NZ533322A - Substituted 4-phenyltetrahydroisoquinolines, method for the production thereof, the use thereof as medicaments, in addition to a medicament containing same - Google Patents
Substituted 4-phenyltetrahydroisoquinolines, method for the production thereof, the use thereof as medicaments, in addition to a medicament containing sameInfo
- Publication number
- NZ533322A NZ533322A NZ533322A NZ53332202A NZ533322A NZ 533322 A NZ533322 A NZ 533322A NZ 533322 A NZ533322 A NZ 533322A NZ 53332202 A NZ53332202 A NZ 53332202A NZ 533322 A NZ533322 A NZ 533322A
- Authority
- NZ
- New Zealand
- Prior art keywords
- methyl
- tetrahydro
- dichloro
- isoquinolin
- phenyl
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
-
- A—HUMAN NECESSITIES
- 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
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- 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
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
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- 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
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/16—Central respiratory analeptics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
Compounds of formula (I), 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
New Zealand Paient Spedficaiion for Paient Number 533322
533322
1
Description
Substituted 4-phenyltetrahydroisoquinolines, process for their preparation, their use as medicament, and medicament containing them
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, CI, Br, I, CN, NO2, OH, NH2, CaH2a+1. CqqH2qq-i, ®^bH2b+1 ■ COORIO, OCORIO, CORIO or Ox-(CH2)y-phenyl; a and b in the groups CaH2a+l and OCfc,H2b+1 independently of one another 1, 2, 3,4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms;
qq 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms;
R10 HorCcH2c+1;
c 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H
r8
r4
atoms to be replaced by F atoms, x zero or 1;
y zero, 1, 2, 3 or 4;
where the phenyl ring in the group Ox-(CH2)y-phenyl is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, CI, Br, CN, NO2, OH, NH2 or CdH2d+i:
2
d 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms,
or
R1, R2, R3 and R4
independently of one another heteroaryl, it being possible for zero, 1, 2, 3 or 4
N atoms, zero or 1 oxygen atom or zero or 1 S atom to be present as ring atoms;
or
R1, R2, R3 and R4 10 independently of one another CONR11R12 or NR11R12;
R11 and R12
independently of one another H, CeH2e+1, CrrH2rr-l;
e 1, 2, 3, 4, 5, 6, 7 or 8,
rr 3, 4, 5, 6, 7, or 8,
it being possible for one or more H atoms in the groups CeH2e+1 and
CrrH2rr-1 to be replaced by F atoms and for one or more CH2 groups to be replaced by O or NR13;
R13 HorCfH2f+i;
f 1, 2, 3 or 4, it being possible for one or more H k20 atoms 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
R11 and R12
together with the N atom to which they are bonded a 5-, 6- or 7-membered ring;
or
R11 and R12
independently of one another COR14, CSR14 or SO2RI4;
R14 CgH2g+i;
3
g 1,2,3,4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms, and it being possible for one or more CH2 groups to be replaced by O or NR13,
or
R1, R2, R3 and R4
independently of one another -Oh-SOj-R15, with h zero or 1;
j zero, 1 or 2;
R15 CkH2k+1,OH, OC1H21+1 orNR17R18;
k 1, 2, 3,4, 5, 6, 7 or 8, it being possible for one or more H
atoms to be replaced by F atoms;
I 1, 2, 3,4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms; 15 R17 and R18
independently of one another H or CmH2m+1!
m 1, 2, 3,4, 5, 6, 7 or 8, it being possible for one or more H atoms in the group CmH2m+i to be replaced by F
atoms and for one or more CH2 groups to be replaced |20 by O, CO, CS or NR19;
R19 H or CnH2n+i:
n 1,2, 3 or 4;
it being possible for one or more H atoms in CnH2n+i 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
but where R2 must always not be equal to H,
R5 H, CpH2p+i, CssH2ss-1 , COR20 or S02R20;
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 8,
it being possible for one or more H atoms in the groups CpH2P+i, CSsH2ss-1 anc' CqH2q+i to be replaced by F atoms and for one or more CH2 groups to be replaced by O or NR21; 10 R21 HorCrH2r+1l r 1,2, 3 or 4;
it being possible for one or more H atoms in CrH2r+i to be replaced by F atoms;
R6 H, F, CI, Br, I, CSH2S+1. CddH2dd-1' 0H' 0CtH2t+1 or OCOR22; 15 sandt 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 ancl ^^tH2t+1to be replaced by F atoms; R22 CuH2u+i;
*20 u 1,2,3 or 4;
it being possible for one or more H atoms in CuH2u+i to be replaced by F atoms;
R7, R8 and R9
independently of one another -Ov-SOw-R23;
v zero or 1;
w zero, 1 or 2;
R23 CnnH2nn+1> CmmH2mm-1'OH, OCppH2pp+i or NR25R26; nn and pp independently of one another 1, 2, 3, 4, 5, 6, 7 or 8, 30 mm 3, 4, 5, 6, 7 or 8,
it being possible for one or more H atoms in CnnH2nn+1 > cmmH2mm-1 and 0CppH2pp+1 to be replaced by F atoms; R25 and R26
independently of one another H, CN or CZH2Z+1, Czzh^zz-II
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+i, it being possible for one or more H atoms to be replaced by F atoms and it being possible for 10 one or more CH2 groups to be replaced by O, CO, CS
or NR27;
R27 H or CaaH2aa+11 aa 1,2, 3 or 4;
it being possible for one or more H atoms in 15 caaH2aa+1to be replaced by F atoms;
or
R25 and R26
together with the N atom to which they are bonded a 5-, 6- or 7-membered ring,
120 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 CftH2h+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+1 to be replaced by F
atoms, and it being possible for one or more H atoms in the groups
CCcH2cc+1 ancl CyyH2yy-i to replaced by F atoms and for one or more
CH2 groups to be replaced by NR31 and for a CH2 group to be replaced by O;
R31 H, C|<kH2kk+1 - COR65 or S02R65;
kk 1,2, 3, or 4;
it being possible for one or more H atoms to be replaced by F atoms,
R65 H, CxxH2XX+1 I
xx 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms;
or
R31 forms together with a 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, zero or 1 S atoms and zero or 1 O atoms,
which is unsubstituted or substituted by up to three substituents selected from the group consisting of F, CI, Br, I, ^00^200+1 • NR70R71;
R70 and R71
independently of one another H, CuuH2uu+1 ancl COR72;
R72 H, CwH2w+i;
00, uu and w independently of one another 1,2,3, 4, 5, 6, 7 or 8;
it being possible for one or more H atoms in the groups C00H200+1. Cuu^uu+I or ^w^2vy+1 to be replaced by F atoms;
7
or
R7, R8 and R9
independently of one another H, F, CI, Br, I, NO2, CN, OH, NH2, CeeH2ee+1»
CwwH2ww-1- OCffH2ff+i, 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 CeeH2ee+1 • 10 CwwH2ww-1 and ocffH2ff+1t0 be replaced by F atoms;
R40 and R41
H,CttH2tt+1 or C(NH)NH2;
tt 1,2, 3,4, 5, 6, 7 or8;
it being possible for one or more H atoms in the group CftH2tt+1 to be 15 replaced by F atoms and for one or more CH2 groups to be replaced by O or NR44;
R44 HorCggH2gg+1;
gg 1,2, 3,4, 5, 6, 7 or 8;
it being possible for one or more H atoms in the group >20 cggH2gg+1to be replaced by F atoms, and it being possible for R44 together with a (CH2) group of R40 or R41 and the N atom to which they are jointly bonded to form a 5- or 6-membered ring,
or
R40 and R41
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 to 30 be replaced by F atoms;
8
but where two substituents from the group of R7, R8 and R9 may not simultaneously be OH or OCH3
and where at least one of the radicals R7, R8 or R9 must be selected from the group consisting of CONR40R41, -OvSOwR23, NR32COR30, NR32CSR30
and NR32SC>bbR30;
and the pharmaceutical^ 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, CI, Br, I, CN, NO2, OH, NH2, CaH2a+i, cycloalkyl with 3, 4, 5 or 6 C atoms, OCbH2b+l, COORIO;
a and b independently of one another 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms;
R10 HorCcH2c+1;
c 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms;
or
R1, R2, R3 and R4
independently of one another 5- or 6-membered heteroaryl selected from the group consisting of pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl and oxazolyl;
or
R1, R2, R3 and R4
independently of one another CONR11R12 or NR11R12;
R11 and R12
independently of one another H, CeH2e+<| f 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+1 and CrrH2rr-1 to be replaced by F atoms
9
or
R11 and R12
independently of one another hydroxyethyl, N.N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl;
or
R11 and R12
together with the N atom to which they are bonded a pyrrolidine, piperidine, N-methylpiperazine, piperazine or morpholine ring;
or
R11 and R12
independently of one another COR14, CSR14, CONHR14, CSNHR14 or S02R14;
R14 CgH2g+i;
R1, R2, R3 and R4
independently of one another OSO3H, SO3H, SO2R15, with
R15 CkH2k+1, 0C|H2|+1 or NR17R18;
k 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms;
1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms;
R17 and R18
independently of one another H, CmH2m+1 > 'n 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+1 to be replaced by F
atoms;
R19 H or CnH2n+i:
n 1, 2, 3 or 4;
it being possible for one or more H atoms in CnH2n+l to be replaced by F atoms;
or
R17 and R18
together with the N atom to which they are bonded a 5- or 6-membered ring;
but where R2 must always not be equal to H,
#10 R5 H,CpH2p+i;
p 1,2, 3 or 4;
it being possible for one or more H atoms in CpH2p+i to be replaced by F atoms;
R6 H, CsH2s+1 . OCtH2t+l or OCOR22;
sandt it being possible for one or more H atoms in CuH2u+i to be replaced by F atoms;
R7, R8 and R9
independently of one another OSO3H, SO3H or SC>2R23;
independently of one another 1, 2, 3 or 4;
it being possible for one or more H atoms in CsH2s+1 and OCtH2t+i to be replaced by F atoms;
R22 CUH2U+I;
u 1,2, 3 or 4;
R23 CnnH2nn+1 > CmmH2mm-1' ^CppH2pp+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;
11
R25 and R26
independently of one another H, CN, 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+1 to be replaced by F atoms;
R27 H or CaaH2aa+1 J aa 1, 2, 3 or 4;
it being possible for one or more H atoms in
CaaH2aa+1 to be rePlacecl by F atoms;
or
R25 and R26
together with the N atom to which they are bonded a 5- or 15 6-membered ring;
or
R27 and a 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 NR32S02R30;
R30 H, OH, CCcH2cc+1 > CyyH2yy-i' 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+11
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+1 to be replaced by F atoms, and it being possible for one or more H atoms in the groups
12
CCcH2cc+1 and CyyH2yy-1 to be replaced by F atoms and for one or more
CH2 groups to be replaced by NR31 and for a CH2 group to be replaced by O;
R31 H, C|<kH2kk+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, CxxH2XX+1:
xx 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms;
or
R31 together with a 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 group consisting of pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thienyl, thiazolyl and oxazolyl,
which are unsubstituted or substituted by up to three substituents selected from the group consisting of F, CI, Br, I, Coo^2oo+1> NR70R71,
R70 and R71
independently of one another H, CuuH2uu+1 or COR72;
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 groups Coo^2oo+1> ^uu^2uu+1 or CyyH2w+1 to be replaced by F atoms;
or
R7, R8 and R9
independently of one another H, F, CI, Br, I, NO2, CN, OH, NH2, CeeH2ee+1'
CwwH2ww-1> OCffH2ff+1. NR40R41, CONR40R41, COOR42, COR42 or
OCOR42;
13
ee and ff independently of one another 1, 2, 3 or 4;
ww 3, 4, 5 or 6,
it being possible for one or more H atoms in the groups CeeH2ee+1 • cwwh2ww-1 and 0CffH2ff+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 be replaced by F atoms;
or
R40 and R41
to be selected independently of one another hydroxyethyl,, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl;
or
R40 and R41
together with the N atom to which they are bonded form a ring selected from the group consisting of pyrrolidine, piperidine, N-methyl-piperazine, piperazine and morpholine;
R42 HorChhH2hh+1!
hh 1,2, 3 or 4;
it being possible for one or more H atoms in the group ChhH2hh+1 to be replaced by F atoms;
but where two substituents from the group of R7, R8 and R9 may not simultaneously be OH or OCH3
and where at least one of the radicals R7, R8 or R9 must be selected from the group consisting of CONR40R41, -OvSOwR23, NR32COR30, NR32CSR30
and NR32SObbR30;
and the pharmaceutical^ acceptable salts and trifluoroacetates thereof.
14
Particular preference is given to compounds of the formula I in which the meanings are:
R1, R2, R3 and R4
independently of one another H, F, CI, Br, OH, NH2, CaH2a+l. cycloalkyl with 3,4, 5 or 6 C atoms, OCbH2b+11 a and b in the groups CaH2a+1 and OCbH2b+1 independently of one another 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms;
or
R1, R2, R3 and R4
independently of one another NR11R12;
R11 and R12
independently of one another H, CeH2e+l, CrrH2rr-1;
e 1,2, 3 or 4,
rr 3, 4, 5 or 6,
it being possible for one or more H atoms in the groups CeH2e+l and CrrH2rr-1 to be replaced by F atoms;
or
R11 and R12
together with the N atom to which they are bonded form a ring selected from the group consisting of pyrrolidine, piperidine, N-methylpiperazine, piperazine and morpholine;
or
R11 and R12
independently of one another COR14, CSR14, CONHR14, CSNHR14 or S02R14;
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 5 independently of one another OSO3H, SO3H, SO2RI5;
R15 CkH2k+1 orNR17R18;
k 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms;
R17 and R18
independently of one another H or CmH2m+1 >
m 1, 2, 3,4 or 5, it being possible for one or more H atoms in the group CmH2m+1 to be replaced by F atoms;
or
R17 and R18
together with the N atom to which they are bonded a 5- or 6-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 S02R23;
R23 CnnH2nn+1 or NR25R26;
nn 1,2, 3, 4 or 5,
it being possible for one or more H atoms in CnnH2nn+1to be replaced by F atoms;
R25 and R26
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;
16
it being possible for one or more H atoms in CzH2z+1 to be replaced by F atoms;
R27 H or CaaH2aa+1I 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- or 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
R7, R8 and R9
independently of one another NR32COR30, NR32CSR30 or NR32SC>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 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 and cyyH2yy-1t0 be replaced by F atoms and for one or more CH2 groups to be replaced by NR31 and for a CH2 group to be replaced by O;
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 jointly bonded form a 5- or 6-membered ring;
or
17
R30 pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl or oxazolyl, which are unsubstituted or substituted by a maximum of 3 substituents selected from the group consisting of F, CI, methyl, ethyl, trifluoromethyl, NH2, NHacetyl;
or
R7, R8 and R9
independently of one another H, F, CI, OH, NH2, CeeH2ee+1> CwwH2ww-1> OCffH2ff+i, 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+1>
Cwwh2ww-1 and °CffH2ff+i to be replaced by F atoms;
R40 and R41
H, CttH2tt+1 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 be replaced by F atoms;
or
R40 and R41
independently of one another hydroxyethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl;
or
R40 and R41
together with the N atom to which they are bonded a pyrrolidine, 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+1to be replaced by F atoms;
18
but where two substituents from the group of R7, R8 arid R9 may not simultaneously be OH or OCH3
and where at least one of the radicals R7, R8 or R9 must be selected from the group consisting of CONR40R41, -OvSOwR23, NR32COR30, NR32CSR30 and
NR32SObbR30;
and the pharmaceutical^ acceptable salts and trifluoroacetates thereof.
Very particular preference is given to compounds of the formula I in which the 10 meanings are:
R1, R2, R3 and R4
independently of one another H, F, CI, Br, OH, NH2, CaH2a+1. cycloalkyl with 3, 4, 5 or 6 C atoms, OCbH2b+11 a and b
in the groups CaH2a+l and OCbH2b+l independently of one another
1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms;
or
R1, R2, R3 and R4 120 independently of one another NR11R12;
R11 and R12
independently of one another H, CeH2e+l, 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+l and CrrH2rr-1 to be replaced by F atoms;
or
R11 and R12
19
together with the N atom to which they are bonded form a ring selected from the group consisting of pyrrolidine, piperidine, N-methylpiperazine, piperazine and morpholine;
or
R11 and R12
independently of one another COR14, CSR14, CONHR14, CSNHR14 or S02R14;
R14 CgH2g+i;
g 1, 2, 3 or 4, it being possible for one or more H atoms 10 to be replaced by F atoms;
or
R1, R2, R3 and R4
independently of one another OSO3H, SO3H, S02R15;
R15 CkH2k+1 orNR17R18;
k 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms;
R17 and R18
independently of one another H or CmH2m+<|;
m 1, 2, 3, 4 or 5, it being possible for one or more H ^20 atoms in the group CmH2m+i to be replaced by F
atoms;
or
R17 and R18
together with the N atom to which they are bonded a 5- or 25 6-membered ring;
but where R2 must always not be equal to H;
R5 methyl or trifluoromethyl;
R6 H;
R7, R8 and R9
independently of one another OSO3H, SO3H or S02R23;
R23 CnnH2nn+1 NR25R26;
nn 1,2, 3,4 or 5,
it being possible for one or more H atoms in CnnH2nn+1 to be replaced by F atoms;
R25 and R26
independently of one another H, CN or CZH2Z+-|, 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+1 to be replaced by F atoms;
R27 H or CaaH2aa+1 >
aa 1,2, 3 or 4;
it being possible for one or more H atoms in CaaH2aa+1to 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 atom to which they are bonded a 5- or 6-membered ring;
, R8 and R9
independently of one another NR32COR30, NR32CSR30 or NR32S02R30;
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, 6;
21
it being possible for one or more H atoms in the groups CccH2cc+1 and
CyyH2yy-i to be replaced by F atoms and for one or more CH2 groups to be replaced by NR31 and for a CH2 group to be replaced by O;
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 jointly bonded form a 5- or 6-membered ring;
or
R30 pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl or oxazolyl, which are unsubstituted or substituted by a maximum of 3 substituents selected from the group consisting of F, CI, methyl, ethyl, trifluoromethyl, NH2, NHacetyl;
or
R7, R8 and R9
independently of one another H, F, CI, OH, NH2, CeeH2ee+1 • cwwH2ww-1 • OCffH2ff+i, 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+1» CwwH2ww-1 and OCffH2ff+i to be replaced by F atoms;
R40 and R41
H, CttH2tt+1 or C(NH)NH2:
tt 1,2, 3 or 4;
it being possible for one or more H atoms in the group CttH2tt+1to be replaced by F atoms;
or
R40 and R41
22
independently of one another hydroxyethyl, N.N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl;
or
R40 and R41
together with the N atom to which they are bonded a pyrrolidine, piperidine, N-methylpiperazine, piperazine or morpholine ring; R42 H or ChhH2hh+11 hh 1,2, 3 or 4;
it being possible for one or more H atoms in the group ChhH2hh+1 to be replaced by F atoms;
but where two substituents from the group of R7, R8 and R9 may not simultaneously be OH or OCH3
and where at least one of the radicals R7, R8 or R9 must be selected from the group consisting of -OvSOwR23, NR32COR30, NR32CSR30 and NR32SO55R3O;
and the pharmaceutically acceptable salts and trifluoroacetates thereof.
Very particular specific preference is given to compounds
1) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-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;
) 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;
) 6,8-dichloro-2-methyl-4-(4-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline;
11) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-phenyl]-diethyl-amine
23
12
13
14
15
16
17
18
19
21
22
23
24
I
26
27
28
29
6,8-dichloro-2-methyi-4-(4-piperidin-1-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline; 6,8-dichloro-2-methyl-4-(4-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline; 6,8-dichloro-2-methyl-4-[4-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-isoquinoline;
6,8-dichloro-2-cyclopropyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline; 4-(6,8-dichIoro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine; 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-propylurea;
1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea;
1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;
N-[4-(6-methanesulfonyl-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;
N-[4-(2,6,8-trimethyl-1,2,3,4-tetrahydro-isoquinolin-4-yi)-phenyl]-acetamide;
N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-
acetamide;
N-[4-(8-chloro-2-methyl-6-pyrrolidin-1-yl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-pheriyl]-acetamide;
N-[4-(8-chloro-2-methyl-6-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;
N-{4-[8-chloro-2-methyl-6-(4-methyl-piperazin-1-yl)-1,2,3,4-tetrahydro-isoquinolin-
4-yl]-phenyl}-acetamide;
N-{4-[8-chloro-6-(cyclopropylmethyl-amino)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl]-phenyl}-acetamide;
-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoic acid;
-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-N-methyl-benzamide;
-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-ethyl-2-hydroxy-benzamide;
24
) 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)-phenyl]-acetamide;
33) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine;
34) 2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine;
) 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-isoqiiinolin-4-yl)-phenyl]-butyramide;
37) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]pentanamide;
38) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isobutyramide;
39) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-pheriyl]-2,2-dimethyl-propionamide;
40) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-20 cyclopropanecarboxamide;
41) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yI)-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-trifiuoro-acetamide;
44) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-acetylpiperidine-4-carboxamide;
45) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-30 nicotinamide;
46) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane-sulfonamide;
47
48
49
50
51
52
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55
56
57
58
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60
61
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N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl]-ethanesulfonamide;
N,,N,-dimethylamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-sulfamide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-
propionamide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pentanarnide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isobutyramide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2-dimethyl-propionamide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopropanecarboxamide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclobutanecarboxamide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoIin-4-yl)-phenyl]-cyclopentanecarboxamide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoro-acetamide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-acetylpiperidine-4-carboxamide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-nicotinamide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane-sulforiamide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl]-ethanesulfonamide;
N,,N,-dimethylamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-pheriyl]-sulfamide;
26
63
64 5 65
66
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I 73
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75 76
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N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide;
N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide;
N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pentanamide;
N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isobutyramide;
N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2-dimethyl-propionamide;
N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahyd ro-isoqu inol in-4-yl )-phenyl]-cyclopropanecarboxamide;
N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl]-cyclobutanecarboxamide;
N-[2-(6,8-dich!oro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopentanecarboxamide;
N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyI]-2,2,2-trifluoro-acetamide;
N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoIin-4-yl)-phenyl]-1-acetylpiperidine-4-carboxamide;
N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane-sulfonamide;
N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl]-ethanesuifonamide;
N',N,-dimethylamino-N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-sulfamide;
1-[3-(6,8-dichloro-2-methyi-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;
1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea;
1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-
urea;
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90
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92
27
1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea;
N-{5-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylsulfamoyl]-4-methyl-thiazol-2-yl}-acetamide; N-{5-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylsulfamoyl]-4-methyl-thiazol-2-yl}-acetamide;
N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,2-dimethyl-1H-imidazole-4-sulfonamide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,2-dimethyl-1H-imidazole-4-sulforiamide;
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-sulforiamide;
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;
N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-5-bromo-thiophene-2-sulfonamide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-5-bromo-thiophene-2-sulfonamide;
N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-C,C,C-trifluoro-methanesulfonamide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-C,C,C-trifluoro-methanesulfonamide;
4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoroethanesulfonamide;
3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoro-ethanesulfonamide;
N-ethyl-N'-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonylurea;
2-chloro-5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide;
2-methyl-4-phenyl-6,8-bis-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline;
28
95) 2-amino-N-[4-(6,8-dichloro-2-methyl-1,2,3)4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;
96) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-methylamino-acetamide;
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-1I2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide;
100) 2,6-diamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylj-hexanamide;
101) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pyrrolidine-2-carboxamide;
102) N-<[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isonicotinamide;
103) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-pyrrole-3-carboxamide;
104) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-pyrrole-2-carboxamide;
105) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -methyl-piperidine-4-carboxamide;
106) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,4-dimethyl-1 H-pyrrole-2-carboxamide;
107) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-pheriyl]-4-nitro-1 H-pyrrole-2-carboxamide;
108) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,5-dimethyl-1H-pyrrole-3-carboxamide;
109) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-imidazole-4-carboxamide;
110) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-methanesulfonyl-piperidine-4-carboxamide;
29
111) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,5-dimethyl-1H-pyrazole-4-carboxamide;
112) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-pyrazoIe-4-carboxamide;
113) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-trifluoromethyl-1 H-pyrazole-4-carboxamide;
114) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-methylamino-acetamide;
115) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-10 dimethylamino-acetamide;
116) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyI]-propionamide;
117) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide;
118) 2,6-diamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-hexanamide;
119) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pyrrolidirie-2-carboxamide;
120) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoIin-4-yl)-phenyl]-20 isonicotinamide;
121) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-pyrrole-3-carboxamide;
122) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoliri-4-yl)-phenyl]-1 H-pyrrole-2-carboxamide;
123) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -methyl-piperidine-4-carboxamide;
124) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-
1.4-dimethyl-1 H-pyrrole-2-carboxamide;
125) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-nitro-30 1H-pyrrole-2-carboxamide;
126) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-
2.5-dimethyl-1H-pyrrole-3-carboxamide;
127) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-imidazole-4-carboxamide;
128) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-methanesulfonyl-piperidine-4-carboxamide;
129) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,5-dimethyl-1H-pyrazole-4-carboxamide;
130) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-pyrazole-4-carboxamide;
131) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-0 10 3-trifluoromethyl-1 H-pyrazole-4-carboxamide;
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) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl-20 piperazine-1-carboxamide;
0 137) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-piperidirie-1-carboxamide;
138) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-morpholine-4-carboxamide; 25 139) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pyrrolidine-1 -carboxamide;
140) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-diethyl-urea;
141) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-30 urea;
142) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea;
31
143) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquiriolin-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-(tetrahyd ro-pyran-4-yl )-u rea;
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)-phenyI]-1 -(3-dimethylamino-propyl)-1 -methyl-urea;
147) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-0 10 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-
151)1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin-4-yl-urea;
152) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl-
153) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoliri-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;
156) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-piperidine-1-carboxamide;
157) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-30 morpholine-4-carboxamide;
158) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pyrrolidine-1 -carboxamide;
3-yl-urea;
piperazirie-1 -carboxamide;
32
159) 1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea;
160) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl-piperazine-1 -carboxamide;
161) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pyrrolidine-1 -carboxamide;
162) 1 -[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea;
163) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-10 1,1-dimethyl-urea;
164) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-diethyl-urea;
165) 1 -[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-
3-(2-dimethylamino-ethyl)-urea;
166) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-piperidine-1-carboxamide;
167) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquiriolin-4-yl)-phenyl]-morpholine-4-carboxamide;
168) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-20 formamide;
| 169) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amine;
170) 1 -[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3-dimethyl-urea;
171) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-
4-methyl-piperazine-1-carboxamide;
172) 1 -[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3,3-trimethyl-urea;
173) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-30 piperidine-1-carboxamide;
174) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-pheriyl]-methyl-morpholine-4-carboxamide;
33
175) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-pyrrolidine-1-carboxamide;
176) 1 -[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-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-0 10 amine;
180) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-pyrrolidine-1 -carboxamide;
181) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-piperidine-1 -carboxamide;
182) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3,3-trimethyl-urea;
183) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3-dimethyl-urea;
184) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-20 morpholine-4-carboxamide;
0 185) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-4-methyl-piperazine-1-carboxamide; 186) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-
3-(2-dimethylamino-ethyl)-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) 2-dimethylamino-ethyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-
4-yl)-phenyl]-carbamate;
189) 2-dimethylamino-ethyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-30 4-yl)-phenyI]-carbamate;
190) 2-dimethylamino-ethyl [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate;
34
191) methyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate;
192) ethyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate;
193) isopropyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate;
194) 2,2-dimethyl-propyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylj-carbamate;
195) methyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-0 10 carbamate;
196) isopropyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate;
197) 2,2-dimethyl-propyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate;
198) ethyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate;
199) (R)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide;
200) (S)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-
methanesulfonamide;
0 201) (R)-1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;
202) (S)-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) ethyl 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoate;
207) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid.
and the pharmaceutically acceptable salts thereof.
Exceptionally 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)-benzenesulfonamide;
4) 1 -[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea;
) 1 -[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-(10 urea;
6) N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;
7) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;
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;
) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane-20 sulfonamide;
II) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-ethanesulfonamide;
12) N,,N,-dimethylamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-sulfamide; 25 13) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide;
14) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide;
) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-30 isobutyramide;
16) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopropanecarboxamide;
36
19
17) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclobutanecarboxamide;
18) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoro-acetamide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-acetyl-piperidine-4-carboxamide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-nicotinamide;
21) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane-10 sulfonamide;
22) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-ethanesulfonamide;
23) N'.N'-dimethylamino-N-p^e.S-dichloro^-methyl-I^.S^-tetrahydro-isoquinolin^-yl)-phenyl]-sulfamide;
24) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopropanecarboxamide;
) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -acetyl-piperidine-4-carboxamide;
26) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-20 urea;
I 27) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea;
28) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;
29) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea;
) N-{5-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylsulfamoyl]-4-methyl-thiazol-2-yl}-acetamide;
31) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-30 1,2-dimethyl-1 H-imidazole-4-sulfonamide;
32) N-[4-(6,8-dichloro-2-methyl-1,2,3>4-tetrahydro-isoquinolin-4-yl)-phenyl]-C,C,C-trifluoro-methanesulfonamide;
37
33) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-C,C,C-trifluoro-methanesulfonamide;
34) N-ethyl-N'-4-(6,8-dichIoro-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;
36) 2,6-diamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-hexanamide;
37) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-10 pyrrole-3-carboxamide;
38) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -methyl-piperidine-4-carboxamide;
39) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -methanesulfonyl-piperidine-4-carboxamide;
40) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1H-pyrazole-carboxamide;
41) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-methylamino-acetamide;
42) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-20 dimethylamino-acetamide;
43) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide;
44) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide;
45) 2,6-diamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-hexanamide;
46) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyI]-1 -methyl-piperidine-4-carboxamide;
47) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-30 imidazole-4-carboxamide;
48) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -methanesulfonyl-piperidine-4-carboxamide;
38
49) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,5-dimethyl-1H-pyrazole-4-carboxamide;
50) N-[3-(6,8-dichloro-2-methyi-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-pyrazole-carboxamide;
51) 3-[3-(6,8-dichloro-2-methyl-1,2,3.4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1 -dimethyl-urea;
52) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl-piperazine-1 -carboxamide;
53) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-piperidine-10 1-carboxamide;
54) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-morpholine-4-carboxamide;
55) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pyrrolidine-1 -carboxamide;
56) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-diethyl-urea;
57) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea;
58) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-20 dimethylamino-ethyl)-urea;
59) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(tetrahyd ro-fu ran-3-yl)-u rea;
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-methyl-1-(1-methyl-piperidin-4-yl)-urea;
62) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-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 -(2-30 dimethylamino-ethyl)-1 -methyl-urea;
64) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(3-diethylamirio-propyl)-urea;
39
65) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-methoxy-ethyl)-urea;
66) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin-
3-yl)-urea;
67) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin-
4-yl-urea;
68) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl-piperazine-1 -carboxamide;
69) 1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-
urea;
70) 1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethyIamino-ethyl)-urea;
71) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl-piperazine-1 -carboxamide;
72) 1-[4-(6,8-dichloro-2-methyl-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) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-morpholine-4-carboxamide;
77) N-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-formamide;
78) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-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-isoquiriolin-4-yl)-phenyl]-1,3-dimethyl-urea;
40
81) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-morpholine-4-carboxamide;
82) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-methyl-4-methyl-piperazine-1-carboxamide;
83) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-1-methyl-urea;
84) 2-dimethylamino-ethyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate;
85) 2-dimethylamino-ethyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-10 yl)-phenyl]-carbamate;
86) 2-dimethylamino-ethyl [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate;
87) methyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate;
88) (R or S)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide;
89) (R or S)-1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;
90) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-20 hydroxy-ethyl)-urea;
and the pharmaceutically acceptable salts thereof.
The invention further encompasses the use of the compounds of the formula I for producing a medicament for the treatment of disorders which can be influenced by 25 inhibition of the sodium-proton exchanger of subtype III (NHE3), in which the meanings are:
R1, R2, R3 and R4
independently of one another H, F, CI, Br, I, CN, NO2, OH, NH2, CaH2a+1.
cqqH2qq-1 > 0CbH2b+1 • COOR10, OCOR10, COR10 or Ox-(CH2)y-phenyl;
a and b
41
in the groups CaH2a+i and OCbH2b+i independently of one another 1,2,3,4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms;
qq 3,4, 5, 6, 7 or 8, it being possible for one or more H atoms to be 5 replaced by F atoms;
R10 H or CqH2q+*i j c 1,2,3,4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms,
x zero or 1;
y zero, 1,2,3 or 4;
where the phenyl ring in the group Ox-(CH2)y-phenyl is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, CI, Br, CN, NO2, OH, NH2 or
CdH2d+l!
d 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms,
or
R1, R2, R3 and R4
independently of one another heteroaryl, it being possible for zero, 1, 2, 3 or 4 k20 N atoms, zero or 1 oxygen atom or zero or 1 S atom to be present as ring atoms;
or
R1, R2, R3 and R4
independently of one another CONR11R12 or NR11R12; 25 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,
it being possible for one or more H atoms in the groups CeH2e+1 and 30 CrrH2rr-1 to be replaced by F atoms and for one or more CH2
groups to be replaced by O or NR13;
42
R13 HorCfH2f+i;
f 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms;
or
R13 and a CH2 group of R11 or R12 together with the N atom to which they are bonded a 5- or 6-membered ring;
or
R11 and R12
together with the N atom to which they are bonded a 5-, 6- or >10 7-membered ring;
or
R11 and R12
independently of one another COR14, CSR14 or S02R14; 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 possible for one or more CH2 groups to be replaced by O or NR13,
or
^20 R1, R2, R3 and R4
independently of one another -Oh-SOj-R15, with h zero or 1;
j zero, 1 or 2;
R15 CkH2k+1, OH, OC1H21+1 or NR17R18; 25 k 1,2,3,4, 5, 6, 7 or 8, it being possible for one or more H
atoms to be replaced by F atoms;
I 1, 2, 3,4, 5, 6, 7 or 8, it being possible for one or more H
atoms to be replaced by F atoms;
R17 and R18
independently of one another H or CmH2m+1 >
43
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; H, CpH2p+'ii CssH2ss-1 , COR20 or SO2R2O;
p 1, 2, 3,4, 5, 6, 7 or 8,
ss 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms in CpH2p+i and CssH2ss-1 to be replaced by F atoms R20 CqH2q+i;
q 1, 2, 3,4, 5, 6, 7 or 8,
it being possible for one or more H atoms in CqH2q+i to be replaced by F atoms and for one or more CH2 groups to be replaced by O or NR21;
R21 H or CrH2r+1;
r 1,2, 3 or 4;
it being possible for one or more H atoms in CrH2r+i to be replaced by F atoms;
H, F, CI, Br, I, CsH2s+1, CddH2dd-1' °H' OCtH2t+1 or OCOR22;
s and t
1,2,3,4, 5, 6, 7 or 8, it being possible for one or more H atoms in the group CmH2m+i to be replaced by F atoms and for one or more CH2 groups to be replaced by O, CO, CS or NR19;
R19 HorCnH2n+i;
n 1,2, 3 or 4;
it being possible for one or more H atoms in CnH2n+1 to be replaced by F atoms;
44
independently of one another 1,2,3, 4, 5, 6, 7 or 8;
dd 3,4, 5, 6, 7 or 8, it being possible for one or more H atoms in csH2s+1> cddH2dd-1 and 0CtH2t+1to 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+1 to be replaced by F atoms;
, R8 and R9
independently of one another -CVSOw-R23;
v zero or 1;
w zero, 1 or 2;
R23 CnnH2nn+1> ^rnm^2mm-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 OCppH2pp+i to be replaced by F atoms;
R25 and R26
independently of one another H, CN or CzH2z+i, Czz^zz-I» 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+-| , it being possible for one or more H atoms to be replaced by F atoms and it being possible for one or more CH2 groups to be replaced by O, CO, CS or NR27;
R27 H or CaaH2aa+1 >
aa 1,2, 3 or 4;
it being possible for one or more H atoms in caaH2aa+1to be replaced by F atoms;
or
45
R25 and R26
together with the N atom to which they are bonded a 5-, 6- or 7-membered ring,
or
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 NR32SC)bbR30; 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;
h 1, 2, 3,4, 5, 6, 7 or 8,
it being possible for one or more H atoms in ChH2h+1 to be replaced by F atoms, and it being possible for one or more H atoms in the groups CGcH2cc+1 and CyyH2yy-1 to be replaced by F atoms and for one or more (CH2) groups to be replaced by NR31 and for a (CH2) group to be replaced by O;
R31 H, CfckH2kk+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, 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 forms together with a CH2 group of R30 a 5-, 6- or 7-membered ring; or
46
R30 a 5- or 6-membered heteroaryl with 1, 2, 3 or 4 N atoms, zero or 1 S atoms and zero or 1 O atoms,
which is unsubstituted or substituted by up to three substituents selected from the group consisting of F, CI, Br, I, ^00^200+1' NR70R71;
R70 and R71
independently of one another H, CuuH2uu+1 an<^ COR72;
R72 H,CwH2w+1;
oo, uu and w independently of one another 1,2,3, 4, 5, 6, 7 or 8;
it being possible for one or more H atoms in the groups C00H2oo+1 > CuuH2uu+1 or ^w^2w+1 to be replaced by F atoms;
or
R7, R8 and R9
independently of one another H, F, CI, Br, I, NO2, CN, OH, NH2, CeeH2ee+1' Cwwh2ww-1> 0CffH2ff+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 CeeH2ee+1» CwwH2ww-1 and 0CffH2ff+l 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+lte> be replaced by F atoms and for one or more CH2 groups to be replaced by O or NR44;
47
R44 HorCggH2gg+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+1 to be 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 meanings are:
R1, R2, R3 and R4
independently of one another, H, F, CI, Br, I, CN, NO2, OH, NH2, CaH2a+l. cycloalkyl with 3, 4, 5 or 6 C atoms, OCbH2b+i, COORIO;
a and b independently of one another 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms;
R10 H or CcH2c+1 ;
c 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms;
or
R1, R2, R3 and R4
independently of one another 5- or 6-membered heteroaryl selected from the group consisting of pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl and oxazolyl;
or
48
R1, R2, R3 and R4
independently of one another CONR11R12 or NR11R12;
R11 and R12
independently of one another H, CeH2e+l, 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+1 and CrrH2rr-1 to be replaced by F atoms or
R11 and R12
independently of one another hydroxyethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl;
or
R11 and R12
together with the N atom to which they are bonded a pyrrolidine, piperidine, N-methylpiperazine, piperazine or morpholine ring;
or
R11 and R12
independently of one another COR14, CSR14, CONHR14, CSNHR14 or S02R14;
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, or
R15 CkH2k+1, 0C|H2|+1 or NR17R18;
k 1,2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms;
49
I 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms;
R17 and R18
independently of one another H, CmH2m+1 > 'n 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+1 to be replaced by F atoms;
R19 HorCnH2n+i;
n 1,2, 3 or 4;
it being possible for one or more H atoms in CnH2n+l to be replaced by F atoms;
or
R17 and R18
together with the N atom to which they are bonded a 5- or 6-membered ring;
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 and
CSsH2ss-1 to be replaced by F atoms;
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+i and OCfH2t+l to be replaced by F atoms;
R22 CuH2u+1
u 1,2, 3 or 4;
it being possible for one or more H atoms in CuH2u+1 to be replaced by F atoms;
50
R7, R8 and R9
independently of one another 0S03H, SO3H or SO2R23;
R23 CnnH2nn+1> CmmH2mm-1> OCppH2pp+i 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 OCppH2pp+1 to be replaced bY F atoms;
R25 and R26
independently of one another H, CN, 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+1 to be replaced by F atoms;
R27 H or CaaH2aa+11 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- or 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
R7, R8 and R9
independently of one another NR32COR3Q, NR32CSR30 or NR32S02R30;
51
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 CfoH2h+i 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+i to be replaced by F atoms, and it being possible for one or more H atoms in the groups CCcH2cc+1 and CyyH2yy-1 to be replaced by F atoms and for one or more 10 (CH2) groups to be replaced by NR31 and for a (CH2) group to be replaced by
O;
R31 H, C|<kH2kk+i, COR65 or S02R65;
kk 1,2, 3, or 4;
it being possible for one or more H atoms to be replaced by F atoms, 15 R65 H, CxxH2xX+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 or R30 and the N atom to which they are HO jointly bonded form a 5- or 6-membered ring;
or
R30 a 5- or 6-membered heteroaromatic system selected from the group consisting of pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thienyl, thiazolyl and oxazolyl,
which are unsubstituted or substituted by up to three substituents selected from the group consisting of F, CI, Br, I, C00H200+I. NR70R71,
R70 and R71
independently of one another H, CuuH2uu+<| or 30 COR72;
R72 H, CwH2vv+i;
52
oo, uu and w independently of one another 1, 2, 3 or 4; it being possible for one or more H atoms in the groups ^00^200+1' Ouu^2uu+1 or ^w^vv+l ^ be replaced by F atoms;
or
R7, R8 and R9
independently of one another H, F, CI, Br, I, NO2, CN, OH, NH2, CeeH2ee+1>
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+1» CwwH2ww-1 ancl 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 CftH2tt+l to be replaced by F atoms;
or
R40 and R41
to be selected independently of one another hydroxyethyl,, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl;
or
R40 and R41
together with the N atom to which they are bonded form a ring selected from the group consisting of pyrrolidine, piperidine, N-methyl-piperazine, piperazine and morpholine;
R42 HorChhH2hh+i;
53
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;
and the pharmaceutical^ acceptable salts thereof.
Particular preference is given to the use of compounds of the formula I in which the meanings are:
R1, R2, R3 and R3
independently of one another H, F, CI, Br, OH, NH2, CaH2a+l. cycloalkyl with
3, 4, 5 or 6 C atoms, OCbH2b+11 a and b in the groups CaH2a+i and OCbH2b+l independently of one another 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced 15 by F atoms;
or
R1, R2, R3 and R4
independently of one another NR11R12;
R11 and R12
independently of one another H, CeH2e+l, 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+l and CrrH2rr-1 to be replaced by F 25 atoms;
or
R11 and R12
together with the N atom to which they are bonded form a ring selected from the group consisting of pyrrolidine, piperidine, N-30 methylpiperazine, piperazine and morpholine;
or
54
R11 and R12
independently of one another COR14, CSR14, CONHR14, CSNHR14 or S02R14;
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, SO2RI5; 10 R15 CkH2k+1 orNR17R18;
k 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms;
R17 and R18
independently of one another H or CmH2m+11 15 m 1, 2, 3,4 or 5, it being possible for one or more H
atoms in the group CmH2m+1 to be replaced by F atoms;
or
R17 and R18
120 together with the N atom to which they are bonded a 5- or
6-membered ring;
R5 H, CpH2p+i i CssH2ss-1 ;
p 1,2, 3 or 4;
ss 3, 4, 5 or 6, it being possible for one or more H atoms in CpH2p+i and 25 CssH2ss-1 to be replaced by F atoms;
R6 H, CH3;
R7, R8 and R9
independently of one another OSO3H, SO3H or S02R23;
R23 CnnH2nn+1 or NR25R26;
nn 1,2,3,4 or 5,
55
it being possible for one or more H atoms in CnnH2nn+1to be replaced by F atoms;
R25 and R26
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+1 to be replaced by F atoms;
R27 H or CaaH2aa+11 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- or 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
R7, R8 and R9
independently of one another NR32COR30, NR32CSR30 or NR32S02R30;
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, CH3 or CF3;
cc 1, 2, 3,4, 5 , 6, 7 or 8;
yy 3, 4, 5 or 6;
56
it being possible for one or more H atoms in the groups CccH2cc+1 and cyyH2yy-1 to be replaced by F atoms and for one or more (CH2) groups to be replaced by NR31 and for a (CH2) group to be replaced by O;
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 jointly bonded form a 5- or 6-membered ring;
or
R30 pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl or oxazolyl, which are unsubstituted or substituted by a maximum of 3 substituents selected from the group consisting of F, CI, methyl, ethyl, trifluoromethyl, NH2, NHacetyl;
or
R7, R8 and R9
independently of one another H, F, CI, OH, NH2, CeeH2ee+1> cwwH2ww-1> OCffH2ff+i, 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+1 •
CwwH2ww-1 and OCffH2ff+i to be replaced by F atoms;
R40 and R41
H, CttH2tt+1 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 be replaced by F atoms;
or
R40 and R41
57
independently of one another hydroxyethyl, N.N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl;
or
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;
Q 10 it being possible for one or more H atoms in the group ChhH2hh+1 t0
be replaced by F atoms;
and the pharmaceutical^ acceptable salts thereof.
Very particular preference is given to the use of compounds selected from the group consisting of
1) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyI]-acetamide;
2) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide; 20 3) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide; * 4) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N,N-dimethyl-
benzenesulfonamide;
) 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;
) 6,8-dichloro-2-methyl-4-(4-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline; 30 11) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-phenyl]-diethyl-amine
12) 6,8-dichloro-2-methyl-4-(4-piperidin-1 -yl-phenyl)-1,2,3,4-tetrahydroisoquinoline;
13) 6,8-dichloro-2-methyl-4-(4-pyrrolidin-1 -yl-phenyl)-1,2,3,4-tetrahydroisoquinoline;
58
14) 6,8-dichloro-2-methyl-4-[4-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydroisoquinoline;
) 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-methyl-thiourea;
19) 1 -[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-10 urea;
) 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-isoquinolin-4-yl)-phenyl]-15 acetamide;
23) N-[4-(8-chloro-2-methyl-6-pyrrolidin-1 -yl-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)-phenyl]-acetamide;
25) N-{4-[8-chloro-2-methyl-6-(4-methyl-piperazin-1-yl)-1,2,3,4-tetrahydro-isoquinolin-4-yl]-phenyl}-acetamide;
26) N-{4-[8-chloro-6-(cyclopropylmethyl-amino)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl]-phenyl}-acetamide;
27) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoic 25 acid;
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;
59
31) N-[5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoyl]-guanidine;
32) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;
33) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine;
34) 2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine;
) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide;
36) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-10 butyramide;
37) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]pentanamide;
38) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isobutyramide;
39) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2-dimethyl-propionamide;
40) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopropanecarboxamide;
41) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-20 cyclobutanecarboxamide;
| 42) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopentanecarboxamide;
43) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoro-acetamide;
44) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-acetylpiperidine-4-carboxamide;
45) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-nicotinamide;
46) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane-30 sulfonamide;
47) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl]-ethanesulfonamide;
60
48
49 5 50
51
52
53
54
55
56
57
58
59
60 61
62
63
N\N'-dimethylamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-sulfamide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl propionamide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl butyramide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl pentanamide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl isobutyramide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl dimethyl-propionamide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl cyclopropanecarboxamide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl cyclobutanecarboxamide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl cyclopentanecarboxamide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl trifluoro-acetamide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl acetylpiperidine-4-carboxamide;
N-[3-(6,8-dichloro-2-methyl-1,2,3I4-tetrahydro-isoquinolin-4-yl nicotinamide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl sulfonamide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl ethanesulfonamide;
N\N'-dimethylamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-sulfamide;
N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide;
l)-phenyl]-
l)-phenyl]-
l)-phenyl]-
l)-phenyl]-
l)-phenyl]-2,2-
l)-phenyl]-
l)-phenyl]-
l)-phenyl]-
l)-phenyl]-2,2,2-
l)-phenyl]-1-
l)-phenyl]-
)-phenyl]-methane-
)- phenyl]-
61
64) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide;
65) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pentanamide;
66) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isobutyramide;
67) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2-dimethyl-propionamide;
68) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-110 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-20 sulfonamide;
74) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl]-ethanesulfonamide;
75) N',N'-dimethylamino-N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-sulfamide;
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-30 urea;
79) 1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea;
62
80) N-{5-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylsulfamoyl]-4-methyl-thiazol-2-yI}-acetamide;
81) N-{5-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylsulfamoyl]-4-methyl-thiazol-2-yl}-acetamide;
82) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,2-dimethyl-1H-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-sulfonamide;
84) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-5-chloro-
110 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-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-ethanesulforiamide;
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)-phenoI;
97) 8-methoxy-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;
63
98) 2-(8-amino-2-ethyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenol;
99) 2-(8-amino-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenol;
100) 5-(8-amino-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-methoxy-phenol;
101) 2-methyl-8-nitro-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;
102) 4-(8-amino-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene-1,2-diol;
103) 2,8-dimethyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;
104) 4-(3,4-dichloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline;
105) 4-(3,4-dichloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-8-ylamine;
106) 4-(2,4-dichloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-8-ylamine; 10 107) 4-(3-chloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-8-ylamine;
108) 2,4-dimethyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;
109) 2-butyl-4-phenyl-1,2,3,4-tetrahydro-isoquinolin-8-ylamine;
110) N-(2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-acetamide;
111) 7-chloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 15 112) 8-chloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;
113) 2,6-dimethyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;
114) 6-chloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;
115) 6-methoxy-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;
116) 2-ethyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 20 117) 2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;
118) 6,8-dichloro-2-ethyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;
119) 4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoline;
120) 2-methyl-4-phenyl-6,8-bis-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline;
121) 6,8-dichloro-2-isopropyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 25 122) 5,8-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;
123) 6,8-dichloro-4-(4-fluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline;
124) 6,8-dichloro-2-methyl-4-p-tolyl-1,2,3,4-tetrahydro-isoquinoline;
125) 5,6-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;
126) 6,7-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 30 127) 8-bromo-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;
128) 6,8-dichloro-4-(4-chloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline;
129) 6,8-dichloro-2-cyclopropyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;
64
130) 2-amino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquiriolin-4-yl)-phenyl]-acetamide;
131) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-methylamino-acetamide;
132) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-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]-010 butyramide;
135) 2,6-diamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-hexanamide;
136) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pyrrolidine-2-carboxamide;
137) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isonicotinamide;
138) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-pyrrole-3-carboxamide;
139) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-20 pyrrole-2-carboxamide;
0 140) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-methyl-piperidine-4-carboxamide;
141) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,4-dimethyl-1H-pyrrole-2-carboxamide; 25 142) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-nitro-1 H-pyrrole-2-carboxamide;
143) N-[4-(6,8-dichloro-2-methyI-1,2,3,4-tetrahydro-isoquinoIin-4-yl)-phenyl]-2,5-dimethyl-1H-pyrrole-3-carboxamide;
144) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-30 imidazole-4-carboxamide;
145) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-methanesulfonyl-piperidine-4-carboxamide;
65
146) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,5-dimethyl-1H-pyrazole-4-carboxamide;
147) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-pyrazole-4-carboxamide;
148) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-trifluoromethyl-1 H-pyrazole-4-carboxamide;
149) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-methylamino-acetamide;
150) N[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-dimethylamino-acetamide;
151) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propioriamide;
152) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide;
153) 2,6-diamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-hexanamide;
154) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pyrrolidine-2-carboxamide;
155) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isoriicotinamide;
156) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-pyrrole-3-carboxamide;
157) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-pyrrole-2-carboxamide;
158) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquiriolin-4-yl)-phenyI]-1 -methyl-piperidine-4-carboxamide;
159) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,4-dimethyl-1 H-pyrrole-2-carboxamide;
160) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-nitro-1 H-pyrrole-2-carboxamide;
161) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,5-dimethyl-1H-pyrrole-3-carboxamide;
66
162) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-imidazole-4-carboxamide;
163) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -methanesulfonyl-piperidine-4-carboxamide;
164) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,5-dimethyl-1 H-pyrazole-4-carboxamide;
165) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-pyrazole-4-carboxamide;
166) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-010 trifluoromethyl-1H-pyrazole-4-carboxamide;
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)-phenyl]-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) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl-20 piperazine-1-carboxamide;
0 172) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-piperidine-1-carboxamide;
173) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-morpholine-4-carboxamide; 25 174) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pyrrolidine-1 -carboxamide;
175) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-diethyl-urea;
176) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-30 urea;
177) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea;
67
178) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(tetrahydro-furan-3-yl)-urea;
179) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(tetra hyd ro-py ran-4-y I )-u rea;
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-methyl-urea;
182) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -(2-010 dimethylamino-ethyl)-1-methyl-urea;
183) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(3-dimethylamino-propyl)-urea;
184) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-methoxy-ethyl)-urea;
185) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin-
3-yl-urea;
186) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin-
4-yl-urea;
187) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl-20 piperazine-1-carboxamide;
0 188) 1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea;
189) 3-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-dimethyl-urea;
190) 3-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-diethyl-urea;
191) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-piperidine-1-carboxamide;
192) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-30 morpholine-4-carboxamide;
193) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pyrrolidine-1 -carboxamide;
68
194) 1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea;
195) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl-piperazine-1 -carboxamide;
196) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pyrrolidine-1 -carboxamide;
197) 1 -[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea;
198) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-010 dimethyl-urea;
199) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-pheriyl]-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) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-piperidine-1-carboxamide;
202) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-morpholine-4-carboxamide;
203) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylJ-20 formamide;
0 204) [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) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-4-methyl-piperazine-1-carboxamide;
207) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3,3-trimethyl-urea;
208) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-30 piperidine-1-carboxamide;
209) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl morpholine-4-carboxamide;
69
210
211 5 212
213
214
215
216 15 217
218
219
I 220 221 25 222 223
224
225
N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-pyrrolidine-1-carboxamide;
1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-1-methyl-urea;
1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,3-diethyl-1-methyl-urea;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-formamide;
[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amine;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-pyrrolidine-1 -carboxamide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-piperidine-1 -carboxamide;
1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3,3-trimethyl-urea;
1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3-dimethyl-urea;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-morpholine-4-carboxamide;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-4-methyl-piperazine-1-carboxamide;
1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-1-methyl-urea;
1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,3-diethyl-1 -methyl-urea;
2-dimethylamino-ethyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate;
2-dimethylamino-ethyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate;
2-dimethylamino-ethyl [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate;
70
226) methyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate;
227) ethyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate;
228) isopropyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate;
229) 2,2-dimethyl-propyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate;
230) methyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-010 carbamate;
231) isopropyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate;
232) 2,2-dimethyl-propyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate;
233) ethyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylJ-carbamate;
234) (R)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide;
235) (S)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-
methanesulfonamide;
0 236) (R)-1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;
237) (S)-1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;
238) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;
239) 4-(3-bromo-phenyl)-6,8-dichloro-methyl-1,2,3,4-tetrahydro-isoquinoline;
240) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-hydroxy-ethyl)-urea;
241) ethyl 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoate;
242) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid.
71
and the pharmaceutical^ acceptable salts thereof.
Exceptionally particular preference is given to the use of compounds selected from the 5 group consisting of
1) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;
2) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide;
3) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide;
110 4) 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-tetrahydroisoquinolin-4-yl)-N-ethyl-benzamide;
6) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-propyl-benzamide;
7) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-(2-dimethylamino-ethyl)-benzamide;
8) 6,8-dichloro-2-methyl-4-(4-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline;
9) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine;
) 1 -[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea;
11) 1 -[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-
urea;
12) N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;
13) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoic acid;
14) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-(2-dimethylamino-ethyl)-2-hydroxy-benzamide;
) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;
16) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine;
17) 2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine;
18) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide;
72
19) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -acetyl-piperidine-4-carboxamide;
) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane-sulfonamide;
21) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-ethanesulfonamide;
22) N,,N,-dimethylamino-N-[4-(6,8-dichloro-2-methyl-1,2,3)4-tetrahydro-isoquinolin-4-yl)-phenyl]-sulfamide;
23) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide;
24) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide;
) 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)-pheriyl]-cyclobutanecarboxamide;
28) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoro-acetamide;
29) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -acetyl-piperidine-4-carboxamide;
) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-nicotinamide;
31) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoliri-4-yl)-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;
73
) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -acetyl-piperidine-4-carboxamide;
36) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;
37) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-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-methyl-10 thiourea;
40) N-{5-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-pheriylsulfamoyl]-4-methyl-thiazol-2-yl}-acetamide;
41) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,2-dimethyl-1H-imidazole-4-sulfonamide;
42) N-[4-(6,8-dichloro-2-methyl-1 ^.S^-tetrahydro-isoquinolin^-yO-phenylJ-C.C.C-trifluoro-methanesulfonamide;
43) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-C,C,C-trifluoro-methanesulfonamide;
44) N-ethyl-N'-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-20 benzenesulfonylurea;
I 45) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-dimethylamino-acetamide;
46) 2,6-diamino N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-hexanamide;
47) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-pyrrole-3-carboxamide;
48) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -methyl-piperidine-4-carboxamide;
49) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -30 methanesulfonyl-piperidine-4-carboxamide;
50) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyi]-1 H-pyazole-4-carboxamide;
74
51) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-methylamirio-acetamide;
52) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-dimethylamino-acetamide;
53) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide;
54) 2-amino-N-[3-(6I8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide;
55) 2,6-diamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-110 phenyl]-hexanamide;
56) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -methyl-piperidine-4-carboxamide;
57) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-imidazole-4-carboxamide;
58) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-methanesulfonyl-piperidine-4-carboxamide;
59) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,5-dimethyl-1H-pyrazole-4-carboxamide;
60) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-20 pyrazole-4-carboxamide;
I 61) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-dimethyl-urea;
62) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl-piperazine-1 -carboxamide; 25 63) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-piperidine-1-carboxamide;
64) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-morpholine-4-carboxamide;
65) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoIin-4-yl)-phenyl]-30 pyrrolidine-1-carboxamide;
66) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-diethyl-urea;
75
67) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea;
68) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyi]-3-(2-dimethylamino-ethyl)-urea;
69) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(tetrahyd ro-fu ra n-3-y I )-u rea;
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-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -(2-dimethylamino-ethyl)-1-methyl-urea;
74) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(3-dimethylamino-propyl)-urea;
75) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-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) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl piperazine-1 -carboxamide;
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-isoquinoliri-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea;
81) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl piperazine-1 -carboxamide;
82) 1 -[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea;
76
83) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1 -dimethyl-urea;
84) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-diethyl-urea;
85) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea;
86) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-morpholine-4-carboxamide;
87) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-10 formamide;
88) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amine;
89) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-formamide;
90) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amine;
91) 1 [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3,3-trimethyl-urea;
92) 1 [3-(6,8-dich!oro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3-20 dimethyl-urea;
93) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-morpholine-4-carboxamide;
94) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-4-methyl-piperazirie-1-carboxamide;
95) 1 [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-1-methyl-urea;
96) 2-dimethylamino-ethyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate;
97) 2-dimethylamino-ethyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-30 yl)-phenyl]-carbamate;
98) 2-dimethylamino-ethyl [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate;
77
99) methyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate;
100) (R or S)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide;
101) (R or S)-1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;
102) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-hyd roxy-ethyl )-u rea;
103) ethyl 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoate; 110 104) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-y!)-benzoic acid.
and the pharmaceutically acceptable salts thereof.
If the compounds of the formula I contain one or more centers of asymmetry, these 15 may have both the S and the R configuration. The compounds may be in the form of optical isomers, of diastereomers, of racemates or of mixtures thereof.
The defined alkyi radicals and partly or completely fluorinated alkyi radicals may be both straight-chain and branched. Groups CaH2a-l and their analogs as far as 20 CyyH2yy-i mean either the corresponding alkenyls, cycloalkyls, cycloalkylalkyls or alkylcycloalkyls.
Appropriate heteroaryls are, in particular, 2- or 3-thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 1,2,3-triazol-1-, -4- or 5-yl, 25 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 1,2,3-oxadiazol-4- or 5-yl, 1,2,4-oxadiazol-3-or 5-yl, 1,3,4-oxadiazol-2-yl or -5-yl, 2-, 4-or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or 5-yl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 3- or
4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 30 1-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or
8-isoquinolyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 3-,
-, 6-, 7- or 8-quinoxalinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl. The corresponding
78
N-oxides of these compounds are additionally encompassed, that is to say, for example, 1-oxy-2-, 3- or 4-pyridyl.
Of these, the 5- or 6-membered heterocycles are preferred. The particularly preferred 5 heterocycles are imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl and oxazolyl.
The terminal CH3 groups in an alkyi chain are also regarded as CH2 units and are in this connection viewed as CH2 groups.
0 10
Methods for preparing the compounds used are also described.
Thus, the substances described herein can be prepared starting from the benzylamine precursors IV. These in turn can, if not obtainable commercially, be synthesized by 15 standard processes from the corresponding benzyl chlorides or bromides III.
x = CI, Br
III IV
The benzylamines IV obtained in this way are alkylated in a manner known to the skilled worker with the appropriately substituted alpha-bromoacetophenone compounds V.
79
R8
R9^rf^pR7
x.
R8
R4
VI
The alpha-bromacetophenone compounds V can be obtained from the corresponding acetophenone precursors by bromination in processes known from the literature. The desired tetrahydroisoquinolines I can be obtained by known processes by reduction of the carbonyl group in VI and subsequent acid-catalyzed cyclization of the corresponding alcohols VII (cf. Tetrahedron Lett.; 1989, 30, 5837; Org. Prep. Proced. Int.; 1995, 27, 513).
NaBH.
VI
[H+]
VII
80
When R6 is not equal to H, the desired compounds of the formula I can be prepared for example from the iodides VIII by halogen/metal exchange and subsequent nucleophilic attack of the intermediate organolithium species on the carbonyl group (cf. Chem. Pharm. Bull.; 1995, 43,1543).
VIII IX
The tertiary alcohols synthesized in this way can be converted by known methods into other derivatives.
Alkyl-branched analogs (I) are prepared by alkylating the corresponding diphenylacetic esters X in the alpha position by known methods. The desired product XI can be converted by standard processes into the corresponding amides XII, which are converted into the desired tetrahydroisoquinolines I in a Pictet-Spengler-analogous reaction (cf. Tetrahedron; 1987,43,439; Chem. Pharm. Bull.; 1985, 33, 340).
81
1. LDA
2. R6-X
XI
1. NaOH
2. SOCI2
3. R5-NH2
HCHO/LiAIH,
XII
Compounds of the type I are described in the published specifications WO 01 32 624 and WO 01 32 625 as norepinephrine, dopamine and serotonin reuptake inhibitors.
However, these patent applications protect exclusively compounds in which R1 and R2 I may be exclusively H. It has emerged, however, with the compounds according to the invention that at least for R2 it is necessary that R2 is not equal to H. In addition, it was not possible to detect by means of an exemplary compound of the compounds according to the invention any inhibitory properties on the described receptors, so that 10 the described compounds differ distinctly both in structure and in their pharmacological properties from the compounds described in the patent applications mentioned.
In addition, compounds of type I are described in the patent specification EP 11 13 007 as estrogen agonists and antagonists. It was possible to show that the compounds 15 according to the invention show no activity on said receptors, so that the structural differences of the compounds according to the invention result in distinctly different pharmacological properties in this regard too.
82
It was possible to show that compounds of the formula I are excellent inhibitors of the sodium-hydrogen exchanger (NHE) - especially of the sodium-hydrogen exchanger of subtype 3 (NHE3).
On the basis of these properties, the compounds are suitable for the treatment of disorders caused by oxygen deficiency. The compounds are, as a result of their pharmacological properties, outstandingly suitable as antiarrhythmic medicaments with a cardioprotective component for prophylaxis of infarction and for treatment of 10 infarction, and for the treatment of angina pectoris, in which connection they also inhibit or greatly reduce in a preventive manner the pathophysiological processes associated with the development of ischemia-induced damage, in particular in the induction of ischemia-induced cardiac arrhythmias. Because of their protective effects against pathological hypoxic and ischemic situations, the compounds of the formula I 15 which are used according to the invention can, as a result of inhibition of the cellular Na+/H+ exchange mechanism, be used as medicaments for the treatment of all acute or chronic damage induced by ischemia or disorders induced primarily or secondarily thereby. This relates to the use thereof as medicaments for surgical interventions, e.g. in organ transplantations, in which cases the compounds can be used both to protect 20 the organs in the donor before and during removal, to protect removed organs for I example on treatment with or storage thereof in physiological bath fluids, as well as during the transfer into the recipient organism. The compounds are likewise valuable medicaments with a protective action during the performance of angioplastic surgical interventions, for example on the heart as well as peripheral vessels. In accordance 25 with their protective action against ischemia-induced damage, the compounds are also suitable as medicaments for the treatment of ischemias of the nervous system, especially of the CNS, in which connection they are suitable for example for the treatment of stroke or of cerebral edema. In addition, the compounds of the formula I which are used according to the invention are likewise suitable for the treatment of 30 types of shock, such as, for example, of allergic, cardiogenic, hypovolemic and bacterial shock.
83
In addition, the compounds induce an improvement in the respiratory drive and are therefore used to treat respiratory conditions associated with the following clinical conditions and diseases: disturbance of central respiratory drive (e.g. central sleep apnea, sudden infant death, postoperative hypoxia), muscle-related breathing disorders, breathing disorders after long-term ventilation, breathing disorders associated with altitude adaptation, obstructive and mixed type of sleep apnea, acute and chronic pulmonary disorders with hypoxia and hypercapnia.
The compounds additionally increase the tone of the muscles of the upper airways, so that snoring is suppressed.
A combination of an NHE inhibitor with a carbonic anhydrase inhibitor (e.g. acetazolamide), the latter inducing metabolic acidosis and thus itself increasing respiratory activity, proves to be advantageous due to an enhanced effect and reduced use of active ingredient.
It has emerged that the compounds used according to the invention have a mild laxative effect and accordingly can be used advantageously as laxatives or if there is a risk of constipation, in which case the prevention of the ischemic damage associated with constipation in the intestinal region is particularly advantageous.
It is additionally possible to prevent the formation of gall stones.
The compounds of the formula I used according to the invention are furthermore distinguished by a strong inhibitory effect on the proliferation of cells, for example of 25 fibroblast cell proliferation and the proliferation of smooth muscular muscle cells. The compounds of the formula I are therefore suitable as valuable therapeutic agents for diseases in which cell proliferation represents a primary or secondary cause, and can therefore be used as antiatherosclerotic agents, agents to prevent late complications of diabetes, cancers, fibrotic disorders such as pulmonary fibrosis, hepatic fibrosis or 30 renal fibrosis, organ hypertrophies and hyperplasias, in particular for prostate hyperplasia or prostate hypertrophy.
84
The compounds used according to the invention are effective inhibitors of the cellular sodium-proton antiporter (Na/H exchanger) which is elevated in numerous disorders (essential hypertension, atherosclerosis, diabetes, etc.), also in those cells which are readily amenable to measurements, such as, for example, in erythrocytes, platelets or 5 leukocytes. The compounds used according to the invention are therefore suitable as excellent and simple scientific tools, for example in their use as diagnostic agents for determining and distinguishing different types of hypertension, but also of atherosclerosis, of diabetes, proliferative disorders etc. The compounds of the formula I are moreover suitable for preventive therapy to prevent the development of high 110 blood pressure, for example of essential hypertension.
It has additionally been found that NHE inhibitors show a beneficial effect on serum lipoproteins. It is generally acknowledged that blood lipid levels which are too high, so-called hyperlipoproteinemias, represent a considerable risk factor for the development 15 of arteriosclerotic vascular lesions, especially coronary heart disease. The reduction of elevated serum lipoproteins therefore has exceptional importance for the prophylaxis and regression of atherosclerotic lesions. The compounds used according to the invention can therefore be used for the prophylaxis and regression of atherosclerotic lesions by eliminating a causal risk factor. With this protection of the vessels against 20 the syndrome of endothelial dysfunction, compounds of the formula I are valuable | medicaments for the prevention and treatment of coronary vasospasms, of atherogenesis and of atherosclerosis, of left-ventricular hypertrophy and of dilated cardiomyopathy, and thrombotic disorders.
Said compounds are therefore advantageously used for producing a medicament for the prevention and treatment of sleep apneas and muscle-related respiratory disorders; for producing a medicament for the prevention and treatment of snoring; for producing a medicament for lowering blood pressure; for producing a medicament for the prevention and treatment of disorders induced by ischemia and reperfusion of 30 central and peripheral organs, such as acute renal failure, stroke, endogenous states of shock, intestinal disorders etc.; for producing a medicament for the treatment of late damage from diabetes and chronic renal disorders, in particular of all inflammations of
85
the kidneys (nephritides) which are associated with increased protein/albumin excretion; for producing a medicament for the treatment of infection by ectoparasites in human and veterinary medicine; for producing a medicament for the treatment of said disorders in combinations with hypotensive substances, preferably with angiotensin 5 converting enzyme (ACE) inhibitors, with diuretics and saluretics such as furosemide, hydrochlorothiazide, pseudoaldosterone antagonists and aldosterone antagonists; with adenosine receptor modulators, in particular with adenosine receptor activators (A2 agonists); and with angiotensin receptor antagonists.
110 The administration of sodium-proton exchange inhibitors of the formula I as novel medicaments for lowering elevated blood lipid levels, and the combination of sodium-proton exchange inhibitors with hypotensive medicaments and/or medicaments with hypolipidemic activity is claimed.
Medicaments which comprise a compound I can in this connection be administered orally, parenterally, intravenously, rectally, transdermally or by inhalation, the preferred administration being dependent on the particular characteristics of the disorder. The compounds I may moreover be used alone or together with pharmaceutical excipients, both in veterinary medicine and in human medicine.
The excipients suitable for the desired pharmaceutical formulation are familiar to the skilled worker on the basis of his expert knowledge. Besides solvents, gel formers, suppository bases, tablet excipients, and other active ingredient carriers, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavorings,
preservatives, solubilizers or colors.
For a form for oral administration, the active compounds are mixed with additives suitable for this purpose, such as carriers, stabilizers or inert diluents, and converted by conventional methods into suitable dosage forms such as tablets, coated tablets,
hard gelatin capsules, aqueous, alcoholic or oily solutions. Examples of inert carriers which can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. It is moreover possible
86
for the preparation to take place both as dry granules and as wet granules. Examples of suitable oily carriers or solvents are vegetable or animal oils such as sunflower oil or fish liver oil.
For subcutaneous or intravenous administration, the active compounds used are converted, if desired with the substances customary for this purpose, such as solubilizers, emulsifiers or other excipients, into a solution, suspension or emulsion. Examples of suitable solvents are: water, physiological saline or alcohols, e.g. ethanol, propanol, glycerol, as well as sugar solutions such as glucose or mannitol solutions, or 0 10 else a mixture of the various solvents mentioned.
Suitable as pharmaceutical formulation for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active ingredient of the formula I in a pharmaceutically acceptable solvent such as, in particular, ethanol or 15 water, or a mixture of such solvents.
The formulation may, if required, also contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers, and a propellant gas. Such a preparation normally contains the active ingredient in a concentration of about 0.1 to 10, in 20 particular of about 0.3 to 3, % by weight.
The dosage of the active ingredient of the formula I to be administered, and the frequency of administration, depend on the potency and duration of action of the compounds used; additionally also on the nature and severity of the disorder to be 25 treated and on the sex, age, weight and individual responsiveness of the mammal to be treated.
On average, the daily dose of a compound of the formula I for a patient weighing about 75 kg is at least 0.001 mg/kg, preferably 0.01 mg/kg, to a maximum of 10 mg/kg, 30 preferably 1 mg/kg, of body weight. For acute episodes of the disorder, for example immediately after suffering a myocardial infarction, higher and, in particular, more frequent dosages may also be necessary, e.g. up to 4 single doses a day. Up to
87
200 mg a day may be necessary, in particular on i.v. administration, for example for a patient with infarction in the intensive care unit.
Descriptions of experiments and examples:
List of abbreviations used:
retention time trifluoroacetic acid high performance liquid chromatography equivalent liquid chromatography mass spectroscopy mass spectroscopy chemical ionization room temperature tetrahydrofuran
0-[(ethoxycarbonyl)-cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate dimethyl sulfoxide absolute decomposition dimethylformamide
General:
The retention times (Rt) indicated below relate to LCMS measurements with the
following parameters:
Method A:
stationary phase: Merck Purospher 3fj2 x 55 mm mobile phase: 95% H2O (0.05% TFA)-» 95% acetonitrile; 4 min; 95%
acetonitrile; 1.5 min -» 5% acetonitrile; 1 min; 0.5 ml/min, 30 30°C.
Rt TFA HPLC 10 eq LCMS MS CI RT 15 THF TOTU
DMSO abs. 20 decomp. DMF
Method B: stationary phase:
Merck Purospher 3//2 x 55 mm
88
mobile Phase:
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.
Method B1: stationary phase: mobile phase
Method C: stationary phase: solvent:
flow rate:
stop time: temperature:
Method D: stationary phase: solvent:
flow rate:
YMC, J'sphere ODS H80 4jj 2 x 20 mm
0 min 90% H2O (0.05% TFA) 1.9 min-95% acetonitrile;
95% acetonitrile to 2.4 min; 10% acetonitrile 2.45 min;
1 ml/min.
Merck LiChroCart 55-2 Purospher STAR RP 18e solvent A: acetonitrile/water 90:10 + 0.5% HCOOH solvent B: acetonitrile/water 10:90 + 0.5% HCOOH 0.75 ml/min solvent B[%]
95.0 95.0 5.0 5.0 95.0 95.0
time[min]
0.00
0.50
1.75
4.25
4.50
.00
6.20 min
40°C
Merck RP18 Purospher STAR, 55 x 2 mm, 3 y particle size, solvent A: acetonitrile + 0.08% HCOOH solvent B: water + 0.1 % HCOOH 0.45 ml/min time[min] solvent B[%]
0 95
89
7
9
8
95 5
temperature:
room temperature
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, at 60°C, a solution of 39.9 g of bromine (1.0 eq) in 60 ml of acetic acid is added dropwise. After 1.5 h, the reaction mixture is allowed to cool to room temperature and is added to 1 I of ice-water. The precipitate is filtered off with suction, washed with water and dried, with 60 g of the title compound being isolated (melting point: 192°C).
Intermediate 3: N-{4-[2-(2,4-Dichloro-benzylamino)-acetyl]-phenyl}-acetamide; 37.1 g (0.195 mol) of intermediate 1 are introduced into 400 ml of dioxane, and a solution of 60 g (0.234 mol) of intermediate 2 in 600 ml of dioxane is added. 134 ml of triethylamine are added, and the mixture is stirred at room temperature for 4 h. After standing overnight, the precipitate is filtered off and the filtrate is concentrated in ci
CI
90
vacuo. The residue is taken up in ethyl acetate, washed with NaHCC>3 and H2O, dried with MgS04 and concentrated. The oily residue resulting thereby is triturated with an ethyl acetate/ether mixture, resulting in 36 g of intermediate 3 in the form of a crystalline solid (melting point: 115-117°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 for *10 30 min and at room temperature for a further hour. For workup, the reaction mixture is concentrated and the residue is partitioned between 1 N HCI and ethyl acetate. The aqueous phase is separated off, adjusted to pH 9 and extracted twice with ethyl acetate. The combined organic phases are dried with MgSC>4 and concentrated. The crude 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 dichloromethane and, at 0°C, 250 ml of conc. H2SO4 are added dropwise. The mixture is stirred at 0°C for 2 h and at room temperature for 1 h. For workup, the reaction mixture is added to ice-k20 water, and the precipitate is filtered off with suction. The precipitate is taken up in
300 ml of 1 N NaOH and extracted three times with ethyl acetate. Drying of the organic phases and concentration affords a crude product which is triturated with diisopropyl ether, whereupon 11.7 g of the compound of the example are isolated as a crystalline solid (melting point: 205-206°C).
1 a: N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide-hydrochloride;
91
CIH
CI
An analytical sample (100 mg) of the title compound from example 1 is suspended in 10 ml of 2 N HCI, and THF is added until a clear solution is produced. It is concentrated in vacuo, and the residue is triturated with ether and filtered off with 5 suction, whereupon the title compound is obtained as a crystalline solid (Rt = 3.807 min (method A); melting point.: 125°C with decomposition).
Example 2:
2a: (+)-4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene-10 sulfonamide hydrochloride;
2b: (+)-3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene-sulfonamide hydrochloride;
2c: (-)-4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene-sulfonamide acetate; 15 2d: (-)-3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene-sulfonamide acetate;
(+ and -)
2a/2c 2b/2d
Intermediate 1: 2,4-Dichlorobenzyl-(methyl)-amine is prepared by methods known from the literature (J. Med. Chem.; 1984, 27,1111).
92
Intermediate 2: 2-[(2,4-Dichloro-benzyl)-methyl-amino]-1 -phenyl-ethanone;
Intermediate 1 is reacted with 2-bromo-1 -phenyl-ethanone in the manner described in example 1, intermediate 3. Workup in an analogous manner and purification on silica gel affords the desired alkylation product in good yield as a yellowish oil (Rt =
4.188 min (method A); MS(CI+) = 308.2/310.2).
Intermediate 3: 2-[(2,4-Dichloro-benzyl)-methyl-amino]-1 -phenyl-ethanol;
Intermediate 2 is reduced with sodium borohydride in the manner described in example 1, intermediate 4. Once monitoring of the reaction indicates complete • 10 conversion, the mixture is concentrated and the residue is taken up in ethyl acetate. It is washed twice with H2O, dried with MgS04 and freed of solvent. The crude product, which is obtained in quantitative yield, can be reacted further without further purification (Rt = 4.149 min (method A); MS(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 and cooled to 0°C. This solution is added dropwise to 55 ml of precooled conc. H2SO4 and then stirred at room temperature for two hours. For workup, the mixture is poured onto ice and made strongly alkaline with 6 N NaOH. Three extractions with dichloromethane 020 are carried out. The combined organic phases are dried with MgS04 and concentrated. The oily crude product is purified on silica gel, resulting in intermediate 4 in a yield of 53% (Rt = 4.444 min (method A); MS(CI+) = 292.2/294.2).
4a: (-)-6,8-Dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline trifluoroacetate; 25 4b: (+)-6,8-Dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline trifluoroacetate; Intermediate 4 is separated into the two enantiomers by HPLC on a chiral phase.
chiral column: Chiralpak OD 250 x 4.6 cm;
solvent: n-heptane/isopropanol 7:3 + 0.1% TFA;
flow rate: 1 ml/min;
Rt((-)-enantiomer/4a) = 9.340 min;
Rt((+)-enanti°mer/4b) = 20.327 min.
93
2a: (+)-4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene-sulfonamide hydrochloride;
2b: (+)-3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene-5 sulfonamide hydrochloride;
A suspension of 500 mg (1.7 mmol) of intermediate 4a in 10 ml of dichloromethane is introduced at 0°C into 1.2 ml of chlorosulfonic acid. The mixture is stirred at 0°C for one hour and at room temperature for a further hour. A further 5 ml of chlorosulfonic acid is added and the mixture is stirred at room temperature for one hour. For workup, 10 it is poured onto ice and adjusted to pH 8 with NaHCC>3. Three extractions with ethyl acetate are carried out. The combined organic phases are dried with Na2S04 and freed 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 complete, the reaction solution is concentrated and the residue is partitioned between H2O and ethyl acetate.
The organic phase is separated off and the aqueous phase is extracted once more with ethyl acetate. The combined organic phases are dried with Na2S04 and the solvent is removed in vacuo. Subsequent chromatography on silica gel affords 335 mg of a mixture of example 2a and 2b in the form of a yellow amorphous solid. Further purification on a preparative HPLC affords 212 mg of the para-substituted title (20 compound 2a, plus 58 mg of the meta isomer 2b.
Conditions for the preparative HPLC.
chiral column: Chiralpak AS 250 x 4.6 mm;
solvents: n-heptane/ethanol/methanol/acetonitrile 20:1.5:0.5:0.5 flow rate: 1 ml/min;
Remain fraction) = 14.145 min (-»2a);
Rt(subsidiary fraction) = 11.623 min (—>2b).
Both fractions were dissolved in methanol/2 N HCI mixture and freeze dried, and it was possible to obtain the title compounds 2a and 2b in the form of crystalline solids.
94
(Rt(2a) = 3.630 min (method A); MS(2a),(ES+) =371.3/373.3 (M++H)/ 412.3/ 414.3 (M++CH3CN); Rt (2b) = 3.668 min (method A); MS(2b),(ES+) =371.3/373.3 (M++H)/ 412.3/414.3 (M++CH3CN).
2c: (-)-4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene-sulfonamide acetate;
2d: (-)-3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene-sulfonamide acetate;
The title compound is synthesized by the method described under 2a/2b, using 10 intermediate 4b as starting compound. The purification and separation from the meta isomer which is to be expected takes place under the following conditions:
chiral column: Chiralpak AS 250 x 4.6/12 mm;
solvent: acetonitrile flow rate: 1 ml/min;
Remain fraction)= 4.394 min (-»2c);
Rt(subsidiary fraction) = 4.130 min (-»2d).
The purified products are each taken up in a 10% acetic acid solution and freeze dried, resulting in the desired acetates as slightly yellowish solids (Rt(2c) = 3.656 min
( (method A); MS(ES+) =371.1/373.1 (M++H)/412.1/414.1 (M++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;
CIH
95
6,8-Dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline (intermediate 4, example 2) was introduced in portions into chlorosulfonic acid (6.6 ml). The mixture was subsequently stirred at 40°C for one hour. The reaction mixture was then cooled to room temperature and an ice/water mixture was added. The precipitate which 5 separated out during this was filtered off with suction and taken up in ethyl acetate which, after washing with saturated brine was dried over magnesium sulfate. Subsequent concentration afforded 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonyl chloride as a solid crude product, a portion of which (150 mg) was directly introduced in portions into dimethylamine solution (5 ml, approx. 10 40% in water) cooled to 10°C. The resulting suspension was subsequently stirred at this temperature for 1.5 h. Then ice-water was added and, after extraction three times with ethyl acetate, the combined ethyl acetate phases were washed with saturated brine and dried over magnesium sulfate. The residue was taken up with water and, after addition of 2 N HCI, freeze dried. The crude product obtained in this way was 15 then purified by preparative HPLC.
Conditions:
stationary phase: Merck Purospher RP18 (10//M) 250 x 25 mm mobile phase: 90% H2O (0.05% TFA)-» 90% acetonitrile; 40 min; flow rate:
ml/min
The fractions containing the product were combined, the acetonitrile was stripped off in a rotary evaporator, and the aqueous phase was washed with saturated potassium carbonate solution and then extracted three times with ethyl acetate. The combined ethyl acetate phases were washed with saturated brine, dried over magnesium sulfate and concentrated. The residue was taken up in water and, after addition of 2 N HCI, freeze dried. 80 mg of a pale solid were obtained. This consisted of ~80% of the desired compound, in addition to -20% of a regioisomer (Rt = 4.000 min (method A);
MS(CI+) = 399.1).
96
Example 4:
4a: 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamideI hydrochloride;
CIH
Intermediate 1:4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-benzenesulfonyl chloride
At 0°C, 1 mmol of 6,8-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline (intermediate 4, example 2) is introduced into 1 ml of chlorosulfonic acid and stirred at 10 room temperature for 3 hours. For workup, the reaction mixture is poured onto ice, adjusted to pH 7 to 8 with 1 N NaOH and extracted twice with ethyl acetate. The combined ethyl acetate phases are dried with Na2S04 and concentrated in a rotary evaporator. The crude product obtained in this way is reacted further without further purification.
Intermediate 2: 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene-sulfonamide
319 mg of intermediate 1 are suspended in 6 ml of 25% strength ammonia and heated to 90°C. After 3 h, the mixture is diluted with H2O and extracted with ethyl acetate. The
organic phase is separated off and dried with Na2S04, resulting in 165 mg of the title compound.
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 ethereal HCI is added. After stirring at room temperature for 30 minutes, the precipitate is
97
filtered off with suction and dried, resulting in 136 mg of the hydrochloride in the form of a yellowish solid.
4b: 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide, 5 acetate;
AcOH
255 mg of intermediate 2, example 8, are mixed with 5 ml of glacial acetic acid, and 50 ml of H2O is added. Filtration of sparingly soluble constituents is followed by freeze drying, 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;
CIH
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, the alkylation product can be isolated in a yield of 69%.
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Intermediate 2:1-(4-Bromo-phenyl)-2-[(2,4-dichloro-benzyl)-methyl-amino]-ethanol; Intermediate 1 is reduced to the corresponding alcohol with 2 equivalents of NaBH4 in analogy to the manner described for intermediate 4, example 1, and the alcohol can be isolated in a yield of 86%.
Intermediate 3:4-(4-Bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoline;
.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, atO°C, 15 ml of conc. #10 H2SO4 are added. After stirring at room temperature for 2 hours, the reaction mixture is poured onto ice and made alkaline with 6 N NaOH. Three extractions with dichloromethane are carried out. The combined organic phases are dried with MgS04 and concentrated. For further purification, the residue is chromatographed on silica gel, resulting in 2.6 g of the title compound as a yellowish oil.
4-(4-Bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline,
hydrochloride;
300 mg of 4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline are 20 stirred in 2 N HCI at room temperature. The resulting precipitate is filtered off with suction and dried.
Example 6; 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid;
99
4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid;
.57 g (15 mmol) of 4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline (example 5, intermediate 3) are dissolved in 150 ml of abs. DMF/benzene (1:1). After the solution has been degassed, under argon 1.18 g 5 (4.5 mmol) of triphenylphosphine and 1.17 g (9 mmol) of Ca(HCC>2)2 are added. After renewed flushing with argon, 867 mg (0.75 mmol) of Pd(PPh3)4 are added and carbon monoxide is passed into the solution. The mixture is stirred at 120°C. After six hours at 120°C and standing overnight under argon, a further 867 mg (0.75 mmol) of Pd(PPh3)4 were added and stirring at 120°C and passing carbon monoxide into the Q 10 solution were continued for eight hours. After again standing overnight, 135 mg of
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 ethyl acetate. Three extractions with 2 N NaOH are carried out. The combined aqueous phases are adjusted to pH 6 with 6 N HCI and extracted three times with ethyl acetate. 15 The organic phases are dried with MgS04 and freed of solvent. The residue is purified on silica gel using a dichloromethane/methanol mixture, resulting in 420 mg of the title compound (Rt = 4.025 min (method A); MS(CI+) = 336.1/338.1).
Example 7: 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-ethyl-0 20 benzamide, trifluoroacetate;
146 mg (0.43 mmol) of 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid (see example 6) are dissolved in 5 ml of DMF, and 1.0 equivalent of triethylamine is added. At 0°C, a solution of 141 mg (0.43 mmol) TOTU in 3 ml of DMF 25 is added. The mixture is stirred at 0°C for 30 min and at room temperature for 30 min. This solution is then added at 0°C to a solution of 0.28 ml of 2 M ethylamine solution and 0.06 ml (0.043 mmol) of triethylamine in 5 ml of DMF, and the reaction mixture is
100
stirred at room temperature for three hours. For workup, the solvent is distilled off in vacuo, and the residue is taken up in ethyl acetate and washed twice with 1 N KOH and once with H2O. The organic phase is dried with Na2S04 and concentrated. Chromatography on silica gel (dichloromethane/methanol 95:5) is used for further purification. Further purification on a preparative HPLC (acetonitrile/H20/trifluoroacetic 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-10 benzamide, trifluoroacetate;
TFA
The title compound can be prepared by the method described in example 7 starting from n-propylamine and 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid (see example 6).
(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;
(X & /
TFA
CI
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).
101
Example 10: 6,8-Dichloro-2-methyl-4-(4-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline, trifluoroacetate;
0
CI
TFA
CI
456 mg (1.4 mmol) of CS2CO3, 6.75 mg (0.03 mmol) of palladium acetate and 28 mg (0.045 mmol) of 2,2-bis-(diphenylphosphino)-1,1-binaphthyl are introduced into 5 ml of abs. toluene. Under argon, a solution of 0.104 ml (1.2 mmol) of morpholine in 2.5 ml of abs. DMF, and a solution of 371 mg (1.0 mmol) of 4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline in 2.5 ml of abs. toluene are added, and the mixture 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 /methanol 95:5), resulting in 350 mg of the desired morpholine derivative. After a further purification on a preparative HPLC it is possible to isolate 160 mg of the corresponding trifluoroacetate in the form of a colorless solid.
Example 11: [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-phenyl]-diethyl-amine, trifluoroacetate;
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 ci
TFA
CI
102
the amount of Pd catalyst and phosphine ligand. The desired trifluoroacetate can be isolated as a colorless solid after preparative HPLC.
Example 12: 6,8-Dichloro-2-methyl-4-(4-piperidin-1-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline, trifluoroacetate;
The desired piperidine derivative can be obtained starting from piperidine and 4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline (example 5, intermediate 3) in analogy to the method described in example 10.
Example 13: 6,8-Dichloro-2-methyl-4-(4-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline, hydrochloride;
The reaction is carried out in analogy to the method described in example 10, starting from pyrrolidine and 4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline (example 5, intermediate 3). The product obtained after purification by chromatography is taken up in the DMSO/acetonitrile mixture, whereupon a precipitate separates out. This is filtered off, dissolved in 2 N HCI and freeze dried, resulting in the title compound of a colorless solid.
ci
TFA
Example 14: 6,8-Dichloro-2-methyl-4-[4-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-isoquinoline, trifluoroacetate;
103
TFA
Reaction of N-methyl-piperazine and 4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline (example 5, intermediate 3) by the method described in example 10 affords the title compound in the form of a colorless solid.
Example 15: 6,8-Dichloro-2-cyclopropyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline, trifluoroacetate;
o
TFA
6 ^
Intermediate 1:
Cyclopropyl-(2,4-dichloro-benzyl)-amine;
.25 g (30 mmol) of 2,4-dichlorobenzaldehyde are introduced into 140 ml of methanol and, at room temperature, a solution of 1.71 g (30 mmol) of cyclopropylamine is added. The mixture is stirred at room temperature for 40 min and then 1.42 g (37.5 mmol) of NaBhfy 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 MgS04 and concentrated. The crude product obtained in this way, in the form of a slightly yellowish oil, can be reacted further without further purification.
Intermediate 2: 2-[Cyclopropyl-(2,4-dichloro-benzyl)-amino]-1 -phenyl-ethanone;
104
Intermediate 1 is reacted with alpha-bromoacetophenone in the presence of triethylamine in dioxane by the method described in example 1, intermediate 3. For workup, the solvent is distilled off, and the residue is taken up in ethyl acetate. It is washed twice with H2O and twice with 2 N HCI, dried with MgS04 and concentrated. 5 The crude product obtained in this way can be reacted further without further purification.
Intermediate 3: 2-[Cyclopropyl-(2,4-dichloro-benzyl)-amino]-1 -phenyl-ethanol; Intermediate 2 is reduced with NaBH4 in analogy to the method described in # 10 example 1, intermediate 4. For workup, the mixture is concentrated, and the residue is partitioned between 1 N HCI and ethyl acetate. The aqueous phase is separated off and extracted once more with ethyl acetate. The combined organic phases are dried with MgS04 and the solvent is removed in vacuo.
6,8-Dichloro-2-cyclopropyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline, trifluoroacetate; Intermediate 3 (1.9 g) is dissolved without further purification in 10 ml of dichloromethane and cyclized with conc. H2SO4 by the method described in example 1. For workup, the reaction mixture is poured onto ice. The organic phase is separated off, and the aqueous phase is extracted once more with dichloromethane.
The combined organic phases are dried with MgSC>4 and freed of solvent.
Chromatography on silica gel (n-heptane/ethyl acetate 5:1 3:1) affords 200 mg of a yellowish oil, which is subjected to further purification on a preparative HPLC. This results in 184 mg of the title compound as trifluoroacetate.
Example 16:16a: (-)-N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylj-acetamide;
16b: (+)-N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;
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;
solvent: acetonitrile;
flow rate: 1 ml/min;
Rt((-)-enantiomer/16a) = 5.856 min;
Rt((+)-enanti°mer/16b) = 8.613 min.
Example 17: 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine, hydrochloride;
Intermediate 1:
4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine; 15 3.0 g (8.6 mmol) of N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide (example 1) are dissolved in 100 ml of 20% strength sodium ethanolate solution and heated under reflux for four hours. A further 2.0 g (29.4 mmol) of solid sodium ethanolate are added, and the mixture is heated under reflux for three more hours. For workup, the solvent is removed in vacuo, and the residue is taken up 20 in 200 ml of H2O and extracted twice with dichloromethane. The combined organic phases are dried with MgSC>4 and concentrated. Further purification by
106
chromatography on silica gel (ethyl acetate/heptane 1:1) results in the aniline as a yellowish oil in quantitative yield.
4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine, hydrochloride;
200 mg (0.65 mmol) of 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine are dissolved in 30 ml of ethanolic HCI. The clear solution is concentrated in vacuo. The residue is triturated in ether, filtered off with suction and dried,
whereupon it was possible to isolate 208 mg of the desired hydrochloride.
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 temperature for 1.5 hours. A solution of 2.5 eq of ethyl isocyanate in acetone is added dropwise at room temperature, and the solution is heated to reflux. For workup, the mixture is concentrated in vacuo, and the residue is taken up in H2O and extracted twice with ethyl acetate. The aqueous phase is acidified 20 with 6 N HCI, and the resulting precipitate is filtered off with suction. Washing with ethyl acetate and drying in vacuo affords the title compound in good yield.
Example 19:1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-propylurea;
107
CI
CI
A solution of 0.17 g (2.0 mmol) of n-propyl isocyanate in toluene is added dropwise to a stirred solution of 500 mg (1.63 mmol) of 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (see example 17) in 15 ml of toluene. After one hour at 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 with H2O 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-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 HCI and THF. The clear solution is concentrated in vacuo, and the residue is triturated with ether and filtered off with 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;
CI
a
108
Proceeding in analogy to the method described in example 19 and starting from 500 mg (1.63 mmol) of 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (see example 17) and 220 mg (3.0 mmol) of methyl isothiocyanate allows 245 mg of the desired thiourea to be isolated.
Example 21:1 -[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethylurea;
Preparation takes place in analogy to a method described in example 19, starting from 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (500 mg; 1.63 mmol) and ethyl isocyanate (284 mg/4 mmol).
21a: 1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea, hydrochloride;
Conversion into the corresponding hydrochloride takes place in analogy to the method described in example 19a.
Example 22: N-[4-(6-Methanesulfonyl-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylj-acetamide;
CI
CI
CIH
109
Intermediate 1: (4-Methanesulfonyl-benzyl)-methyl-amine is synthesized starting from 1-bromomethyl-4-methanesulfonylbenzene and methylamine in a manner known to the skilled worker.
The title compound is prepared in analogy to the synthetic route indicated in example 1, starting from (4-methanesulfonyl-benzyl)-methyl-amine (intermediate 1) and N-[4-(2-bromo-acetyl)-phenyl]-acetamide (example 1, intermediate 2).
Example 23: N-[4-(2,6,8-Trimethyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;
The synthetic route detailed in example 1 is followed, starting from (2,4-dimethyl-benzyl)-methyl-amine, which can be prepared from 1-bromomethyl-2,4-dimethyl-benzene and methylamine in a manner known to the skilled worker, and N-[4-(2-bromo-acetyl)-phenyl]-acetamide (example 1, intermediate 2).
Example 24: N-[4-(6-Bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;
The synthetic route detailed in example 1 is followed, starting from (4-bromo-2-chloro-benzyl)-methyl-amine, which can be prepared from 4-bromo-1-bromomethyl-2-chloro-benzene and methylamine in a manner known to the skilled worker, and N-[4-(2-bromo-acetyl)-phenyl]-acetamide (example 1, intermediate 2).
Br
110
Example 25: N-[4-(8-Chloro-2-methyl-6-pyrrolidin-1-yl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;
X
CI
1.02 g (3.12 mmol) of CS2CO3, 8.8 mg (0.04 mmol) of palladium acetate and 36.1 mg (0.06 mmol) of 2,2-bis-diphenylphosphino-1,1-binaphthyl are introduced into 6.5 ml of abs. toluene under argon. At room temperature, a solution of 512 mg (1.3 mmol) of N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide (example 24) in 4 ml of abs. DMF, and a solution of 111 mg (1.56 mmol) of pyrrolidine in 4 ml of DMF are added, and the mixture is heated at 100°C for 7 hours. For workup, 10 the solvent is removed in vacuo, and the residue is taken up in dichloromethane. Insoluble constituents are filtered off, and the filtrate is concentrated. The residue is chromatographed on silica gel with a dichloromethane/methanol mixture, and it is possible to isolate 360 mg of the compound of the example.
25a: N-[4-(8-Chloro-2-methyl-6-pyrrolidin-1 -yl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylj-acetamide, hydrochloride;
X
CIH
320 mg of N-[4-(8-chloro-2-methyl-6-pyrrolidin-1-yl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide are dissolved in 20 ml of ethanolic HCI, stirred at room temperature 20 for 30 min and concentrated. The residue is taken up in H2O and freeze dried.
Example 26: N-[4-(8-Chloro-2-methyl-6-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylj-acetamide, trifluoroacetate;
111
xTFA
Preparation takes place in analogy to the method described in example 25, starting from N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-acetamide (example 24) and morpholine. The chromatography on silica gel was followed by a further purification on a preparative HPLC.
Example 27: N-{4-[8-Chloro-2-methyl-6-(4-methyl-piperazin-1-yl)-1,2,3,4-tetrahydro-isoquinolin-4-yl]-phenyl}-acetamide;
X
Preparation takes place in analogy to the method described in example 25, starting from N-[4-(6-Bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide (example 24) and N-methyl-piperazine.
I
27a: N-{4-[8-Chloro-2-methyl-6-(4-methyl-piperazin-1 -yl)-1,2,3,4-tetrahydro-isoquinolin-15 4-yl]-phenyl}-acetamide, hydrochloride;
X
x HCI
CI
220 mg of N-{4-[8-Chloro-2-methyl-6-(4-methyl-piperazin-1-yl)-1,2,3,4-tetrahydro-isoquinolin-4-yl]-phenyl}-acetamide are dissolved in a little methanol, diluted with 2 N HCI and freeze dried, resulting in 226 mg of the desired hydrochloride.
112
Example 28: N-{4-[8-Chloro-6-(cyclopropylmethyl-amino)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl]-phenyl}-acetamide, hydrochloride;
Preparation takes place in analogy to the method described in example 25, starting from N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide (example 24) and C-cyclopropyl-methylamine. The chromatography on silica gel was followed by a further purification on a preparative HPLC. The purified compound was dissolved in 1 N HCI, diluted with H2O and freeze dried.
Example 29: 5-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoic acid;
Intermediate 1: Ethyl 5-acetyl-2-hydroxy-benzoate is prepared from 5-acetyl-2-hydroxy-benzoic acid by acid-catalyzed esterification in a manner known to the skilled worker.
Intermediate 2: Ethyl 5-(2-bromo-acetyl)-2-hydroxy-benzoate is prepared from ethyl 5-acetyl-2-hydroxy-benzoate by a known method in analogy to the process described in example 1, intermediate 2.
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).
x HCI
CI
113
-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoic acid; 6.8 g (18 mmol) of ethyl 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoate are hydrolyzed in an ethanol/2 N KOH mixture in a manner known to 5 the skilled worker, resulting in 5.4 g of the free acid.
29a: 5-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoic acid, sodium salt;
352 mg (1 mmol) of the free acid 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-
isoquinolin-4-yl)-2-hydroxy-benzoic acid are dissolved in 10 ml of 0.1 M NaOH, diluted with 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-N-15 methyl-benzamide, trifluoroacetate;
The title compound can be prepared starting from 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoic acid in a TOTU-mediated reaction with methylamine in analogy to the method described in example 7.
Example 31: 5-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-ethyl-2-hydroxy-benzamide, trifluoroacetate;
114
CI
TFA
CI
The title compound can be prepared starting from 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoic acid in a TOTU-mediated reaction with ethylamine in analogy to the method described in example 7.
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 reaction with N1,N1-dimethyl-ethane-1,2-diamine in analogy to the method described in example 7.
Example 33: N-[5-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoyl]-guanidine;
2.52 g of potassium tert-butoxide are added to a solution of 2.39 g (25 mmol) of guanidine hydrochloride in 15 ml of abs. DMF and stirred at room temperature for 45 min. A solution of 950 mg (2.5 mmol) of ethyl 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoate (example 29, intermediate 3) in 10 ml 20 of abs. DMF is added, and the mixture is stirred at room temperature for four hours. After no further increase in conversion is detectable, the precipitate is removed by filtration with suction and the solvent is removed in vacuo. The residue is taken up in
CI
a.
115
2 N HCI and extracted twice with dichloromethane. The aqueous phase is adjusted to a pH of about 10 with KOH, whereupon the desired acylguanidine separates out as a colorless precipitate. Filtration with suction and drying affords 793 mg of the title compound.
Example 34: N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;
N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide; The desired meta-acetanilide is prepared in analogy to the synthetic route indicated for example 1, starting from N-(3-acetyl-phenyl)-acetamide and 2,4-dichlorobenzyl-(methyl)-amine (example 1, intermediate 1) in four analogous stages.
Example 35: 3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine;
Acetyl is eliminated from N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide (example 34) by the method described in example 17, intermediate 1, in the presence of sodium ethanolate.
Example 36: 2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine;
CI
CI
CI
Intermediate 1: N-[2-(2-Bromo-acetyl)-phenyl]-acetamide;
116
31 g (0.175 mol) of N-(2-Acetylphenyl)-acetamide (prepared by acylation of 2-aminoacetophenone with acetyl chloride as described by Fuerstner, Alois; Jumbam, Denis N.; Tetrahedron; 48; 29; 5991-6010, (1992)) are dissolved in 200 ml of glacial acetic acid. 127 ml of 33% strength HBr in glacial acetic acid are added and then, at 5 room temperature, 8.75 ml (0.175 mol) of bromine are slowly run in. The mixture is stirred at room temperature overnight. The mixture is stirred into 1.5 I of ice-water, and the precipitated product is filtered off with suction, thoroughly washed with ice-water and dried in vacuo. The crude product contains, according to HPLC and NMR, some precursor and dibrominated product, but is pure enough (about 85% strength) for 10 further reaction.
Yield: 43 g
Intermediate 2: N-(2-{2-[(2,4-Dichloro-benzyl)-methyl-amino]-acetyl}-phenyl)-acetamide;
12.4 g (65.24 mmol) of 2,4-dichloro-N-methylbenzylamine (example 1, intermediate 1) are dissolved in 200 ml of dioxane. To this are added 19.96 g of the crude product from the preceding bromination, likewise dissolved in 200 ml of dioxane, and 45 ml of triethylamine. The mixture is stirred at room temperature overnight and then filtered. The filtrate is evaporated, and the residue is taken up in ethyl acetate and washed with 20 saturated sodium bicarbonate solution and brine, dried over sodium sulfate and i concentrated in a rotary evaporator. The crude product (20.4 g) is pure enough according to NMR for further reaction.
Intermediate 3: N-(2-{2-[(2,4-Dichloro-benzyl)-methyl-amino]-1 -hydroxy-ethyl}-phenyl)-25 acetamide;
g of the crude product from the preceding stage (about 50 mmol) are dissolved in 200 ml of methanol and cooled to < 5°C in an icebath. To this are added, while stirring vigorously, 4.3 g (109 mmol) of sodium borohydride in portions so that the internal temperature does not exceed 10°C. The mixture is then stirred in the icebath for 30 30 min and at RT for 1 h. After standing overnight, the mixture is evaporated, and the residue is taken up in ethyl acetate, washed 3* with water and 1 * with brine, dried
117
over sodium sulfate and concentrated in a rotary evaporator. The crude product (19.4 g) is reacted further without purification.
Intermediate 4:1-(2-Amino-phenyl)-2-[(2,4-dichloro-benzyl)-methyl-amino]-ethanol; 5 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 to 10-12 with 20% strength NaOH. The product is extracted with ethyl acetate, and the combined extracts are washed with brine, dried over sodium sulfate and evaporated. 010 The crude product (9.9 g) contains some sodium chloride, but this does not interfere with further reaction.
2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine;
9.9 g of the crude product from the preceding stage are dissolved in 350 ml of 15 chloroform. While cooling in an icebath, 123 ml of conc. sulfuric acid are added dropwise. The mixture is stirred in the icebath for 2 h and is then allowed slowly to reach RT and is finally heated at 50°C overnight. The cooled mixture is poured onto ice and made alkaline (pH >10) with sodium hydroxide solution. The organic phase is separated off, the aqueous phase is back-extracted 2* with methylene chloride, and 20 the combined organic phases are washed with water and NaCI, dried over sodium 0 sulfate and evaporated.
General method for preparing the compounds of examples 37 to 77:
154 mg (0.5 mmol) of the title compounds from example 35, example 36 or 25 example 17, intermediate 1, are introduced into 5 ml of dichloromethane, and 0.076 ml (0.55 mmol) of triethylamine is added. At 0°C, a solution of 1.1 equivalents (0.55 mmol) of an acid chloride in 5 ml of dichloromethane is added, and the mixture is stirred overnight while warming up. For workup, it is filtered and freed of solvent. The residue is dissolved in 20 ml of ethyl acetate and washed once each with 5% strength 30 NaHC03 solution and 5% strength NaCI solution, and dried. Evaporation of the solvent is followed by final purification on a preparative HPLC.
118
Table 1:
Example
Precursor 1/ aniline
Precursor 2/ acid chloride
Product
37
NHj c,rr^
a
Ex. 17, int. 1
"V
0
tfa yCX
38
Nh2
Ex. 17, Int. 1
o
TFA
uv\
CI
39
NHj
°Yn
Ex. 17, Int. 1
0
O: tfa xpcx
40
nh2
aYp
Ex. 17, Int. 1
V
0
Jsf ci-v^556;^an tfa yCX
41
nihj
Ex. 17, Int. 1
>v
0
hA<
cl~y^trsi tfa
119
42
nh2
XX/N\
c!
Ex. 17, Int. 1
o tfa
43
nh2
cYT^
Ex. 17, Int. 1
°Y°
0
HN^
44
nh2
c'YYi
Ex. 17, Int. 1
°Y°
0
hn^O
tfa ci
45
nh2
C'y^A,
Ex. 17, Int. 1
0
tfa
XXX
46*
nh2
cirri yv\
ci
Ex. 17, Int. 1
°^v
0
■^a
47
nhj clrrS
Ex. 17, Int. 1
qK
N
/o tfa xpcx ci
120
48
nh2
yX
ci
Ex. 17, Int. 1
ov ,0 CI
°*< hn ^
tfa
XpO-.
a
49
nh2
cYp yvN-s Ex. 17, Int. 1
<\ ,o
CI
0, ,0 hn tfa
^(pCX
50
nh2
C,YT^
Ex. 17, Int. 1
°v ,0
vo' \ ,o.
N CI
0, ,0 v hn"' n^*
ckx*^JL tfa xpcx
51
t^ynn,
TJC^
Ex. 35
^Ya
0
cnr
Cl^^Jk tfa
KSKs*k
52
(TT
Ex. 35
0
q"r^
aYY^ ™
53
cr
Ex. 35
0
OrY^
aYV^i tfa
VjA^-N^
54
XpC-^
Ex. 35
-V
0
QrY^
CIWk tfa
121
55
(^jfNH2
Ex. 35
V
0
QrV*
ciYYN tfa ci
56
xx^"v
Ex. 35
'V
0
nrV^
'w' 0
CI^X tfa
"kjA^
57
xx-^
Ex. 35
°y
0
a"r°
°'YVS tfa ci
58
xjon\
Ex. 35
°T°
Or"T°
c'^nx tfa
CI
59
xjx^N^
Ex. 35
0
cri*
ck ii 1
vA^-N\
60
l^yNH,
xx^
Ex. 35
"Oy"
o
<?T°X
avy\ TFA
61
^jfNH2 xx^N^
ci
Ex. 35
O1"
N
crV^
ciy^x tfa
122
62
CI
Ex. 35
°v ,0
v.v
^ CI
nr o' %
CiYy\ TFA
63
XjOnV.
Ex. 35
0, ,0 v ^sC
— CI
V 00
C>Y^X TFA
yk^N-s
64
Ex. 35
0s ,0
v
\ /wv
N ^Cl rrNx^
LI) o o C'Y^Yl TFA
65
Ex. 36
^Y°
0
$y-
Yy > TFA
66
W^NH2
Ex. 36
^YCI
0
cy~
c|v^A Y 1 1 ^
67
XjC/n^
Ex. 36
0
OLhju^
H IT I TFA
68
XpC-NV Ex. 36
V
o
SVr
"yyS
tfa
123
69
XA^-n\
CI
Ex. 36
V
0
SV*
Vn
70
Ex. 36
V1
0
•jy*'
TFA
71
a,
Ex. 36
°Y°
0
Clw\
TFA
72
^r^NHj
XJOn\
Ex. 36
°Y"
o
TFA
a
73
Ex. 36
0
SS1*
"YYS
TFA
74
■^5S
Ex. 36
^\a o
^"'Pr
75
Ex. 36
°s ,0
s
CI
0-V
Cl^cc
TFA
124
76
Ex. 36
CI
CkV/
TFA
CI
77
XpC-N\
Ex. 36
°s ,0
\
N CI
fi\ 0^ .0
wr
TFA
") Product precipitates from the reaction solution and requires no further purification
Example 78:1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea, trifluoroacetate;
0.355 mmol of the compound of example 35 is dissolved in 5 ml of dry acetonitrile, and 0.39 mmoi of ethyl isocyanate is added. After standing overnight with exclusion of moisture, the solvent is removed and the crude product is purified on a preparative HPLC, resulting in the title compound as a colorless solid.
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 and methyl isothiocyanate by the method described in example 78.
125
Example 80:1-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;
The process is analogous to example 78, starting from the compound of example 36 5 and ethyl isocyanate. For workup, the resulting precipitate is filtered off with suction and washed with acetonitrile, resulting in the desired ethylurea as a colorless solid.
Example 81:1-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea, trifluoroacetate;
Ck
^ ^ ^ TFA
ii
The compound of example 36 and methyl isothiocyanate are reacted in analogy to the method described in example 78.
Example 82: N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-15 ethanesulfonamide, hydrochloride;
307.1 mg (1 mmol) of the compound of example 35 are dissolved in 10 ml of pyridine 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 temperature.
For workup, the solvent is removed in vacuo, the residue is taken up in ethyl acetate and washed with H2O. The organic phase is dried with MgSC>4 and concentrated. The
126
crude product is chromatographed on silica gel. The sulfonamide obtained in this way is dissolved in a THF/2 N HCI mixture and again concentrated in vacuo, resulting in 208 mg of the desired hydrochloride.
Example 83: N-[3-(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 the compound of example 35 and methanesulfonyl chloride.
Example 84: N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl]-ethanesulfonamide, hydrochloride;
ci
The process is analogous to the method described in example 82, starting from the 15 compound of example 17, intermediate 1, and ethanesulfonyl chloride.
Example 85: N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide, hydrochloride;
O, ,0 HN ^
127
The process is analogous to the method described in example 82, starting from the compound of example 17, intermediate 1, and methanesulfonyl chloride.
Example 86: 86a: (-)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-5 phenyl]-acetamide;
86b: (+)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;
(+ and -) Q
2.0 g of the title compound from example 34 are separated on a chiral phase, resulting 10 in about 1.0 g of the two enantiomeric acetamides 86a and 86b.
chiral column: Chiralpak ADH/31 250 x 4.6 mm;
solvent: acetonitrile;
flow rate: 1 ml/min;
Rt((-)-enantiomer/86a) = 5.541 min;
Rt((+)-enantiomer/86b) = 7.033 min.
General method for preparing the compounds of examples 87 to 98 1.0 mmol of 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (example 17, intermediate 1)or 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-20 4-yl)-phenylamine (example 35) is introduced into 10 ml of pyridine and, at 0°C, a solution of 1.2 equivalents of the appropriate sulfonyl chloride (see table 2) in 5 ml of dichloromethane is added dropwise. The mixture is stirred at room temperature. A catalytic amount of DMAP is added depending on the progress of the reaction and, where appropriate, the reaction temperature is increased to 50°C until no further 25 increase in conversion can be detected. For workup, the mixture is concentrated and the residue is partitioned between ethyl acetate and saturated NaHCC>3 solution. The
128
organic phase is separated off and washed once more with saturated NaHC03 solution and H20, dried with Na2SC>4 and concentrated. For further purification, the crude product obtained in this way is chromatographed on silica gel. The products obtained in this way are converted into the corresponding hydrochlorides by dissolving 5 the substances in 2 N HCI or ethanolic HCI and freeing off solvent, resulting in the desired HCI salts.
Purification in a preparative HPLC system results in the corresponding products as trifluoroacetates.
• Table 2:
Example
Precursor 1/ aniline
Precursor 2/ acid chloride
Product
87
NHj
Ex. 17, Int. 1
oN ,0
FY Cl
F
°* -°
cb
TFA
CI
88
NHZ
CI
Ex. 17, Int. 1
f4'V
F^^-"" ^Cl c'YYi
CI
88a
NHj
TjC-N-v.
Ex. 17, Int. 1
4v
F^^ ^Cl
°V°JkF
HN" *^^F
ck^X ctH
yCX
89
NH2
Ex. 17, Int. 1
S \
CI
"Vn
129
89a nh2
Ex. 17, int. 1
Br-^Xto
CI
Ov ,0
Ns hn" V\
AH U *
c'YYI cih
90
nh2
ct
Ex. 17, Int. 1
-CCHo
CI
V°
hn"
O
XpC-n^
a
90a nh2
CI
Ex. 17, Int. 1
bi v
hn"
i^N
0
c,yVI «
CI
91
nh2
c'YT^
Ex. 17, Int. 1
\
°V-°
TXV-
vjjns n v x c'TTI
yvNN
91a nr2
Ex. 17, Int. 1
c>^r \
°v° yy > cih
"s^k^
92
nhj
Ex. 17, Int. 1
v?
0, ,0 P1
hn^T^n-
cYp
130
92a nh2
Ex. 17, Int. 1
oj V/ <^c,
I
0. ,0 P'
cih
93
OrNH*
Ex. 35
Ov ,0 F. .SC
fY a
F
i if * * L J o o
X3CX
CI
94
CI
Ex. 35
FJ v°
^Cl rf?sCf'
CI
94a
^yhh'
XX^nx
CI
Ex. 35
f4 V°
pr^
T j 1 C!H
CI
95
^ynh'
XJC-N\
CI
Ex. 35
j~\j
Br-^s/^S=0 CI
\ II v
LI) o o
XX/Nv
96
a
Ex. 35
-U?4»
CI
j^o rr"^
Cj oAo
TpC-^
ci
n—4.
a. 0
96a
XJOn\
Ex. 35
Tv if n^\s^s=0 CI
Cj cA>
QW^\ cih ycx a
131
97
CI
Ex. 35
\
If
,TY X-
|IJ O 0
97a rr
Ex. 35
\
rvv^
IjJ 0--0 II 1 C,H
98
Ex. 35
°i
\ / 01
CJ °'j°
General method for synthesizing the compounds of examples 99 to 110 Preparation of the amine component
4.0 mmol of the aromatic aldehyde (see table 3) are stirred with 8.0 mmol of the aliphatic amine (see table 3) in methanol at room temperature for 2 hours and then, depending on the progress of the reaction, 0.67 to 2.0 eq of NaBKty are added in portions. After standing at room temperature overnight, the solvent is removed and the residue is taken up in 1 N HCI. It is extracted with dichloromethane. The aqueous phase is adjusted to a pH of 11 to 12 with NaOH and again extracted with dichloromethane. The organic phases are dried with MgS04 and concentrated in a rotary evaporator. Further purification takes place by chromatography on silica gel or on a preparative HPLC.
Preparation of the bromo ketone component
The bromo ketone building blocks are synthesized by methods known from the literature, starting from commercial acetophenones by treatment with bromine in glacial acetic acid in analogy to example 1, intermediate 2.
132
The compounds of examples 100 to 111 can be prepared starting from the amine and bromo ketone components shown in table 3 in analogy to the synthetic route shown in example 1 (alkylation of the amine component by the bromo ketone component, subsequent reduction with NaBH4 and final H2SC>4-mediated cyclization).
The resulting tetrahydroisoquinolines can be converted into the corresponding salts in a manner known to the skilled worker.
Table 3:
Example No.
Aromatic aldehyde
Aliphatic amine
Amine component
Bromo ketone component
Compound of example
99
°X1
s^CHO
—nh2
9 o wo x ¥
fv "NH2 sx ^br *)
fy nh,
100
"TX
—nh2
%
a^^jl cih
^XX
101
O
0
1
o
—nh2
■isl ^br
CIH
102
y^CHO CI
^—nh2
&
aH
103
F
CHO
F"\-F F
—nh2
F^F
o^Br it o f^tf
133
104
C'T1
kj^CHO CI
y~m2
CI '
&
T^Y
105
CI
—nh2
&
106
c'"CL
k^CHO CI
—nh2
"TJUk
F
^Br f
cih
107
Y^CHO CI
—nh2
CI
.Br cih
108
k^-CHO
—nh2
IJLa x ^Br Cr
■^xj qh
109
—nh2
aXXX
110
Br
—nh2
KjUk
^jl cih cpcx
*) Synthesis described in: Lang et al., DE-A 24 36 263
General method for preparing the compounds of examples 111 to 124 0.358 mmol of the acids indicated in table 4 are dissolved in 1 ml of DMF, and 0.221 ml (1.30 mmol) of diisopropylethylamine is added. At 0°C, a solution of 128 mg (0.390 mmol) of TOTU in 1 ml of DMF is added dropwise. After addition of a solution of 100 mg (0.325 mmol) of the amine component indicated in table 4, in 2 ml of DMF, the mixture is stirred at room temperature overnight. For workup, insoluble constituents are filtered off and washed with 20 ml of ethyl acetate. The filtrate is washed twice with
134
saturated NaHCC>3 solution and once with 5% strength NaCI solution, dried and concentrated.
The crude products which still contain Boc protective groups are deprotected without 5 further purification (see below: general method for eliminating the Boc protective groups). Workup of building blocks without Boc protection is followed by purification by preparative HPLC, with the desired compounds of the examples being obtained as trifluoroacetates.
^ 10 General method for preparing the compounds of examples 124 to 147
0.358 mmol of the acids indicated in table 4 are dissolved in 1 ml of DMF, and 0.221 ml (1.30 mmol) of diisopropylethylamine is added. At 0°C, 151 mg (0.975 mmol) of diethylcarbodiimide, a solution of 132 mg (0.975 mmol) of HOBt in 1 ml of DMF, and 20 mg (0.162 mmol) of DMAP are added. After addition of a solution of the amine 15 component indicated in table 4, in 2 ml of DMF, the mixture is stirred at room temperature overnight. For workup, insoluble constituents are filtered off and washed with 20 ml of ethyl acetate. The filtrate is washed twice with saturated NaHC03 solution and once with 5% strength NaCI solution, dried and concentrated.
The crude products which still contain Boc protective groups are deprotected without ^ further purification (see below: general method for eliminating the Boc protective groups). Workup of building blocks without Boc protection is followed by purification by preparative HPLC, with the desired compounds of the examples being obtained as trifluoroacetates.
General method for eliminating Boc protective groups The resulting crude products are stirred in 5 ml of a 10% strength solution of trifluoroacetic acid in dichloromethane at room temperature for one hour. The residue from evaporation in vacuo is purified on a preparative HPLC, with the desired 30 compounds of the examples being obtained as trifluoroacetates.
Table 4:
135
Example No.
Acid component
Amine component
Compound of example
111
f H
Aw o 1
nhj
Vn
CI
Ex.17, int. 1
0
,jl _,NH. H u 2
aYiC'
TFA
a
112
S i H0 ny0vt<
o 1 .
nh2
j
■ '
a
»Aa
CkT^Y"
TFA
a
113
nh2
aYri
CI
•1
hjM-
"m, TFA
a
136
114
Ayr nh,
0
°r6.
ci
Jv^NH,
Hi tfa ct
115
"Vty ijwj
VJM
a
0
0
aV!#V/\
TFA
a
116
AVx nhj nhj
VYi a
0
Jl .NH,
wY
NHj ksJL^N^ TFA
a
117
-Xjv nh,
"Yn yvNv a . v'
>
°yv\ .TFA
kJk^
a
118
"*0
nh2
XJov a
go a
119
HoA^Nn nhj c'YYi
Vv-^s ci cVyS tfa ci
137
120
4s o
x nhj
"YYi a
/ti
CIVVS tfa
^PCX
a
121
0
»Vi nhj
"YYi ■
'W'v a
0
fj ^
tfa a
122
nhj
Wi
VjM
a
O nh'
aYYi tfa kA^
a
123
0
h
HOATNN ij no,
nhj aYYi a J
>
aM
O nc>i
Qy^jA tfa yknx a
124
° / h°Vnh nhj ci o ,
tfa a
125
n h nhj xa a
A>
A, n
0 H
tfa kA>^
ci
138
126
"\v
NHj
CI
£°<
y o
CK^I
1 1 TFA
a
127
HO
NHj
°rin a
tV>
|f J H
tfa a
128
o i>
H
NHj a
X'
/v S
0 H
aY'>Yi TFA
ct
129
if ^
HO
n'
H
NHj clYp a J
>
-Cf*'
TL^n
/W n
0 H
asNTs^T' tfa
S/N^S a
130
KO-^V'Y
0/NH,
XX/n^
a
Ex.35
jyrr kJk^N\ TFA Q
131
XJC^
CI
oVr kJk^N\ TFA
a
139
132
Q/Nn,
a rYY^
Kf? o
TFA
a
133
jylY
Q.NH,
a'v!\/>
a frV^
0
TFA
a
134
»Vty
NHj
CI
rvV^
Kf? o ksJk,Nv TFA
a
135
\3C-^
a ryV?
Kj? o cVYi m a
136
syV-
\K-^
CI
fVr°
a\jiS^JL TFA CI
137
£2*.
a
■ (Vy0"
VA tfa a
140
138
o
X
[TyNKj a
rrM?
ct
139
HO-V-1
irvNH* XjC-n^
a aV^'
°YYS
Cl
140
NH,
/yNH.
CI
NH,
CrV?
K^f> o 1
«YYS ^
a
141
NO,
/wNHj c'Y1m
VN/NN
Cl ,
NO.
rvV4
■y 0
TFA
XpCX
a
142
^yHHt
Cl
CY^W"
• y^ °
ayV TFA kjA^NN a
143
~*ts
*~N
H
/V-N^
ct rySr1"
•y o ayyk TFA
a
141
144
"°AU/
a
Cl
145
^ H
or
Cl v«
TFA
a
146
n°
^-N H
fYNHj
. a
A
rr
0
0lYr^iri TFA
a
147
IT
H0 if/1
H
/yNH,
a j
A
h (i n r^TN^^.
TFA
Cl
Example 148:1-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-
2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (95 mg, compound of example 36) is introduced into 4 ml of acetonitrile and, while stirring, 27 mg of ethyl isothiocyanate are added. After standing at room temperature for 15 hours, the solvent is removed in vacuo, and the residue is purified on a preparative
142
HPLC. The trifluoroacetate obtained in this way is taken up in water and made alkaline with K2CO3. The aqueous phase is extracted with ethyl acetate. The organic phase is separated off, dried with MgS04 and concentrated. The residue is taken up in dilute
HCI and freeze dried, resulting in 36 mg of the title compound.
Example 149:1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-thiourea, hydrochlorides;
4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (50 mg, compound of example 17, intermediate 1) are introduced into 4 ml of THF, and ethyl isothiocyanate (14 mg) is added. After heating to reflux for 2 hours, the reaction solution is concentrated and heated at 85°C to 2 hours. The crude product obtained in this way is purified on a preparative HPLC. Further treatment of the trifluoroacetate 15 obtained in this way as described in example 148 affords 33 mg of the desired hydrochloride after freeze drying.
Example 150:1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-thiourea, trifluoroacetate;
143
3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (50 mg, compound of example 35) are dissolved in 3 ml of THF and, while stirring, 14 mg of ethyl isothiocyanate are added. After heating to reflux for 2 hours, the reaction solution is concentrated and heated at 85°C for 2 hours. The crude product obtained in this way 5 is purified on a preparative HPLC, becoming 66 mg of the title compound.
Example 151: 3-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-dimethyl-urea, hydrochloride;
Cl
Intermediate 1:4-nitrophenyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]carbamate, hydrochlorides;
3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (350 mg, compound of example 35) are dissolved in 17.5 ml of dichloromethane and, while ^ 15 stirring, 230 mg of 4-ntirophenyl chloroformate are added. After 4.5 hours, a further 0.1 equivalent (23 mg) of 4-nitrophenyl chloroformate were added, and the solution was stirred overnight. For workup, the resulting precipitate is filtered off and washed with dichloromethane. The title compound obtained in this way can be reacted further without further purification.
3-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1 -dimethyl-urea, hydrochloride;
mg of 4-nitrophenyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]carbamate hydrochlorides (intermediate 1) are suspended in 3.5 ml of 25 dichloromethane and, while stirring, a solution of 3.7 mg of dimethylamine in 1 ml of dichloromethane is added dropwise. After 1 hours, the mixture is diluted with
144
dichloromethane and washed with aqueous K2CO3 solution. The organic phase is separated and washed twice with saturated K2CO3 solution, dried with MgS04 and concentrated. The residue is taken up in dilute HCI and freeze dried, resulting in 29 mg of the title compound.
The following examples are prepared in analogy to the method described in example 151, starting from intermediate 1 and the appropriate amine components:
145
Table 5:
Example No.:
Structure
152
r"Y
CY
Cl
153
o
0
aYYl Cl a
154
o o
°xxb* °
a
155
rrvC Kfp o yCX
a j
156
/ r fYNYNs/ a a
C!
157
or
°
Cl
146
The following examples were prepared in analogy to the method described in example 151. THF was used as solvent, and the reactions were carried out in a closed reaction vessel. Reaction temperatures of 85°C were necessary for examples 159 to 166. Compound of example 167 was purified by preparative HPLC.
Table 6:
Example No.:
Structure
159
Chiral
Nv^x0 q^yS a
WNS
160
(Yr"
„ . T V:
a a
161
prV0
c I
ci ci
162
!^YnY°
T '"V"
cYYS a S yuxa A
Cl
148
163
y ^
vAa v a 1
a
164
rrW
i i I
Nv c.^OCa \
YYi a •
Cl
165
T "*1
Vn t
VVNn 1 a
166
fYNr°
. Y V<
c'YVS ci ^
yVNs a
Cl
167
fTYNY°
T NY^
01yVx] a VN
a. •
ci
149
Example 168: N-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methylpiperazine-1-carboxamide, hydrochloride;
Intermediate 1: 4-Nitrophenyl [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]carbamate, hydrochlorides;
[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (200 mg, comparative example 36) are dissolved in 10 ml of dichloromethane and, while stirring, 131 mg of 4-nitrophenyl chloroformate are added. After 3.5 hours, the resulting precipitate is filtered off with suction and washed with dichloromethane. The crude product obtained in this way is recrystallized from dichloromethane, resulting in 159 mg of the title compound.
N-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methylpiperazine-1 -carboxamide, hydrochloride;
mg of 4-nitrophenyl [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]carbamate hydrochlorides are suspended in 2 ml of dichloromethane, and a solution of 3.2 mg of 1-methylpiperazine in 1 ml of dichloromethane is added. After 1 hours, the mixture is diluted with dichloromethane and washed with aqueous K2CO3
solution. The organic phase is separated and washed twice with saturated K2CO3
solution, dried with MgS04 and concentrated. The residue is taken up in dilute HCI
and freeze dried, resulting in 13 mg of the title compound.
Cl
Cl
Ci
The following examples are prepared in analogy to the method described for example 168.
7:
150
Example No.:
Structure
169
Ol x
8 1^ 1 Cl yOv a
170
T^N^N''
aYyS 1
Cl
171
Osl
Xs N-^n-^v av^A L
\pkXci ^
Cl
172
Ok t jT^tr'N
qyyS O
ci a
173
Cx A
a"T^Ti a ^-°
y^Ns
Cl
174
if*8*! ° y N'^n-'X
civrS k>
Cl
Cl
175
f^l f 1
a^^A.
IB' a sA^nx T ci a
151
Example 176: N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl-piperazine-1 -carboxamide, hydrochlorides:
Cl
Intermediate 1:4-Nitrophenyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-5 4-yl)-phenyl]carbamate, hydrochlorides:
4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (200 mg, compound of example 17, intermediate 1) are dissolved in 10 ml of dichloromethane and, while stirring, 131 mg of 4-nitrophenyl chloroformate are added. After 4.5 hours, the resulting precipitate is filtered off with suction and washed with dichloromethane. 10 The crude product obtained in this way is recrystallized twice from dichloromethane, resulting in 254 mg of the title compound.
N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl-piperazine-1 -carboxamide, hydrochlorides:
15 mg of 4-nitrophenyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]carbamate hydrochloride are suspended in 2 ml of dichloromethane, and a solution of 3.2 mg of 1-methylpiperazine in 1 ml of dichloromethane is added. After stirring for 5 hours and standing overnight, the mixture is diluted with dichloromethane and washed with aqueous K2CO3 solution. The organic phase is separated and 20 washed twice with saturated K2CO3 solution, dried with MgS04 and concentrated. The residue is taken up in dilute HCI and freeze dried, resulting in 13 mg of the title compound.
The following examples are prepared in analogy to the method described for
example 176.
152
8:
Example No.:
Structure
177
0
' l
N0
ck-J^ a
C!
178
*
O
XAT
a r'S
vo^
Cl
153
179
N^N"' C! fS
CI
180
0
01 cb yL,Nv
Cl
181
6 c,
"TXS a
Cl
182
A O
a a a
183
'A-,
6^°
°Wsa.
yvNx "
a
Example 184: N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]formamide, hydrochloride;
154
N O
4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (200 mg, compound of example 17, intermediate 1) is dissolved in 1 ml of formic acid and 5 heated to reflux for 15 min. After standing overnight, the mixture is added to an ice/water mixture and extracted twice with ethyl acetate. The combined organic phases are dried with MgSC>4 and concentrated. The residue is taken up in dichloromethane and washed with saturated NaHC03 solution. The phases are separated and the aqueous are extracted three times more with dichloromethane. Drying of the organic 10 phases (MgS04) and removal of the solvent by distillation afford 167 mg of crude product. 10 mg are dissolved in dilute HCI and freeze dried, resulting in 11 mg of the title compound.
Example 185: [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-15 phenyl]methyl-amine, hydrochloride
Cl
N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]formamide (150 mg, compound of example 184) are dissolved in 2.5 ml of THF and, at 50°C 20 under argon, added dropwise to a solution of 0.45 ml of a 1 M solution of lithium
155
aluminum hydride/THF in 2.5 ml of THF. The mixture is heated to reflux for 1 hour. After standing overnight, a further 0.22 ml of a 1 M lithium aluminum hydride solution are added at 50°C, and the mixture is heated to reflux for a further hour. For workup, the solvent is removed and the residue is partitioned between dichloromethane and aqueous HCI. The phases are separated and the aqueous are extracted three times with dichloromethane, The combined organic phases are dried with with MgS04 and concentrated. Further purification takes place on a preparative HPLC. The product obtained in this way is taken up in an NaHC03 solution and extracted with dichloromethane. Drying of the organic phase with MgS04 affords 80 mg of the free base. 10 mg are taken up in diluted HCI and freeze dried, resulting in 10 mg of the title compound.
Example 186:1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3-dimethyl-urea, hydrochlorides;
The title compound is prepared by the method described for example 151, starting from [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]methyl-amine (example 185), 4-nitrophenyl chloroformate and methylamine (20 jj\, 2 M in THF) resulting in 9 mg of the desired hydrochloride.
o c
Ci
156
The following compounds are prepared in analogy to example 186 starting from [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]methyl-amine (example 185), 4-nitrophenyl chloroformate and the appropriate amine components:
Table 9:
Example No.:
Structure
157
187
0
T ci VA a
Cl
188
.i I
"
a
189
g^o
°TV> °
Cl
190
0
^NAN-^I
rS
a^^SX a iVi
Cl
191
?
I10
c,wS 01
a
158
192
0
"-N N
X k CIH
o x CIH TJXJL
Ci
193
0
cS C,H
Ci-^wA,
Cl
Example 194: N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]formamide
Ci
3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoqulnolin-4-yl)-phenylamine (600 mg, compound of example 35) is dissolved in 2.4 ml of formic acid and heated to reflux for 15 min. After standing overnight, the mixture is added to a mixture of ice/water and
159
saturated NaHC03 solution and extracted three times with dichloromethane. The combined organic phases are dried with MgSC>4 and concentrated, resulting in 588 mg of the title compound.
Example 195: [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amine, hydrochloride;
N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]formamide 10 (588 mg, compound of example 194) is dissolved in 10 ml of THF and, at 50°C under argon, added to a solution of 1.8 ml of a 1 M solution of lithium aluminum hydride in THF. The mixture is heated to reflux for 1 hour. After standing overnight, a further 2 ml of a 1 M lithium aluminum hydride solution are added at 50°C, and heated to reflux for a further 30 min. For workup, ice is added and the aqueous phase is extracted four 15 times with ethyl acetate. The combined organic phases are dried with MgS04 and concentrated. Further purification takes place on a preparative HPLC. The product obtained in this way is taken up in NaHCC>3 solution and extracted with ethyl acetate. Drying of the organic phase with MgSC>4 affords 270 mg of the free base. 45 mg are taken up in diluted HCI and freeze dried, resulting in 45 mg of the title compound.
The compounds of the following examples can be prepared starting from [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]methylamine
160
(example 195), 4-nitrochloroformate and the appropriate amine components by the method described for example 151:
Table 10:
Example No.:
Structure
196
rrv° .
I Cl
Ci
161
197
pXO
o
Cl
198
I I
fYY"
Ks? o y JL C1
a
199
pjyk k^y o aW^
y^X a a
200
I ry rYr0
°W^i yJk a
Cl
201-
i ry fYY°
o . .
a"irVS
UUL a a
162
202
0V0
Ci
203 -
i r
0
VA
I Cl a
Example 204: 2-Dimethylaminoethyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate, hydrochloride;
a
mg of 4-nitrophenyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyljcarbamate hydrochloride (see example 151, intermediate 1) are suspended in 1.5 ml of dichloromethane while stirring under an argon atmosphere, and a solution of
3 mg of 2-dimethylaminoethanol in 0.5 ml of dichloromethane is added, and the mixture is stirred for 6 hours. After standing overnight, water, dichloromethane and saturated NaHC03 solution are added, and the organic phase is separated. The dichloromethane phase is washed three times with saturated NaHCC>3 and dried with MgSC>4, and the solvent is removed in vacuo. The crude product obtained in this way is purified on a preparative HPLC. The product fractions are concentrated and partitioned between ethyl acetate and saturated NaHC03 solution. The organic phase is separated off, dried with MgS04 and concentrated. The residue is taken up in dilute HCI and freeze dried, resulting in 5 mg of the title compound.
In an analogous manner, the corresponding isomers 2-dimethylaminoethyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]carbamate hydrochloride and 2-dimethylaminoethyl [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate hydrochloride are prepared starting from 4-nitrophenyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate hydrochloride and 4-nitrophenyl [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate hydrochloride.
164
Table 11:
Example No.:
Structure
205
o I
A,—^
ct
206
n t i ci c!
Cl
Example 207: Methyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylj-carbamate, hydrochloride;
mg of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yI)-phenylamine (example 35) are introduced under an argon atmosphere into 1.5 ml of dichloromethane while stirring, and a solution of 4.6 mg of methyl chloroformate in 0.5 ml of dichloromethane is added. After stirring for 6 hours and standing overnight, i
165
further 2.3 mg of methyl chloroformate are added, and the mixture is stirred for 5 hours. For workup, the solvent is removed, and the residue is taken up in dilute HCI and freeze dried, resulting in 20 mg of the title compound.
The following carbamates can be prepared in an analogous manner starting from the appropriate anilines 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine and 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine.
Table 12:
Example No.:
i~ *
Structure
208
fYY^"
if' a
- a
209
frVY
y o 1
QvsA ci '
XXX
a
210
ifYNY0^
Kf? o aVi<?sA a
VCX
a
166
211
X-Cl $
c"pO.
Cl
212
I 1
N CT^
01 (fS
clrA
CI
213
Qi V c'P6N_ Cl
Cl
214
0
A,
01 o ^
vON.
CI
167
Example
215a: (+)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide, hydrochloride;
215b:: (-)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide, hydrochloride;
y o' o
Cl
96 mg of racemic N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]methanesulfonamide (see example 83) are separated into the enantiomers on a chiral preparative HPLC.
chiral column: Chiralpak AD 250 x 50 mm; 20 yc/;
solvent: heptane:ethanol:methanol: 10:1:1;
flow rate: 50 ml/min;
the resulting enantiomers are dissolved in dilute HCI and freeze dried, resulting in 37 mg of each of the title compounds 215a and 215b. The enantiomeric purity is 15 determined on a chiral HPLC.
chiral column: Chiralpak AD-H/31 250 x 4.6 mm;
solvent: heptane:ethanol:methanol: 10:1:1;
flow rate: 1 ml/min;
Rt (enantiomer eluting first) = 6.84 min; 100% ee;
Rt (enantiomer eluting second) = 8.02 min, 100% ee.
Example
216a: (+)-1 -[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethylurea, hydrochloride;
216b: (-)-1 -[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethylurea, hydrochloride;
168
Ci
316 mg of racemic 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-
phenyl]-3-ethylurea (compound of example 80) are separated into the enantiomers on a chiral preparative HPLC.
chiral column: Chiralpak OD 250 x 50 mm, 20/y;
solvent: heptane:ethanol:isopropanol: 50:2:1; 0.3% diethylamin flow rate: 50 ml/min;
The enantiomers are subjected separately to further purification on a preparative HPLC. The resulting products are partitioned between saturated NaHC03 solution and ethyl acetate, and the organic phase is separated off, dried with MgSC>4 and freed of solvent. Dissolving the residue in dilute HCI and freeze drying affords 37 mg of the enantiomer eluting first and 58 mg of that eluting second. The enantiomeric purity is determined by analytical HPLC.
chiral column: Chiralpak OD 250 x 4.6 mm;
solvent: heptane:ethanol:isopropanol: 50:2:1; (0.3% diethylamine);
flow rate: 10 ml/min;
Rt (enantiomer eluting first) = 9.22 min; 100% ee;
Rt (enantiomer eluting second) = 9.96 min, 98% ee.
Example 217: N-[3-(6,8-Difluoro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide, hydrochloride;
169
rrv
L^y o
F
F
Intermediate 1:2,4-Difluorobenzylmethylamine
2,4-Difluorobenzylmethylamine can be prepared in a manner known to the skilled worker starting from 2,4-difluorobenzaldehyde (cf. example 1, intermediate 1).
N-[3-(6,8-Difluoro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]acetamide, hydrochloride;
The title compound can be prepared by the synthetic route described in example 1 starting from N-(3-acetylphenyl)acetamide and 2,4-difluorobenzylmethylamine (intermediate 1).
Example 218:4-(3-Bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydro isoquinoline, hydrochloride;
Cl
170
The title compound can be prepared by the synthetic route described in example 1 starting from 2,4-dichlorobenzylmethylamine (see example 1) and 2-bromo-1-(3-bromophenyl)ethanone as alkylating agent.
Example 219:1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl-3-(2-hydroxyethyl)urea
509 mg (1 mmol) of 4-nitrophenyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroiso-10 quinolin-4-yl)-phenyl]carbamate hydrochlorides (compound of example 151,
intermediate 1) are dissolved in 15 ml of absolute DMF and, at 0°C, a solution of 67.2 mg (1.1 mmol) of 2-aminoethanol in 10 ml of DMF is added. The mixture is stirred at room temperature for three hours and then the solvent is removed in vacuo. The residue is partitioned between ethyl acetate and saturated NaHC03 solution. The 15 organic phase is separated off and the aqueous is extracted twice more with ethyl acetate. The combined organic phases are washed with saturated NaCI solution, dried with MgSC>4 and concentrated. Chromatography on silica gel (dichloromethane/methanol) affords 265 mg of the title compound.
Example 220: Ethyl 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoate
171
Intermediate 1: 3-Acetylbenzoic acid is prepared in a manner known to the skilled worker from 3-acetylbenzonitrile by hydrolysis of the nitrile group.
Intermediate 2: Ethyl 3-acetylbenzoate is prepared from intermediate 1 in a manner known to the skilled worker.
Intermediate 3: Ethyl 3-(2-bromoacetyl)benzoate is synthesized in analogy to the 10 method described in example 1, intermediate 2, from ethyl 3-acetylbenzoate (intermediate 2).
Ethyl 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoate,
Starting from ethyl 3-(2-bromoacetyl)benzoate (intermediate 3) and 2,4-dichlorobenzyl-15 methylamine (example 1, intermediate 1) it is possible to proceed further in analogy to the synthetic route described in example 1, resulting in ethyl 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoIin-4-yl)benzoate after alkylation reaction, reduction and ring-closure reaction.
Example 221: 3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzoic acid;
172
500 mg of ethyl 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoate (compound of example 220) are dissolved in 15 ml of methanol, and 10 ml of 2 N of 5 KOH are added. After one hour at 50°C, the mixture is concentrated in vacuo and the residue is partitioned between water and ether. The aqueous phase is adjusted to a pH of about 6 with 2 N HCI, and the resulting precipitate is filtered off with suction. Drying affords 304 mg of the title compound as a colorless solid.
Analytical data for the compounds of examples 1 to 221:
173
ble 13:
Ex.
Structure
Rt
[min]
Method
MS, [M+I-Tj
MS-Method
Remarks
1
J.
a
1,60
B
349,1/350,1/ 351,0
ESI
m.p.: 205-206 °C
1a
X
y5^ oh
1,60
B
349,2/351,2
ESI
m.p.: 125 °C (decomp.)
2a
\-nhs fl
CIH
aYY"
a
3,63
t
A
371,3/373,3 412,3/414,3
J
ESI
M
enantiomer
2b
% -,° (j^V'S"NH2
a^OC C,H
XXX
3,67
A
371,3/373,3 412,3/414,3
ESI
H
enantiomer
2c
°\ „nk,
fl
AcOH
cl i
3,66
A
371,1/373,1 412,1/414,1
ESI
(-)
enantiomer
174
2d
(J, .0
pj-s*
A®®"*
VA^-N-v
1,56
B
371,1/373,1 412,1/414,1
ESI
(-)
enantiomer
3
\jv fl i[ CIH
a
4,00
A
399,1/401,1
Cl
4a
°VNHj erf
CIH
""Y^Yi
VjA^Nv a
3,59
A
371,2/373,2 412,2/414,2
ESI
4b
0vNH,
o*]f
AcOH
Xd a
1,58
B
371,0/372,0/ 373,0/373,9
ESI
CL 1 CIH
yp<-
>
4,57
A
J
369,9/371,9/ 373,9
Cl
6
COOH
OH
xa a
4,03
•v
A
336,1/338,1
Cl
175
7
TFA
4,17
A
363,3/365,3
Cl
8
TFA
"YYi yk^k
Cl
1,88
B
377,3/379,3
Cl
.
9
VH-^y f5^ TFA
°Yi1
yk^x a
1,45
B
406,3/408,3
Cl
0
TFA
°YYi y—nV
a
4,37
A
377.1/379,1
J
Cl
11
y
TFA
yk^
a
>
4,05
A
363,2/365,2
ESI
12
. 0
TFA
*xxx a
■>
3,79
A
375,2/377,2
ESI
176
9
13
OH
aY"vS
ka—mx.
a
4,92
A
361,2/363,2
ESI
<}>
14
li tfa v^A
Uv-NN a
4,08
A
390,2/392,2
ESI
tfa .
ijov
4,80
A
318,2/320,2
Cl
A
16a xa a
1,61
>
B
349,1/350,1/ 351,1
j
ESI
(-)
enantiomer
A
16b
°yyS
a
1,61
B
349,1/350,1/ 351,1
ESI
(+)
enantiomer
nhj
■%
17
a-_^JC ■ *hci
XXX
a
0,91
B
307,1/309,0
ESI
177
18
Vv*v
ST
(V^A. cw
XpCX
Cl
1,63
B
442,0/444,0
ESI
19
4,00
A
392,2/394,2
ESI
19a
CU. ^ JL CW
xa a
1,80
B
392,1/394,1
ESI
8
HN^N*^
• aTT^
Yv1^
1,67
B
380,1/382,2
j
ESI
21
HN^vN'^>s-
XXa
;
1,68
B
378,3/380,2
ESI
m.p.: 218-220 °C
21a
Hijf^-K^-- ;
W
kp~^->k
■%
1,68
B
378,1/379,1/ 380,1
ESI
178
22
X
-P I
;svv\
T^CX
0,32
B
359,1
717,3/718,3/ 719,3
ESI
23
^x
1,60
B
309,2/310,1
ESI
24
X
^YYi
Y^-nn
1,67
B
393,0/394,0/3 96,0/397,0
ESI
«A
GrV?
xxx
1,85
B
384,1/386,1
J
ESI
25a
»A
n Y »
cl f
1,78
B
384,1/385,1/ 386,2
ESI
26
X
o 9
xtfa.
1,46
B
400,1/401,2/ 401,2
ESI
179
i / a
27
"O T
0.27
B
413,2/414,2/ 415,2
ESI
27a cuS ,h°
cl
0,25
B
413,2/414,2/ 415,2
ESI
28
„A
^ 9
• XHCI yOk a
1,65
B
384,2/385,2 386,2
ESI
29
1,67
B
352,0/353,0/ 354,0
ESI
29a
QH 0
£VN».
Cl t
1,68
B
</
352,0/353,0/ 354,0
ESI
oh o
VyS tfa-yC^x a
1,68
B
365,1/366,1/ 367,0/368,0
ESI
180
180
31
(JyV
C'YYS TFA
1,79
B
379,1/380,1/ 381,1
ESI
32
OH 0 j
(VSr-^
qYYI ' *TFA
6
1,47
B
422,1/423,1/ 424,1/425,1
ESI
33
OH 0 NH,
NH;
1,46
B
393,1/394,1/ • 395,1
ESI
34
nrV.
Cl
1,63
B
349,0/350,1/ 351,0
ESI
X|X/N^
1,17
B
"307,0/308,1/ 309,1
ESI
36
^Y^NHj
1,66
B
307,0/308,0/ 309,1
ESI
181
37
hn^"' Qv^^Js. TFA
2,35
C
363,3/365,3
ESI
38
a^^OC TFA
yCX
2,43
C
377,3/379,3
ESI
39
a-^OC ™
UsX
a
2,49
C
391,3/393,3
ESI
40
hn'^y'
TFA
2,43
7
C
377,3/379,3
J
ESI
41
h^|<
TFA
yk^-Nv.
2,48
C
391,3/393,3
ESI
42
TFA
a
%
2,40
C
375,3/377,3
ESI
182
w
43
XpC-'X
a
2,45
C
389,3/391,3
ESI
44
a
2,52
C
403,4/405,4
ESI
45
ipy^
TFA
XpCX
a
2,49
C
403,2/404,2
ESI
46
£°r xpcx a
2,36
>
C
. 460,4/462,4
j
ESI
47
360
j^Jj N a I TFA
2,35
C
412,2/414,3
ESI
48
0% ,Q
"V
HN >s*
XpCX
a
■v
2,29
C
385,3/387,3
ESI
183
too
184
184
55
nY
W1 o
"YYS tfa
Y^Nn
2,49
C
391,3/393,3
ESI
56
(yV4.
0
Vy^i a
2,41
C
375,3/377,3
ESI
57
QT'T^
tfa
2,47
C
389,3/391,3
ESI
58
QrY°
a. JL W^i TFA ys/NN .
2,52
C
403,4/405,4
ESI
59
crT*
Y^A tfa SjA^
>
2,48
C
J
403,2/404,2
ESI
60
O-T^
°yyl tfa a
2^4
C
460,4/462,4
ESI
185
61
a"T°
tfa
2,36
C
412,2/414,3
ESI
62
CT oo avY^Ti ™ kfks*>,
cl
2,32
C
385,3/387,3
ESI
63
cx °°
oi^JL WA
cl
2,38
C
399,3/401,3
ESI
64
LJ o* ^0 tfa
Ij^VNn cl
2,41
C
414,4/416,4
ESI
65
0
w-
°\/\A
YY ^| tfa y^s a
> • 2,30
C
J
363,3/365,3
ESI
66
CkyvA
ll I TFA
yk/'k a
2,41
"v
C
377,3/379,3
ESI
67
ckywk li hT i TFA •LA^n\
a
2,52
C
391,3/393,3
ESI
186
68
SVr
YP
a
2,41
C
377,3/379,3
ESI
69
0
wy
Cl
2,45
C
391,3/393,3
ESI
70
jsy*
VyS
TFA
2,36
C
375,3/377,3
ESI
71
VrS
a
2,44
C
389,3/391,3
ESI
72
iJ^N^ TFA Cl
2,51
>
C
-403,4/405,4
ESI '
73
J$y*
VtX F
a
2,70
C
403,2/404,2
ESI
74
"L^S^k TP* o
■v
2,30
C
460,4/462,4
ESI
187
75
Olv
Yb
TFA
Cl
2,41
C
385,3/387,3
ESI
76
fll os ,o L 'I vV' V^ki'sv/
a^/OC
TFA
2,49
C
399,3/401,3
ESi
77
III
L '1 -V'
Vs!ry
TFA
a
2,55
C
414,4/416,4
ES!
78
ar~
XX/Ns a
1,72
B
378,3/380,3
ESI
79
err
"XXX ™
a
1,74
>
B
*380,3/382,3
ESI
80
Clx_ cl^0C
a
1,75
B
378,3/380,3
ESI
81
Cl 1
YW
yUk tfa a
■%
1,68
B
380,3/382,3
ESI
188
82
KJ 0 °
VV] 091 yCNN
a
1,71
B
399,0/400,0/ 401,0/402,0/ 403,0
ESI
83
r-vV
(i J 0 0
ci-Y^YX cih UL-nN
a
1,66
B
385,0/386,0/ 387,0
ESI
84
HN'
a
1,69
B
399,0/400,0/ 401,0/402,0
ESI
85
v
"xpa"
1,64
B
385,0/386,0/ 387,0/388,0
J
ESI
86a rry
XpC-^
Cl
>
1,64
B
349,3/351,3
ESI
Enantiomer
86b
CxY
kfS*' 0
1*63
B
349,3/351,3
ESI
(+)
Enantiomer
189
87
o, ,o ;s' f s
• tfa
VVNn a.
1,97
B
439,0/441,1
ESI
88
XM
YTi cl
1,83
B
453,0/455,0
ESI
88a
V >F
n"ss^%
|| oh aYY'
1,83
B
453,0/455,0
ES!
89
0v y°
.v'
>y Br
°YYi •yk^k
Cl
2,01
>
B
531,0/533,0/
j
534,9
ESI
89a
6, ,o V
KJ Br
"YYi 081
cl
2,02
-*
B
531,0/533,0/ 534,9
ESI
190
1
90
v v_ TXVn
°YYi -vA/N^
a
1,78
B
525,1/527,1
ESI
90a
"5>>
6
a\y\/k cih a
1,79
B
525,1/527,1
ESI
91
q, ,o f xv-
0 s
"m a
1,63
B
465,1/467,1
ESI
91a
0 0
iflV-
6 s ;
T cih -
*Tp6.
1,64
B
J
465,1/467,1
ESI
92
Os ,0 p a
1,81
•>
B
499,1/501,1/ 503,1
ESI
191
191
92a
0 o P
rS N~
CI^JX C,H
xpcx
Cl
1,82
B
499,1/501,1/ 503,1
ESI •
fj 0* *0
93
a
1,99
B
439,0/441,1
ESI
ifYV^S
KJ 0 0 F F
94
XpC-N-v a
1,87
B '
453,0/455,0
ESI
(fY oAoff
94a
CIH
a
1,87
B
453,0/455,0
ESI
95
K
f^V.N A5/
(T <A> yCNN
Q
y
2,01
B
j
531,0/533,0/ 535,0
ESI
96
_ H XV-K
Cpvs >-
XpC-N^
Cl
1,75
B
525,0/527,0
ESI
192
96a rV^H-
O 0" "0 t~
vn «
1,75
B
525,0/527,0
ESI
97
j, ri-
ifV;CN
||J - 0' 0
tja
1,66
B
465,0/467,0
ESI
97a
/
—-N
^ N X>~ '
fV ;s* N
|M o' o
084
Y^NN
1,66
B
465,0/467,0
ESI
98
Q
i
1,81
B
499,1/501,1/ 503,1
ESI
99
9> owo
I ¥
fy NH,
a
1
405,1/407,1
ES!
m.p.: 122 °C
100
cl>rV^i
III CIH
a
4'm
A
292,2/294,2
Ci see Ex. 2; intermediate 4
193
100a
(-) 1 T i TFA
ci
see Ex. 2; intermediate 4a
100b
(+) TXX™
cl
see Ex. 2; intermediate 4b
101
III cth a
4,43
A
326,0/328,0
ESI
102
cih
Cl
4,23
A
306,1/308,0
ESI
103
^ y
/
c
2,84
>
C
j 360,0
ESI
104
C'S^T^1 °^°
2,79
C
320,0/322,0
ES!
105
•%
2,64
C
291,9/293,9
ESI
194
106
F
OH
a
4,26
A
310,0/312,0
ESI
107
Ck X
II 1 011 a
4,43
A
306,1/308,1 '
ESI
108
a^V\ OH
4,11
A
292,0/294,0
ESI
109
c^r^) ^
a — ^
4,28
A
292,0/294,0
ESI
110
(f^T^i CIH
Br
4,05
A
j
302,0/304
ESI
111
wA--NH'
kyJs^N^ TFA
a
1,37
■%
D
364,4/366,4
ESI
195
112
■AA
TFA
Cl
1,44
D
378,4/380,4
ESI
113
„„Xa
Ov0u. ~
a
1,51
D
392,4/394,4
ESI
114
0
hn-^Y^
TFA
a
1,51
D
378,3/380,3
ESI
115
HN-V^
6
TFA
a
1,58
D
392,4/394,4
j
ESI
116
o w^Y*
jo
OWS NHj
TFA . .
a
1,04
D
435,5/437,5
ESI
■
117
.
aYrYi Uv^
a
1,67
D
404,4/406,4
ESI
196
118
"XpQk ~
a
2,08
D
412,3/414,3
ESI
119
ayA tfa a
2,27
D
400,4/402,4
ESI
120
°yA tfa a
2,37
D
400,4/402,4
ESI
121
Til
(S ^
a
1,54
D
432,5/434,5
j
ESI
122
tfa
SjAs^x a
1,70
D
428,5/430,5
ESI
123
xM
O n°»
tfa cl
2,55
D
445,4/447,4
ESI
197
124
"06. -
c(
2,43
D
428,5/430,5
ESI
125
Q 8
VyS tfa
Cl
1,88
D
401,4/403,4
ESI
126
xfe-/
i 1 / ■ 0
tfa kA^v.
a
2,31
D
496,5/498,5
ESI
127
o .
0^
VvN tfa
Uvns a
2,14
>
D
429,4/431,4 j
ESI
128
0
i!x>
h aY^jAsj tfa y^s
2,07
D
401,4/403,4
ESI
129
o tslf
"f i>
0s
"YY] tfa kJk/N^
Cl
2,44
D
469,4/471,4
ESI
198
130
rVyr
TFA •
a
1,55
D
378,4/380,4
ESI
131
frvy o 1
TFA
a
1.52
D
392,4/394,4
ESI
132
(fYV1^
o kJL^-N^ TFA
a
1,63
D
378,3/380,3
ESI
133
h r ryv^
kf' °
kJk^Nv. TFA a
1,64
D
392,4/394,4
ESI
134
7
frV^
k**1 0
a
1,14
D
^435,5/437,5
ESI
135
CrY? ^XX m a
1,62
*
D
404,4/406,4 '
ESI
199
136
Kf? o
Yy\ ™
Cl
2,16
D
412,3/414,3
ESI
137
(yYC-
Kj) o avY5!?sVi TFA
ct
2,31
D
400,4/402,4
ESJ
138
cyv9
o owvj tfa a
2,41
D
400,4/402,4
ESI
139
o yvn tfa a
1,62
D
432,5/434,5
ESI
140
CMI
o
«VyS tfa k^is^Nv.
Ci
1,76
D
J
428,5/430,5
ESI
141
J10'
ryW
Kf? 0
""YYi ^
a
2,54
D
445,4/447,4
ESI
200
142
O'Vr
Kf1 0
tfa a
2,50
D
428,5/430,5
ESI
143
' (W*
aYY\ tta a
1,95
D
401,4/403,4
ESI
144
o
"YY) tfa yv-\
a
2,34
D
496,5/498,5
ESI
145
OV^YS • TFA-
a
2,31
D
429,4/431,4
ESI
146 .
oV^
Kf? o
°YY] nA
vv^
a
>
2,11
D
J
401,4/403,4
ESI
147
CX o ,
• a
2,48
-j
D
469,4/471,4
ESI
201
148
Cl irV"V
s
2,36
B
394,2
ESI
149
Cl r ii i T « »
•j1 a
2,35
B
394,2
ESI
-
150
r^l) S
■tfe^'JL L Jl I
Sjl TFA
2,35
B
394,2
ESI
151
fvYN
YT i a a
2,15
B
378,2
ESI
152
ry
(X^
a
TpuL a a
1,64
>
B
J 433,3
ESI
153
^vO
o ci^X Cl lyk.NN a
2,56
B~
418,3
ESI
154
r~?
rvV^1
K^t* o av^Jk, c,
a
-v
2,16
B
420,2
ESI
202
155
Cr Y°
"tpa. °
Cl
2,34
B
404,2
ESI
156
r fYNYNs/
o yCX
Cl
2,43
B
406,2
ESI
157
frY-
Kj? o yCX °
a
2,12
B
364,2
ESI
158
CTT ^
Cky^-Y-L a a a
1,65
B
421,2
ESI
159
ChirsI
CkY^Y^S a
)
2,23
B
J
420,3
ESI
160
<Fo
2,25
■%
B
434,3
ESI
161
,, I "NnO
Nf^Yi a k-*1^
kAA a
1,72
B
461,4
ESI
203
162
fyr
T ^
VYS 01 S
ykAC1 X
Cl
1,68
B
449,4
ESI
163
fYV
a 1
a
1,62
B
435,3
ESI
164
(X N T a I
cSrvS S
yX* X
Cl
1,71
B
435,3
ESI
165
frNr°
i
^fyS ?
Cl
2,21
B
408,3
ESI
166
frV
• V' Vti aYYi a N
a
Cl
1,88 ?
B
J 427,3
ESI
167
fyY3
S[ NY^
aYvS a
Cl
1,80
B
427,3
ESI
168
CX A arr^ OL
a ci
%
1,59
B
433,3
ESI
204
169
CXx
II I Cl Cl
2,12
B
364,2
ESI
170
CIv^s^A I
Cl
Cl
2,12
B
378,2
ESI
171
CXi
Y^NAiT\
VA a ^
Y^Nn a
2,34"
B
406,3
ESI
172
"o5l a a
2,44
B
418,3
ESI
173
' (Xx
Y^nan'\
aYTNi «Uo yk^Nv.
a
2,11
B
420,3
ESI
174
CXX
aYV^ LJ>
Cl a
2,25
B-
J
404,3
ESI
175
CXr^N^Jk
Xxi ;
a
0,90
B"
421,5
ESI
176
0
nAN^
rS
CIv^A 01
iJk^Nv. Cl a
•v
1,52
B
433,3
ESI
205
177
I
S°
CI^X ci
Ci
2,34
B
404,3
ESI
178
x
. N Ijl Cl jfS
C,TT^ '
Cl
2,11
B
364,2
ESI
179
V
JL I*'
c D
CI^^X Ci
2,17
B
378,3
ES!
180
C. |fS ^
Y!k'NN Cl
2,51
B
406,3
j
ESI
181
9 i N N'"s,-'Nv
P c. ^Xjk Cl
• • Cl
1,59
B
421,2
ESI
182
A0 ■
jf a
"OCX
Cl
2',47
B
418,2
ESI
206
183
I
(b
To
XUL
a
2,16
B
420,2
ESI
184
N^O
c,TT^
Cl
2,02
B
335,2
ESI
185
N"
01 n a Y
C'YT>
Cl
1,92
B
321,2
ESI
186
0
"-N^N
- 6'
CIYY^
Cl
1,05
C
378,4
j
ESI
187
O
fS
C'YYS a a
>
0,92
C
447,5
ESI
188
o
-NAN^
vA a
Cl
■j
1,10
C
392,5
ESI
207
189
ci c,yV^
Cl
1,24
C
432,5
ESI
190
0
rS
ci clTi^
Cl
1,10
C
434,5
ESI
191
0
w>
V Cl ciyV^
Cl
1,15
c
418,4
ESI
192
X
^"N N
irS S C,H
kj x clH
ci^^A,
kfk^-u^
Cl
0,93 >
c
435,4
j
ESI
193
0
v-n'No rS CIH
aYv(
Cl
1,22
•*
c
420,5
ESI
208
194
XpOx
Cl
2,04
C
335,4
ESI
195
Cl fl | Cl Sj^
lA/NN
a
0,90
C
321,3
ESI
196
^-,N^NO
o yX a a
2,48
B
418,3
ESI
197
pXO
c,vY^A KftX a a
2,62
B
432,3
J
ESI
198
I I
fyV"
Kj? o
WS Y<x a a
2,32
B
392,3
ESI
199
rrVN"
Kf? o aYVi ykA a
CI
•4
2,19
B
378,2
ESI
209
200
i r>
(7Y
01
Cl
2,16
B
434,3
ESI
201
i rr
(YY^
aYVS
XfUL aa a
1,61
B
447,4
ESI
202
NyO
0
vA
CUk. °Cl a
1,59
B
435,3
ESI
203
i r fYV^ °VV\
I/J. a a
2,57 >
B
J 420,3
ESI
204
aY^Y
VI ' 0
a
1,71
B
422,2
ESI
210
205
CI
a
1,70
B
422,3
ESI
206
CXJUA
°X^U. a a
1,68
B
422,3
ESI
207
o
Q~^
' ^Z
o o=( o /
2,34
B
365,1
ESI
208
fVY^
I T i Cl a
1,18
C
379,4
ESI
209
frVY
o 1 aVN/s ci
GG.
1,24
C
j
393,4
ESI
210
j-yV-4-
•Ls*' o aV?V^i a
Cl
1,38
C
'421,5
ESI
211
211
nV
01 6
0lrr^
' Cl
1,13
C
365,4
ESI
212
Cl /k
CkM
Cl
1,26
C
. 393,4
ESI
213
■ py aWi 01
Cl
1,40
C
421,5
ESI
214
A -a 6^
Vn
Cl
1,20
C
379,4
J
ESI
215a 215b
CrX QrX
y^x° xcV
a a
385,2
ESI
216a 216b cm, ax *o5u. "xxi .
a a
378,1
ESI
217
err
Ftp6.a i
1,86
B
317,2
ESI
212
218
cr
Cl
1,27
C
370,2
ESI
219
h h
■ 0
XJO'K
a
0,99
B1
394,1/396,2
ESI
220
a
1,24
B1
364,1/366,1
ESI
221
0
fy'oh a
1,02
B1
336,1/338,1
ESI
Pharmacological data:
Description of test:
In this test, the recovery in the intracellular pH (pHj) after an acidification is ascertained, which is initiated if the NHE is capable of functioning, even under bicarbonate-free conditions. For this purpose, the pHj was determined using the pH-
sensitive fluorescent dye BCECF (Calbiochem, the precursor BCECF-AM is employed). The cells were initially loaded with BCECF. The BCECF fluorescence was 10 determined in a "Ratio Fluorescence Spectrometer" (Photon Technology International, South Brunswick, N.J., USA) at excitation wavelengths of 505 and 440 nm and an emission wavelength of 535 nm and converted into the pHj using calibration curves.
The cells were incubated in NH4CI buffer (pH 7.4) (NH4CI buffer: 115 mM NaCI,
mM NH4CI, 5 mM KCI, 1 mM CaCl2,1 mM MgS04, 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 loading.
213
The intracellular acidification was induced by adding 975 /A of an NH4CI-free buffer (see below) to 25 //I aliquots of the cells incubated in NH4CI buffer. The subsequent rate of pH recovery was recorded for two minutes with NHE1, five minutes with NHE2 and three minutes with NHE3. To calculate the inhibitory potency of the tested 5 substances, the cells were initially investigated in buffers with which a complete or absolutely no pH recovery took place. For complete pH recovery (100%), the cells were incubated in Na+-containing buffer (133.8 mM NaCI, 4.7 mM KCI, 1.25 mM CaCl2,1.25 mM MgCl2, 0.97 mM Na2HPC>4, 0.23 mM NaH2P04, 5 mM Hepes, 5 mM glucose, a pH of 7.0 is adjusted with 1 M NaOH). To determine the 0% value, the cells 10 were incubated in an Na+-free buffer (133.8 mM choline chloride, 4.7 mM KCI,
1.25 mM 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 tested were made up in the Na+-containing buffer. The recovery of the intracellular pH at each test concentration of a substance was expressed as a percentage of the 15 maximum recovery. The IC50 value for the particular substance for the individual NHE
subtypes was calculated from the pH recovery percentages using the Sigma-Plot program.
Claims (26)
1. A 4-phenyltetrahydroisoquinoline of the formula I 5 in which the meanings are: R1, R2, R3 and R4 independently of one another H, F, Cl, Br, I, CN, NO2, OH, NH2, CaH2a+1. CqqH2qq-i, OCbH2b+1. COORIO, OCORIO, CORIO or Ox-(CH2)y-phenyl; a and b 10 in the groups CaH2a+l and OCbH2b+1 independently of one another 1,2,3,4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms; qq 3,4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms; 15 R10 HorCcH2c+1; c 1, 2, 3,4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms, x zero or 1; y zero, 1, 2, 3 or 4; 20 where the phenyl ring in the group Ox-(CH2)y-phenyl is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, Br, CN, NO2, OH, NH2 or cdH2d+i; d 1, 2, 3 or 4, it being possible for one or more H atoms 25 to be replaced by F atoms, or 216 R1,R2, R3 and R4 independently of one another heteroaryl, it being possible for zero, 1, 2, 3 or 4 N atoms, zero or 1 oxygen atom or zero or 1 S atom to be present as ring atoms; 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, 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 and 0^2^-1 to be replaced by F atoms and for one or more CH2 groups to be replaced by O or NR13; R13 HorCfH2f+i; f 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; or R13 and a CH2 group of R11 or R12 together with the N atom to which they are bonded a 5- or 6-membered ring; or R11 and R12 together with the N atom to which they are bonded a 5-, 6- or 7-membered ring; or R11 and R12 independently of one another C0R14, CSR14 or S02R14; 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 217 possible for one or more CH2 groups to be replaced by O or NR13, or R1, R2, R3 and R4 independently of one another -Oh-SOj-R15, with h zero or 1; j zero, 1 or 2; R15 CkH2k+1, 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; R17 and R18 independently of one another H or CmH2m+11 m 1,2,3,4, 5, 6, 7 or 8, it being possible for one or more H atoms in the group CmH2m+1to be replaced by F atoms and for one or more CH2 groups to be replaced by O, CO, CS or NR19; R19 HorCnH2n+1! n 1,2, 3 or 4; it being possible for one or more H atoms in CnH2n+i 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 with 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, 218 R5 H, CpH2p+i t CssH2ss-1 , COR20 or SO2R2O; p 1, 2, 3,4, 5, 6, 7 or 8, ss 3, 4, 5, 6, 7 or 8, R20 CqH2q+1; q 1, 2, 3,4, 5, 6, 7 or 8, it being possible for one or more H atoms in the groups CpH2p+i, CSsH2ss-1 and CqH2q+1to be replaced by F atoms and for one or more CH2 groups to be replaced by O or NR21; R21 HorCrH2r+i; r 1,2, 3 or 4; it being possible for one or more H atoms in CrH2r+1 to be replaced by F atoms; R6 H, F, Cl, Br, I, 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> Cd<jH2dd-1 anC' ^^^2t+1 to be replaced by F atoms; R22 CuH2u+1". u 1,2, 3 or 4; it being possible for one or more H atoms in CuH2u+1 to be replaced by F atoms; R7, R8 and R9 independently of one another -OvSO\ArR23; v zero or 1; w zero, 1 or 2; R23 CnnH2nn+1' CmmH2rnm-1 > ^pp^2pp+1 or NR25R26; nn and pp independently of one another 1,2,3, 4, 5, 6, 7 or 8, mm 3, 4, 5, 6, 7 or 8, 219 it being possible for one or more H atoms in CnnH2nn+1. CmmH2mm-1 and OCppH2pp+1to be replaced by F atoms; R25 and R26 independently of one another H, CN or CzH2z+1. CzzH2zz-1 '> 5 z 1, 2, 3,4, 5, 6, 7 or 8; zz 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms and, in CzH2z+1. it being possible for one or more H atoms to be replaced by F atoms and it being possible for 10 one or more CH2 groups to be replaced by O, CO, CS or NR27; R27 H or CaaH2aa+1! aa 1,2, 3 or 4; it being possible for one or more H atoms in 15 OaaH2aa+i to be replaced by F atoms; or R25 and R26 together with the N atom to which they are bonded a 5-, 6- or 7-membered ring, 020 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 25 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+1; bb 2 or 3; 30 cc 1, 2, 3,4, 5, 6, 7 or 8; yy 3,4, 5, 6, 7 or 8; 220 h 1,2,3,4,5,6, 7 or 8, it being possible for one or more H atoms in ChH2h+1 to be replaced by F atoms, and it being possible for one or more H atoms in the groups CccH2cc+1 anc* CyyH2yy_i to &e replaced by F atoms and for one or more CH2 groups to be replaced by NR31 and for a CH2 group to be replaced by O R31 H, C|<|<H2kk+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, 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 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, zero or 1 S atoms and zero or 1 O atoms, which is unsubstituted or substituted by up to three substituents selected from the group consisting of F, Cl, Br, I, C00H200+I > NR70R71; R70 and R71 independently of one another H, CuuH2uu+1 anc' COR72; R72 H, CwH2W+1I 00, uu and w independently of one another 1, 2, 3,4, 5, 6, 7 or 8; it being possible for one or more H atoms in the groups CqoH2oo+1> ^uu^uu+I or Cw^vv+I to be replaced by F atoms; 221 R7, 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 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 CeeH2ee+1 > Cwwh2ww-1 and 0CffH2ff+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+1 to be replaced by F atoms and for one or more CH2 groups to be replaced by O or NR44; R44 H Or CggH2gg+1; gg 1, 2, 3, 4, 5, 6, 7 or 8; it being possible for one or more H atoms in the group CggH2gg+i to be replaced by F atoms, and it being possible for R44 together with a (CH2) group of R40 or R41 and the N atom to which they are jointly bonded to form a 5- or 6-membered ring; or R40 and R41 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 to be replaced by F atoms; but where two substituents from the group of R7, R8 and R9 may not simultaneously be OH or OCH3 222 and where at least one of the radicals R7, R8 or R9 must be selected from the group consisting of CONR40R41, -OvSOwR23, NR32COR3C), NR32CSR30 and NR32SC)bbR30; and the pharmaceutically acceptable salts and trifluoroacetates 5 thereof.
2. A compound of the formula I as claimed in claim 1, in which the meanings are: R1.R2, R3 and R4 independently of one another, H, F, Cl, Br, I, CN, NO2, OH, NH2, CaH2a+l> 10 cycloalkyl with 3,4, 5 or 6 C atoms, OCbH2b+i, COORIO; a and b independently of one another 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; R10 HorCcH2c+1; 15 c 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; or R1, R2, R3 and R4 independently of one another 5- or 6-membered heteroaryl selected from the (20 group consisting of pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl and oxazolyl; or R1, R2, R3 and R4 independently of one another CONR11R12 or NR11R12; 25 R11 and R12 independently of one another H, CeH2e+l, CrrH2rr-1; e 1,2, 3 or 4, rr 3, 4, 5 or 6, it being possible for one or more H atoms in the groups 30 CeH2e+1 and CrrH2rr-1 to be replaced by F atoms or 223 R11 and R12 independently of one another hydroxyethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl; or R11 and R12 together with the N atom to which they are bonded a pyrrolidine, piperidine, N-methylpiperazine, piperazine or morpholine ring; or R11 and R12 independently of one another COR14, CSR14, CONHR14, CSNHR14 or S02R14; 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,with R15 C|<H2k+1, 0C|H2|+1 or NR17R18; k 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; I 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; R17 and R18 independently of one another H, CmH2m+1, 'n 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 F atoms; R19 HorCnH2n+i; 224 n 1,2, 3 or 4; it being possible for one or more H atoms in CnH2n+l to be replaced by F atoms; or 5 R17 and R18 together with the N atom to which they are bonded a 5- or 6-membered ring; but where R2 must always not be equal to H, R5 H, CpH2p+i; 10 p 1,2,3 or 4; it being possible for one or more H atoms in CpH2p+i to be replaced by F atoms; R6 H, CsH2S+1 , OCtH2t+i or OCOR22; s and t 15 independently of one another 1, 2, 3 or 4; it being possible for one or more H atoms in CsH2s+1 and OCtH2t+i to be replaced by F atoms; R22 CuH2U+I; u 1,2, 3 or 4; (20 it being possible for one or more H atoms in CuH2u+1 to be replaced by F atoms; R7, R8 and R9 independently of one another OSO3H, SO3H or S02R23; R23 CnnH2rm+1> CmmH2rnm-1> OCpp^2pp+1 or NR25R26; 25 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 OCppH2pp+i to be replaced by F atoms; 225 R25 and R26 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; 5 z 1,2,3,4,5 or 6; it being possible for one or more H atoms in CzH2z+1 to be replaced by F atoms; R27 H or CaaH2aa+11 aa 1,2, 3 or 4; 10 it being possible for one or more H atoms in CaaH2aa+i to be replaced by F atoms; or R25 and R26 together with the N atom to which they are bonded a 5- or 15 6-membered ring; or R27 and a CH2 group of R25 or R26 together with the N atom to which they are bonded a 5- or 6-membered ring; or 120 R7, R8andR9 independently of one another NR32COR30, NR32CSR30 or NR32S02R30; 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+1; 25 cc 1, 2, 3,4, 5, 6, 7 or 8; yy 3,4, 5, 6; h 1,2, 3 or 4; it being possible for one or more H atoms in Cfo^h+i to be replaced by F atoms, and it being possible for one or more H atoms in the groups 226 CCcH2cc+1 and CyyH2yy-i to be replaced by F atoms and for one or more CH2 groups to be replaced by NR31 and for a CH2 group to be replaced by O; R31 H, Ck|<H2kk+1' COR65 or SO2R65; kk 1,2, 3, or 4; 5 it being possible for one or more H atoms to be replaced by F atoms, R65 H, CxxH2xx+i; xx 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; or 10 R31 together with a 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 group consisting of pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, 15 thienyl, thiazolyl and oxazolyl, which are unsubstituted or substituted by up to three substituents selected from the group consisting of F, Cl, Br, I, CooH2oo+1. NR70R71, R70 and R71 |20 independently of one another H, CuuH2uu+1 or COR72; R72 H, CwH2w+1I 00, uu and w independently of one another 1,2, 3 or 4; it being possible for one or more H atoms in the groups 25 CqoH2oo+1 > OyyH2uu+1 or CyyH2w+1 to be replaced by F atoms; or R7, R8 and R9 independently of one another H, F, Cl, Br, I, NO2, CN, OH, NH2, CeeH2ee+1> 30 CWWH2WW-1. OCffH2ff+i, NR40R41, CONR40R41, COOR42, COR42 or OCOR42; 227 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' 5 cwwh2ww-1 and OCffH2ff+i to 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 CttH2tt+1 to be 10 replaced by F atoms; or R40 and R41 to be selected independently of one another hydroxyethyl,, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, 15 N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl; or R40 and R41 together with the N atom to which they are bonded form a ring selected 20 from the group consisting of pyrrolidine, piperidine, N-methyl- piperazine, piperazine and morpholine; R42 HorChhH2hh+i: hh 1,2, 3 or 4; it being possible for one or more H atoms in the group ChhH2hh+1to 25 be replaced by F atoms; but where two substituents from the group of R7, R8 and R9 may not simultaneously be OH or OCH3 and where at least one of the radicals R7, R8 or R9 must be selected from the group consisting of CONR40R41, -OvSOwR23, NR32COR30, NR32CSR30 and 30 NR32SObbR30; and the pharmaceutically acceptable salts and trifluoroacetates thereof. 228
3. A compound of the formula I as claimed in claims 1 or 2, in which the meanings are: R1, R2, R3 and R4 independently of one another H, F, Cl, Br, OH, NH2, CaH2a+1. cycloalkyl with 3, 4, 5 or 6 C atoms, OCbH2b+11 a and b in the groups CaH2a+i and OCbH2b+l independently of one another 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; or R1, R2, R3 and R4 independently of one another NR11R12; R11 and R12 independently of one another H, CeH2e+l, 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+l and Cn-^rr-l to be replaced by F atoms; or R11 and R12 together with the N atom to which they are bonded form a ring selected from the group consisting of pyrrolidine, piperidine, N-methylpiperazine, piperazine and morpholine; or R11 and R12 independently of one another COR14, CSR14, CONHR14, CSNHR14 or S02R14; R14 CgH2g+i; g 1, 2,3 or 4, it being possible for one or more H atoms to be replaced by F atoms; 229 or R1, R2, R3 and R4 independently of one another OSO3H, SO3H, S02R15; R15 C|<H2k+1 orNR17R18; 5 k 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; R17 and R18 independently of one another H or CmH2m+1 J m 1, 2, 3,4 or 5, it being possible for one or more H 10 atoms in the group CmH2m+1to be replaced by F atoms; or R17 and R18 together with the N atom to which they are bonded a 5- or 15 6-membered ring; but where R2 must always not be equal to H; R5 methyl or trifluoromethyl; R6 H; R7, R8 and R9 20 independently of one another 0S03H, SO3H or S02R23; R23 CnnH2nn+1 or NR25R26; nn 1,2, 3,4 or 5, it being possible for one or more H atoms in CnnH2nn+1to be replaced by F atoms; 25 R25 and R26 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; 30 it being possible for one or more H atoms in CZH2Z+1 to be replaced by F atoms; 230 R27 H or CaaH2aa+l! aa 1,2, 3 or 4; it being possible for one or more H atoms in CaaH2aa+1 to be replaced by F atoms; 5 or R25 and R26 together with the N atom to which they are bonded a 5- or 6-membered ring, or 10 R27 and a 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 NR32S02R30; 15 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, 6; 20 it being possible for one or more H atoms in the groups CccH2cc+1 and cyyH2yy-1t0 be replaced by F atoms and for one or more CH2 groups to be replaced by NR31 and for a CH2 group to be replaced by O; R31 H, methyl, ethyl, CF3, CH2CF3, acetyl, propionyl, methanesulfonyl or ethanesulfonyl; 25 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 or 30 oxazolyl, which are unsubstituted or substituted by a maximum of 3 231 substituents 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+i, 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 groups CeeH2ee+1« Oww^2ww-1 and OCffH2ff+i to be replaced by F atoms; R40 and R41 H, CttH2tt+1 or C(NH)NH2: tt 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 R40 and R41 independently of one another hydroxyethyl, N,N-dimethylaminoethyl, 120 N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl; or R40 and R41 together with the N atom to which they are bonded a pyrrolidine, 25 piperidine, N-methylpiperazine, piperazine or morpholine ring; R42 HorChhH2hh+1! hh 1,2, 3 or 4; it being possible for one or more H atoms in the group ChhH2hh+1 to be replaced by F atoms; 30 but where two substituents from the group of R7, R8 and R9 may not simultaneously be OH or OCH3, 232 and where at least one of the radicals R7, R8 or R9 must be selected from the group consisting of CONR40R41, -OvSOwR23, NR32COR30, NR32CSR30 and NR32SC)bbR30; and the pharmaceutical^ acceptable salts and trifluoroacetates thereof. 5
4. A compound of the formula I as claimed in claims 1-3 in which the meanings are: R1, R2, R3 and R4 independently of one another H, F, Cl, Br, OH, NH2, CaH2a+i, cycloalkyl with 3, 4, 5 or 6 C atoms, OCbH2b+i; 10 aandb in the groups CaH2a+i and OCbH2b+l independently of one another 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; or 15 R1, R2, R3 and R4 independently of one another NR11R12; R11 and R12 independently of one another H, CeH2e+l, CrrH2rr-1; e 1,2, 3 or 4, |20 rr 3,4,5 or 6, it being possible for one or more H atoms in the groups CeH2e+i and CrrH2rr-1 to be replaced by F atoms; or 25 R11 and R12 together with the N atom to which they are bonded form a ring selected from the group consisting of pyrrolidine, piperidine, N-methylpiperazine, piperazine and morpholine; or 30 R11 and R12 233 independently of one another COR14, CSR14, CONHR14, CSNHR14 or S02R14; R14 CgH2g+i; g 1, 2, 3 or 4, it being possible for one or more H atoms 5 to be replaced by F atoms; or R1, R2, R3 and R4 independently of one another OSO3H, SO3H, SO2RI5; R15 CkH2k+1 orNR17R18; 10 k 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; R17 and R18 independently of one another H or CmH2m+11 m 1, 2, 3, 4 or 5, it being possible for one or more H 15 atoms in the group CmH2m+1to be replaced by F atoms; or R17 and R18 together with the N atom to which they are bonded a 5- or 120 6-membered ring; but where R2 must always not be equal to H; R5 methyl or trifluoromethyl; R6 H; R7, R8 and R9 25 independently of one another OSO3H, SO3H or SO2R23; R23 ^nnH2nn+1 or NR25R26; nn 1,2, 3,4 or 5, it being possible for one or more H atoms in CnnH2nn+1to be replaced by F atoms; 30 R25 and R26 234 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+1 to be replaced by F atoms; R27 H or CaaH2aa+11 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- or 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 R7, R8 and R9 independently of one another NR32COR30, NR32CSR30 or NR32S02R30; 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 and CyyH2yy-i to be replaced by F atoms and for one or more CH2 groups to be replaced by NR31 and for a CH2 group to be replaced by O; R31 H, methyl, ethyl, CF3, CH2CF3, acetyl, propionyl, methanesulfonyl or ethanesulfonyl; 235 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 5 R30 pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl or oxazolyl, which are unsubstituted or substituted by a maximum of 3 substituents selected from the group consisting of F, Cl, methyl, ethyl, trifluoromethyl, NH2, NHacetyl; or ®10 R7, R8 and R9 independently of one another H, F, Cl, OH, NH2, CeeH2ee+1. cwwH2ww-1 • OCffH2ff+l, NR40R41, CONR40R41, COOR42 or OCOR42, ee and ff independently of one another 1,2, 3 or 4; 15 ww 3,4, 5 or 6, it being possible for one or more H atoms in the groups CeeH2ee+1 > CwwH2ww-1 and OCffH2ff+i to be replaced by F atoms; R40 and R41 H. CttH2tt+1 . or C(NH)NH2; 020 tt 1,2,3 or 4; it being possible for one or more H atoms in the group CttH2tt+1 to be replaced by F atoms; or R40 and R41 25 independently of one another hydroxyethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl; or R40 and R41 30 together with the N atom to which they are bonded a pyrrolidine, piperidine, N-methylpiperazine, piperazine or morpholine ring; 236 10 R42 HorChhH2hh+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; but where two substituents from the group of R7, R8 and R9 may not simultaneously be OH or OCH3, and where at least one of the radicals R7, R8 or R9 must be selected from the group consisting of -OvSOwR23, NR32COR30, NR32CSR30 and NR32SObbR30; and the pharmaceutically acceptable salts and trifluoroacetates thereof.
5. A compound of the formula I characterized in that it is selected from the group consisting of: I) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide; 15 2) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide; 3) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide; 4) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N,N-dimethyl-benzenesulfonamide; 5) 4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline; 20 6) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid; 7) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-ethyl-benzamide; 8) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-propyl-benzamide; 9) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-(2-dimethylamino-ethyl)-benzamide; 25 10) 6,8-dichloro-2-methyl-4-(4-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline; 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-30 isoquinoline; 15) 6,8-dichloro-2-cyclopropyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline; 16) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine; 237 10 15 17 18 19 20 21 22 23 24 25 26 20 27 28 29 25 30 31 30 32 33 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-propylurea; 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea; 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea; N-[4-(6-methanesulfonyl-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide; N-[4-(2,6,8-trimethyl-1,2,3,4-tetrahydro-isoquinoliri-4-yl)-phenyl]-acetamide; N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]- acetamide; N-[4-(8-chloro-2-methyl-6-pyrrolidin-1-yl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide; N-[4-(8-chloro-2-methyl-6-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide; N-{4-[8-chloro-2-methyl-6-(4-methyl-piperazin-1-yl)-1,2,3,4-tetrahydro-isoquinolin- 4-yl]-phenyl}-acetamide; N-{4-[8-chloro-6-(cycIopropylmethyl-amino)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl]-phenyl}-acetamide; 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoic acid; 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-N-methyl-benzamide; 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-ethyl-2-hydroxy-benzamide; 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-(2-dimethylamino-ethyl)-2-hydroxy-benzamide; N-[5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoyl]-guanidine; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide; 3-(6,8-dichloro-2-methyl-1,2,3I4-tetrahydro-isoquinolin-4-yl)-phenylamine; 238 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-1,2I3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-5 butyramide; 37) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]pentanamide; 38) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isobutyramide; 10 39) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2-dimethyl-propionamide; 40) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopropanecarboxamide; 41) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-15 cyclobutanecarboxamide; 42) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopentanecarboxamide; 43) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoro-acetamide; 20 44) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-i acetylpiperidine-4-carboxamide; 45) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-nicotinamide; 46) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-metharie-25 sulfonamide; 47) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl]-ethanesulfonamide; 48) N,,N'-dimethylamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-sulfamide; 30 49) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide; 239 50) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide; 51) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pentanamide; 5 52) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isobutyramide; 53) N-[3-(6,8-dichloro-2-methyl-1,2,3I4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2-dimethyl-propionamide; 54) N-[3-(6,8-dichloro-2-methyM,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-10 cyclopropanecarboxamide; 55) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclobutanecarboxamide; 56) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopentanecarboxamide; 15 57) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoro-acetamide; 58) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -acetylpiperidine-4-carboxamide; 59) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-20 nicotinamide; 60) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane-sulfonamide; 61) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl]-ethanesulfonamide; 25 62) N',N,-dimethylamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-sulfamide; 63) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide; 64) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-30 butyramide; 65) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pentanamide; 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 240 N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isobutyramide; N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2-dimethyl-propionamide; N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]cyclopropanecarbox-amide; N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl]-cyclobutanecarboxamide; N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopentanecarboxamide; N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoro-acetamide; N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-acetylpiperidine-4-carboxamide; N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane-sulfonamide; N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl]-ethanesulfonamide; N'.N'-dimethylamino-N-p-Ce.S-dichloro^-methyl-I^.S^-tetrahydro-isoquinolin^-yl)-phenyl]-sulfamide; 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea; 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea; 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea; 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea; N-{5-[4-(6,8-dichloro-2-methyl-1,2,3.4-tetrahydro-isoquinolin-4-yl)-phenylsulfamoyl]-4-methyl-thiazol-2-yl}-acetamide; N-{5-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylsulfamoyl]-4-methyl-thiazol-2-yl}-acetamide; 241 82) N-[4-(6,8-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-isoquinolin-4-yl)-phenyl]-1,2-dimethyl-1H-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)-phenyI]-5-bromo-thiophene-2-sulforiamide; 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-ethyI-N'-4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonylurea; 93) 2-chloro-5-(6I8-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; 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; 97) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-dimethylamino-acetamide; 242 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; 100) 2,6-diamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-hexanamide; 101) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pyrrolidine-2-carboxamide; 102) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isonicotinamide; 103) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-pyrrole-3-carboxamide; 104) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-pyrrole-2-carboxamide; 105) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -methyl-piperidine-4-carboxamide; 106) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,4-dimethyl-1 H-pyrrole-2-carboxamide; 107) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-nitro-1 H-pyrrole-2-carboxamide; 108) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,5-dimethyl-1H-pyrrole-3-carboxamide; 109) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-imidazole-4-carboxamide; 110) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-methanesulfonyl-piperidine-4-carboxamide; 111) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,5-dimethyl-1H-pyrazole-4-carboxamide; 112) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoIin-4-yl)-phenyl]-1 H-pyrazole-4-carboxamide; 113) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-trifluoromethyl-1H-pyrazole-4-carboxamide; 243 114) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-methylamino-acetamide; 115) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-dimethylamino-acetamide; 5 116) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide; 117) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide; 118) 2,6-diamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-0 10 phenylj-hexanamide; 119) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pyrrolidine-2-carboxamide; 120) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isonicotinamide; 15 121) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-pyrrole-3-carboxamide; 122) N-[3-(6,8-dichloro-2-methyI-1 ,23,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-pyrrole-2-carboxamide; 123) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -methyl-20 piperidine-4-carboxamide; 0 124) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]- 1.4-dimethyl-1 H-pyrrole-2-carboxamide; 125) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-nitro-1 H-pyrrole-2-carboxamide; 25 126) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]- 2.5-dimethyl-1H-pyrrole-3-carboxamide; 127) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-imidazole-4-carboxamide; 128) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-30 1 -methanesulfonyl-piperidine-4-carboxamide; 129) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,5-dimethyl-1H-pyrazole-4-carboxamide; 244 130) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoIin-4-yl)-phenyl]-1 H-pyrazole-4-carboxamide; 131) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyI]-3-trifluoromethyl-1H-pyrazole-4-carboxamide; 5 132) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-pheriyl]-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-0 10 thiourea; 135) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoliri-4-yl)-phenyl]-1,1-dimethyl-urea; 136) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl-piperazine-1 -carboxamide; 15 137) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-piperidine-1-carboxamide; 138) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-morpholine-4-carboxamide; 139) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-20 pyrrolidine-1-carboxamide; 0 140) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-diethyl-urea; 141) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea; 25 142) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamirio-ethyl)-urea; 143) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(tetrahydro-furan-3-yl)-urea; 144) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylJ-30 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; 245 10 146 147 5 148 149 150 151 152 15 153 154 155 156 157 158 20 25 30 159 160 161 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -(3-dimethylamino-propyl)-1 -methyl-urea; 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-(2-dimethylamirio-ethyl)-1-methyl-urea; 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(3-dimethylamino-propyl)-urea; 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-methoxy-ethyl )-u rea; 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin- 3-yl-urea; 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin- 4-yl-urea; N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl-piperazine-1 -carboxamide; 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea; 3-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-dimethyl-urea; 3-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-diethyl-urea; N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-piperidine-1-carboxamide; N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-morpholine-4-carboxamide; N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pyrrolidirie-1-carboxamide; 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea; N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl-piperazine-1-carboxamide; N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pyrrolidine-1 -carboxamide; 246 10 162 163 164 165 166 167 168 15 169 170 171 172 173 20 25 30 174 175 176 177 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea; 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-dimethyl-urea; 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-diethyl-urea; 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]- 3-(2-dimethylamino-ethyl)-urea; N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-piperidine-1-carboxamide; N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoIin-4-yl)-phenyl]-morpholine-4-carboxamide; N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-formamide; [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amine; 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3-dimethyl-urea; N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl- 4-methyl-piperazine-1-carboxamide; 1-[4-(6,8-dichioro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3,3-trimethyl-urea; N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-piperidine-1 -carboxamide; N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-morpholine-4-carboxamide; N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-pyrrolidine-1 -carboxamide; 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylJ-3-(2-dimethylamino-ethyl)-1-methyl-urea; 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,3-diethyl-1 -methyl-urea; 247 178) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-formamide; 179) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amine; 5 180) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-pyrrolidine-1-carboxamide; 181) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-piperidine-1 -carboxamide; 182) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-0 10 1,3,3-trimethyl-urea; 183) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3-dimethyl-urea; 184) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoIin-4-yl)-phenyl]-methyl-morpholine-4-carboxamide; 15 185) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-4-methyl-piperazine-1-carboxamide; 186) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]- 3-(2-dimethylamino-ethyl)-1-methyl-urea; 187) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-20 3,3-diethyl-1-methyl-urea; 0 188) 2-dimethylamino-ethyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin- 4-yl)-phenyl]-carbamate; 189) 2-dimethylamino-ethyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate; 25 190) 2-dimethylamino-ethyl [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate; 191) methyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate; 192) ethyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-30 carbamate; 193) isopropyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate; 248 194) 2,2-dimethyl-propyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate; 195) methyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate; 5 196) isopropyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate; 197) 2,2-dimethyl-propyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylj-carbamate; 198) ethyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-10 carbamate; 199) (R)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide; 200) (S)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide; 15 201) (R)-1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea; 202) (S)-1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4.-yl)-phenyl]-3-ethyl-urea; 203) N-[3-(6,8-dichloro-2-methyl-1 f2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-20 acetamide; 204) 4-(3-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoline; 205) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-hydroxy-ethyl)-urea; 206) ethyl 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoate; 25 207) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid! - and the pharmaceutical^ acceptable salts thereof
6. A compound of the formula I as claimed in claim 1, selected from the group 30 consisting of: 1) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide; intellectual Property Office of N.Z. 29 AUG 2005 8™" if* 8 U . 249 2) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide; 3) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide; 4) 1 -[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-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)-phenyl]-acetamide; 7) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-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-methy!-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-ethanesulfonamide; 12) N',N'-dimethylamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-sulfamide; 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-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclobutanecarboxamide; 18) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoro-acetamide; 250 5 21 22 19) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -acetyl-piperidine-4-carboxamide; 20) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-nicotinamide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane-sulfonamide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-ethanesulfonamide; 23) N,,N,-dimethylamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-10 yl)-phenyl]-sulfamide; 24) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopropanecarboxamide; 25) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -acetyl-piperidine-4-carboxamide; 15 26) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea; 27) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea; 28) 1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-20 urea; 29) 1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyI]-3-methyl-thiourea; 30) N-{5-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylsulfamoyl]-4-methyl-thiazol-2-yl}-acetamide; 25 31) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,2-dimethyl-1H-imidazole-4-sulfonamide; 32) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-C,C,C-trifluoro-methanesulfonamide; 33) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-C,C,C-30 trifluoro-methanesulfonamide; 34) N-ethyl-N'-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonylurea; 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 251 N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-dimethylamino-acetamide; 2)6-diamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoliri-4-yl)-phenylj-hexanamide; N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1H-pyrrole-3-carboxamide; N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-methyl-piperidine-4-carboxamide; N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-methanesulfonyl-piperidine-4-carboxamide; N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1H-pyrazole-carboxamide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-methylamino-acetamide; N-[3-(6,8-dichloro-2-methyl-1,2!3>4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-dimethylamino-acetamide; 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide; 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide; 2,6-diamino-N-[3-(6,8-dichloro-2-methyI-1,2,3.4-tetrahydro-isoquinolin-4-yl)-phenyl]-hexanamide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-methyl-piperidine-4-carboxamide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1H-imidazole-4-carboxamide; N-[3-(6,8-dichloro-2-methyl-1,2,3.4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-methanesulfonyl-piperidine-4-carboxamide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,5-dimethyl-1H-pyrazole-4-carboxamide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1H-pyrazole-carboxamide; 252 5 53 54 51) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-dimethyl-urea; 52) N-[3-(6,8-dichloro-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl-piperazine-1-carboxamide; N-[3-(6,8-dichioro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-piperidine-1-carboxamide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-morpholine-4-carboxamide; 55) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoIin-4-yl)-phenyl]-10 pyrrolidine-1-carboxamide; 56) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1 -diethyl-urea; 57) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea; 15 58) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea; 59) 1 -[3-(6,8-dichioro-2-methyl-1,2,3.4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(tetrahydro-furan-3-yl)-urea; 60) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-20 (tetrahydro-pyran-4-yl)-urea; | 61) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-methyl-1 -(1 -methyl-piperidin-4-yl)-urea; 62) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquiriolin-4-yl)-phenyl]-1-(3-dimethylamino-propyl)-1-methyl-urea; 25 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-diethylamino-propyl)-urea; 65) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-30 methoxy-ethyl)-urea; 66) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin-3-yI)-urea; 253 67) 1 -[3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin-4-yl-urea; 68) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl-piperazine-1-carboxamide; 5 69) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea; 70) 1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea; 71) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl-0 10 piperazine-1-carboxamide; 72) 1 -[4-(6,8-dichloro-2-methyl-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; 15 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) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-20 morpholine-4-carboxamide; 0 77) N-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-formamide; 78) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-formamide; 79) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3,3-25 trimethyl-urea; 80) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3-dimethyl-urea; 81) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-morpholine-4-carboxamide; 30 82) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-4-methyl-piperazine-1 -carboxamide; 254 83) 1 -[3-(6,8-d ichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-1-methyl-urea; 84) 2-dimethylamine-ethyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate; 85) 2-dimethylamino-ethyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-pheny1]-carbamate; 86) 2-dimethylamino-ethyl [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate; 87) methyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate; 88) (R or S)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide; 89) (R or S)-1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea; 90) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-hydroxy-ethyl)-urea; and from the pharmaceutically acceptable salts thereof.
7. The use of a compound of the formula I and of the pharmaceutically acceptable salts thereof for producing a medicament for the treatment of disorders which can be influenced by inhibition of the sodium-proton exchanger of subtype III (NHE3), in which the meanings are: R1, R2, R3 and R4 independently of one another H, F, Cl, Br, I, CN, NO2, OH, NH2, CaH2a+l, CqqH2qq-i, OCbH2b+1, COORIO, OCORIO, CORIO or Ox-(CH2)y-phenyl; a and b in the groups CaH2a+l and OCbH2b+l independently of one another 1,2,3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms; qq 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms; R10 HorCcH2c+1; 255 c 1,2,3,4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms, x zero or 1; y zero, 1, 2, 3 or 4; 5 where the phenyl ring in the group Ox-(CH2)y-phenyl is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, Br, CN, NO2, OH, NH2 or CdH2d+l! d 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms, or R1, R2, R3 and R4 independently of one another heteroaryl, it being possible for zero, 1, 2, 3 or 4 N atoms, zero or 1 oxygen atom or zero or 1 S atom to be present as ring R1, R2, R3 and R4 independently of one another CONR11R12 or NR11R12; R11 and R12 20 independently of one another H, CeH2e+1, CrrH2rr-1; ^ e 1, 2, 3,4, 5, 6, 7 or 8, rr 3, 4, 5, 6, 7, or 8, it being possible for one or more H atoms in the groups CeH2e+1 and 15 atoms; or 25 CrrH2rr-1to be replaced by F atoms and for one or more CH2 groups to be replaced by O or NR13; R13 HorCfH2f+i; f 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; 30 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; 256 or R11 and R12 together with the N atom to which they are bonded a 5-, 6- or 7-membered ring; or R11 and R12 independently of one another COR14, CSR14 or S02R14; 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 possible for one or more CH2 groups to be replaced by O or NR13, or R1, R2, R3 and R4 independently of one another -Oh-SOj-R15, with h zero or 1; j zero, 1 or 2; R15 CkH2k+1, OH, 0C|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; R17 and R18 independently of one another H or CmH2m+11 m 1, 2, 3,4, 5, 6, 7 or 8, it being possible for one or more H atoms in the group CmH2m+1to be replaced by F atoms and for one or more CH2 groups to be replaced by O, CO, CS or NR19; R19 H or CnH2n+1 i n 1,2, 3 or 4; 257 it being possible for one or more H atoms in CnH2n+l to be replaced by F atoms; or R17 and R18 5 together with the N atom to which they are bonded a 5-, 6- or 7-membered ring; or R19 and a CH2 group of R17 or R18 together with the N atom to which they are bonded a 5- or 6-membered ring; 10 R5 H, Cph^p+i, CssH2ss-1 , COR20 or SO2R2O; p 1, 2, 3,4, 5, 6, 7 or 8, ss 3,4, 5, 6, 7 or 8, is being possible for one or more H atoms in CpH2p+i and CssH2ss-1to be replaced by F atoms, R20 CqH2q+i; 15 q 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms in CqH2q+i to be replaced by F atoms and for one or more CH2 groups to be replaced by O or NR21; R21 HorCrH2r+i; 120 r 1,2,3 or 4; it being possible for one or more H atoms in CrH2r+i to be replaced by F atoms; R6 H, F, Cl, Br, I, CsH2s+1> Ccjc|H2dd-1> 0H> OCtH2t+1 or OCOR22; s and t 25 independently of one another 1,2,3, 4, 5, 6, 7 or 8; dd 3,4, 5, 6, 7 or 8, it being possible for one or more H atoms in CsH2s+1. CddH2dd-1 and OCtH2t+1 to be replaced by F atoms; R22 CuH2u+i; u 1, 2, 3 or 4; 258 it being possible for one or more H atoms in CuH2u+1 to be replaced by F atoms; , R8 and R9 independently of one another -OvSO\atR23; v zero or 1; w zero, 1 or 2; R23 CnnH2nn+1> ^mmH2mm-1> ®H, 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 ®nd OCppH2pp+"| to be replaced by F atoms; R25 and R26 independently of one another H, CN or CZH2Z+1, CzzH2zz^ '> z 1, 2, 3,4, 5, 6, 7 or 8; zz 3,4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms and, in CZH2Z+1, it being possible for one or more H atoms to be replaced by F atoms and it being possible for one or more CH2 groups to be replaced by O, CO, CS or NR27; R27 H or CaaH2aa+1I 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-, 6- or 7-membered ring, or 259 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 NR32SOkkR30; 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+l; 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 F atoms, and it being possible for one or more H atoms in the groups CCcH2cc+1 and CyyH2yy-i to be replaced by F atoms and for one or more CH2 groups to be replaced by NR31 and for a (CH2) group to be replaced by O; R31 H, C|<kH2kk+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, CxxH2XX+1! xx 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; or R31 forms together with a 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, zero or 1 S atoms and zero or 1 O atoms, 260 which is unsubstituted or substituted by up to three substituents selected from the group consisting of F, Cl, Br, I, CooH2OO+1» NR70R71; R70 and R71 independently of one another H, CuuH2uu+1 and COR72; R72 H, CwH2w+i; 00, uu and w independently of one another 1,2,3, 4, 5, 6, 7 or 8; it being possible for one or more H atoms in the groups CqoH2oo+1> ^uu^2uu+1 or ^w^2w+1 to be replaced by F atoms; or R7, 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 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 CeeH2ee+1> Oww^2ww-1 and OCffH2ff+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+ito be replaced by F atoms and for one or more CH2 groups to be replaced by O or NR44; R44 H Or CggH2gg+1; gg 1,2, 3,4, 5, 6, 7 or 8; 261 it being possible for one or more H atoms in the group CggH2gg+i to be replaced by F atoms, and it being possible for R44 together with a (CH2) group of R40 or R41 and the N atom to which they are jointly bonded to form a 5- or 6-5 membered ring, or R40 and R41 with the N atom to which they are bonded a 5- or 6-membered ring; R42 HorChhH2hh+1i 0 10 hh 1,2,3,4, 5, 6, 7 or 8; it being possible for one or more H atoms in the group ChhH2hh+1 *° be replaced by F atoms.
8. The use as claimed in claim 7, characterized in that compounds of the formula I are 15 used, in which the meanings are: R1, R2, R3 and R4 independently of one another, H, F, Cl, Br, I, CN, NO2, OH, NH2, CaH2a+1. cycloalkyl with 3, 4, 5 or 6 C atoms, OCt>H2b+l. COORIO; a and b ^20 independently of one another 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; R10 HorCcH2c+1; c 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; 25 or R1, R2, R3 and R4 independently of one another 5- or 6-membered heteroaryl selected from the group consisting of pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl and oxazolyl; 30 or R1, R2, R3 and R4 262 independently of one another CONR11R12 or NR11R12; R11 and R12 independently of one another H, CeH2e+l, CrrH2rr-1; e 1,2, 3 or 4, 5 rr 3,4,5 or 6, it being possible for one or more H atoms in the groups CeH2e+l and CrrH2rr-1 to be replaced by F atoms or R11 and R12 110 independently of one another hydroxyethyl, N,N-dimethylaminoethyl, N,N-diethyiaminoethyl, pyrrolidinoethyi, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl; or R11 and R12 15 together with the N atom to which they are bonded a pyrrolidine, piperidine, N-methylpiperazine, piperazine or morpholine ring; or R11 and R12 independently of one another COR14, CSR14, CONHR14, CSNHR14 20 or S02R14; > 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 25 R1, R2, R3 and R4 independently of one another OSO3H, SO3H, SO2R15, or R15 CkH2k+1, 0C|H2|+1 or NR17R18; k 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; 30 I 1,2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; 263 and R18 independently of one another H, CmH2m+1,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+i to be replaced by F atoms; R19 H or CnH2n+1l n 1,2, 3 or 4; it being possible for one or more H atoms in CnH2n+1 to be replaced by F atoms; and R18 together with the N atom to which they are bonded a 5- or 6-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 and CSsH2ss-1 to be replaced by F atoms; 9 20 R6 H, CsH2s+1 , OCtH2t+1 or OCOR22; s and t independently of one another 1, 2, 3 or 4; it being possible for one or more H atoms in CSH2S+1 and OCtH2t+l to be replaced by F atoms; 25 R22 CuH2u+i; u 1,2, 3 or 4; it being possible for one or more H atoms in CUH2U+1 to be replaced by F atoms; R7, R8 and R9 30 independently of one another OSO3H, SO3H or SO2R23; R17 10 or R17 15 264 R23 CnnH2nn+1» CmmH2mm-1'0CppH2pp+i or NR25R26; nn and pp independently of one another 1, 2, 3, 4 or 5, mm 3, 4, 5 or 6, 5 it being possible for one or more H atoms in CnnH2nn+1 > ^mm^2mm-1 and OCppH2pp+*i to be replaced by F atoms; R25 and R26 independently of one another H, CN or CZH2Z+1, in which the first CH2 group bonded to the nitrogen is replaced by CO or 10 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+1 to be replaced by F atoms; R27 H or CaaH2aa+11 15 aa 1,2,3 or 4; it being possible for one or more H atoms in CaaH2aa+i to be replaced by F atoms; or R25 and R26 '20 together with the N atom to which they are bonded a 5- or 6-membered ring; or R27 and a CH2 group of R25 or R26 together with the N atom to which they are bonded a 5- or 6-membered ring; 25 or R7, R8 and R9 independently of one another NR32COR30, NR32CSR30 or NR32S02R30; R30 H, OH, CccH2cc+1» CyyH2yy-1 - pyrrolidinyl or piperidinyl, in which rings a CH2 group may be replaced by O or NR33; 30 R32 and R33 independently of one another H or ChH2h+i; 265 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 groups CCcH2cc+1 and CyyH2yy-1 to be replaced by F atoms and for one or more (CH2) groups to be replaced by NR31 and for a (CH2) group to be replaced by 0; R31 H, C|<kH2kk+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.C^xx+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 or R30 and the N atom to which they are jointly bonded form a 5- or 6-membered ring; or R30 a 5- or 6-membered heteroaromatic system selected from the group consisting of pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thienyl, thiazolyl and oxazolyl, which are unsubstituted or substituted by up to three substituents selected from the group consisting of F, Cl, Br, I, CqoH2OO+1 • NR70R71, R70 and R71 independently of one another H, CuuH2uu+1 or COR72; R72 H, CwH2w+1! 00, uu and w independently of one another 1, 2, 3 or 4; 266 it being possible for one or more H atoms in the groups ^00^200+1' Cuu^2uu+1 or ^wH2vv+1 to be replaced by F atoms; or R7, R8 and R9 independently of one another H, F, Cl, Br, I, NO2, CN, OH, NH2, CeeH2ee+1' CwwH2ww_i, 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+1 > Cww^2ww-1 ar)d OCffH2ff+i to be replaced by F atoms; R40 and R41 H, CttH2tt+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+i to be replaced by F atoms; or R40 and R41 to be selected independently of one another hydroxyethyl,, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl; or R40 and R41 together with the N atom to which they are bonded form a ring selected from the group consisting of pyrrolidine, piperidine, N-methyl-piperazine, piperazine and morpholine; R42 HorChhH2hh+i: hh 1, 2, 3 or 4; 267 it being possible for one or more H atoms in the group ChhH2hh+1 to be replaced by F atoms.
9. The use as claimed in claim 7, characterized in that the meanings in formula I are: R1, R2, R3 and R4 independently of one another H, F, Cl, Br, OH, NH2, CaH2a+l. cycloalkyl with 3,4, 5 or 6 C atoms, OCfc,H2b+l I a and b in the groups CaH2a+l and OCbH2b+l independently of one another 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; or R1, R2, R3 and R4 independently of one another NR11R12; R11 and R12 independently of one another H, CeH2e+l, 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+1 and CrrH2rr-1 to be replaced by F atoms; or R11 and R12 together with the N atom to which they are bonded form a ring selected from the group consisting of pyrrolidine, piperidine, N-methylpiperazine, piperazine and morpholine; or R11 and R12 independently of one another COR14, CSR14, CONHR14, CSNHR14 orS02R14; R14 CgH2g+i; 268 g 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; or R1, R2, R3 and R4 5 independently of one another OSO3H, SO3H, SO2RI5; R15 CkH2k+1 orNR17R18; k 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; R17 and R18 10 independently of one another H or CmH2m+1> m 1, 2, 3,4 or 5, it being possible for one or more H atoms in the group CmH2m+1t0 be replaced by F atoms; or 15 R17 and R18 together with the N atom to which they are bonded a 5- or 6-membered ring; R5 H, CpH2p+i, CssH2ss-1; p 1,2, 3 or 4; |20 ss 3,4, 5 or 6, it being possible for one or more H atoms in CpH2p+i and CSsH2ss-1 to be replaced by F atoms; R6 H, CH3; R7, R8 and R9 independently of one another OSO3H, SO3H or S02R23; 25 R23 CnnH2nn+1 or NR25R26; nn 1,2, 3,4 or 5, it being possible for one or more H atoms in CnnH2nn+1to be replaced by F atoms; R25 and R26 269 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+1 to be replaced by F atoms; R27 H or CaaH2aa+11 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- or 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 R7, R8 and R9 independently of one another NR32COR30, NR32CSR30 or NR32S02R30; 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, CH3 or CF3; cc 1, 2, 3,4, 5 or 6; yy 3,4, 5, 6, 7 or 8; it being possible for one or more H atoms in the groups CccH2cc+1 and CyyH2yy-i to be replaced by F atoms and for one or more (CH2) groups to be replaced by NR31 and for a (CH2) group to be replaced by O; R31 H, methyl, ethyl, CF3, CH2CF3, acetyl, propionyl, methanesulfonyl or ethanesulfonyl; 270 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 or oxazolyl, which are unsubstituted or substituted by a maximum of 3 substituents 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+1» Oww^2ww-1» OCffH2ff+i. 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+1» cwwh2ww-1 and 0CffH2ff+1t0 be replaced by F atoms; R40 and R41 H, CttH2tt+1 or C(NH)NH2 ; tt 1,2, 3 or 4; it being possible for one or more H atoms in the group CttH2tt+l to be replaced by F atoms; or R40 and R41 independently of one another hydroxyethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl; or R40 and R41 together with the N atom to which they are bonded a pyrrolidine, piperidine, N-methylpiperazine, piperazine or morpholine ring; 271 R42 HorChhH2hh+1! hh 1,2, 3 or 4; it being possible for one or more H atoms in the group ChhH2hh+1 to be replaced by F atoms. 5
10. The use as claimed in claim 7, characterized in that the compounds of the formula I are selected from the group consisting of: 1) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide; 10 2) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide; 3) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide; 4) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N,N-dimethyl-benzenesulfonamide; 5) 4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline; 15 6) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid; 7) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-ethyl-benzamide; 8) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-propyl-benzamide; 9) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-(2-dimethylamino-ethyl)-benzamide; 20 10) 6,8-dichloro-2-methyl-4-(4-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline; ' 11) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-phenyl]-diethyl-amine 12) 6,8-dichloro-2-methyl-4-(4-piperidin-1 -yl-phenyl)-1,2,3,4-tetrahydroisoquinoline; 13) 6,8-dichloro-2-methyl-4-(4-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline; 14) 6,8-dichloro-2-methyl-4-[4-(4-methyl-piperazin-1 -yl)-phenyl]-1,2,3,4-tetrahydro-25 isoquinoline; 15) 6,8-dichloro-2-cyclopropyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline; 16) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine; 17) 1 -[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-propylurea; 30 18) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea; 272 19 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl- urea; 20) N-[4-(6-methanesulfonyl-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide; 5 21) N-[4-(2,6,8-trimethyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide; 22) N-[4-(6-bfomo-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; 10 24) N-[4-(8-chloro-2-methyl-6-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide; 25) N-{4-[8-chloro-2-methyl-6-(4-methyl-piperazin-1 -yl)-1,2,3,4-tetrahydro-isoquinolin-4-ylJ-phenyl}-acetamide; 26) N-{4-[8-chloro-6-(cyclopropylmethyl-amino)-2-methyl-1,2,3,4-tetrahydro-15 isoquinolin-4-yl]-phenyl}-acetamide; 27) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoic acid; 28) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-N-methyl-berizamide; 20 29) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-ethyl-2-hydroxy-l 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-25 benzoylj-guanidine; 32) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide; 33) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine; 34) 2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine; 30 35) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]- propionamide; 273 10 36 37 5 38 39 40 41 42 15 43 44 45 20 \ 46 47 25 48 49 30 50 51 N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide; N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]pentanamide; N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isobutyramide; N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2-dimethyl-propionamide; N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopropanecarboxamide; N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclobutanecarboxamide; N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopentanecarboxamide; N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoro-acetamide; N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-acetylpiperidine-4-carboxamide; N-[4-(6,8-dichloro-2-methyl-1,2,3I4-tetrahydro-isoquinolin-4-yl)-phenyl]-nicotinamide; N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane-sulfonamide; N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl]-ethanesulfonamide; N'.N'-dimethylamino-N-^^e.S-dichloro^-methyl-I^.S^-tetrahydro-isoquinolin^-yl)-phenyl]-sulfamide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide; N-[3-(6,8-dichloro-2-methy!-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pentanamide; 52 53 54 55 56 57 58 59 60 61 62 63 64 274 N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isobutyramide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2-dimethyl-propionamide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopropanecarboxamide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylJ-cyclobutanecarboxamide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-cyclopentanecarboxamide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoro-acetamide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-acetylpiperidine-4-carboxamide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-nicotinamide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane-sulfonamide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl]-ethanesulfonamide; N,,N,-dimethylamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoIin-4-yl)-phenyl]-sulfamide; N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide; N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide; N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pentanamide; N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isobutyramide; N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2-dimethyl-propionamide; 68 69 70 71 72 73 74 75 76 77 78 79 80 81 275 N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopropanecarboxamide; N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl]-cyclobutanecarboxamide; N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-cyclopentanecarboxamide; N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoro-acetamide; N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-acetylpiperidine-4-carboxamide; N-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane-sulforiamide; N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- phenyl]-ethanesulfonamide; N,,N,-dimethylamino-N-[2-(6,8-dichloro-2-methyl-1,2,3I4-tetrahydro-isoquinoliri-4-yl)-phenyl]-sulfamide; 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoIin-4-yl)-phenyl]-3-ethyl-urea; 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea; 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea; 1-[2-(6,8-dichIoro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea; N-{5-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylsulfamoyl]-4-methyl-thiazol-2-yl}-acetamide; N-{5-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylsulfamoyl]-4-methyl-thiazol-2-yl}-acetamide; N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,2-dimethyl-1 H-imidazole-4-sulfonamide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,2-dimethyl-1H-imidazole-4-sulfonamide; 276 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; 5 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-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-010 trifluoro-methanesulfonamide; 89) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-C,C,C-trifluoro-methariesulfonamide; 90) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoroethanesulfonamide; 15 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-isoquiriolin-4-yl)-benzenesulfonylurea; 93) 2-chloro-5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)- 20 benzenesulfonamide; 0 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; 25 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; 102) 4-(8-amino-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene-1,2-diol; 30 103) 2,8-dimethyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 104) 4-(3,4-dichloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline; 105) 4-(3,4-dichloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-8-ylamine; 277 106) 4-(2,4-dichloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-8-ylamine; 107) 4-(3-chloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-8-ylamine; 108) 2,4-dimethyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 109) 2-butyl-4-phenyl-1,2,3,4-tetrahydro-isoquinolin-8-ylamine; 5 110) N-(2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-aeetamide; 111) 7-chloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 112) 8-chloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 113) 2,6-dimethyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 114) 6-chloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 10 115) 6-methoxy-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 116) 2-ethyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 117) 2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 118) 6,8-dichloro-2-ethyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 119) 4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoline; 15 120) 2-methyl-4-phenyl-6,8-bis-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline; 121) 6,8-dichloro-2-isopropyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 122) 5,8-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 123) 6,8-dichloro-4-(4-fluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline; 124) 6,8-dichloro-2-methyl-4-p-tolyl-1,2,3,4-tetrahydro-isoquinoline; 20 125) 5,6-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 126) 6,7-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 127) 8-bromo-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 128) 6,8-dichloro-4-(4-chloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline; 129) 6,8-dichloro-2-cyclopropyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 25 130) 2-amino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide; 131) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-methylamino-acetamide; 132) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-30 dimethylamino-acetamide; 133) 2-amino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide; 278 134) 2-amino-N-[6-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide; 135) 2,6-diamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquiriolin-4-yl)-phenyl]-hexanamide; 5 136) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pyrrolidine-2-carboxamide; 137) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isonicotinamide; 138) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-10 pyrrole-3-carboxamide; 139) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-pyrrole-2-carboxamide; 140) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yI)-phenyl]-1 -methyl-piperidine-4-carboxamide; 15 141) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,4-dimethyl-1H-pyrrole-2-carboxamide; 142) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-nitro-1 H-pyrrole-2-carboxamide; 143) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,5-20 dimethyl-1 H-pyrrole-3-carboxamide; I 144) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-imidazole-4-carboxamide; 145) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -methanesulfonyl-piperidine-4-carboxamide; 25 146) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,5-dimethyl-1H-pyrazole-4-carboxamide; 147) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-pyrazole-4-carboxamide; 148) N-[4-(6,8-dichloro-2-methyI-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-30 trifluoromethyl-1 H-pyrazole-4-carboxamide; 149) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-methylamino-acetamide; 279 150) N[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-dimethylamino-acetamide; 151) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propioriamide; 5 152) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide; 153) 2,6-diamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylj-hexanamide; 154) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-0 10 pyrrolidine-2-carboxamide; 155) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isonicotinamide; 156) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-pyrrole-3-carboxamide; 15 157) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-pyrrole-2-carboxamide; 158) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -methyl-piperidine-4-carboxamide; 159) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,4-20 dimethyl-1 H-pyrrole-2-carboxamide; 9 160) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-nitro-1 H-pyrro!e-2-carboxamide; 161) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,5-dimethyl-1H-pyrrole-3-carboxamide; 25 162) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-imidazole-4-carboxamide; 163) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -methanesulfonyl-piperidine-4-carboxamide; 164) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,5-30 dimethyl-1 H-pyrazole-4-carboxamide; 165) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-pyrazole-4-carboxamide; 280 166) N-[3-(6,8-dichloro-2-methyl-1 ^.S^-tetrahydro-isoquinolin^-yO-phenyQ-S-trifluoromethyl-1 H-pyrazole-4-carboxamide; 167) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-thiourea; 5 168) 1 -[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-thiourea; 169) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-thiourea; 170) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-010 dimethyl-urea; 171) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl-piperazine-1 -carboxamide; 172) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-piperidine-1-carboxamide; 15 173) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-morpholine-4-carboxamide; 174) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-pheriyl]-pyrrolidine-1 -carboxamide; 175) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-20 diethyl-urea; 4P 176) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea; 177) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea; 25 178) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(tetrahydro-furan-3-yl)-urea; 179) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(tetrahydro-pyran-4-yl)-urea; 180) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -methyl-30 1 -(1 -methyl-piperidin-4-yl)-urea; 181) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-(3-dimethylamino-propyl)-1-methyl-urea; 281 182) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -(2-dimethylamirio-ethyl)-1-methyl-urea; 183) 1 -[3-(6,8-dichloro-2-methyI-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(3-dimethylamino-propyl)-urea; 5 184) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-methoxy-ethyl)-urea; 185) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridiri-3-yl-urea; 186) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin-010 4-yl-urea; 187) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl-piperazine-1 -carboxamide; 188) 1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea; 15 189) 3-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1 -dimethyl-urea; 190) 3-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-diethyl-urea; 191) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-piperidirie-20 1-carboxamide; ^ 192) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-morpholine-4-carboxamide; 193) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pyrrolidine-1 -carboxamide; 25 194) 1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamirio-ethyl)-urea; 195) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl-piperazine-1 -carboxamide; 196) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-30 pyrrolidine-1 -carboxamide; 197) 1 -[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea; 282 198) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-dimethyl-urea; 199) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-diethyl-urea; 200) 1 -[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea; 201) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-piperidine-1-carboxamide; 202) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-morpholine-4-carboxamide; 203) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-formamide; 204) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyI]-methyl-amine; 205) 1 -[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3-dimethyl-urea; 206) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-4-methyl-piperazine-1-carboxamide; 207) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3,3-trimethyl-urea; 208) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-piperidine-1 -carboxamide; 209) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-morpholine-4-carboxamide; 210) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-pyrrolidine-1 -carboxamide; 211) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-1-methyl-urea; 212) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,3-diethyl-1-methyl-urea; 213) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-formamide; 283 214) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amine; 215) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-pyrrolidine-1 -carboxamide; 5 216) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-piperidine-1-carboxamide; 217) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-pheriyl]-1,3,3-trimethyl-urea; 218) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3-#10 dimethyl-urea; 219) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-morpholine-4-carboxamide; 220) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-4-methyl-piperazine-1-carboxamide; 15 221) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-1 -methyl-urea; 222) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,3-diethyl-1 -methyl-urea; 223) 2-dimethylamino-ethyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-20 yl)-phenyl]-carbamate; # 224) 2-dimethylamino-ethyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate; 225) 2-dimethylamino-ethyl [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate; 25 226) methyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate; 227) ethyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate; 228) isopropyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-30 carbamate; 229) 2,2-dimethyl-propyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate; 4 284 230) methyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate; 231) isopropyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate; 5 232) 2,2-dimethyl-propyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate; 233) ethyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate; 234) (R)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]- 10 methanesulfonamide; 235) (S)-N-[3-(6,8-dichloro-2-methyl-1>2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide; 236) (R)-1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea; 15 237) (S)-1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea; 238) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide; 239) 4-(3-bromo-phenyl)-6>8-dichloro-methy!-1,2,3,4-tetrahydro-isoquinoline; 20 240) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-hydroxy-ethyl)-urea; 241) ethyl 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoate; 242) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid 25 and from the pharmaceutically acceptable salts thereof.
11. The use as claimed in claim 7, characterized in that the compounds of the formula I are selected from the group consisting of: 1) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]- 30 acetamide; 2) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide; 3) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide; inteiiemiucti Property Office of N.Z. 90 ^ I 4 - i \ ■ 285 4) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-berizoic acid; 5) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-ethyl-benzamide; 6) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-propyl-benzamide; 7) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-(2-dimethylamino-5 ethyl)-benzamide; 8) 6,8-dichloro-2-methyl-4-(4-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline; 9) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine; 10) 1 -[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea; MO 11) 1 -[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;
12) N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide; 13) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoic 15 acid; 14) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-(2-dimethylamino-ethyl)-2-hydroxy-benzamide; 15) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide; 20 16) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine; ) 17) 2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine; 18) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide; 19) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-acetyl- 25 piperidine-4-carboxamide; 20) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane-sulfonamide; 21) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-ethanesulfonamide; 30 22) N,,N'-dimethylamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-sulfamide; 286 23) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide; 24) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide; 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)-pheriyl]-cyclobutanecarboxamide; 28) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoro-acetamide; 29) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -acetyl-piperidine-4-carboxamide; 30) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-nicotinamide; 31) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane-sulfonamide; 32) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-ethanesulfonamide; 33) N,,N,-dimethylamino-N-[3-(6,8-dichloro-2-methyl-1,2,3I4-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)-phenyI]-1 -acetyl-piperidine-4-carboxamide; 36) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea; 37) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea; 38) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea; 287 39) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea; 40) N-{5-[3-(6,8-dichIoro-2-methyl-1,2,3,4-tetrahydro-isoquinoIin-4-yl)-phenylsulfamoyl]-4-methyl-thiazol-2-yl}-acetamide; 41) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,2-dimethyl-1H-imidazole-4-sulfonamide; 42) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-C,C,C-trifluoro-methanesulfonamide; 43) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoIin-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 N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-hexanamide; 47) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-pyrrole-3-carboxamide; 48) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -methyl-piperidine-4-carboxamide; 49) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -methanesulfonyl-piperidine-4-carboxamide; 50) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 H-pyrazole-4-carboxamide; 51) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-methylamino-acetamide; 52) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-dimethylamino-acetamide; 53) 2-amino-N-[3-(6,8-dichloro-2-methyI-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; 288 55 56 5 57 58 59 10 60 61 15 62 63 64 20 65 66 25 67 68 30 69 70 2,6-diamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-pheriyl]-hexanamide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-methyl-piperidine-4-carboxamide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1H-imidazole-4-carboxamide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-methanesulfonyl-piperidine-4-carboxamide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,5-dimethyl-1H-pyrazole-4-carboxamide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1H-pyrazole-4-carboxamide; 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1 -dimethyl-urea; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl-piperazine-1 -carboxamide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-piperidine-1-carboxamide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-morpholine-4-carboxamide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pyrrolidine-1 -carboxamide; 3-[3-(6,8-dichloro-2-methyl-1 ^.S^-tetrahydro-isoquinolin^-yO-phenylJ-l ,1 -diethyl-urea; 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea; 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-d imethylam ino-ethyl )-u rea; 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(tetrahydro-furan-3-yl)-urea; 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(tetrahydro-pyran-4-yl)-urea; 289 71) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -methyl-1 -(1 -methyl-piperidin-4-yl)-urea; 72) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -(3-dimethylamino-propyl)-1-methyl-urea; 73) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1 -(2-dimethylamino-ethyl)-1-methyl-urea; 74) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(3-dimethylamlno-propyl)-urea; 75) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-methoxy-ethyl)-urea; 76) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin- 3-yl-urea; 77) 1 -[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin- 4-yl-urea; 78) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl piperazine-1 -carboxamide; 79) 1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea; 80) 1 -[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea; 81) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-4-methyl piperazine-1-carboxamide; 82) 1 -[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea; 83) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-dimethyl-urea; 84) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1 -diethyl-urea; 85) 1 -[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea; 86) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-morpholine-4-carboxamide; 290 87 >10 N-[4-(6,8-d ichloro-2-methyl-1,2,3,4-tetrahyd ro-isoqu inol in-4-yl )-phenyl]-formamide; [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amine; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-formamide; [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amine; 1 [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3,3-trimethyl-urea; 1 [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3-dimethyl-urea; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-morpholine-4-carboxamide; N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-4-methyl-piperazine-1-carboxamide; 1[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-1-methyl-urea; 2-dimethylamino-ethyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate; 2-dimethylamino-ethyl [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate; 2-dimethylamino-ethyl [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate; methyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamate; 100) (R or S)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide; 101) (R or S)-1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-30 ethyl-urea; 102) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-hydroxy-ethyl)-urea; 88 5 89 90 91 92 93 15 94 95 96 20 \ 97 98 25 99 291 103) ethyl 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoate; 104) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic acid and from the pharmaceutically acceptable salts thereof. 5 12. The use of a compound I as claimed in claim 7 for producing a medicament for the treatment or prophylaxis of disorders of respiratory drive.
13. The use of a compound I as claimed in claim 7 for producing a medicament for the 0 treatment or prophylaxis of respiratory disorders, in particular sleep-related respiratory 10 disorders such as sleep apneas.
14. The use of a compound I as claimed in claim 7 for producing a medicament for the treatment or prophylaxis of snoring.
15 15. The use of a compound I as claimed in claim 7 for producing a medicament for the treatment or prophylaxis of acute and chronic renal disorders, particularly of acute renal failure and of chronic renal failure.
16. The use of a compound I as claimed in claim 7 for producing a medicament for the 0 20 treatment or prophylaxis of disorders of intestinal function.
17. The use of a compound I as claimed in claim 7 for producing a medicament for the treatment or prophylaxis of disorders of biliary function. 25
18. The use of a compound I as claimed in claim 7 for producing a medicament for the treatment or prophylaxis of ischemic states of the peripheral and central nervous system and of stroke.
19. The use of a compound I as claimed in claim 7 for producing a medicament for the 30 treatment or prophylaxis of ischemic states of peripheral organs and limbs. tateiiectual Property Offices of fsi.Z. 29 AUG 2005 RECEIVED 53 3 3 2 2 292
20. The use of a compound I as claimed in claim 7 for producing a medicament for the treatment of states of shock.
21. The use of a compound I as claimed in claim 7 for producing a medicament for use 5 in surgical operations and organ transplantations.
22. The use of a compound I as claimed in claim 7 for producing a medicament for the preservation and storage of transplants for surgical procedures. 10
23. The use of a compound I as claimed in claim 7 for producing a medicament for the treatment of disorders in which cell proliferation represents a primary or secondary cause.
24. The use of a compound I as claimed in claim 7 for producing a medicament for the 15 treatment or prophylaxis of disorders of lipid metabolism.
25. The use of a compound I as claimed in claim 7 for producing a medicament for the treatment or prophylaxis of infestation by ectoparasites. 20
26. A medicine comprising an effective amount of a compound I as claimed in claim 1. 293 A compound according to claim 1, substantially as herein described or exemplified. A compound according to claim 5, substantially as herein described or exemplified. A use according to claim 7, substantially as herein described or exemplified. A medicine according to claim 26, substantially as herein described or exemplified. Intellectual Property Office of N.Z. y 29 AUG 2005
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10159714 | 2001-12-05 | ||
| PCT/EP2002/012990 WO2003048129A1 (en) | 2001-12-05 | 2002-11-20 | Substituted 4-phenyltetrahydroisoquinolines, method for the production thereof, the use thereof as medicaments, in addition to a medicament containing same |
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| Publication Number | Publication Date |
|---|---|
| NZ533322A true NZ533322A (en) | 2006-02-24 |
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| Application Number | Title | Priority Date | Filing Date |
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| NZ533322A NZ533322A (en) | 2001-12-05 | 2002-11-20 | Substituted 4-phenyltetrahydroisoquinolines, method for the production thereof, the use thereof as medicaments, in addition to a medicament containing same |
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| EP (1) | EP1453810B1 (en) |
| JP (1) | JP4510457B2 (en) |
| KR (1) | KR20050044724A (en) |
| CN (1) | CN100497314C (en) |
| AR (1) | AR037620A1 (en) |
| AT (1) | ATE425968T1 (en) |
| AU (1) | AU2002356689B2 (en) |
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| DE (1) | DE50213372D1 (en) |
| DK (1) | DK1453810T3 (en) |
| EC (1) | ECSP045138A (en) |
| ES (1) | ES2324528T3 (en) |
| HK (1) | HK1072597A1 (en) |
| HR (1) | HRP20040507A2 (en) |
| HU (1) | HUP0600854A2 (en) |
| IL (1) | IL162316A0 (en) |
| MA (1) | MA27147A1 (en) |
| MX (1) | MXPA04005343A (en) |
| MY (1) | MY157371A (en) |
| NO (1) | NO326650B1 (en) |
| NZ (1) | NZ533322A (en) |
| OA (1) | OA12740A (en) |
| PE (1) | PE20030726A1 (en) |
| PL (1) | PL369313A1 (en) |
| PT (1) | PT1453810E (en) |
| RS (1) | RS48004A (en) |
| RU (1) | RU2298003C2 (en) |
| TN (1) | TNSN04100A1 (en) |
| TW (1) | TWI281860B (en) |
| UA (1) | UA77042C2 (en) |
| WO (1) | WO2003048129A1 (en) |
| ZA (1) | ZA200403711B (en) |
Families Citing this family (21)
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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 |
| TW200526626A (en) | 2003-09-13 | 2005-08-16 | Astrazeneca Ab | Chemical compounds |
| DE102004046492A1 (en) * | 2004-09-23 | 2006-03-30 | Sanofi-Aventis Deutschland Gmbh | Substituted 4-phenyltetrahydroisoquinolines, process for their preparation, their use as medicament, and medicament containing them |
| US20060111393A1 (en) * | 2004-11-22 | 2006-05-25 | Molino Bruce F | 4-Phenyl substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine and serotonin |
| DE102005001411A1 (en) * | 2005-01-12 | 2006-07-27 | Sanofi-Aventis Deutschland Gmbh | Substituted 4-phenyltetrahydroisoquinolines, process for their preparation, their use as medicament, and medicament containing them |
| AU2006215399B2 (en) | 2005-02-18 | 2010-12-09 | Astrazeneca Ab | Antibacterial piperidine derivatives |
| JP2008531671A (en) * | 2005-03-04 | 2008-08-14 | アストラゼネカ アクチボラグ | Compound |
| DE102005044817A1 (en) * | 2005-09-20 | 2007-03-22 | Sanofi-Aventis Deutschland Gmbh | Substituted 4-phenyltetrahydroisoquinolines, process for their preparation, their use as medicament, and medicament containing them |
| DE102006012545A1 (en) | 2006-03-18 | 2007-09-27 | Sanofi-Aventis | Substituted 2-amino-4-phenyl-dihydroquinolines, process for their preparation, their use as medicament, and medicament containing them |
| PL2384318T3 (en) * | 2008-12-31 | 2018-04-30 | 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 |
| 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 |
| US9034899B2 (en) | 2009-05-12 | 2015-05-19 | Albany Molecular Research, Inc. | Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof |
| RU2684097C2 (en) * | 2012-08-21 | 2019-04-04 | Эрделикс, Инк. | Compounds and methods for inhibiting nhe-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal diseases |
| RS58969B1 (en) | 2013-04-12 | 2019-08-30 | Ardelyx Inc | Nhe3-binding compounds and methods for inhibiting phosphate transport |
| CN103788084A (en) * | 2014-03-02 | 2014-05-14 | 湖南华腾制药有限公司 | Tetrahydroisoquinoline derivative and synthesis method thereof |
| MY182318A (en) | 2014-07-25 | 2021-01-19 | Taisho Pharmaceutical Co Ltd | Phenyl tetrahydroisoquinoline compound substituted with heteroaryl |
| 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. |
| JP7292207B2 (en) | 2017-01-09 | 2023-06-16 | アルデリックス， インコーポレイテッド | Compounds Useful for Treating Gastrointestinal Disorders |
| WO2018129557A1 (en) | 2017-01-09 | 2018-07-12 | Ardelyx, Inc. | Inhibitors of nhe-mediated antiport |
| IL303799A (en) * | 2020-12-18 | 2023-08-01 | Shanghai Jemincare Pharmaceutical Co Ltd | Benzoheterocycle substituted tetrahydroisoquinoline compound |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19951702A1 (en) * | 1999-10-27 | 2001-05-03 | Aventis Pharma Gmbh | Use of 2-amino-3,4-dihydroquinazolines for the manufacture of a medicament for the treatment or prophylaxis of diseases caused by ischemic conditions |
| EP1246805A1 (en) * | 1999-11-03 | 2002-10-09 | Albany Molecular Research, Inc. | 4-phenyl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine and serotonin |
| DK1246806T3 (en) * | 1999-11-03 | 2008-06-16 | Amr Technology Inc | Aryl and heteroaryl-substituted tetrahydroisoquinolines and their use in blocking the reuptake of norepinephrine, dopsmin 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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- 2002-11-20 WO PCT/EP2002/012990 patent/WO2003048129A1/en active Application Filing
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- 2002-11-20 HU HU0600854A patent/HUP0600854A2/en unknown
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