O I O o «M» O / u. JL o ( jL Cr -o y Ή O u7\ / o U. U. __________________________________________________ ... . . - . . .. CM o CO O rS «r— *t—
142
012740 143
012740 144
Standart procedure for the préparation of the example compounds 111 to 124: 0,358 mmol of the acid component, which are listed in table 4, are dissolved in 1 mlDMF and 0,221 ml (1,30 mmol) of Diisopropylethylamine are added. At 0 °C a solutionof 128 mg (0,390mmol) TOTU is added followed by a solution of the aminecomponent, listed in table 4. After the resulting solution was kept at room températureovernight, the reaction mixture is filtered and the filter is washed with 20 ml of ethylacetate. The filtrate is washed twice with sat. NaHCO3-sol., followed by 5 % NaCI-sol.The organic layers are dried using MgSO4 and the solvent evaporated i. vac.
Those obtàined crude products, which still contain Boc-protecting groups, are ‘~deprotected following the procedure given below, without further purification. Theabove obtàined crude products, which are not Boc-protected are purified on a HPLC,by which the example compounds are obtàined as the correspondingTrifluoroacetates.
Standart procedure for the préparation of the example compounds 125 to 147: 0,358 mmol of the acid component, which are listed in table 4, are dissolved in 1 mlDMF and 0,221 ml (1,30 mmol) of Diisopropylethylamine are added. At 0 °C, 151 mg(0,975 mmol) Diethylcarbodiimide, a solution of 132 mg (0,975 mmol) HOBt in 1 mlDMF and 20 mg (0,162 mmol) DMAP are added, followed by a solution of the aminecomponent, listed in table 4, in 2 ml DMF. The solution is kept at room températureovernight. For the working up, the reaction mixture is filtered and the filter is washedwith 20 ml of ethyl acetate. The filtrate is washed twice with sat. NaHCO3-sol„ followedby 5 % NaCI-sol. The organic layers are dried using MgSO4 and the solventevaporated i. vac.
Those obtàined crude products, which still contain Boc-protecting groups, aredeprotected following the procedure given below, without further purification. Theabove obtàined crude products, which are not Boc-protected are purified on a HPLC,by which the example compounds are obtàined as the correspondingTrifluoroacetates.
Standart procedure for the deprotection of the Boc-groups: 012740 145
The obtained crude products are dissolved in 5 ml of a 10 % solution of Trifluoro-aceticacid in Dichloromethane for 1 h at room température. The reaction mixture isevaporated i. vac. and the resulting residues are purified by HPLC. The examplecompounds are obtained as Trifluoro acétates.
Tabelle 4:
Example-No. Acid component Amine component Example compound 111 JUyy 0 1 NK, T hn"^nh’ ifS CK U CK a LJ Cl Lxn\ TFA 112 ηΛ\<Κ< O 1 nh2 T CK U L> ck yy Cl LJ Cl Lxn\ TFA 113 „0^ NH„ ΙΊ ifS cix LJ. LJI CK Cl L. Cl tfa 114 "VfT nh2 T p «Âp CK U lj CK 1 | Cl •K^N^ TFA et 012740
OV 146
012740 147
012740 148
149
012740 150
012740 151
Example 148:1-[2-(6,8-Dichioro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]- 3-ethyl- thiourea-Hydrochloride sait
5 2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (95 mg, example 36) was dissolved in acetonitrile (4 ml) and isothiocyanato-ethane (27 mg)was added to the stirred solution. After standing for 15 h at room température thesolvent was removed and the residue purified by préparative HPLC. The productcontaining fractions were combined and the acetonitrile was removed in vaccuo. After 10 addition of potassium carbonate the aqueous phase was extracted with ethyl acetate.
The organic layer was separated, dried (magnésium sulphate), filtered and concentrated in vaccuo. The residue was dissolved in water/2N hydrochloric acid and freeze dried to give 36 mg of the title compound. 012740 152
Example 149:1-(4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]- 3-ethyl- thiourea-Hydrochloride sait
4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylarnine (50 mg, 5 example 17, intermediate 1 ) was dissolved in tetrahydrofurane (4 ml) and isothiocyanato-ethane (14 mg) was added to the stirred solution. After 2h at refluxtempérature the solution was concentrated and the residue kept for 2 h at 85°C. Thecrude product was purified by preparativè HPLC. The product containing fractionswere combined and the acetonitrile was removed in vaccuo. After addition of 10 potassium carbonate the aqueous phase was extracted with ethyl acetate. The organiclayer was separated, dried (magnésium sulphate), filtered and concentrated in vaccuo.The residue was dissolved in water/2N hydrochloric acid and freeze dried to give 33mg of the title compound. 15 Example 150:1 -(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-thiourea-Trifluoroacetic acid sait
3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (50 mg,example 35) was dissolved in tetrahydrofurane (3 ml) and isothiocyanato-ethane (14 20 mg) was added to the stirred solution. After 2h at reflux température the solution wasconcentrated and the residue kept for 2 h at 85°C. The crude product was purified bypréparative HPLC. The product containing fractions were combined and the solventwas removed in vaccuo to give 66 mg of the title compound. 012740 153
Example 151:3-[3-(6,8-DichIoro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-dimethyl- urea - Hydrochloride sait
Cl
Cl
Intermediate 1: [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic acid 4- nitro-phenyl ester - Hydrochloride sait 3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (350 mg,example 35) was dissolved in dichloromethane (17.5 ml) and 4-nitrophenyl-chloroformate (230 mg) was added to the stirred solution. After 4.5 h an additional 0.1équivalents of 4-nitrophenyl-chloroformate (23 mg) was added and the mixture stirredover night. The precipitate was removed by suction, washed with dichloromethane anddried under vacuum. The product (545 mg) was used in the next step without furtherpurification. 3-(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1 -dimethyl-urea - Hydrochloride sait [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester - Hydrochloride sait (35 mg) was suspended in dichloromethane(3.5 ml). Under stirring dimethylamine (3.7 mg) dissolved in dichloromethane (1 ml)was added. After 1 h dichloromethane, water and saturated potassium carbonatesolution were added. The organic layer was separated, washed two times withsaturated potassium carbonate solution, dried over magnésium sulphate, filtered andconcentrated in vacuo. The residue was dissolved in water/2N hydrochloric acid andfreeze dried to give 29 mg of the title compound. 012740 154
The following examples were synthesised analogously to example 4 using therespective amine. Sometimes préparative HPLG purification was required.Table 5:
Example Structure 152 M ° « CK LA. .A cl Cl 153 •^ΝγΟ L 0 CK 1 Cl LA ^K Cl 154 |f H CK 1 Cl iLL ^*K Cl 155 f Ά ° ck A Cl LA Cl 156 r rrNvN^ AA o Ck γΊ Cl l^ Lx-i'K Cl 157 if sA O ck 1 ci LA Cl 155 012740
The following examples were prepared analogously to example 151. But THF wasused as solvent in a closed vial. For examples 159 and 166 a reaction température of85°C was required. Example 20 required préparative HPLC purification.
Table 6:
Example Structure 159 Clx AL Chiral I | I LA Nv^ X A LA Cl 160 ck ( ς Ά LA 161 CK Av i Ά- -K a - - LA x/L ci Cl 162 rvv Clx AA· Aci S LA . m Cl N Cl 163 Cl\ AL ryv la À ci v LA Cl 012740 156 164 ci\ Q -ΝγΟ Νκ c \ Cl I /k Κί^ Cl 165 'Ί rV> ci\ Cl 166 CK Τ/'Κγ- Cl , X Cl Cl 167 (I νκί CK C, U O Cl Cl
Example 168: 4-Methyl-piperazine-1-carboxylic acid [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide - Hydrochloride sait
5 Intermediate 1 :[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]- carbamic acid 4- nitro-phenyl ester - Hydrochloride sait 2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (200 mg, example 36) was dissolved in dichloromethane (10 ml) and 4-nitrophenyl- chloroformate (131 mg) was added to the stirred solution. After 3.5 h the precipitate 012740 157 was removed by suction, washed with dichloromethane and dried. The crude materialwas re-crystalized from dichloromethane to give 159 mg of the titie compound. 4-Methyl-piperazine-1-carboxylic acid [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- 5 isoquinolin-4-yl)-phenyl]-amide - Hydrochloride sait [2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin’4-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester - Hydrochloride sait (15 mg) was suspended in dichloromethane (2ml). Under stirring 1-methyl-piperazine (3.2 mg) dissolved in dichloromethane (1 ml) 10 was added. After 1 h dichloromethane, water and saturated potassium carbonatesolution were added. The organic layer was separated, washed two times withsaturated potassium carbonate solution, dried over magnésium sulphate, filtered andconcentrated in vacuo. The residue was dissolved in water/2N hydrochloric acid andfreeze dried to give 13 mg of the titie compound. 15
The foliowing examples were synthesised analogously to example 168:
Table 7:
Example Structure 169 |f £ N^V ck iPT 1 Cl __ Cl 170 ( Xk ] NANZ CK O 1 OL ci Cl 171 (T Cl> OC S c < Cl 012740 158 172 CK β Çr Cl A Cl 173 CK β Ç[ Ά Cl kz-o Cl 174 CK ( Cl Cl 175 A î 1 CK çc 1 Cl Cl
Example 176: 4-Methyl-piperazine-1-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide - Hydrochloride sait
5 Intermediate 1 : [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic acid 4- nitro-phenyl ester - Hydrochloride sait 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (200 mg,example 17, intermediate 1) was dissolved in dichloromethane (10 ml) and 4-nitrophenyl-chloroformate (131 mg) was added to the stirred solution. After 4.5 h the 10 precipitate was removed by suction, washed with dichloromethane and dried. Thecrude material was re-crystalized twice from dichloromethane to give 254 mg of thetitle compound. 012740 159 4-Methyl-piperazine-1-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide - Hydrochloride sait [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic acid 4-5 nitro-phenyl ester - Hydrochloride sait (15 mg) was suspended in dichloromethane (2 ml). Under stirring 1-methyl-piperazine (3.2 mg) dissolved in dichloromethane (1 ml)was added. After 5 h of stirring and standing over night dichloromethane, water andsaturated potassium carbonate solution were added. The organic layer was separated,washed two times with saturated potassium carbonate solution, dried over magnésium 10 sulphate, filtered and concentrated in vacuo. The residue was dissolved in water/2Nhydrochloric acid and freeze dried to give 13 mg of the title compound.
The following examples were synthesised analogously to example 176:Table 8:
Example Structure 177 Cl- τ Cl LA Cl 178 0 Λ | I Cl ( A3 Cl· LA Cl 179 o νΆ| 1 Cl ] JL 1 Ô Cl· LA Cl 160 012740
Example 184: N-[4-(6,8-Dichloro-2-methyl-1 ^.S^-tetrahydro-isoquinolin^-ylJ-phen^
5 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)>phenylamine (200 mg, example 17, intermediate 1) was dissolved in formic acid (1 ml) and kept for 15 min at reflux température. After standing over night an ice/water mixture was added followed by ethyl acetate. After separating the organic layer the aqueous phase was again 161 012740 extracted with ethyl acetate. The combined organic layers were dried (magnésiumsulphate), filtered and concentrated in vacuo. The residue was dissolved in a mixtureof dichloromethane and saturated sodium bicarbonate solution. The organic layer wasseparated and the aqueous phase was extracted 3 times with dichloromethane. Theorganic layers were combined, dried (magnésium sulphate), filtered and concentratedin vacuo to yield 167 mg crude material. 10 mg of this material was dissolved inwater/2N hydrochloric acid and freeze dried to give 11 mg of the title compound.
Example 185: [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoIin-4-yl)-phenylJ-
At 50°C under stirring and argon atmosphère N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-formamide (150 mg, example 27) dissolved intetrahydrofurane (2.5 ml) was added to a 1 M solution of lithium aluminiumhydride intetrahydrofurane (0.45 ml) diluted with tetrahydrofurane (2.5 mi). After the addition themixture was heated to reflux température for 1 h. After standing over night at roomtempérature the mixture was heated to 50°C and further lithium aluminiumhydridesolution (0.22 ml) was added. The mixture was heated to reflux température and after1 h the mixture was cooled, ice added and the tetrahydrofurane removed in vaccuo.The residue was dissolved in dichloromethane and hydrochloric acid. The aqueouslayer was extracted three times with dichloromethane, the organic layers werecombined, dried (magnésium sulphate) and concentrated. The crude material waspurified by préparative HPLC. The product containing fractions were combined and theacetonitrile was removed in vaccuo. After addition of sodium bicarbonate the aqueousphase was extracted with dichloromethane. The organic layer was separated, dried(magnésium sulphate), filtered and concentrated in vaccuo to yield 80 mg of the saitfree base. 10 mg of the base was dissolved in water/2N hydrochloric acid and freezedried to give 10 mg of the title compound. 162 012740
Example 186:1 -[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]- 1,3-dimethyl- urea - Hydrochloride sait
A002955438A
Following the procedure described in example 151 using [4-(6,8-dichloro-2-methyl-1,2)3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amine, 4-nitrophenyl-chloroformateand methylamine (20 μΙ, 2 molar in THF) 9 mg of the title compound was obtained. 10 The following examples were synthesised analogously to example 186:Table 9:
Example Structure 187 0 fl /τ'! •L Mk CK L Cl 1 ci ^hK Cl 188 CK o \ CA Cl 163
189 CK Q et \AK Cl 190 0 ''Ν'Ί'Ι^'ι A CK ^J Cl Cl 191 O rû n CK Cl LJ -^AK Cl - 192 0 Ô Μ CIH CIH CK if^i LJ Cl 193 CK ok CIH LJ Uak Cl
Example 194: N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl] formamide 164
012749 3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (600 mg,example 35) was dissolved in formic acid (2.4 ml) and kept for 15 min at refluxtempérature. After standing over night an ice/water mixture was added followed by 5 ethyl acetate and saturated sodium bicarbonate solution. The organic layer wasseparated and the aqueous phase was extracted 3 times with dichloromethane. Theorganic layers were combined, dried (magnésium sulphate), filtered and concentratedin vacuo to yield 588 mg of the title compound. 10 Example 195: [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-
At 50°C under stirring and argon atmosphère N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl3-formamide (588 mg, example 194) dissolved in 15' tetrahydrofurane (10 ml) was added to a 1 M solution of lithium aluminîumhydride intetrahydrofurane (1.8 ml). After the addition the mixture was heated to refluxtempérature for 1 h. After standing over night at room température the mixture washeated to 50°C and further lithium aluminîumhydride solution (2 ml) added. Themixture was heated to reflux température and after 0.5 h the mixture was cooled and 20 ice added. The aqueous phase was 4 times extracted with ethyl acetate. The organiclayers were combined, dried (magnésium sulphate) and concentrated. The crudematerial was purified by préparative HPLC. The product containing fractions werecombined and the acetonitrile was removed in vaccuo. After addition of sodiumbicarbonate the aqueous phase was extracted with ethyl acetate. The organic layer 25 was separated, dried (magnésium sulphate), filtered and concentrated in vaccuo to 012740 165 yield 270 mg of the sait free base. 45 mg of the base was dissolved in water/2Nhydrochloric acid and freeze dried to give 45 mg of the tîtle compound.
Following the procedure described in example 151 using [3-(6,8-dichloro-2-methyl-5 1,2,3Atetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amine, 4-nitrophenyl-chloroformate and the respective amine the following urea dérivatives were prepared:
Table 10:
Example Structure 196 Clx A o A α LA Cl 197 Clx ( "ψίγΟ A o çx A 01 Cl 198 1 1 -γΝγΝ^ A ° -- CK LA A α Cl 199 (f γ/”γΝ^ A ° Cl\ AL" la. A α Cl 012740 166 200 Clx^ A 1 O -Ν·χ^χΝχΑ O Cl X Cl 201 i ry .'ΝΧ^·'ΝχΑ xA O CK A •x^N Cl Cl AA X Cl 202 i N A A O cix A Cl Cl AA X Cl 203 i r fl Ά AN^ xA o cl\ A Cl AA X Cl
Example 204: [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic acid 2- dimethylamino-ethyl ester - Hydrochloride sait
5 Under stirring and argon atmosphère [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic acid 4- nitro-phenyl ester - hydrochloride sait (15mg, example 151, intermediate 1) was suspended in dichloromethane (1.5 ml) and 2- 012740 167 j dimethylamino-ethanol (3 mg) dissolved in dichloromethane (0.5 ml) was added. Afterstirring for 6 h and standing over night dichloromethane, water and saturatedpotassium carbonate solution were added. The organic layer was separated, washedthree times with saturated potassium carbonate solution, dried over magnésiumsulphate, filtered and concentrated in vacuo. The crude material was purified bypréparative HPLC. The product containing fractions were combined and theacetonitrile was removed in vaccuo. After addition of sodium bicarbonate the aqueousphase was extracted with ethyl acetate. The organic layer was separated, dried(magnésium sulphate), filtered and concentrated in vaccuo. The residue was dissolvedin water/2N hydrochloric acid and freeze dried to give 5 mg of the title compound.
Following the procedure described in the example above the following carbamates were prepared starting from 2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyiamine and 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine, respectively.
Table 11:
Example Structure 205 I θ'ΎΎ Cl Ci Cl 206 'γ'Ν x^x Cl Cl Cl
Example 207: [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic acid methyl ester - Hydrochloride sait 012740 168
Under stirring and argon 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (15 mg, example 35) was dissolved in dichloromethane (1.5 ml) andmethyl chloroformate (4.6 mg) dissolved in dichloromethane (0.5 ml) was added. After 5 stirring for 6 h and standing over night additional chloro formate (2.3 mg) was added.Stirring was continued for 5 h, then the solvent was removed and the residue wasdissolved in water/2N hydrochloric acid and freeze dried to give 20 mg of the titlecompound. 10 Following the procedure described in the example above the following carbamateswere prepared starting from 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, respectively. 15 Table 12:
Example Structure 208 o Γ ï 1 ci Cl 209 Pr νγ•CsîJ o 1 ci çOn. Cl 210 fYNY°^ o Clx^XxT. Cl ψζλ Cl 012740 169
Example 215a: (+)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide - Hydrochloride sait 5 215b: (-)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]- methanesulfonamide - Hydrochloride sait 012740 170
Cl
Cl
Cl
Racemic N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesUlfonamide (96 mg, example 83) was resolved by chiral préparative HPLC. 5 Chiral phase: Chiralpak AD 250 X 50 mm; 20 μ;
Solvent: Heptane:Ethanol:Methanol: 10:1:1;
Flow rate: 50 ml/min
The residue was dissolved in water/2N hydrochloric acid and freeze dried to give 37mg of the first eluting and 37 mg of the second eluting enantiomer. 10 The enantiomeric purity was determined by analytical HPLC.column: Chiralpak AD-H/31 250x4.6 mm mobile Phase: heptane:ethanol:methanol 10:1:1, flow: 1 ml/min.
First eluting enantiomer: 6.84 min, 100% ee, MS (ES+, M+H+): 385.2
Second eluting enantiomer: 8.02 min, 100% ee, MS (ES+, M+H+): 385.2 15
Example 216a: (+)-1 -[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea - Hydrochloride sait 216b: (-)-1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyi]-3-20 ethyl-urea - Hydrochloride sait
Cl
N N
O
Cl
Cl
Cl 012740 171
Racemic 1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3- ethyl-urea (316 mg, example 80) were resolved by chiral préparative HPLC.
Chiral phase: Chiralpak OD 250 X 50 mm; 20 μ;
Solvent: Heptane:Ethanol:iso-Propanol: 10:1:1; 0,3% Diethylamine;
Flow rate: 50 ml/min
The enantiomers were separately further purified using préparative HPLC. The productcontaining fractions were combined and the acetonitrile was removed in vaccuo. Afteraddition of sodium bicarbonate the aqueous phase was extracted with ethyl acetate.The organic layer was separated, dried (magnésium sulphate), filtered andconcentrated in vaccuo. The residue was dissolved in water/2N hydrochloric acid andfreeze dried to give 37 mg of the first eluting and 58 mg of the second elutingenantiomer.
The enantiomeric purity was determined by analytical HPLC. column: Chiralpak OD-20 250x4.6 mm mobile Phase: heptane:ethanol:iso-propanol 50:2:1 (+ 0.3% diethylamine), flow: 1ml/min.
First eluting enantiomer: 9.22 min, 100% ee, MS (ES+, M+H+): 378.1
Second eluting enantiomer: 9.96 min, 98% ee, MS (ES+, M+H+): 378.1
Example 217: N-[3-(6,8-Difluoro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide - Hydrochloride sait
Intermediate 1: 2,4-Difluorobenzyl-methyl-amine was prepared starting from 2,4-Difluoro-benzaldehyd by standart procedures. N-[3-(6,8-Difluoro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide -Hydrochloride sait; 012740 172
Starting from N-(3-Acetyl-phenyl)-acetamide and 2,4-Difluorobenzyl-methyl-amine(intermediate 1) the title compound can be prepared following the procedure describedin example 1. 5 Example 218: 4-(3-Bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoline - Hydrochloride sait
Following the procedure described in example 1 starting from 2,4-dichloro-benzaldehyde and using 2-bromo-1 -(3-bromo-phenyl)-ethanone as alkylating reagent 10 780 mg of the title compound we obtained.
Example 219: 1 -[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoline-4-yl)-phenyl]-3-(2-hydroxy-ethyl)-urea;
15 509 mg (1,0 mmol) [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl]-carbamic-acid 4-nitro-phenyl-ester-Hydrochloride (example 151, intermediate1) were dissolved in 15 ml DMF and at 0 °C a solution of 67,2 mg (1,1 mmol) of 2-Aminoethanol in 10 ml DMF was added. After stirring for 3 h at room température thesolvent was removed i. vac. The residue was dissolved in ethylacetate and washed 20 with sat. NaHCO3-solution. The organic layer was separated and the aqueous layer was extracted twice with ethylacetate. The combined organic layers were washed with sat. NaCI-solution, dried (MgSO4) and concentrated. Purification by silica gel chromatography (dichloromethane/methanol) yielded 265 mg of the title compound. 012740 173
Example 220: 3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoline-4-yl)-benzoic-acid-ethyl-ester,
Interrmediate 1: 3-Acetyl-benzoic-acid can be prepared by literature procedures. 5
Intermediate 2:3-Acetyl-benzoic-acid-ethyl-ester can be synthesized starting fromIntermediate 1 by standart procedures.
Intermediate 3: 3-(2-Bromo-acetyl)-benzoic-acîd-ethyl-ester was prepared analoguosly10 to Example 1, Intermediate 2, starting from 3-Acetyl-benzoic-acid-ethyl-ester (Intermediate 2). 3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-fsoquinoIine-4-yl)-benzoic-acid-ethyl-esterStarting from 3-(2-Bromo-acetyl)-benzoic-acid-ethyl-ester (Intermediate 3) and 15 Dichloro-benzyl-methyl-amine (Example 1, Intermediate 1 ), the title compound can beprepared by the méthode described in example 1.
Example 221: 3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoline-4:yl)-bënzoic-acid;
500 mg 3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoline-4-yl)-benzoic-acid-ethyl-ester (Example 220) were dissolved in 15 ml methanol and treated with 10 ml ofa 2 N KOH-solution. After 1 h at 50 °C the solvent was removed i. vac. The residue 174 012740 was taken up in water and was washed with ether. The aqueous phase was seperated and 2 N HCl was added until a pH-value of about 6 was reached. The precipitate was filtered off by suction and dried to give 304 mg of the title compound. 012740 175
Analytical data for the compounds of examples 1 to 221 :Table 13:
Ex. Structure Rt[mi n] Metho d MS [M+H+] MS- Meth od -Λ 1 1,60 B 349,1/350,1/ 351,0 ESI m.p.: 205-206 °C 1a CIH YrS 1,60 B 349,2/351,2 ESI m.p.: 125 °C . -V (decomp.) 2a °\ nh2 CIH °ΪΎΊ 3,63 A 371,3/373,3 ESI (+)-enantiomer 412,3/414,3 2b |Tj νη· dx^-^JL c,h 3,67 A 371,3/373,3 412,3/414,3 ESI (+)-enantiomer 2c % „NH2 1^1 /""j AcOH 0,yyS 3,66 A 371,1/373,1 ESI (-)-enantiomer 412,1/414,1 012740 176 2d (f A"° ΓΥ ΝΗΐ 1,56 B 371,1/373,1 412,1/414,1 ESI (-)-enantiomer AcOH 3 Ck °yU ° i Y TO. CI CIH 4,00 A 399,1/401,1 Cl 4a CK Y XNH2 o*f Y ça Cl CIH 3,59 A ”371,2/373,2 412,2/414,2 ESI ** 4b Ck I °s'^NH2 ου ô XX Cl AcOH 1,58 B 371,0/372,0/ 373,0/373,9 ESI 5 Cl-x Br Y αχ Cl CIH 4,57 A 369,9/371,9/ 373,9 Cl 6 eu ÇOOH Y ça CIH 4,03 A 336,1/338,1 Cl 177
7 ο JL TFA 4,17 A 363,3/365,3 ci 8 JL TFA 1,88 B 377,3/379,3 Cl 9 °γ^Ν- TFA 1,45 B 406,3/408,3 Cl 10 0 TFA vn yLn 4,37 A 377.1/379,1 Cl 11 U TFA F 4,05 A 363,2/365,2 ESI 12 0 TFA ειΊΓΎ< yn\ Cl 3,79 A 375,2/377,2 ESI 178 0,2740
13 Q CIH 4,92 A 361,2/363,2 ESI 14 ô ï TFA clYYi 4,08 A 390,2/392,2 ESI =- 15 TFA 4,80 A 318,2/320,2 Cl 16a  CIVF> 1,61 B 349,1/350,1/ 351,1 ESI (-)-enantiomer 16b  F 1,61 B 349,1/350,1/ 351,1 ESI (+)-enantiomer 17 nh2 a^^JL xHC1 0,91 B 307,1/309,0 ESI 012740 179
18 °i T Φ 1,63 B 442,0/444,0 ESI Ck _ JL UH-I Cl ίίΊ 19 eu 4,00 A 392,2/394,2 ESI |l Xa A—- A 19a eu M 1 CH rvA 1,80 B 392,1/394,1 ESI . -. Cl s hn^iA Λ 20 Ck Ο Wl 1,67 B 380,1/382,2 ESI Cl X HN N ^ As 21 ck \A XX Cl 1,68 B 378,3/380,2 ESI m.p.: 218-220 °C A 21a eu JL cih XX Ci 1,68 B 378,1/379,1/ 380,1 ESI 012740 180
22 Λ Os ,o " s ' Ji λχχ 0,32 Β 359,1 717,3/718,3/ 719,3 ESI 23 Λ . - γχ 1,60 Β 309,2/310,1 ESI - 24 „Λ 1,67 Β 393,0/394,0/3 96,0/397,0 ESI 25 „Λ <ν? OCX 1,85 Β 384,1/386,1 ESI 25a Λ ΛΊ j «η 1,78 Β 384,1/385,1/ 386,2 ESI 26 Λ Ογ»5 1,46 Β 400,1/401,2/ 401,2 ESI 012740 181
27 Λ 0.27 B 413,2/414,2/ 415,2 ESI 27a HljT^ "O t AL 0,25 B 413,2/414,2/ 415,2 ESI 28 O X X <A 1,65 B 384,2/385,2 386,2 ESI 29 th P LÀA 1,67 B 352,0/353,0/ 354,0 ESI 29a OH O jjy^ps‘ONa XJC/A Cl 1,68 B 352,0/353,0/ 354,0 ESI - 30 OH O O” °'ΎύΊ tfa Cl 1,68 B 365,1/366,1/ 367,0/368,0 ESI 012740 182 31 oh 9 1,79 B 379,1/380,1/ 381,1 ESI φ αΥχΐ Cl A TFA OH J I U A 32 0ΚΊΓ^Χι xTFA -J * Cl 1,47 B 422,1/423,1/ 424,1/425,1 ESI =- OH A 9 ?*> 33 c'YYi Cl X 1,46 B 393,1/394,1/ 395,1 ESI f χΥ 34 ΎΧ Cl -Nx 1,63 B 349,0/350,1/ 351,0 ESI f| ^x/NH2 35 A Cl 1,17 B 307,0/308,1/ 309,1 ESI (| N y^NH2 36 C'V 1,66 B 307,0/308,0/ 309,1 ESI Cl 012740 183 37 I ό 2,35 C 363,3/365,3 ESI Clx TFA OCX Cl HnX/\ A, 38 Ck Λ 1 TFA 2,43 C 377,3/379,3 ESI Cl hn-As/ A 39 Ck ï TFA 2,49 C 391,3/393,3 ESI |l Cl HnAj/ JL » Ai 40 cl\ Z^X\ TFA OCk Cl 2,43 C 377,3/379,3 ES, "A: Ai 41 cix Μ /kX TFA OCX Cl 2,48 C 391,3/393,3 ESI Az A 42 Ck M /^À TFA OCX Cl 2,40 C 375,3/377,3 ES, 012740 184 43 hîy3 ό 2,45 C 389,3/391,3 ESI Ck x/vA TFA €Ck Cl HN η 44 ~Ck ψι TFA OCX Cl 2,52 C 403,4/405,4 ESI — «X; AS F 45 Clx T TFA OCX Cl 2,49 C 403,2/404,2 ESI 46 ôHr V\ 2,36 C 460,4/462,4 ESI H? iPl A U 47 Clx A TFA 2,35 C 412,2/414,3 ESI ÇLnx Cl 0. z° Ά HN-'S\ Δ 48 Ck. 1 TFA iVi 2,29 C 385,3/387,3 ESI Cl 01274· 185
49 Οχ ζ° *s" ΗΙ'Γ"'-'' TFA 2,37 C 399,3/401,3 ESI 50 Οχ ζ° 'V κι TFA JÇXA 2,42 C 414,4/416,4 ESI 51 ûT CI'SYZ^V] TFA kXx/N\ Cl 2,37 G 363,3/365,3 ESI 52 rrNY^ 0 c'YYi TFA 2,44 C 377,3/379,3 ESI 53 çùp^ eu JL ΗΊΙ TFA Cl 2,51 C 391,3/393,3 ESI - 54 σ-/· ciy%a tfa 2,44 C 377,3/379,3 ESI 012740 186 55* Ck X XX Cl y/ k TFA Λ 2,49 G 391,3/393,3 ESI X, Y O 56 Clx Xy k TFA 2,41 C 375,3/377,3 ESI - XyX^ =- Cl X, χΎ 57 Clx. U S TFA 2,47 C 389,3/391,3 ESI Cl X r"ï° 58 Ck X TFA 2,52 C 403,4/405,4 ESI Cl X X y?' 59 Clx ΪΎ k TFA 2,48 C 403,2/404,2 ESI Cl fXj XY 60 Ck Xjl jX δ TFA 2,34 C 460,4/462,4 ESI γ*ΧΝχ. / 012740 187
61 Clx ni Cl Ί TFA NX 2,36 C 412,2/414,3 ESI γ\/ J θ' «b * 62 Cls, XX S TFA 2,32 C 385,3/387,3 ESI Cl H 0 0 - 63 Cl\ LX, TFA „IK 2,38 C 399,3/401,3 ESI Cl —· - — y ολο 64 Clx Xi S TFA 2,41 c 414,4/416,4 ESI XX Cl X. x„x > TFA 65 a\ Ol Cl 2,30 c 363,3/365,3 ESI - ç ψχ 1 TFA K 66 cl γΧ Cl 2,41 c 377,3/379,3 ESI G TFA 67 Ck 4 xÂ/N. Cl 2,52 c 391,3/393,3 ESI 012740 188
68 ο αΌ0- - Cl 2,41 C 377,3/379,3 ESI 69 r^Çi Ο Wr χα ™ - Cl 2,45 C 391,3/393,3 ESI 70 $Α Ύυ TFA 2,36 , C 375,3/377,3 ESI 71 θ ΤΑ3 CI\rx^55i^X, 'L-A^'K TFA Cl 2,44 C 389,3/391,3 ESI 72 TFA 2,51 C 403,4/405,4. ESI 73 \w "ça.:. 2,70 C 403,2/404,2 ESI 74 Ο-ΛοrA ™ r 2,30 C 460,4/462,4 ESI 012740 189 75 eu T fîî^ 1 %"°Aff zN\ TFA 2,41 C 385,3/387,3 ESI k^z 1 %-° TFA 76 Clx 9 2,49 C 399,3/401,3 ESI 77 Clx o Cl îî °s zO T Y TFA 2,55 C 414,4/416,4 ESI .- ( '''ky zN^-N^/ ï 78 Cl\ a Cl 1,72 B 378,3/380,3 ESI \zÿf s 79 Clx O Cl tfa 1,74 B 380,3/382,3 ESI 80 Ck I ( szSA "Ax z^· A- 1,75 B 378,3/380,3 ESI a Ψν TFA 81 Ck Q 1,68 B 380,3/382,3 ESI Cl 012740 190 82 |ί C'V Cl JJ CIH x/Nx 1,71 B 399,0/400,0/ 401,0/402,0/ 403,0 ESI A ° ° 83 CK ? CIH \/Nx 1,66 B 385,0/386,0/ 387,0 ESI Cl °x ,O S ' HN" 11 84 CK. O χ·\ CIH Yx 1,69 B 399,0/400,0/ 401,0/402,0 ESI Cl °x z° HN"S\ Ί 85 Ck 0 Cl \J X*X CIH \XNX 1,64 B 385,0/386,0/ 387,0/388,0 ESI rVr 86a CK û Cl Yx 1,64 B 349,3/351,3 ESI (-)-enantiomer σΥ 86b CK O Cl Yx 1,63 B 349,3/351,3 ESI (+)-enantiomer 012740 191
87 eu (ί a Cl ,ô fs^ F XxÿsJ I TFA 1,97 B 439,0/441,1 ESI f Ί 88 ax "T 1,83 B 453,0/455,0 ESI O r Ί 88a ax [ T CIH 1,83 B 453,0/455,0 ESI O .89 C!\ 9 °v ,O 'V' JTO y Br 2,01 B 531,0/533,0/ 534,9 ES, 89a eu ? Cl o, ,0 -z ÇQ Br zX CIH x/N\ 2,02 B 531,0/533,0/ 534,9 ESI 192 012740
90 V „ V- T X.W ô "Υχί Cl 1,78 B 525,1/527,1 ESI 90a %"° 8 V TXX^ - Ô ει'Ύ^Τι CIH 1,79 B 525,1/527,1 ESI 91 V ΑΧ Cl 1,63 B 465,1/467,1 ESI 91a °s A ci ' jL CIH Cl 1,64 B 465,1/467,1 ESI 92 V^J;1 ''ÇxÎx.'' Cl 1,81 B 499,1/501,1/ 503,1 ESI 012740 193
92a o. .o P1's" J CIH yL\ Cl 1,82 B 499,1/501,1/ 503,1 ESI 93 JJ o"'o Clx. Js. il ίΓ 1 TFAY^\ 1,99 B 439,0/441,1 ESI 94 ÇrX^ Cl 1,87 B 453,0/455,0 ESI 94a o OXZ) 7 9> /2 o rA 1 ÿ Tl Tl 1,87 B 453,0/455,0 ESI 95 rf fl 1 <A> [IJ ο' o 2,01 B 531,0/533,0/ 535,0 ESI - 96 <vHX^~V ÇToAo /- XXxn^ 1,75 B 525,0/527,0 ESI 012740 194 96a Xc Cl H JCV-N J r- 1,75 B 525,0/527,0 ESI CIH 97 c,v^ O 0 0 1,66 B 465,0/467,0 ESI " V l^n \ =- Cl 97a O Ji o' 'o CIH 1,66 B 465,0/467,0 ESI LJ Cl \χΝ 98 |j ap \=N .N. JX- O* '0 fc| 1,81 B 499,1/501,1/ 503,1 ESI Cl f| CI O o r v Y'NH, 99 Cl., (I K 405,1/407,1 ESI m.p.:122°C Cl || L> 100 xc Cl I CIH 4,44 A 292,2/294,2 Cl s. Ex.2; Intermediate 4 012740 195
100a (-) Il T i TFA Cl s. Ex.2; Intermediate 4a 100b W Tl T 1 ™ s. Ex.2; Intermediate 4b 101 Cl 4,43 A 326,0/328,0 ESI 102 ΟΠ 4,23 A 306,1/308,0 ESI 103 fVyS F'7XF 2,84 C 360,0 ESI - 104 O z> ° >- 2,79 C 320,0/322,0 ESI 105 2,64 C 291,9/293,9 ESI 012740 196
106 Cl F T 4,26 A 310,0/312,0 ESI Y Cl -''η cih 107 -X Cl ό CIH 4,43 A 306,1/308,1 ESI -- 108 eu Cl U ? Υγ CIH 4,11 A 292,0/294,0 ESI 109 eu cr D 9 '"'η cih 4,28 A 292,0/294,0 ESI 110 ( Br Y η cih 4,05 A 302,0/304 ESI 111 eu Y πΛ TFA Cl 1,37 D 364,4/366,4 ESI 012740 197
112 TFA Cl 1,44 D 378,4/380,4 ESI 113 ΛΑ ΎΧΧ ™ Cl 1,51 D 392,4/394,4 ESI 114 hJÇnh‘ αΎΎ^ TFA Cl 1,51 D 378,3/380,3 ESI 115 "fk""· C'YYi TFA Cl 1.58 D 392,4/394,4 ESI 116 hA^ Jo TFA Cl 1,04 D 435,5/437,5 ESI 117 Λ5 TFA *Ϋ<Α Cl 1,67 D 404,4/406,4 ESI 012740 198 118 <χ 0 tS ô X TFA 2,08 D 412,3/414,3 ESI ç Cl XX 119 O I HN^ Λ X 2,27 D 400,4/402,4 ESI eix TFA L X^ Cl 120 o 5 Î1 ΙΪΊ X 2,37 D 400,4/402,4 ESI Ck TFA X X^ Cl 121 X hn γ X Λ X 1,54 D 432,5/434,5 ESI . Ck i 1 TFA V Us Cl 122 ο I χ ”ï Ί y 1,70 D 428,5/430,5 ESI Ck TFA X Ux Cl 123 X HQ, y NOj 2,55 D 445,4/447,4 ES, Ck T J TFA X x^ Cl 012740 199 124 Ck ό . 2,43 D 428,5/430,5 ESI Cl ô- TFA 125 A ΐΓι 5 n Ύ 1,88 D 401,4/403,4 ESI Cl- TFA kA à 126 A Xx/ oz 2,31 D 496,5/498,5 ESI Clx ι^Ίι TFA Ά Cl 127 Zi -N H 2,14 D 429,4/431,4 ESI Cl- TFA Zz kA Cl 128 11 liî V Ή .. . 2,07 D 401,4/403,4 ESI Cl- ÎT r TFA Z, kA Cl 129 F O \2-F ΗΝΧ|Γ V > Ή 2,44 D 469,4/471,4 ES» a- TFA A kA Cl 012740 200 130 eu îÿyy 0 1,55 D 378,4/380,4 ESI V Cl TFA 131 eu. rrVf o 1 1.52 D 392,4/394,4 ESI V TFA Cl 132 eu (YYN Y o 1,63 D 378,3/380,3 ESI V U^.NX TFA Cl 133 S ιίΎ'κ NHs eu 1,64 D 392,4/394,4 ESI kJ U^NX TFA Cl 134 nh2 Y ° 1,14 D 435,5/437,5 ESI eu TFA ~ · Cl 135 eu Y? TFA 1,62 D 404,4/406,4 ESI kJ Cl 012740 201 136 Cl- r Cl k^ o Γι TFA kA 2,16 D 412,3/414,3 ·/ ESI 137 CI·. O 2,31 D 400,4/402,4 ESI XK, TFA kJJ K/k Cl 138 CI- 2,41 D 400,4/402,4 ESI Γ'ι TFA kJ k^k Cl 139 KÂÀJ Vy^ CK (1 J ° 1,62 D 432,5/434,5 ESI \ TFA ψΐ ^NX Cl 140 ryW x^ o ' 1,75 D 428,5/430,5 ESI Civ ΥΊι XK TFA V sUx Cl 141 NO, [1 yki 0 2,54 D 445,4/447,4 ESI ck ''K TFA kJL ^X Cl 012740 202 142 cix Ç Cl ρλ4η ΓΊ TFA kA 2,50 D 428,5/430,5 ESI 143 σΑ Cl. A TFA 1,95 D 401,4/403,4 ESI Ak Cl 144 V yvO"· H 0 2,34 D 496,5/498,5 ESI Clx fl TFA uk Cl 145 γτ"Λ'ν CI- n TFA 2,31 D 429,4/431,4 ESI Cl 146 σ A Cl. 'yÿ>' AA O A TFA 2,11 D 401,4/403,4 ESI - LA Cl γυβυ^Γ 147 cix. ÇJ o A T F F γΊ tfa 2,48 D 469,4/471,4 ESI kJ kA Cl 012740 203 148 Cl «Λ ( J 01 yy^ S 2,36 B 394,2 ESI ci <γΝγΝχΧ 149 cAAj zV s 2,35 B 394,2 ESI ΐ Cl 150 α-ψτ 2,35 B 394,2 ESI I TFA - fVNY^ γ^ O 151 CL 2,15 B 378,2 ESI ΊΠ fl ci Y-Y Cl r rV γ'γΜ Y O 152 ciw 1 Cl 1,64 B 433,3 ESI I T À Cl ~-Y - Cl - U 153 2,56 B 418,3 ESI αΎ^τ Y Cl ΎΚ Cl g ^nynO 154 Y 0 2,16 B 420,2 ESI CIYY Cl --- Cl 012740 204 15.5 ( c,v Ci O X ci 2,34 B 404,2 ESI r •ίγΝγΝ^ À 0 156 C1w L Cl 2,43 B 406,2 ESI Cl (i ^γΝγΝ^ X 0 157 I Cl 2,12 364,2 ESI LA X/N\ Cl Q .ΝγΝ^γ O 1 158 arX Cl x. Cl 1,65 B 421,2 ESI Cl 159 f x/ γχΝχγ^Ο Chiral a L>fR 2,23 B 420,3 ESI Cl 160 ( Ύγ ^γΝγ° ς Xi 1 ci 2,25 B 434,3 ESI là Cl 161 Û ΓΝΥ° a L—N'· 1,72 B 461,4 ESI ΧΧ,Νχ Cl Cl 012740 205 162 Ck AA Cl γΜ T \ci s Cl Ak 1,68 B 449,4 ESI 163 Ck γΝγ° T L ci v 1,62 B 435,3 ESI La Cl ' Cl ^ΑγΟ 164 Ck "Çc V \ À° A 1,71 B 435,3 ESI Cl « 165 Ck V 2,21 B 408,3 ESI VA Cl 166 Ck (i W -γΑγΟ A V Ύ ci AA 1,88 B 427,3 ESI La Cl Cl 167 Ck 1 ^γΝγθ A NYL A ci La 1,80 B 427,3 ESI va ^/L ci Cl 168 Ck ( çc LAq ί Va ci 1,59 B 433,3 ESI Cl ci 012740 206
169 CK O Cl X’-'Ar 'l Cl 2,12 B 364,2 ESI 170 CK Cl 1 Cl 2,12 B 378,2 ESI 171 CK J Çc Cl ûv 2,34 B 406,3 ESI 172 CK ί Cl Cl 2,44 B 418,3 ESI 173 CK II 'Çc Cl 'η Cl k^-o 2,11 B 420,3 ESI 174 CK 1 Cl 3-Â--C?Ό Cl 2,25 B 404,3 ESI 175 CK oc Cl 9 i 1 Cl Cl 0,90 B 421,5 ESI 176 CK P Cl O N'U'N^) -K Cl Cl 1,52 B 433,3 ESI 012740 207 177 Cl- Cl X PO T ci -AA 2,34 B 404,3 ESI 0 kA N N 178 Cl JL In Cl 2,11 B 364,2 ESI Cl 0 N N 179 Cl JL In Cl- VA 2,17 B 378,3 ESI LJ Cl Cl ( 1 k 180 2,51 B 406,3 ESI Cl- 'Ίί^^Γ Cl Λ—Α 181 ( -J Cl 1,59 B 421,2 ESI Cl- ΤΎ J, Cl Cl Le 182 A 2,47 B 418,2 ESI Cl-, Y Cl LA Cl 012740 208
183 eu O lAhl^ 2,16 B 420,2 ESI çc Cl I ci 184 CK ( ç Cl N^O 5 CI 2,02 B 335,2 ESI -- 185 CK Cl Cl ç Cl l< ό Là 1,92 B 321,2 ESI 186 Cl CK P Cl ί 1,05 C 378,4 ESI 187 CK Q Cl ο 'ΐΛΐ'''') X Lis?! JC Cl Cl ^IK 0,92 C 447,5 ESI - 188 CK ( Q Cl O >Aljlx X cl ^ΓΚ 1,10 C 392,5 ESI 012740 209
189 CK 1,24 C 432,5 ESI χΛ^κ Cl Cl 190 CK Ô^° çc5k . Cl Cl 1,10 C 434,5 ESI 191 CK O Q *χΑ^ικ Cl Cl 1,15 C 418,4 ESI - 192 CK O Îj >r /N"Γί"1 Cl CIH CIH 0,93 C 435,4 ESI o >Λν"^ Λ CIH 193 CK ÇXJX Cl 1,22 C 420,5 ESI 012740 210 194 Ck ÇT 2,04 C 335,4 ESI 'Ç Cl Cl fA Cl 195 eu 0,90 C 321,3 ESI V \z\ Cl c .C 0 196 Civ 9 A 01 2,48 B 418,3 ESI Cl 197 Civ. ( <γΑγθ A O 2,62 B 432,3 ESI g A Cl Cl ( 1 1 -γΝγΝ^ 198 Civ, ÇC A α 2,32 B 392,3 ESI Cl ( %Α*γΝ^ C ° 199 Civ. ce A α 2,19 B 378,2 ESI Cl 012740 211 200 Cl· V ά (γγΟ Υγ ο (X a 2,16 B 434,3 ESI ( i <Y χΧ ο 201 Cl· 1,61 B 447,4 ESI γ 3k aci Cl I YZ (? I I /γΖγΝχΧxX 0 202 - Cl· 1,59 B 435,3 ESI γ 1 ci ci Cl ( i r -γγχχ sX 0 203 Clx, 2,57 B 420,3 ESI Y X a Cl 5vny°^/x‘nX Z 0 a 1 204 Os Y Zk a 1,71 B 422,2 ESI a 012740 212 205 Ο I N 0 1,70 B 422,3 ESI CK 9 9 Cl A. Cl \xXN\ Cl (j Ά J i 206 CK O Ά. ci χ/\ Cl 1,68 B 422,3 ESI - Cl γύνύ°" AA o 207 Cl ΥΊ Cl 2,34 B 365,1 ESI Cl (i A o 208 CK I Cl 1,18 C 379,4 ESI Ul Cl ( YŸY o 1 209 CK A Cl 1,24 C 393,4 ESI La Cl 210 Clx, ( ΎΝγθχΧ^χr 0x Cl 1,38 C 421,5 ESI LA ζΝχ Cl 012740 213 211 1,13 C 365,4 ESI Cl eu ό Ç Cl Ôk ΑΛ Cl (i Ί 212 Clx H Y 1,26 C 393,4 ESI LA Cl A 213 g □ Y 1,40 C 421,5 ESI CK X Cl Cl 214 Cl 0 Zo ό k 1,20 C 379,4 ES» CK XnK Cl 215a 215b 1 a X çrX ° °ΜΚ\ Cl yCk 385,2 ESI - 216a 216b «X ΧΛ 1, OA, 378,1 ESI ( ΎΪ ° 217 F iXr Cl 1,86 B 317,2 ESI T*' 012740 214 218 Cl À 1,27 C 370,2 ESI Ck LÀ Cl ( V Y ^°HÀ 0 219 Ck 0,99 B1 394,1/396,2 ESI LÀ " Cl O Γ /%rÀQ^\ 220 Ck LÀ sÀ 1,24 B1 364,1/366,1 ESI LÀ Cl O f ''''^ψΌΗ 221 Ck 'À 1,02 B1 336,1/338,1 ESI LÀ Cl 012740 215
Pharmacological data:
Description of test:
In this test, the recovery in the intracellular pH (pHj) after an acidification isascertained, which is initiated if the NHE is capable of functioning, even underbicarbonate-free conditions. For this purpose, the pHj was determined using the pH-sensitive fluorescent dye BCECF (Calbiochem, the precursor BCECF-AM isemployed). The cells were initially loaded with BCECF. The BCECF fluorescence wasdetermined in a "Ratio Fluorescence Spectrometer” (Photon Technology International,South Brunswick, N.J., USA) at excitation wavelengths of 505 and 440 nm and anémission wavelength of 535 nm and converted into the pHj using calibration curves.The cells were incubated in NH4CI buffer (pH 7.4) (NH4CI buffer: 115 mM NaCI, 20 mM NH4CI, 5 mM KCI, 1 mM CaCl2,1 mM MgSO4, 20 mM Hepes, 5 mM glucose, 1 mg/ml BSA; a pH of 7.4 is adjusted with 1 M NaOH) even during the BCECF ioading.The intracellular acidification was induced by adding 975 pl of an NH4CI-free buffer(see below) to 25 μΙ aliquots of the cells incubated in NH4CI buffer. The subséquentrate of pH recovery was recorded for two minutes with NHE1, five minutes with NHE2and three minutes with NHE3. To calculate the inhibitory potency of the testedsubstances, the cells were initially investigated in buffers with which a complété orabsolytely no pH recovery took place. For complété pK recovery (100%),-the cellswere incubated in Na+-containing buffer (133.8 mM NaCI, 4.7 mM KCI, 1.25 mMCaCl2, 1.25 mM MgCl2, 0.97 mM Na2HPO4, 0.23 mM NaH2PO4, 5 mM Hepes, 5 mMglucose, a pH of 7.0 is adjusted with 1 M NaOH). To détermine the 0% value, the cellswere incubated in an Na+-free buffer (133.8 mM choline chloride, 4.7 mM KCI,
1.25 mM CaCl2, 1.25 mM MgCl2, 0.97 mM K2HPO4, 0.23 mM KH2PO4, 5 mM Hepes,5 mM glucose, a pH of 7.0 is adjusted with 1 M NaOH). The substances to be testedwere made up in the Na+-containing buffer. The recovery of the intracellular pH ateach test concentration of a substance was expressed as a percentage of themaximum recovery. The IC50 value for the particular substance for the individual NHE 012740 216 subtypes was calculated from the pH recovery percentages using the Sigma-Plotprogram.
Results: 5 Table 14:
Example IC50 ΕμΜ], (NHE3) Example IC50 [RM], (NHE3) 1a 0,075 119 0,682 2a 0,082 144 0,695 2 b 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 (34)

  1. 217 DEAV2001/0072 012740 Patent daims 1. A 4-phenyltetrahydroisoquinoline of the formula I
    10 15 20 in which the meanings are: «« R1, R2, R3 and R4 independently of one another H, F, Cl, Br, I, CN, NO2, OH, NH2, CaH2a+i>OqqH2qq-i> OCpH2b+i> COOR10, OCOR10, COR10 or Ox-(CH2)yphenyl;a and b in the groups CaH2a+i and OCt>H2b+i independently of one another 1,2, 3,4, 5, 6, 7 or 8, it being possible for one or more H atoms to bereplaced by F atoms; qq 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to bereplaced by F atoms; R10 HorCcH2c+l; c 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more Hatoms to be replaced by F atoms, x zéro or 1 ; y zéro, 1,2, 3 or 4; where the phenyl ring in the group Ox-(CH2)y-phenyl isunsubstituted or substituted by 1-3 substituents selected fromthe group consisting of F, Cl, Br, CN, NO2, OH, NH2 orCdH2d+i: d 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms, 25 012740 218 R1, R2, R3 and R4 independently of one another heteroaryl, it being possible for zéro, 1, 2, 3 or 4 N atoms, zéro or 1 oxygen atom or zéro or 1 S atom to be présent as ring atoms; or R1, R2, R3 and R4 independently of one another CONR11R12 or NR11R12; R11andR12 independently of one another H, CeH2e+i, 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+i andcrrH2rr-1t0 be replaced by F atoms and for one or more CH2groups to be replaced by O or NR13; R13 H or CfH2f+i ; f 1,2, 3 or 4, it being possible for one or more Hatoms to be replaced by F atoms; or R13 and a CH2 group of R11 or R12 together with the N atom to which they are bonded a 5- or 6-membered ring;or R11andR12 together with the N atom to which they are bonded a 5-, 6- or7-membered ring; or R11 and R12 independently of one another COR14, CSR14 or SO2RI4; R14 CgH2g+i; 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 012740 219 10 15 20 25 30 possible for one or more CH2 groups to be replaced byOorNR13, or R1, R2, R3 and R4 independently of one another -Oh-SOj-R15, withh zéro or 1 ; j zéro, 1 or 2; R15 CkH2k+1, OH, OC|H2|+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; R17and R18 independently of one another H or CmH2m+i ; m 1,2,3,4, 5, 6, 7 or 8, it being possible for one or more H atoms in the group CmH2rn+-| to be replaced by Fatoms and for one or more CH2 groups to be replacedbyO, CO, CSorNR19; R19 HorCnH2n+i;n 1, 2, 3 or 4; it being possible for one or more H atoms inθηΗ2η+1 t0 replaced by F atoms; or R17andR18 together with the N atom to which they are bonded a 5-, 6- or7-membered ring;or R19 and a CH2 group of R17 or 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+j ( CssH2ss.-| i COR20 or SO2R20; 012740 220 p 1,2, 3, 4, 5, 6, 7 or 8, ss 3, 4, 5, 6, 7 or 8, R20 CqH2q+l ; q 1,2, 3, 4, 5, 6, 7 or up to 8, it being possible for one or more H atoms in the groups CpHgp+i,CssH2ss-1 and CqH2q+1to be replaced by F atoms and for one ormore CH2 groups to be replaced by O or NR21 ; R21 H or CrH2r+i ; r 1,2, 3 or up to 4; it being possible for one or more H atoms in CrH2r+i to bereplaced by F atoms; R6 H, F, Cl, Br, I, CsH2s+1 , CddH2dd-1 > OH, OCtH2t+i or OCOR22;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 ' csh2s+1 > cddH2dd-1 and 0CtH2t+1to 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+i to bereplaced by F atoms; R7, R8 and R9 independently of one another-Ov-SOw-R23;v zéro or 1; w zéro, 1 or 2; R23 θηηΗ2ηη+1 < CmmH2mm-1 » OH, OCppH2pp+i 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, it being possible for one or more H atoms in CnnH2nn+1 >cmmH2mm-1 and θΟρρΗ2ρρ+1 to be replaced by F atoms; 012740 221 R25 and R26 independently of one another H, CN or CzH2z+1 » θζζΗ2ζζ-1 ; 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+-j , it being possible for one or more H atomsto be replaced by F atoms and it being possible forone or more CH2 groups to be replaced by O, CO, CSorNR27; R27 H or CaaH2aa+l!aa 1,2,3 or 4; it being possible for one or more H atoms incaaH2aa+1t0 be replaced by F atoms; or R25 and R26 together with the N atom to which they are bonded a 5-, 6- or7-membered ring,or R27 and a CH2 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;R30 H, CccH2cc+1 , cyyH2yy-1, pyrrolidinyl or piperidinyl, in which rings a CH2 group may be replaced by O or NR33; R32 and R33 independently of one another H or ChH2h+i ;bb 2 or 3; cc 1, 2, 3, 4, 5, 6, 7 or 8; yy 3, 4, 5, 6, 7 or 8; h 1,2, 3, 4, 5, 6, 7 or 8, 012740 222 it being possible for one or more H atoms in ChHgh+l to be replaced by F atoms, and it being possible for one or more H atoms in the groups cccH2cc+1 and cyyH2yy-l to be replaced by F atoms and for one or more CH2 groups to be replaced by NR31 and for one CH2 group to be replaced by O; R31 H, CkkH2kk+1. COR65 or SO2 R65 ;kk 1,2, 3, or 4; it being possible for one or more H atoms to be replaced by Fatoms, R65 H, CxxH2xx+i ; xx 1,2, 3 or 4, it being possible for one or more H atomsto be replaced by F atoms; or R31 forms together with a CH2 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, zéro or 1 Satoms and zéro or 1 O atoms, which is unsubstituted or substituted by up to threesubstituents selected from the group consisting of F, Cl, Br, I,θοο^2οο+1> NR70R71; R70 and R71 independently of one another H, CuuH2uu+1 andCOR72; R72 H, CyvH2w+1> 00, uu and w independently of one another 1,2,3,4, 5,6,7or 8; it being possible for one or more H atoms in the groups θοο^2οο+1 » ^uu^2uu+1 or θνν^2νν+1 to be replaced by F atoms; 012740 223 R7, R8 and R9 independently of one another H, F, Cl, Br, I, NO2, CN, OH, NH2, ΟθθΗ2θθ+ι,CwwH2ww-1> OCffH2ff+i, NR40R41, CONR40R41, COOR42, COR42 orOCOR42, 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 0CffH2ff+11° be replaced by F atoms; R40 and R41 H,CttH2tt+lorC(NH)NH2;tt 1,2,3,4,5,6, 7 or 8; it being possible for one or more H atoms in the group CflH2tt+i to bereplaced by F atoms and for one or more CH2 groups to be replacedby O or NR44; R44 H ΟΓ 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+i to be replaced by F atoms, or - R40 and R41 - with the N atom to which they are bonded a 5- or 6-membered ring; R42 HorChhH2hh+i: hh 1,2,3,4,5, 6, 7 or 8; it being possible for one or more H atoms in the group ChhH2hh+1be replaced by F atoms; with the proviso that not two substituents from the group R7, R8 and R9 cansimultaneously be OH and OCH3 224 012740 and that at least one of the substituants R7, R8 and R9 must be selected from thegroup consisting of CONR40R41, -OV-SOW-R23, NR32COR30, NR32CSR30 andNR32SObbR30; and the pharmaceutically acceptable salts and trifluoroacetates thereof.
  2. 2. A compound I as claimed in claim 1, in which the meanings are R1, R2, R3 and R4 independently of one another, H, F, Cl, Br, I, CN, NO2, OH, NH2, CaH2a+i,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 ormore H atoms to be replaced by F atoms; R10 HorCcH2c+1; c 1, 2, 3 or 4, it being possible for one or more H atoms to be replacedby F atoms; or R1, R2, R3 and R4 independently of one another 5- or 6-membered heteroaryl selected from thegroup consisting of pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl,thiazolyl and oxazolyl; or R1, R2, R3andR4 independently of one another CONR11R12 or NR11R12; R11 and R12 independently of one another H, CeH2e+i, CrrH2rr-1 ; e 1,2, 3 or 4, rr 3,4,5 or 6, it being possible for one or more H atoms in the groups CeH2e+i and CrrH2rr-l to be replaced by F atoms or 012740 225 R11 and R12 independently of one another hydroxyethyl, N.N-dimethylaminoethyl, Ν,Ν-diethylaminoethyI, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl; or R11andR12 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, CSNHR14orSC>2R14; R14 CgH2g+i; 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 OSO3H, SO3H, SO2R15, withR15 CkH2k+i, OC|H2|+1 or NR17R18; k 1,2,3 or 4, it being possible for one or more H atoms to bereplaced by F atoms; I 1,2, 3 or 4, it being possible for one or more H atoms to bereplaced by F atoms; R17andR18 independently of one another H or CmH2m+1. in which thefirst CH2 group bonded to the nitrogen is replaced by CO andthe second CH2 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; R19 HorCnH2n+i; 012740 226 η 1,2, 3 or 4; it being possible for one or more H atoms in CnH2n+i to be replaced by F atoms; or R17andR18 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+-j ; p 1,2, 3 or 4; it being possible for one or more H atoms in CpH2p+i to be replacedby F atoms; R6 H, CsH2s+-| , OCtH2t+l or OCOR22;s and t independently of one another 1,2, 3 or 4; it being possible for one or more H atoms in CSH2S+1 and OCtH2t+ito be replaced by F atoms; R22 CuH2u+i; u 1,2, 3 or 4; it being possible for one or more H atoms in CuH2u+ito be replacedby F atoms; R7, R8 and R9 independently of one another OSO3H, SO3H or SO2R23; R23 θηη^2ηη+1 » CmmH2mm-1 > θθρρ^2ρρ+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+1.cmmH2mm-1 and 0CppH2pp+1 to be replaced by F atoms; 227 012740 R25andR26 independently of one another H, CN, or CZH2Z+1 . in which the first CH2 group bonded to the nitrogen is replaced by CO or CS and the second CH2 is replaced by NR27; z 1,2,3,4,5 or 6; it being possible for one or more H atoms in CzH2z+ito be replaced by F atoms; R27 H or CaaH2aa+1 îaa .1,2,3 or 4; it being possible for one or more H atoms inCaaH2aa+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;or R27 and a CH2 group of R25 or R26 together with the N atomto which they are bônded a 5- or 6-membered ring; or R7, R8 and R9 independently of one another NR32COR30, NR32CSR30 or NR32SQ2R30;R30 H, OH, CccH2cc+1 > cyyH2yy-1 » pyrrolidinyl or piperidinyl, in whichrings a CH2 group may be replaced by O or NR33; R32 and R33 cc yyh it being possible for one or more H atoms in CftH2h+i to be replaced by F independently of one another H or ChH2h+i ;1,2,3,4,5, 6, 7 or 8; 3, 4, 5 or 6; 1.2. 3 or 4: atoms, and it being possible for one or more H atoms in the groupsCCcH2cc+1 and GyyH2yy-1 t° be replaced by F atoms and for one or more 012740 228 CH2 groups to be replaced by NR31 and for one CH2 group to be replaced by O; R31 H, Ck|<H2kk+1, COR65 or SO2 R65;kk 1,2, 3, or 4; it being possible for one or more H atoms to be replaced by F atoms,R65 H, ΟχχΙ^χχ+ι; 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 CH2 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 groupconsisting of pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl,thienyl, thiazolyl and oxazolyl, which is unsubstituted or substituted by up to threesubstituents selected from the group consisting of F, Cl, Br, I,CooH2oo+1,NR70R71, R70 and R71 independently of one another H, CuuH2uu+1 orCOR72; R72 H, C\/v^2w+1 > 00, uu and w independently of one another 1,2,3 or 4;it being possible for one or more H atoms in the groupsθοο^2οο+1 > ^uu^2uu+1 or θνν^2νν+1b® replaced by Fatoms; or R7, R8 and R9 independently of one another H, F, Cl, Br, I, NO2, CN, OH, NH2, CeeH2ee+1»cwwH2ww-1. 0CffH2ff+1« NR40R41, CONR40R41, COOR42, COR42 orOCOR42; 012740 229 ee and ff independently of one another 1,2,3 or 4; ww 3, 4, 5 or 6, it being possible for one or more H atoms in the groups CeeH2ee+-j > 5 Cwwh2ww-1 and °CffH2ff+1 to be replaced by F atoms; R40 and R41 H, CttH2tt+1 or C(NH)NH2;tt 1,2, 3, 4, 5, 6, 7 or 8; it being possible for one or more H atoms in the group CttH2tt+i to be10 replaced by F atoms; or R40 and R41 to be seiected independently of one another hydroxyethyl,,Ν,Ν-dimethylaminoethyl, Ν,Ν-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 seiected20 from the group consisting of pyrrolidine, piperidine, N-methyl- piperazine, piperazine and morphoiine; R42 HorChhH2hh+i: hh 1,2, 3 or 4; it being possible for one or more H atoms in the group ChhH2hh+1to25 be replaced by F atoms; with the proviso that not two substituents from the group R7, R8 and R9 cansimultaneously be ÔH and OCH3; and that at least one of the substituents R7, R8 and R9 must be seiected from thegroup consisting of CONR40R41, -OV.SOW‘R23, NR32COR30, NR32CSR30 and 30 NR32SObbR30; and the pharmaceutically acceptable salts and trifluoroacetates thereof. 012740 230
  3. 3. A compound I as claimed in claim 1 or 2, in which the meanings are R1, R2, R3 and R4 independently of one another H, F, Cl, Br, OH, NH2, CaH2a+1 > cycloalkyl with 3, 4, 5 or 6 C atoms, OCfc>H2b+l ! a and b in the groups CaH2a+i and OCpH2b+i independently of one another 1,2, 3 or 4, it being possible for one or more H atoms to be replacedby F atoms; or R1, R2, R3 and R4 independently of one another NR11R12; R11 and R12 independently of one another H, CeH2e+i, CrrH2rr-1 ;e 1,2, 3 or 4, rr 3, 4, 5 or 6, it being possible for one or more H atoms in thegroups CeH2e+i and CrrH2rr-i to be replaced by Fatoms; or R11andR12 together with the N atom to which they are bonded form a ring selectedfrom the group consisting of pyrrolidine, piperidine, N-methylpiperazine, piperazine and morpholine; or R11 and R12 independently of one another COR14, CSR14, CONHR14, CSNHR14orSO2R14; R14 CgH2g+i; g 1,2,3 or 4, it being possible for one or more H atoms to be replaced by F atoms; 012740 231 or R1, R2, R3 and R4 independently of one another OSO3H, SO3H, SO2R15; R15 CkH2k+l orNR17R18; k 1,2,3 or 4, it being possible for one or more H atoms to be replaced by F atoms; R17andR18 independently of one another H or CmH2m+i ;m 1,2,3,4 or 5, it being possible for one or more H atoms in the group CmH2m+1t0 be replaced by Fatoms; or R17and 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 methyi or trifluoromethyl; R6 H; R7, R8 and R9 independently of one another OSO3H, SO3H or SO2R23; R23 CnnH2nn+1 or NR25R26; nn 1,2, 3, 4 or 5, it being possible for one or more H atoms in CnnH2nn+1to bereplaced by F atoms; R25andR26 independently of one another H, CN or CzH2z+1 in which thefirst CH2 group bonded to the nitrogen is replaced by CO orCS and the second CH2 is replaced by NR27;z 1, 2, 3, 4, 5 or 6; it being possible for one or more H atoms in CzH2z+i to be replaced by F atoms; 012740 232 R27 H or CaaH2aa+1 > aa 1,2, 3 or 4; it being possible for one or more H atoms in CaaH2aa+1to be replaced by F atoms; or R25 and R26 together with the N atom to which they are bonded a 5- or6-membered ring,or R27 and a CH2 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 NR32SO2R30;R30 H, OH, CccH2cc+1 » cyyH2yy-1 > pyrrolidinyl or piperidinyl, in which rings a CH2 group may be replaced by O or NR33; R32 and R33 H, methyl or CF3;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 andCyyH2yy-i to be replaced by F atoms and for one or more CH2 groups to bereplaced by NR31 and for one CH2 group to be replaced by O; R31 H, methyl, ethyl, CF3, CH2CF3, acetyl or propionyl methanesulfonyl orethanesulfonyl; or R31 together with a CH2 group of R30 and the N atom to which they are jointlybonded form a 5- or 6-membered ring; or R30 pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl oroxazolyl, which are unsubstituted or substituted by a maximum of 3 012740 233 substituants selected from the group consisting of F, Cl, methyl, ethyl, trifluoromethyl, NH2, NHacetyl; or R7, R8 and R9 5 independently of one another H, F, Cl, OH, NH2, 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, 5 or 6, 10 it being possible for one or more H atoms in the groupe CeeH2ee+1 > Cwwh2ww-1 and 0CffH2ff+1t0 b® replaced by F atoms; R40 and R41 H, CttH2tt+1 or C(NH)NH2îtt 1,2, 3 or 4; 15 it being possible for one or more H atoms in the group CttH2tt+l to be replaced by F atoms; or R40andR41 independently of one another hydroxyethyl, N,N-dimethylaminoethyl,20 Ν,Ν-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+1tobe replaced by F atoms; 30 with the proviso that not two substituents from the group R7, R8 and R9 cansimultaneously be OH and OCH3; 012740 234 and that at least one of the substituants R7, R8 and R9 must be selected from thegroup consisting of CONR40R41, -Ov-SOW‘R23, NR32COR30, NR32CSR30 andNR32SObbR30; and the pharmaceutically acceptable salts and trifluoroacetates thereof.
  4. 4. A compound I as claimed in daims 1 - 3, in which the meanings are R1, R2, R3andR4 independently of one another H, F, Cl, Br, OH, NH2, CaH2a+1 > cycloalkyl with3, 4, 5 or 6 C atoms, OCbH2b+1 ;a and b in the groups CaH2a+i and OCbH2b+i independently of one another 1,2, 3 or 4, it being possible for one or more H atoms to be replacedby F atoms; or R1, R2, R3 and R4 independently of one another NR11R12; R11 and R12 independently of one another H, CeH2e+i, CrrH2rr-1 ;e 1,2, 3 or 4, rr 3, 4, 5 or 6, it being possible for one or more H atoms in thegroups CeH2e+i and CrrH2rr-i to be replaced by Fatoms; or R11andR12 together with the N atom to which they are bonded form a ring selectedfrom the group consisting of pyrrolidine, piperidine, N-methylpiperazine, piperazine and morpholine; or R11andR12 012740 235 independently of one another COR14, CSR14, CONHR14, CSNHR14 orSC>2R14; R14 CgHgg+i; g 1,2,3 or 4, it being possible for one or more H atomsto be replaced by F atoms; or R1, R2, R3 and R4 independently of one another OSO3H, SO3H, SO2RI5; R15 CkH2k+i orNR17R18; k 1, 2,3 or 4, it being possible for one or more H atoms to bereplaced by F atoms; R17andR18 independently of one another H or CmH2m+-j ;m 1,2, 3,4 or 5, it being possible for one or more H atoms in the group CmH2m+i to be replaced by Fatoms; or R17andR18 together with the N atom to which they are bonded a 5- or6-membered ring; but where R2 must always not be equal to H; R5 methyl or trifluoromethyl; R6 H; R7, R8 and R9 independently of one another OSO3H, SO3H or SO2R23; R23 θηη^2ηη+1 θ'" NR25R26; nn 1,2, 3,4 or 5, it being possible for one or more H atoms in CnnH2nn+1 to bereplaced by F atoms; R25 and R26 012740 236 independently of one another H, CN or CzH2z+1 in which thefirst CH2 group bonded to the nitrogen is replaced by CO orCS and the second CH2 is replaced by NR27;z 1,2, 3, 4, 5 or 6; it being possible for one or more H atoms in CzH2z+1to 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 inCaaH2aa+1to be replaced by F atoms; or R25 and R26 together with the N atom to which they are bonded a 5- or6-membered ring,or R27 and a CH2 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 NR32SO2R30;R30 H, OH, CccH2cc+1 > cyyH2yy-1 > pyrrolidinyl or piperidinyl, in which rings a CH2 group may be replaced by O or NR33; R32 and R33 H, methyl or CF3;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 andCyyH2yy-ito be replaced by F atoms and for one or more CH2 groups to bereplaced by NR31 and for one CH2 group to be replaced by O; R31 H, methyl, ethyl, CF3, CH2CF3, acety, or propionyl methanesulfonyl or ethanesulfonyl; 012740 . 237 or R31 together with a CH2 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 oroxazolyl, which are unsubstituted or substituted by a maximum of 3substituents selected from the group consisting of F, Cl, methyl, ethyl,trifiuoromethyl, NH2, NHacetyl; or R7, R8 and R9 independently of one another H, F, Cl, OH, NH2, CeeH2ee+1, cwwH2ww-1 >0CffH2ff+1, NR40R41, CONR40R41, COOR42 or OCOR42,ee and ff independently of one another 1,2,3 or 4;ww 3, 4, 5 or 6, it being possible for one or more H atoms in the groups CeeH2ee+-j,Cwwh2ww-1 and OcffH2ff+1to be replaced by F atoms; R40 and R41 H, CttH2tt+l or C(NH)NH2;tt 1,2, 3 or 4; it being possible for one or more H atoms in the group CttH2tt+11° bereplaced by F atoms; or R40 and R41 independently of one another hydroxyethyl, N,N-dimethylaminoethyl,Ν,Ν-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl,piperazinoethyl, morpholinoethyl or piperidinoethyl; or R40 and R41 together with the N atom to which they are bonded a pyrrolidine, piperidine, N-methylpiperazine, piperazine or morpholine ring; 238 012740 R42 H or ChpH2hh+1 '< hh 1,2, 3 or 4; it being possible for one or more H atoms in the group ChhH2hh+1to be replaced by F atoms; with the proviso that not two substituents from the group R7, R8 and R9 cansimultaneously be OH and OCH3; and that at least one of the substituents R7, R8 and R9 must be selected from thegroup consisting of -OV-SOW'R23, NR32COR30, NR32CSR30 and NR32SOfc,bR30'>and the pharmaceutically acceptable salts and trifluoroacetates thereof.
  5. 5. A compound of the formula I, which 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; 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; 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; 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; 012740 239 13. 6,8-dichloro-2-methyi-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-isoquinolin-4-yl)-phenyl]-3- 10 methyl-thiourea; 19. 1-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylj-3-ethyl-urea; 20. N-[4-(6-methanesulfonyl-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl3-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)-phenylj-acetamide; 20 24. N-[4-(8-chloro-2-methyl-6-morpho,in-4-yl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenylj-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-1,2,3I4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoicacid; 28. 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinotin-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; 012740 240 30. 5-(6,8-dichloro-2-methyI-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-(2-dimethyIamino-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-isoquinoIin-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-yl)-phenyljpentanamide; 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-dimeîhyl-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-isoquinoiin-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 -aeetylpiperidine-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; 012740 241 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-t©ti'ahydro-isoquinolin-4-yl)-phenyl]-butyramide; 51. N43-(6,8-dichloro-2-methyl-1,2,3Atetrahydro-isoquinolin-4-yl)-phenyl]- 10 pentanamide; 52. N-[3-(6,8-dîchloro-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)-phenyl3-2,2- dimethyl-propionamide; 15 54.. N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl3- cyclopropanecarboxamide; 55. N-[3-(6,8-dichloro-2-methy1-1,2,3,4-t®trahydro-isoquinolin-4-yl)-phenyl]- cyclobutanecarboxamide; 56. N-[3-(6,8-dichloro-2-methyl-1,2^44etrahydiO-isoqiiiriolin-4-yl)-phenyl]- 20 cyclopentanecarboxamide; 57. N-[3-(6,8-dichloro-2-methyl-1,2,3)4t®ti'ahydro-isoquinolin-4-yl)-phenyl]-2,2,2- trifluoro-acetamide; 58. N-[3-(6,8-dichloro-2-methyl-1,2,3,4-t©trahydro-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-su If onam ide; 61. N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl]- 30 ethanesulfonamide; 62. N'.N'-dimethylamino-N-tS-Ce.S-dichloro^-methyl-I^.S^-tetrahydro-isoquinolin- 4-yl)-phenyl]-sulfamide; 012740 242 63. N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinorm-4-yl)-phenyl]-propionamide; 64. N-[2-(6,8-dich!oro-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]-isobutyramide; 67. N-“t2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylJ-2,2-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; 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 -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-metbyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- pheriyl]-ethanesulfonamide; 75. N'.N'-dimethylamino-N-p-ie.e-dichloro^-methyl-I^.S^-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-thiourea; 78. 1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea; 012740 243 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)-phenylsulfamoyl]-4-methyl-thiazol-2-yl}-acetamide; 81. N-{5-[3-(6,8-dichloro-2-methyl-1,2,3,4-îetrahydro-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-dimethyl-1H-imidazole-4-sulfonamide; 83. N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoIin-4-yl)-phenyl]-1,2-dimethyl-1H-imidazole-4-sulfonamide; 84. N-^-ie.e-dichloro^-methyl-I^.S^-tetrahydro-isoquinolin^-yO-phenylJ-S-chloro-1,3-dimethy1-1H-pyrazole-4-sulfonamide; 85. N-[3-(6,8-dichIoro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyt]-5-chloro-1,3-dimethyl-1 H-pyrazole-4-sulfonamide; 86. N-[4-(6,8-dichloro-2-methyl-1,2,3,4-îetrahydro-isoquinolin-4-yl)-phenyl3-5-bromo-thiophene-2-sulfonamide; 87. N-[3-(6,8-dÎchloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-5-bromo-thiophene-2-sulîonamide; 88. N-[4-(6,8-dichtoro-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-yl)-phenyl]-C,C,C-trifluoro-methanesulfonamide; 90. 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolÎn-4-yl)-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; 92. N-ethyl-N'-4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonylurea; 93. 2-chloro-5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide; 94. 2-methyl-4-phenyl-6,8-bis-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline; 012740 244 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-ÿl)- 10 phenyl]- butyramide; 100. 2,6-Diamino-hexanoic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydrorisoquinolin-4-yl)- phenyl]-amide;
  6. 101. Pyrrolidine-2-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 15 102. N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]- isonicotinamide; 103. 1 H-Pyrrole-3-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 104. 1 H-Pyrrole-2-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- 20 isoquinolin-4- yl)-phenyl]-amide; 105. 1 -Methyl-piperidine-4-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 106. 1,4-Dimethyl-1 H-pyrrole-2-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 25 107. 4-Nitro-1 H-pyrrole-2-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4- tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 108. 2,5-Dimethyl-1 H-pyrrole-3-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 109. 1 H-lmidazole-4-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro 30 isoquinolin- 4-yl)-phenyl]-amide; 110. 1 -Methanesulfonyl-piperidine-4-carboxylic acid [4-(6,8-dichloro-2-methyl- 1,2,3,4- tetrahydro-isoquinolin-4-yl)-phenyl]-amide; 012740 245 111. 3,5-Dimethyl-1 H-pyrazole-4-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 112. 1 H-Pyrazole-4-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin- 4-yl)-phenyl]-amide; 113. 3-Trifluoromethyl-1 H-pyrazole-4-carboxylic acid [4-(6,8-dichloro-2-methyl- 1,2,3,4- tetrahydro-isoquinolin-4-yl)-phenyl]-amide; 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-dimethylaminq-acetarnide; 116. 2-Amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylj- propionamide; 117. 2-Amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]- butyramide; 11 8. 2,6-Diamino-hexanoic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl]-amide;
  7. 119. Pyrrolidine-2-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 120. N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isonicotinamide; 121. 1 H-Pyrrole-3-carboxylic acid [3-(6,8-dichioro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide; 122. 1 H-Pyrrole-2-carboxylic acid [3-(6,8-dichloro-2-methyi-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 123. 1 -Methyl-piperidine-4-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 124. 1,4-Dimethyl-1 H-pyrrole-2-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 125. 4-Nitro-1 H-pyrroie-2-carboxylic acid [3-(6,8-dichloro-2-methyi-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 126. 2,5-DimethyI-l H-pyrrole-3-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-teîrahydro- isoquinolin-4-yl)-phenyl]-amide; 012740 246 127. 1 H-lmidazole-4-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoiin- 4-yl)-phenyl]-amide; 128. 1 -Methanesulfonyl-piperidine-4-carboxylic acid [3-(6,8-dichloro-2-methyl- 1,2,3,4- tetrahydro-isoquinolin-4-yl)-phenyl]-amide; 129. 3,5-Dimethyl-1H-pyrazole-4-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide; 130. 1 H-Pyrazole-4-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin- 4-yl)-phenyl]-amide; 131 ; 3-Trifluoromethyl-1 H-pyrazole-4-carboxylic acid [3-(6,8-dichloro-2-methyl- 1,2,3,4- tetrahydro-isoquinolin-4-yl)-phenyl]-amide; 132. 1 -[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-thiourea; 133. 1 -[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-thiourea; 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-isoquinolin-4-yl)-phenyl]-1,1 -dimethyl- urea; 136. 4-Methyl-piperazine-1 -carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide;
  8. 137. Piperidine-1-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide;
  9. 138. Morpholine-4-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahÿdro-isoquinolin-4-yl)-phenyl]-amide;
  10. 139. Pyrrolidine-1 -carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 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; 142. 1 -[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea; 012740 247 143. 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; 145. 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; 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)-phenylJ-1 -(2-dimethylaminq-ethyl)-1-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; 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. 4-Methyl-piperazine-1 -carboxylic acid [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yI)-phenyl]-amide; 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]-1,1 -diethyl- urea;
  11. 156. Piperidine-1 -carboxylic acid (2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide;
  12. 157. Morpholine-4-carboxylic acid (2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide;
  13. 158. Pyrrolidine-1 -carboxylic acid [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 012740 248 159. 1 -(2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea; 160. 4-Methyl-piperazine-1 -carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide;
  14. 161. Pyrroiidine-1 -carboxylic acid (4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 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)-phenyI]-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. Piperidine-1 -carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide;
  16. 167. Morpholine-4-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 168. N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-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)-phenÿl]-1,3-dimethyl- urea; 171. 4-Methyl-piperazine-1 -carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-methyl-amide; 172. 1 -(4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3,3-trimethyl- urea;
  17. 173. Piperidine-1 -carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-methyl-amide;
  18. 174. Morpholine-4-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-methyl-amide; 012740 249
  19. 175. Pyrrolidine-1 -carboxylic acid (4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amide; 176. 1 -[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-1 -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; 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;
  20. 180. Pyrrolidine-1 -carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amide;
  21. 181. Piperidine-1 -carboxylic acid (3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-methyl-amide; 182. 1 -[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-Îsoquinolin-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;
  22. 184. Morpholine-4-carboxylic acid (3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoiin-4- yl)-phenyl]-methyl-amide; 185. 4-Methyl-piperazine-1 -carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-methyl-amide; 186. 1 -(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl]-3-(2-dimethylamino-ethyl)-1 -methyl-urea; 187. 1-(3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,3-diethyl-1-methyl-urea; 188. (3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid 2- dimethylamino-ethyl ester; 189. (4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid 2- dimethylamino-ethyl ester; 190. (2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid 2- dimethylamino-ethyl ester; 0127 4 0 250 191. [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid methyl ester; 192. [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid ethyl ester; 193. [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid isopropyl ester; 194. [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid 2,2- dimethyl-propyl ester; 195. [4"-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid methyl ester; 196. [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid isopropyl ester; 197. [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid 2,2- dimethyl-propyl ester; 198. [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid ethyl ester; 199. (+)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl)-methanesulfonamide; 200. (-)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide; 201. (+)-1 -[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea; 202. (-)-1 -[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea; 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. 3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid ethylester; 207. 3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid. 012740 251 and the pharmaceutically acceptable salts thereof.
  23. 191. Piperidine-1-carboxylic acid [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide;
  24. 192. Morpholine-4-carboxylic acid [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide;
  25. 193. Pyrrolidine-1-carboxylic acid [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 30 012740 284 194. 1 -[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-u rea; 195. 4-Methyl-pîperazine-1-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-amide;
  26. 196. Pyrrolidine-1-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yi)-phenyl]-amide; 197. 1-(4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylJ-3-methyl-urea; 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; 200. 1 -(4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea;
  27. 201. Piperidine-1-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide;
  28. 202. Morpholine-4-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-amide; 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; 205. 1-(4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyt]-1,3-dimethyl- urea; 206. 4-Methyi-piperazine-1-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-methyl-amide; 207. 1 -(4-(6,8-Dichloro-2-methyi-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3,3-trimethyl- urea;
  29. 208. Piperidine-1-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-methyl-amide;
  30. 209. Morpholine-4-carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-methyl-amide; 012740 285
  31. 210. Pyrrolidine-1 -carboxylic acid [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-methyl-amide; 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-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-amine;
  32. 215. Pyrrolidine-1 -carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-methyl-amide;
  33. 216. Piperidine-1-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenylj-methyl-amide; 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;
  34. 219. Morpholine-4-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4- yl)-phenyl]-methyl-amide; 220. 4-Methyl-piperazine-1-carboxylic acid [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro- isoquinolin-4-yl)-phenyl]-methyl-amide; 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. [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid 2- dimethylamino-ethyl ester; 224. [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl3-carbamicacid 2- dimethylamino-ethyl ester; 225. [2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid 2- dimethylamino-ethyl ester; 012740 286 226. [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid methyl ester; 227. [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid ethyl ester; 228. [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid isopropyl ester; 229. [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid 2,2- dimethyl-propyl ester; 230. [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-càrbamicacid methyl ester; 231. [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid isopropyl ester; 232. [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-Îsoquinolin-4-yl)-phenyl]-carbamicacid 2,2- dimethyl-propyl ester; 233. [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid ethyl ester; 234. (+)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide; 235. (-)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide; 236. (+)-1 -[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea; 237. (-)-1 -[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phënyl]-3-ethyl-urea; 238. N-[3-(6,8-Difluoro-2-methyl-1,2,3,4-tetrahydro-isoqiiinolin-4-yl)-phenylj-acetamide; 239. 4-(3-Bromo-phenyl)-6,8-dichloro-2-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; 241. 3-(6,8-Diçhloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid ethylester; 242. 3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid. 012740 287 and the pharmaceutically acceptable salts thereof.
OA1200400166A 2001-12-05 2002-11-20 Substituted 4-phenyltetrahydroisoquinolines, method for the production thereof, the use thereof as medicaments, in addition to a medicament containingsame. OA12740A (en)

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DE10312963A1 (en) * 2003-03-24 2004-10-07 Aventis Pharma Deutschland Gmbh Substituted 4-phenyltetrahydroisoquinolines, process for their preparation, their use as medicament, and medicament containing them
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WO2018129556A1 (en) * 2017-01-09 2018-07-12 Ardelyx, Inc. Compounds and methods for inhibiting nhe-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders
WO2010078449A2 (en) * 2008-12-31 2010-07-08 Ardelyx, Inc. Compounds and methods for inhibiting nhe-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders
US10543207B2 (en) 2008-12-31 2020-01-28 Ardelyx, Inc. Compounds and methods for inhibiting NHE-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders
KR20120034644A (en) 2009-05-12 2012-04-12 알바니 몰레큘라 리써치, 인크. Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
CA2880432C (en) * 2012-08-21 2023-03-14 Ardelyx, Inc. Compounds and methods for inhibiting nhe-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders
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JP6903923B2 (en) * 2016-01-22 2021-07-14 大正製薬株式会社 A drug containing a phenyltetrahydroisoquinoline compound substituted with a heteroaryl as an active ingredient.
CN110267944B (en) 2017-01-09 2024-03-08 阿德利克斯股份有限公司 Compounds useful for the treatment of gastrointestinal disorders
JP2020505333A (en) 2017-01-09 2020-02-20 アルデリックス， インコーポレイテッド Inhibitors of NHE-mediated antiport
IL303799A (en) * 2020-12-18 2023-08-01 Shanghai Jemincare Pharmaceutical Co Ltd Benzoheterocycle substituted tetrahydroisoquinoline compound

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ES2304984T3 (en) * 1999-11-03 2008-11-01 Amr Technology, Inc. TETRA-HYDROISOQUINOLINAS OF ARILICA AND HETEROARILICA SUBSTITUTION AND ITS USE TO BLOCK THE RECOVERY OF NOREPINEFRINE, DOPAMINE AND SEROTONINE.
AU784280B2 (en) * 1999-11-03 2006-03-02 Albany Molecular Research, Inc. 4-phenyl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine and serotonin
EP1113007A1 (en) * 1999-12-24 2001-07-04 Pfizer Inc. Tetrahydroisoquinoline compounds as estrogen agonists/antagonists
DE10019062A1 (en) * 2000-04-18 2001-10-25 Merck Patent Gmbh Use of known and new 2-guanidino-4-aryl-quinazoline derivatives as NHE-3 inhibitors useful for the treatment of e.g. hypertension, thrombosis, cardiac ischemia, peripheral and CNS ischemia

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