CA2471217A1

CA2471217A1 - Substituted 4-phenyltetrahydroisoquinolinium salts, method for production and use thereof as a medicament and medicaments comprising the same

Info

Publication number: CA2471217A1
Application number: CA002471217A
Authority: CA
Inventors: Armin Hofmeister; Hans-Jochen Lang; Uwe Heinelt; Markus Bleich; Klaus Wirth
Original assignee: Individual
Current assignee: Sanofi Aventis Deutschland GmbH
Priority date: 2001-12-22
Filing date: 2002-12-09
Publication date: 2003-07-10
Also published as: TW200304823A; AU2002361028A1; JP4495462B2; ATE325100T1; AU2002361028A8; WO2003055880A3; WO2003055880A2; JP2005524616A; PE20030721A1; MXPA04005796A; EP1465870B1; EP1465870A2; DE50206706D1; DE10163914A1

Abstract

Compounds of formula (I), where R1 to R10 have the meanings given in the claims are particularly suitable as anti-hypertensives, for the reduction or prevention of ischaemic induced injury, as medicament for operative intervention in the treatment of ischaemia of the nervous system, stroke, cerebral oedema, shock, disrupted respiration, treatment of snoring, as laxative, as agent against ectoparasites, for prevention of gallstone formation, as antiatherosclerotic, as agent against late diabetic complications, carcinogenic disease states, fibrotic diseases, endothelial dysfunctions, organ hypertrophias and hyperplasias. Said compounds are inhibitors of cellular sodium/proton antiporters, influence serum lipoproteins, and can be used for prophylaxis and regression of atherosclerotic changes.

Description

Description Substituted 4-phenyltetrahydroisoquinolinium salts, process for their preparation, their use as medicament, and medicament containing them The invention relates to compounds of the formula I
R10-~ ~yR8 N'~nR6 in which the meanings are:
R1, R2, R3 and R4 independently of one another H, F, CI, Br, I, CN, N02, OH, NH2, CaH2a+1, CqqH2qq_1, OCbH2b+1, COOR50, OCOR50, COR50 or Ox-(CH2)Yphenyl;
aandb in the groups CaH2a+1 and OCbH2b+1 independently of one another 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms;
qq 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms to be replaced by F atoms;
R50 H or CcH2c+1;
c 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H
atoms to be replaced by F atoms, x zero or 1;
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, N02, OH, NH2 or CdH2d+1;
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 independently of one another CONR11 R12 or NR11 R12;
R11 and R12 independently of one another H, CeH2e+1, CrrH2rr-1;
a 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 H or CfH2f+1;
f 1, 2, 3 or 4, it being possible for one or more H
atoms to be replaced by F atoms;
or R13 and a 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 S02R14;
R14 CgH2g+1;
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 i 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, OCIH21+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+1;
m 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms in the group CmH2m+1 to be replaced by F
atoms and for one or more CH2 groups to be replaced by O; CO, CS or NR19;
R19 H or CnH2n+1 n 1, 2, 3 or 4;
it being possible for one or more H atoms in CnH2n+1 to be replaced by F atoms;
or R17 and R18 together with the N atom to which they are bonded a 5-, 6- or 7-membered ring;

' CA 02471217 2004-06-22 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;
R5 and R6 independently of one another CpH2p+1, 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+1;
q 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms in the groups CpH2p+1, CssH2ss-1 and CqH2q+1 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+1 to be replaced by F atoms;
R7 H, F, CI, Br, I, CSH2s+1, CddH2dd-1 ~ OH, OCtH2t+1 or OCOR22;
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 and OCtH2t+1 to be replaced by F atoms;
R22 CuH2u+1;
a 1, 2, 3 or 4;
it being possible for one or more H atoms in CuH2u+1 to be replaced by F atoms;
R8, R9 and R10 independently of one another -O~-SOw-R23;
v zero or 1;
w zero, 1 or 2;
R23 C~nH2nn+1 ~ CmmH2mm-1 ~ OH, OCppH2pp+1 or NR25R26;

nn and pp independently of one another 1, 2, 3, 4, 5; 6, 7 or 8, mm 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms in CnnH2nn+1 5 CmmH2mm-1 and OCppH2pp+1 to be replaced by F atoms;
R25 and R26 independently of one another H, CN or CZH2z+1. CzzH2zz_1;
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+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+1 as 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 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 R8, R9 and R10 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;
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 and CyyH2yy_1 to be replaced by F atoms and for one or more CH2 groups to be replaced by O or NR31;
R31 H, CkkH2kk+1 ~ COR65;
kk 1, 2, 3, or 4;
it being possible for one or more H atoms to be replaced by F
atoms, R65 H, C~H2~+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, which is unsubstituted or substituted by up to three substituents selected from the group consisting of F, CI, Br, I, CooH2oo+1~ NR70R71;
R70 and R71 independently of one another H, CuuH2uu+1 and COR72;
R72 H, CvvH2vv+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 CooH2oo -+1 ~ CuuH2uu+1 or CvvH2vv+1 to be replaced by F atoms;
or R8, R9 and R10 independently of one another H, F, Cl, Br, 1, N02, CN, OH, NH2, CeeH2ee+1 CN,N,H2~,N,_1, OC~H2~+1, NR40R41, CONR40R41, COOR42, COR42 or OCOR42, eg 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 C~,~"H2,~,W_1 and OC~H2~+1 to be replaced by F atoms;
R40 and R41 H or CttH2tt+1.
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+1 to be replaced by F atoms, or R40 and R41 with the N atom to which they are bonded a 5- or 6-membered ring;
R42 H or ChhH2hh+1 hh 1, 2, 3, 4, 5, 6, 7 or 8;
it being possible for one or more H atoms in the group ChhH2hh+1 to be replaced by F atoms;
Y fluorine, chlorine, bromine, iodine, hydroxyl and all anionic forms of pharmacologically acceptable mono-, di- or tricarboxylic acids or sulfonic acids;
and the pharmaceutically acceptable salts and trifluoroacetates thereof.
Preference is given to compounds of the formula I in which the meanings are:
R1, R2, R3 and R4 independently of one another, H, F, CI, Br, I, CN, N02, OH, NH2, CaH2a+1 cycloalkyi with 3, 4, 5 or 6 C atoms, OCbH2b+1, COOR50;
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;
R50 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 imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl and oxazolyl;
or R1, R2, R3 and R4 independently of one another CONR11 R12 or NR11 R12;
R11 and R12 independently of one another H, CeH2e+1, CrrH2rr-1;
a 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+1;
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 OS03H, S03H, S02R15, with R15 CkH2k+1, OCIH21+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 or C,~H2m+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+1 to be replaced by F
atoms;
R19 H or CnH2n+1 n 1, 2, 3 or 4;
it being possible for one or more H atoms in CnH2n+1 to be replaced by F atoms;

or R17 and R18 together with the N atom to which they are bonded a 5- or 6-membered ring;
5 R5 and R6 independently of one another CPH2p+1;
p 1, 2, 3 or 4;
it being possible for one or more H atoms in Cp.H2p+1 to be replaced by F atoms;

10 R7 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+1 to be replaced by F atoms;
R22 CuH2u+1;
a 1,2,3or4;
it being possible for one or more H atoms in CuH2u+1 to be replaced by F atoms;
R8, R9 and R10 independently of one another OS03H, S03H or S02R23;
R23 CnnH2nn+1 ~ CmmH2rnm-1 ~ OCppH2pp+1 or NR25R26;
nn and pp independently of one another 1, 2, 3, 4 or 5, mm 3, 4, 5 or 6, it being possible for one or more H atoms in CnnH2nn+1 CmmH2mm-1 and OCppH2pp+1 to be replaced by F atoms;
R25 and R26 independently of one another H, CN, CZH2Z+1 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+1 as 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 R8, R9 and R10 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;
cc 1, 2, 3, 4, 5 or 6;
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 CccH2cc+1 and CyyH2yY_1 to be replaced by F atoms and for one or more CH2 groups to be replaced by O or NR31;
R31 H, CkkH2kk+1 or COR65;
kk 1, 2, 3, or 4;

it being possible for one or more H atoms to be replaced by F atoms, _ R65 H, C~H2~+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 is unsubstituted or substituted by up to three substituents selected from the group consisting of F, CI, Br, I, CooH2oo+1~ NR70R71, R70 and R71 independently of one another H, CuuH2uu+1 or COR72;
R72 H, CvvH2w+1;
oo, uu and w independently of one another 1, 2, 3 or 4;
it being possible for one or more H atoms in the groups CooH2oo+1 ~ CuuH2uu+1 or CvvH2vv+1 to be replaced by F
atoms;
or R8, R9 and R10 independently of one another H, F, CI, Br, I, N02, CN, OH, NH2, CeeH2ee+1 C",,~"H2~"N,_1, OC~H2~+1, 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 CN,~,H2~_1 and OC~H2tt+1 to be replaced by F atoms;
R40 and R41 H or CttH2tt+1;
tt 1, 2, 3, 4, 5, 6, 7 or $;
it being possible for one or more H atoms in the group CttH2tt+1 to be replaced by F atoms;
or R40 and R41 i 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 H or ChhH2hh+1 hh 1,2,3or4;
it being possible for one or more H atoms in the group ChhH2hh+1 to be replaced by F atoms;
Y fluorine, chlorine, bromine, hydroxyl and all anionic forms of pharmacologically acceptable mono-, di- or tricarboxylic acids or sulfonic acids;
and the pharmaceutically acceptable salts and trifluoroacetates thereof.
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+1, cycloalkyl with 3, 4, 5 or 6 C atoms, OCbH2b+1 a and b in the groups CaH2a+1 and OCbH2b+1 independently of one another 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms;
or R1, R2, R3 and R4 independently of one, another NR11 R12;
R11 and R12 i independently of one another H, CeH2e+1, CrrH2rr-1;
a 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 or S02R14;
R14 CgH2g+1;
g 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms;
or R1, R2, R3 and R4 independently of one another OS03H, S03H, S02R15;
R15 CkH2k+1 or NR17R18;
k 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms; _ R17 and R18 independently of one another H or CmH2m+1;
m 1, 2, 3, 4 or 5, it being possible for one or more H
5 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 10 6-membered ring;
R5 and R6 independently of one another methyl or trifluoromethyl;
R7 H;
R8, R9 and R10 15 independently of one another OS03H, S03H 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+1 to be replaced by F atoms;
R25 and R26 independently of one another H, CN or CZH2z+1, 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+1 as 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 R8, R9 and R10 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 or 6;
yy 3, 4, 5 or 6;
it being possible for one or more H atoms in the groups CccH2cc+1 and CyyH2yy_1 to be replaced by F atoms and for one or more CH2 groups to be replaced by O or NR31;
R31 H, methyl, ethyl, CF3, CH2CF3, acetyl or propionyl;
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, 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 R8, R9 and R10 independently of one another H, F, CI, OH, NH2, CeeH2ee+1 ~ CwwH2ww-1 OC~H2ff+1, NR40R41, CONR40R41, COOR42 or OCOR42, ee and ff independently of one another 1, 2, 3 or 4; , ww 3, 4, 5 or 6, it being possible for one or more H atoms in the groups CeeH2ee+1 CN,N,H2N,v"_1 and OC~H2~+1 to be replaced by F atoms;
R40 and R41 H or CttH2tt+1;
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 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+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;
Y fluorine, chlorine, bromine, hydroxyl and all anionic forms of pharmacologically acceptable mono-, di- or tricarboxylic acids or sulfonic acids;
and the pharmaceutically acceptable salts and trifluoroacetates thereof.
Very particular preference is given to compounds of the formula I in which the meanings are:
R1 and R3 H;
R2 and R4 independently of one another H, F, CI, Br, OH, NH2, CaH2a+1, cycloalkyl with 3, 4, 5 or 6 C atoms, OCbH2b+1;
a and b in the groups CaH2a+1 and OCbH2b+1 independently of one another 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms;
r or R2 and R4 independently of one another NR11 R12;
R11 and R12 independently of one another H, CeH2e+1, a 1, 2, 3 or 4, it being possible for one or more H atoms in CeH2e+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+1;
g 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms;
or R2 and R4 independently of one another OS03H, S03H, S02R15;

R15 CkH2k+1 or NR17R18;
k 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms;
R17 and R18 independently of one another H or CrnH2m+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;
R5 and R6 independently of one another methyl or trifluoromethyl;
R7 H;
R8, R9 and R10 independently of one another OS03H, S03H 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+1 to be replaced by F atoms;
R25 and R26 independently of one another H, CN or CZH2z+1, 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+1;
as 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 5 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;
i or 10 R8, R9 and R10 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;
15 cc 1, 2, 3, 4, 5 or 6;
yy 3, 4, 5 or 6;
it being possible for one or more H atoms in the groups CccH2cc+1 and CyyH2yy_1 to be replaced by F atoms and for one or more CH2 groups to be replaced by O or NR31;

20 R31 H, methyl, ethyl, CF3, CH2CF3, acetyl or propionyl;
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, 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 R8, R9 and R10 independently of one another H, F, CI, OH, NH2, CeeH2ee+1 ~ CwwH2ww-1 OC~H2~+1, NR40R41, CONR40R41, COOR42 or OCOR42, _ ee and ff independently of one another 1, 2, 3 or 4;
ww 3, 4, 5 or 6, it being possible for one or more H atoms in the groups CeeH2ee+1 C~,H2~,_1 and OC~H2~+1 to be replaced by F atoms;
R40 and R41 H or CttH2tt+1;
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 independently of one another hydroxyethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl;
pipe~azinoethyl, 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+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;
Y fluorine, chlorine, bromine, hydroxyl and all anionic forms of pharmacologically acceptable mono-, di- or tricarboxylic acids or sulfonic acids;
and the pharmaceutically acceptable salts and trifluoroacetates thereof.
Exceptionally particular preference is given to the following tetrahydroisoquinolinium salts:
a. 6,8-dichloro-2,2-dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquinolinium trifluoroacetate;
b. 6,8-dichloro-2,2-dimethyl-4-(4-sulfamoylphenyl)-1,2,3,4-tetrahydroisoquinolinium trifluoroacetate;
c. 4-(4-acetylaminophenyl)-6,8-dichloro-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium iodide;
d. (+)-4-(4-acetylaminophenyl)-6,8-dichloro-2,2-dimethyl-1,2,3,4-tetrahydro-isoqui~olinium iodide;
e. (-)-4-(4-acetylaminophenyl)-6,8-dichloro-2,2-dimethyl-1,2,3,4-tetrahydro-isoquinolinium iodide;
f. (+)-4-(4-acetylaminophenyl)-6,8-dichloro-2,2-dimethyl-1,2,3,4-tetra'hydro-isoquinolinium chloride;
g. 4-(4-aminophenyl)-6,8-dichloro-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium chloride; hydrochloride;
h. 6,8-dichloro-4-[4-(3-ethylureido)phenyl]-2,2-dimethyl-1,2,3,4-tetrahydro-isoquinolinium chloride;
and the pharmaceutically acceptable salts thereof.
The defined alkyl radicals and partly or completely fluorinated alkyl radicals may be both straight-chain and branched. Groups CCaH2a-1 and their analogs as far as CyyH2yy_1 mean either the corresponding alkenyls, cycloalkyls, cycloalkylalkyls or alkylcycloalkyl.
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, 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, 1-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or_ 8-isoquinolyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl. The corresponding 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 heterocycles are imidazolyl, pyrazolyl, pyridyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl and oxazolyl.
Suitable pharmacologically acceptable anions Y are those of the following mono-, di-or tricarboxylic acids or sulfonic acids: acetic acid, adipic acid, citric acid, succinic acid, malic acid, fumaric acid, gluconic acid, glutamic acid, glycerolphosphoric acid, HCI, HBr, lactic acid, malonic acid, malefic acid, methanesulfonic acid, ethanesulfonic acid, nitric acid, di(2-hydroxy-3-carboxylic acid-naphth-1-yl)methane (pamoates), phosphoric acid, sulfuric acid, tartaric acid, toluenesulfonic acid.
In the case of multiply negatively charged acid anions Y it is possible for one or more cations according to the invention to be present.
If the compounds of the formula I contain one or more centers of asymmetry, these 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 terminal CH3 groups in an alkyl chain are also regarded as CH2 units and, in this connection, are understood as CH2-H groups.
Suitable pharmacologically and physiologically or toxicologically acceptable salts of the compounds of the formula I are: the alkali metal salts, preferably sodium or potassium salts, or the alkaline earth metal salts, e.g. calcium or magnesium salts, or the ammonium salts, e.g. salts with ammonia or organic amines or amino acids.

Compounds of the formula I which have one or more basic, i.e. protonatable, groups, or contain one or more basic heterocyclic rings, may also be used in the form of their physiologically acceptable acid addition salts with inorganic or organic acids, for example as hydrochlorides, phosphates, sulfates, methanesulfonates, acetates, lactates, maleates, fumarates, malates, gluconates etc.
The salts of the following acids are very suitable in particular: malefic acid, fumaric acid, succinic acid, malic acid, tartaric acid, methylsulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid.
The published specifications WO 01 32 624 and WO 01 32 625 describe compounds of type I but not as quaternary compounds, as inhibitors of reuptake of norepinephrine, dopamine and serotonin. However, these patent applications protect exclusively compounds in which R1 and R2 may be exclusively H. It has, however, emerged with the compounds of the invention that it is necessary at least for R2 that R2 is not H. It was furthermore not possible with an exemplary compound of the compounds of the invention to detect inhibitory properties on the receptors described, so that the described compounds differ distinctly both structurally and in their pharmacological properties from the compounds described in the patent applications mentioned.
Furthermore, compounds of type I, likewise not as quaternary compounds, are described in the published specification EP 11 13 007 as estrogen agonists and antagonists. It was possible to show that the compounds of the invention show no activity on the receptors mentioned, so that once again the structural differences of the compounds of the invention result in distinctly different pharmacological properties.
German patent application 101 59 714.2 (DEAV2001/0072) proposes the use of 4-phenyltetrahydroisoquinolines as NHE inhibitors. It has now emerged that the analogous quaternary ammonium compounds are equally excellent NHE inhibitors and, in particular, they inhibit NHE3. The compounds of the invention are, however, also distinguished by a distinctly greater solubility in water, which ought to lead to improved excretion through the kidneys.

Methods for preparing the compounds used are also described. The synthesis of the analogous tetrahydroisoquinoiines II has already been described in the German patent application 101 59 714.2 (DEAV2001/0072):

Thus, the compounds according to the invention can be prepared starting from the benzylamine precursors IV. These in turn can, if not obtainable commercially, be synthesized by standard processes from the corresponding benzyl chlorides or benzyl bromides III.

R3 ~ X ~R5 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.

~ /
R1 g~ R1 O
\ V R2 ( \ O
R3 / ~~RS R3 / N~RS

The alpha-bromacetophenone compounds V can be obtained from the corresponding acetophenone precursors by bromination in processes known from the literature.
The desired tetrahydroisoquinolines II 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; J. Med. Chem.; 1973, 16, 342).

NaBH4 OH
R3 / N~R5 VI IH+1 VII

'R5 When R7 is not equal to H, the desired compounds of the formula II can be prepared for example from the iodides VIII by halogen/metal exchange and subsequent nucleophiiic attack of the intermediate organolithium species on the carbonyl group (cf.
Chem. Pharm. Bull.; 1995, 43, 1543).

R10 / Rf / O
R10 \ ' [ R1 i ~N~R5 BuLi OH
R1 \
R3 \ N~RS

VIII II

The tertiary alcohols II synthesized in this way can be converted by known methods into other derivatives.
Alkyl-branched analogs (II) 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 II in a Pictet-Spengler analogous reaction (cf. Tetrahedron; 1987, 43, 439; Chem. Pharm. Bull.; 1985, 33, 340).
R10 /. "°
1. LDA

2. R7-X ~ R~
/ I ~COOR

X XI
1. NaOH
2. SOCIz 3. R5-NHz RS R10 / Kt ~ ~I

HCHO/LiAIH4 R2 / R~ O
~5 R3 ~ HN.R5 II XII
The compounds of the invention can be prepared in a manner known to the skilled worker by alkylation reactions starting from II.

R3 ~R5 Alkylating reagents which can be used are the appropriate halides, methanesulfonates, trifluoromethanesulfonates or else tosylates. The tetrahydroisoquinolinium salts produced in the reaction can easily be converted into other salts by ion exchange chromatography in a known manner.
It was possible to shov~i 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 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
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 transpiantations, in which cases the compounds can be used both to protect the organs in the donor before and during removal, to protect removed organs for example on treatment with or storage thereof in physiological bath fluids, as well as.
during the transfer into the recipient organism. The compounds are likewise valuable medicaments with a protective action during the performance of angioplastic surgical interventions, for example on the heart as well as peripheral vessels. In accordance 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 types of shock, such as, for example, of allergic, cardiogenic, hypovolemic and bacterial shock.
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 ahd 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 5 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 10 renal fibrosis, organ hypertrophies and hyperplasias, in particular for prostate hyperplasia or prostate hypertrophy.
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 15 (essential hypertension, atherosclerosis, diabetes, etc.), also in those cells which are readily amenable to measurements, such as, for example, in erythrocytes, platelets or 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 20 atherosclerosis, of diabetes, proliferative disorders etc. The compounds of the formula I are moreover suitable for preventive therapy to prevent the development of high blood pressure, for example of essential hypertension.
It has additionally been found that NHE inhibitors show a beneficial effect on serum 25 lipoproteins. It is generally acknowledged that blood lipid levels which are too high, so-called hyperlipoproteinemias, represent a considerable risk factor for the development 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 30 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 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 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 the kidneys (nephritides) which are associated with increased proteinlalbumin 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 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.
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 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 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 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 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 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 mglkg, to a maximum of 10 mglkg, 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 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:
Rt retention time TFA trifluoroacetic acid HPLC high performance liquid chromatography eq equivalent LCMS liquid chromatography mass spectroscopy MS mass spectroscopy CI chemical ionization RT room temperature THF tetrahydrofuran TOTU O-[(ethoxycarbonyl)-cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate DMSO dimethyl sulfoxide abs. absolute decomp. decomposition General:
The retention times (Rt) indicated below relate to LCMS measurements with the following parameters:
Method A:
stationary phase: Merck Purospher 3,u2 x 55 mm mobile phase: 95% H20 (0.05% TFA)~ 95% acetonitrile; 4 min; 95%
acetonitrile; 1.5 min --> 5% acetonitriie; 1 min; 0.5 ml/min.
Method A1:
stationary phase: Merck Purospher 3N2 x 55 mm mobile phase: 95% H20 (0.05% TFA)-~ 95% acetonitrile; 3 min; 95%
acetonitrile; 1.5 min -~ 5% acetonitrile; 1 min; 0.5 mllmin.
Method B:
stationary phase: Merck Purospher 3N2 x 55 mm mobile Phase: 0 min 90% H20 (0.05% TFA) 2.5 min-95% acetonitrile;
95% acetonitrile to 3.3 min; 10% acetonitrile 3.4 min;
1 ml/min.
Method C:
stationary phase: Merck Purospher 50 x 2.5 ml mobile phase: 95% H20 (0.1 % HCOOH)-->95% acetonitrile; 5 min; 95%
acetonitrile; 7 min; 0.45 mllmin.
The retention times relate to the MS spectra.
Example 1:
6,8-Dichloro-2,2-dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquinolinium, trifluoroacetate;

I/

cl I F~ O
/ N= F' I _ F
CI
Intermediate 1:
2,4-Dichlorobenzylmethylamine is prepared by methods known from the literature 5 (J. Med. Clhem.; 1984, 27, 1111 ).
Intermediate 2:
2-[(2,4-Dichlorobenzyl)methylamino]-1-phenylethanone;
14.1 g (74.2 mmol) of intermediate 1 are dissolved in 100 ml of dioxane and, at room 10 temperature, a solution consisting of 16.9 g (89 mmol) of 2-bromoacetophenone in 100 ml of dioxane is added dropwise. 51.2 ml (370 mmol) of triethylamine are then added, and the mixture is stirred at room temperature for four hours. After standing overnight, the resulting precipitate is filtered off with suction and the solvent is removed. The residue is dissolved in ethyl acetate and washed with 2 N HCI, H20 and 15 NaHC03, The HCI phase is adjusted to a pH of 12 with KOH and extracted twice with ethyl acetate. The combined organic phases are dried with Na2S04 and concentrated.
Chromatography on silica gel affords 20.6 g of the title compound as a yellow oil (Rt =
4.188 min (method A); MS(CI+) = 308.2/310.2).
20 Intermediate 3:
2-[(2,4-Dichlorobenzyl)methylamino]-1-phenylethanol;
Intermediate 2 (20.6 g; 66.9 mol) is dissolved in 150 ml of abs. methanol and, at 0°C, 5.06 g (133.8 mmol) of sodium borohydride are added in portions. The mixture is stirred at room temperature for two hours. For workup, the solvent is removed in 25 vacuo, and the residue is taken up in ethyl acetate and washed twice with H20. The ethyl acetate phase is dried with Na2S04 and concentrated, resulting in 20 g of crude product which 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-tetrahydroisoquinoline;
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 a precooled concentrated H2S04 and subsequently 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 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 53% yield (Rt = 4.444 min (method A); MS(CI+) _ 292.2/294.2).
6,8-Dichloro-2,2-dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquinolinium, trifluoroacetate;
Intermediate 4 (100 mg) was dissolved in the form of its hydrochloride in acetone (1 ml) in the presence of diisopropylethylamine (58 NI). Methyl iodide (38 NI) was then added dropwise with stirring. The mixture was then stirred at room temperature for two hours and subsequently left to stand for 62 h. Since the reaction was still not complete, further methyl iodide (38 NI) was added and the mixture was heated to reflux.
After two hours, the reaction mixture was cooled and then concentrated to dryness in a rotary evaporator. The residue was purified by preparative HPLC on RP-18 with acetonitrile/water (0.05% TFA), and the pure fractions were combined. The acetonitrile was stripped off and then the aqueous residue was freeze dried. 132 mg of the desired product were obtained as a solid. (Rt = 4.22 min (method A); MS (CI+): 306.0).
Example 2:
6,8-Dichloro-2,2-dimethyl-4-(4-sulfamoylphenyl)-1,2,3,4-tetrahydroisoquinolinium, trifluoroacetate;

~~~S~NHz O
/
O
CI \
F~ O
/ N- F' I _ \ F
CI
Intermediate 1 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide;
A solution of 3.0 g (10 mmol) of 6,8-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline (intermediate 4, example 1 ) in 30 ml of dichloromethane is slowly added dropwise at 0°C to 10 ml (150 mmol) of chlorosulfonic acid. The mixture is stirred at 0°C for one hour and at room temperature for one hour. For workup, the reaction mixture is poured onto ice and a pH of 8 is set with saturated NaHC03 solution. After three extractions with ethyl acetate, the organic phases are dried with Na2S04 and concentrated. The crude product (3.34 g) obtained in this way is suspended in 200 ml of concentrated ammonia and heated to 90°C. After three hours, the solvent is distilled off and the residue is taken up in a little H20 and extracted three times with ethyl acetate. The combined ethyl acetate phases are dried with Na2S04 and concentrated, resulting in 2.76 g of an amorphous crude product. Further purification by separation on a silica gel column (dichloromethane/methanol 95:5) results in 830 mg of the desired sulfonamide.
6,8-Dichloro-2,2-dimethyl-4-(4-sulfamoylphenyl)-1,2,3,4-tetrahydroisoquinolinium, trifluoracetate;
371 mg (1.0 mmol) of intermediate 1 are dissolved in 10 ml of DMF and, at room temperature, 11 eq. of methyl iodide are added. After three hours, the solvent is removed and the residue is digested in H20. Drying over P205 results in 380 mg of crude product which is purified on a preparative HPLC. (Rt = 3.583 min (method A);
MS(ES+) = 385.0/387.0).

Example 3:
3a: 4-(4-Acetylaminophenyl)-6,8-dichloro-2,2-dimethyl-1,2,3,4-tetrahydro-isoquinolinium iodide;

N- \
/
CI \
/ N \ I_ CI
3b: (+)-4-(4-Acetylaminophenyl)-6,8-dichloro-2,2-dimethyl-1,2,3,4-tetrahydro-isoquinolinium iodide;

(+) I-3c: (+)-4-(4-Acetylaminophenyl)-6,8-dichloro-2,2-dimethyl-1,2,3,4-tetrahydro-isoquinolinium chloride;

N-/
CI \
N- CI
/ \
1 ~ cl 3d: (-)-4-(4-Acetylaminophenyl)-6,8-dichloro-2,2-dimethyl-1,2,3,4-tetrahydro-isoquinolinium iodide;

N' \
/
CI \
(-) I - I_ CI

Intermediate 1: .
2,4-Dichlorobenzylmethylamine is prepared by methods known from the literature (J. Med. Chem.; 1984, 27, 1111 ).
Intermediate 2:
N-[4-(2-Bromoacetyl)phenyl]acetamide is synthesized in a manner known to the skilled worker by bromination of N-(4-acetylphenyl)acetamide.
The starting compound (0.256 mol) is introduced into 300 ml of acetic acid and, at i 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 (m.p.: 192°C).
Intermediate 3:
N-(4-{2-[(2,4-Dichlorobenzyl)methylamino]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 vacuo. The residue is taken up in ethyl acetate, washed with NaHC03 and H20, dried with MgS04 and concentrated. The oily residue resulting from this is triturated with an ethyl acetatelether mixture, resulting in 36 g of intermediate 3 in the form of a crystalline solid (m.p.: 115-117°C).
Intermediate 4:
N-(4-{2-[(2,4-Dichlorobenzyl)methylamino]-1-hydroxyethyl}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 stirred at 0°C for 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 MgS04 and concentrated.
The crude product obtained in this way can be reacted further without further purification. _ Intermediate 5:
N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]acetamide;
5 20 g (0.054 mol) of intermediate 4 are dissolved in 250 ml of dichloromethane and, at 0°C, 250 ml of concentrated H2S04 are added dropwise. The mixture is stirred at 0°C
for two hours and at room temperature for a further hour. For workup, the reaction mixture is added to ice 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 10 acetate. Drying of the organic phase and concentration afford a crude product which is triturated with diisopropyl ether, with 11.7 g of the compound of the example being isolated as crystalline solid (m.p.: 205-206°C).
4-(4-Acetylaminophenyl)-6,8-dichloro-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium 15 iodide (example 3a);
2.0 g (5.7 mmol) of intermediate 5 are introduced into 60 ml of abs. DMF and, at room temperature, 3.6 ml (60.0 mmol) of methyl iodide are added. The mixture is stirred at room temperature for three hours and then concentrated in vacuo. The residue is stirred once with a little H20, filtered off with suction and extracted once again with 20 boiling ethyl acetate. Filtration with suction affords 2.65 g of a pale yellow solid as crude product. 1.0 g of this was dissolved in 250 ml of H20 arid extracted with 100 ml of ethyl acetate. The aqueous phase is filtered and concentrated, resulting in 837 mg of the desired ammonium iodide in the form of a colorless solid. (Rt = 3.804 min (method A); MS(ES+) = 363.1/365.1 ).
2.0 g of intermediate 5 were separated into the enantiomers on a chiral phase.
Conditions:
stationary phase: Chiralpak AD 250 x 4.6; 20,um;
mobile phase: acetonitrile flow rate: 1 ml/min Rt (enantiomer 1 ) = 5.856 min, (-) enantiomer, about 850 mg;
Rt (enantiomer 2) = 8.613 min; (+) enantiomer, about 850 mg.
(+)-4-(4-Acetylaminophenyl)-6,8-dichloro-2,2-dimethyl-1,2,3,4-tetrahydro-isoquinolinium iodide (example 3b);
500 mg (1.43 mmol) of the (+) enantiomer of intermediate 5 (enantiomer 2) are reacted with methyl iodide in analogy to the synthesis method indicated in example 3a, resulting in 500 mg of the desired enantiopure ammonium iodide in the form of a colorless solid. (Rt = 1.630 min (method B); MS(ES+) = 363.2/365.2).
(+)-4-(4-Acetylaminophenyl)-6,8-dichloro-2,2-dimethyl-1,2,3,4-tetrahydro-isoquinolinium chloride (example 3c);
g of ion exchange resin (Amberlite IRA-93) are stirred in 2 N NaOH for 30 min and then packed into a column. It is washed with H20 until a pH check indicates a neutral 15 reaction. The exchange resin is stirred twice in 2 N HCI for 15 min, packed into a column and again washed with H20 until a pH check again indicates a neutral reaction. A solution of 400 mg of the compound of example 3b in 60 ml of H20 is passed over the resin (HCI form) prepared in this way and eluted with H20.
Concentration of the product fractions affords 303 mg of the desired chloride salt as colorless solid. (Rt = 1.990 min (method C); MS(ES+) = 363.2/365.2).
(-)-4-(4-Acetylaminophenyl)-6,8-dichloro-2,2-dimethyl-1,2,3,4-tetrahydro-isoquinolinium, iodide (example 3d);
A procedure analogous to the method described for the compound of example 3b, starting from the (-) enantiomer of intermediate 5 (enantiomer 1 ), affords the corresponding enantiopure product 3d with the opposite configuration to 3b.
(Rt =
1.952 min (method A1 ); MS(ES+) = 363.2/365.2).
Example 4: 4-(4-Aminophenyl)-6,8-dichloro-2,2-dimethyl-1,2,3,4-tetrahydro-isoquinolinium chloride, hydrochloride;

NHz CIH
CI
/ N~ CI
CI
3.5 g (7.13 mmol) of 4-(4-acetylaminophenyl)-6,8-dichloro-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium iodide (example 3a) are heated to reflux in 490 ml of 10%
strength HCI and 112 ml of ethanol for two hours. After cooling to room temperature, the mixture is concentrated in vacuo, and the residue is partitioned between H20 and ethyl acetate. The aqueous phase is concentrated to a volume of about 200 ml and subjected to an ion exchange chromatography by the method described in example 3c.
Concentration of the eluate affords 2.1 g of the desired hydrochloride. (Rt =
1.634 min (method A1 ); MS(ES+) = 321,0/323.1 ).
Example 5: 6,8-Dichloro-4-[4-(3-ethylureido)phenyl]-2,2-dimethyl-1,2,3,4-tetrahydro-isoquinolinium chloride;
intermediate 1: 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl-amine;
3.0 g (8.59 mmol) of N-j4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-phenylJacetamide (example 3, intermediate 5) are heated to reflux in 100 ml of strength sodium ethanolate solution. Solid sodium ethanolate is added depending on the progress of the reaction, until complete conversion is achieved. For workup, the solvent is removed and the residue is taken up in H20. It is extracted twice with dichloromethane. The combined organic phases are dried with MgS04 and concentrated. Further purification takes place by chromatography on silica gel with an.
ethyl acetate/heptane mixture, resulting in the aniline compound as a yellow oil.
Intermediate 2: 1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-ethylurea, hydrochloride;
500 mg (1.63 mmol) of 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-phenylamine are introduced into 20 ml of toluene, and a solution of 284 mg (4.0 mmol) of ethyl isocyanate in a little toluene is added dropwise. After one hour at 80°C, a further 180 mg of ethyl isocyanate are added, and the mixture is stirred at 80°C for one hour. For workup, the solvent is removed and the residue is triturated with H20 and ethyl acetate, filtered off with suction and dried, resulting in the title compound as a pale yellowish solid (m.p.: 218-220°C). The ethylurea obtained in this way is converted into the corresponding hydrochloride in a manner known to the skilled worker.
6,8-Dichloro-4-[4-(3-ethylureido)phenyl]-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium chloride;
1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-ethylurea hydrochloride (300 mg, 0.72 mmol) is partitioned between NaHC03 and ethyl acetate.
The resulting precipitate is filtered off with suction, dried and dissolved in 20 ml of DMF. Addition of 1.14 g (8.03 mmol) of methyl iodide is followed by stirring at room temperature for three hours. For workup, the solvent is removed, and the residue is taken up in H20 and extracted with ethyl acetate. The aqueous phase is concentrated in vacuo, and the residue is triturated once again with ethyl acetate and filtered off with suction. The quaternary ammonium salt obtained in this way is subjected to an ion exchange chromatography by the method described in example 3c. Concentration of the eluate affords 90 mg of the desired chloride. (Rt = 2.028 min (method A1 );
MS(ES+) = 392.3,0/394.2).

Pharmacological data:
Description of test:
In this test, the recovery in the intracellular pH (pHi) after an acidification is ascertained, which is initiated if the NHE is capable of functioning, even under bicarbonate-free conditions. For this purpose, the pHi was determined using the pH-sensitive fluorescent dye BCECF (Calbiochem, the precursor BCECF-AM is employed).i The cells were initially loaded with BCECF. The BCECF fluorescence was determined in a "Ratio Fluorescence Spectrometer" (Photon Technology International, South Brunswick, N.J., USA) at excitation wavelengths of 505 and 440 nm and an emission wavelength of 535 nm and converted into the pHi using calibration curves.
The cells were incubated in NH4CI buffer (pH 7.4) (NH4C1 buffer: 115 mM NaCI, mM NH4C1, 5 mM KCI, 1 mM CaCl2, 1 mM MgS04, 20 mM Hepes, 5 mM glucose, 1 mglml BSA; a pH of 7.4 is adjusted with 1 M NaOH) even during the BCECF
loading.
15 The intracellular acidification was induced by adding 975,u1 of an NH4CI-free buffer (see below) to 25 NI aliquots of the cells incubated in NH4C1 buffer. The subsequent rate of pH recovery was recorded for two minutes with NHE1, five minutes with and three minutes with NHE3. To calculate the inhibitory potency of the tested substances, the cells were initially investigated in buffers with which a complete or 20 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 Na2HP04, 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 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 K2HP04, 0.23 mM KH2P04, 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 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.
Results:
IC50 ~rMl~

Example (rNHE3) 0.23 2 0.90 3a 0.67 3c 0.43 4 0.03

Claims

claims 1. A compound of the formula I
in which the meanings are:
R1, R2, R3 and R4 independently of one another H, F, Cl, Br, I, CN, NO2, OH, NH2, C a H2a+1, C qq H2qq-1, OC b H2b+1, COOR50, OCOR50, COR50 or O x-(CH2)y-phenyl;
a and b in the groups C a H2a+1 and OC b 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;
R50 H or C c H2c+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;
where the phenyl ring in the group O x-(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 C d H2d+1;

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 independently of one another CONR11R12 or NR11R12;
R11 and R12 independently of one another H, C e H2e+1, C rr H2rr-1;
a 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 C e H2e+1 and C rr H2rr-1 to be replaced by F atoms and for one or more CH2 groups to be replaced by O or NR13;
R13 H or C f H2f+1;
f 1, 2, 3 or 4, it being possible for one or more H
atoms to be replaced by F atoms;
or R13 and a 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 SO2R14;
R14 C g H2g+1;

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 -O h-SO j-R15, with h zero or 1;
j zero, 1 or 2;
R15 C k H2k+1, OH, OC l H2l+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;
l 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 C m H2m+1;
m 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms in the group C m H2m+1 to be replaced by F
atoms and for one or more CH2 groups to be replaced by O, CO, CS or NR19;
R19 H or C n H2n+1;
n 1, 2, 3 or 4;
it being possible for one or more H atoms in C n H2n+1 to be replaced by F atoms;
or R17 and R18 together with the N atom to which they are bonded a 5-, 6- or 7-membered ring;
or R19 and a CH2 group of R17 of R18 together with the N atom to which they are bonded a 5- or 6-membered ring;

R5 and R6 independently of one another C p H2p+1, C ss H2ss-1, COR20 or SO2R20;
p 1, 2, 3, 4, 5, 6, 7 or 8, ss 3, 4, 5, 6, 7 or 8, R20 C q H2q+1;
q 1, 2, 3, 4, 5, 6, 7 or 8, it being possible for one or more H atoms in the groups C p H2p+1, C ss H2ss-1 and C q H2q+1 to be replaced by F atoms and for one or more CH2 groups to be replaced by O or NR21;
R21 H or C r H2r+1;
r 1, 2, 3 or 4;
it being possible for one or more H atoms in C r H2r+1 to be replaced by F atoms;
R7 H, F, Cl, Br, I, C s H2s+1, C dd H2dd-1, OH, OC t H2t+1 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 C s H2s+1, C dd H2dd-1 and OC t H2t+1 to be replaced by F atoms;
R22 C u H2u+1;
u 1, 2, 3 or 4;
it being possible for one or more H atoms in C u H2u+1 to be replaced by F atoms;
R8, R9 and R10 independently of one another -O v-SO w-R23;
v zero or 1;
w zero, 1 or 2;
R23 C nn H2nn+1, C mm H2mm-1, OH, OC pp H2pp+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, it being possible for one or more H atoms in C nn H2nn+1-C mm H2mm-1 and OC pp H2pp+1 to be replaced by F atoms;
R25 and R26 independently of one another H, CN or C z H2z+1, C zz H2zz-1;
z 1, 2, 3, 4, 5, 6, 7 or 8;
zz 3, 4, 5, 6, 7 or 8, it being possible for one or more H
atoms to be replaced by F atoms and, in C z H2z+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 C aa H2aa+1 aa 1, 2, 3 or 4;
it being possible for one or more H atoms in C aa H2aa+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 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 R8, R9 and R10 independently of one another NR32COR30, NR32CSR30 or NR32SO bb R30;
R30 H, C cc H2cc+1, C yy H2yy-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 C h H2h+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 C h H2h+1 to be replaced by F
atoms, and it being possible for one or more H atoms in the groups C cc H2cc+1 and C yy H2yy-1 to be replaced by F atoms and for one or more CH2 groups to be replaced by O or NR31;
R31 H, C kk H2kk+1, COR65;
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 H2xx+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, which is unsubstituted or substituted by up to three substituents selected from the group consisting of F, Cl, Br, I, C oo H2oo+1, NR70R71;
R70 and R71 independently of one another H, C uu H2uu+1 and COR72;
R72 H, C vv H2vv+1 oo, uu and vv 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 C oo H2oo+1, C uu H2uu+1 or C vv H2vv+1 to be replaced by F atoms;

R8, R9 and R10 independently of one another H, F, Cl, Br, I, NO2, CN, OH, NH2, C ee H2ee+1 C ww H2ww-1, OC ff H2ff+1, 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 C ee H2ee+1 C wwH2ww-1 and OC ff H2ff+1 to be replaced by F atoms;
R40 and R41 H or C tt H2tt+1;
tt 1, 2, 3, 4, 5, 6, 7 or 8;
it being possible for one or more H atoms in the group C tt H2tt+1 to be replaced by F atoms and for one or more CH2 groups to be replaced by O or NR44;
R44 H or C gg H2gg+1;
gg 1, 2, 3, 4, 5, 6, 7 or 8;
it being possible for one or more H atoms in the group C gg H2gg+1 to be replaced by F atoms, or R40 and R41 with the N atom to which they are bonded a 5- or 6-membered ring;
R42 H or C hh H2hh+1;
hh 1, 2, 3, 4, 5, 6, 7 or 8;
it being possible for one or more H atoms in the group C hh H2hh+1 to be replaced by F atoms;
Y fluorine, chlorine, bromine, iodine, hydroxyl and all anionic forms of pharmacologically acceptable mono-, di- or tricarboxylic acids or sulfonic acids;
and the pharmaceutically acceptable salts and trifluoroacetates thereof ;

52a the following compounds being excluded:
8-amino-4-(3,4-dihydroxyphenyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium iodide, 4-hydroxy-2,2-dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquinolinium iodide, and 8-amino-2,2-dimethyl-4-phenyl-1,2;3,4-tetrahydroisoquinolinium iodide.

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, C a H2a+1, cycloalkyl with 3, 4, 5 or 6 C atoms, OC b H2b+1, COOR50;
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;
R50 H or C c H2c+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 imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl and oxazolyl;
or R1, R2, R3 and R4 independently of one another CONR11 R12 or NR11 R12;
R11 and R12 independently of one another H, C e H2e+1, C rr H2rr-1;
a 1, 2, 3 or 4, rr 3, 4, 5 or 6, it being possible for one or more H atoms in the groups C e H2e+1 and C rr H2rr-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 it being possible for one or more H atoms in the group C hh H2hh+1 to be replaced by F atoms;
Y fluorine, chlorine, bromine, iodine, hydroxyl and all anionic forms of pharmacologically acceptable mono-, di- or tricarboxylic acids or sulfonic acids;
and the pharmaceutically acceptable salts and trifluoroacetates thereof;
the following compounds being excluded:
8-amino-4-(3,4-dihydroxyphenyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium iodide, 4-hydroxy-2,2-dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquinolinium iodide, and 8-amino-2,2-dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquinolinium iodide.

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, C a H2a+1, cycloalkyl with 3, 4, 5 or 6 C atoms, OC b H2b+1, COOR50;
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;
R50 H or C c H2c+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 54a independently of one another 5- or 6-membered heteroaryl selected from the group consisting of 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, C e H2e+1, C rr H2rr-1;
a 1, 2, 3 or 4, rr 3, 4, 5 or 6, 6-membered ring;
R5 and R6 independently of one another C p H2p+1;
p 1, 2, 3 or 4;
it being possible for one or more H atoms in C p H2p+1 to be replaced by F atoms;
R7 H, C s H2s+1, OC t H2t+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 C s H2s+1 and OC t H2t+1 to be replaced by F atoms;
R22 C u H2u+1.
u 1, 2, 3 or 4;
it being possible for one or more H atoms in C u H2u+1 to be replaced by F atoms;
R8, R9 and R10 independently of one another OSO3H, SO3H or SO2R23;
R23 C nn H2nn+1, C mm H2mm-1, OC pp H2pp+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 C nn H2nn+1, C mm H2mm-1 and OC pp H2pp+1 to be replaced by F atoms;
R25 and R26 independently of one another H, CN, C z H2z+1 or C z H2z+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 C z H2z+1 to be replaced by F atoms;

R27 H or C aa H2aa+1;
aa 1, 2, 3 or 4;
it being possible for one or more H atoms in C aa H2aa+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 R8, R9 and R10 independently of one another NR32COR30, NR32CSR30 or NR32SO2R30;
R30 H, OH, C cc H2cc+1, C yy H2yy-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 C h H2h+1;
cc 1, 2, 3, 4, 5 or 6;
yy 3, 4, 5 or 6;
h 1, 2, 3 or 4;
it being possible for one or more H atoms in C h H2h+1 to be replaced by F
atoms, and it being possible for one or more H atoms in the groups C cc H2cc+1 and C yy H2yy-1 to be replaced by F atoms and for one or more CH2 groups to be replaced by O or NR31;
R31 H, C kk H2kk+1 or COR65;
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 H2xx+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 is unsubstituted or substituted by up to three substituents selected from the group consisting of F, Cl, Br, I, C oo H2oo+1, NR70R71, R70 and R71 independently of one another H, C uu H2uu+1 or COR72;
R72 H, C vv H2vv+1;
oo, uu and vv independently of one another 1, 2, 3 or 4;
it being possible for one or more H atoms in the groups C oo H2oo+1, C uu H2uu+1 or C vv H2vv+1 to be replaced by F
atoms;
or R8, R9 and R10 independently of one another H, F, Cl, Br, I, NO2, CN, OH, NH2, C ee H2ee+1, C ww H2ww-1, OC ff H2ff+1, 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 C ee H2ee+1, C ww H2ww-1 and OC ff H2ff+1 to be replaced by F atoms;
R40 and R41 H or C tt H2tt+1;
tt 1, 2, 3, 4, 5, 6, 7 or 8;
it being possible for one or more H atoms in the group C tt H2tt+1 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 H or C hh H2hh+1;
hh 1, 2, 3 or 4;
it being possible for one or more H atoms in the group C hh H2hh+1 to be replaced by F atoms;
Y fluorine, chlorine, bromine, hydroxyl and all anionic forms of pharmacologically acceptable mono-, di- or tricarboxylic acids or sulfonic acids;
and the pharmaceutically acceptable salts and trifluoroacetates thereof.
3. A compound of the formula I as claimed in claim 1 or 2, in which the meanings are as follows:
R1, R2, R3 and R4 independently of one another H, F, Cl, Br, OH, NH2, C a H2a+1, cycloalkyl with 3, 4, 5 or 6 C atoms, OC b H2b+1;
a and b in the groups C a H2a+1 and OC b H2b+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, C e H2e+1, C rr H2rr-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 C e H2e+1 and C rr H2rr-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 SO2R14;
R14 C g H2g+1;
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;
R15 C k H2k+1 or NR17R18;
k 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms;
R17 and R18 independently of one another H or C m H2m+1;
m 1, 2, 3, 4 or 5, it being possible for one or more H
atoms in the group C m H2m+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;
R5 and R6 independently of one another methyl or trifluoromethyl;
R7 H;
R8, R9 and R10 independently of one another OSO3H, SO3H or SO2R23;
R23 C nn H2nn+1 or NR25R26;
nn 1, 2, 3, 4 or 5, it being possible for one or more H atoms in C nn H2nn+1 to be replaced by F atoms;
R25 and R26 independently of one another H, CN or C z H2z+1, or C z H2z+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 C z H2z+1 to be replaced by F atoms;
R27 H or C aa H2aa+1;
aa 1, 2, 3 or 4;
it being possible for one or more H atoms in C aa H2aa+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 R8, R9 and R10 independently of one another NR32COR30, NR32CSR30 or NR32SO2R30;
R30 H, OH, C cc H2cc+1, C yy H2yy-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 or 6;
yy 3, 4, 5 or 6;
it being possible for one or more H atoms in the groups C cc H2cc+1 and C yy H2yy-1 to be replaced by F atoms and for one or more CH2 groups to be replaced by O or NR31;
R31 H, methyl, ethyl, CF3, CH2CF3, acetyl or propionyl;
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, 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 R8, R9 and R10 independently of one another H, F, Cl, OH, NH2, C ee H2ee+1, C ww H2ww-1, OC ff H2ff+1, NR40R41, CONR40R41, COOR42 or OCOR42, ee and ff independently of one another 1, 2, 3 or 4;
ww 3, 4, 5 or 6, it being possible for one or more H atoms in the groups C ee H2ee+1, C ww H2ww-1 and OC ff H2ff+1 to be replaced by F atoms;
R40 and R41 H or C tt H2tt+1;
tt 1, 2, 3 or 4;
it being possible for one or more H atoms in the group C tt H2tt+1 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 H or C hh H2hh+1;
hh 1, 2, 3 or 4;
it being possible for one or more H atoms in the group C hh H2hh+1 to be replaced by F atoms;
Y fluorine, chlorine, bromine, hydroxyl and all anionic forms of pharmacologically acceptable mono-, di- or tricarboxylic acids or sulfonic acids;
and the pharmaceutically acceptable salts and trifluoroacetates thereof.
4. A compound of the formula I as claimed in claims 1-3, in which the meanings are:
R1 and R3 H;
R2 and R4 independently of one another H, F, Cl, Br, OH, NH2, C a H2a+1, cycloalkyl with 3, 4, 5 or 6 C atoms, OC b H2b+1;
a and b in the groups C a H2a+1 and OC b H2b+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 R2 and R4 independently of one another NR11R12;
R11 and R12 independently of one another H, C e H2e+1, e 1, 2, 3 or 4, it being possible for one or more H atoms in C e H2e+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 SO2R14;
R14 C g H2g+1;
g 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms;
or R2 and R4 independently of one another OSO3H, SO3H, SO2R15;
R15 C k H2k+1 or NR17R18;
k 1, 2, 3 or 4, it being possible for one or more H atoms to be replaced by F atoms;
R17 and R18 independently of one another H or C m H2m+1;
m 1, 2, 3, 4 or 5, it being possible for one or more H
atoms in the group C m H2m+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;
R5 and R6 independently of one another methyl or trifluoromethyl;
R7 H;
R8, R9 and R10 independently of one another OSO3H, SO3H or SO2R23;
R23 C nn H2nn+1 or NR25R26;
nn 1, 2, 3, 4 or 5, it being possible for one or more H atoms in C nn H2nn+1 to be replaced by F atoms;
R25 and R26 independently of one another H, CN or C z H2z+1, or C z H2z+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 C z H2z+1 to be replaced by F atoms;
R27 H or C aa H2aa+1;
aa 1, 2, 3 or 4;
it being possible for one or more H atoms in C aa H2aa+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 R8, R9 and R10 independently of one another NR32COR30, NR32CSR30 or NR32SO2R30;
R30 H, OH, C cc H2 cc +1, C yy H2 yy -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 or 6;
yy 3, 4, 5 or 6;
it being possible for one or more H atoms in the groups C cc H2 cc +1 and C yy H2 yy -1 to be replaced by F atoms and for one or more CH2 groups to be replaced by O or NR31;
R31 H, methyl, ethyl, CF3, CH2CF3, acetyl or propionyl;
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, 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 R8, R9 and R10 independently of one another H, F, CI, OH, NH2, C ee H2 ee +1, C ww H2 ww-1, OC ff H2 ff +1, NR40R41, CONR40R41, COOR42 or OCOR42, ee and ff independently of one another 1, 2, 3 or 4;
ww 3, 4, 5 or 6, it being possible for one or more H atoms in the groups C ee H2 ee +1 C ww H2N ww -1 and OC ff H2 ff +1 to be replaced by F atoms;

R40 and R41 H or C tt H2 tt +1;
tt 1, 2, 3 or 4;
it being possible for one or more H atoms in the group C tt H2 tt +1 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 H or C hh H2 hh +1 hh 1, 2, 3 or 4;
it being possible for one or more H atoms in the group C hh H2 hh+1 to be replaced by F atoms;
Y fluorine, chlorine, bromine, hydroxyl and all anionic forms of pharmacologically acceptable mono-, di- or tricarboxylic acids or sulfonic acids;
and the pharmaceutically acceptable salts and trifluoroacetates thereof.

5. A compound as claimed in any of claims 1-4, characterized in that they are:
a. 6,8-dichloro-2,2-dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquinolinium trifluoroacetate;
b. 6,8-dichloro-2,2-dimethyl-4-(4-sulfamoylphenyl)-1,2,3,4-tetrahydroisoquinolinium trifluoroacetate;
c. 4-(4-acetylaminophenyl)-6,8-dichloro-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium iodide;
d. (+)-4-(4-acetylaminophenyl)-6,8-dichloro-2,2-dimethyl-1,2,3,4-tetrahydro-isoquinolinium iodide;
e. (-)-4-(4-acetylaminophenyl)-6,8-dichloro-2,2-dimethyl-1,2,3,4-tetrahydro-isoquinolinium iodide;
f. (+)-4-,(4-acetylaminophenyl)-6,8-dichloro-2,2-dimethyl-1,2,3,4-tetrahydro-isoquinolinium chloride;
g. 4-(4-aminophenyl)-6,8-dichloro-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium chloride; hydrochloride;
h. 6,8-dichloro-4-[4-(3-ethylureido)phenyl]-2,2-dimethyl-1,2,3,4-tetrahydro-isoquinolinium chloride;
and the pharmaceutically acceptable salts thereof.

6. The use of a compound 1 as claimed in claim 1 for producing a medicament for the treatment of disorders which can be influenced by inhibition of the sodium-proton exchanger of subtype III (NHE3).

7. The use of a compound 1 as claimed in claim 1 for producing a medicament for the treatment or prophylaxis of disorders of respiratory drive.

8. The use of a compound 1 as claimed in claim 1 for producing a medicament for the treatment or prophylaxis of respiratory disorders, in particular sleep-related respiratory disorders such as sleep apneas.

9. The use of a compound 1 as claimed in claim 1 for producing a medicament for the treatment or prophylaxis of snoring.

10. The use of a compound 1 as claimed in claim 1 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.

11. The use of a compound 1 as claimed in claim 1 for producing a medicament for the treatment or prophylaxis of disorders of intestinal function.

12. The use of a compound 1 as claimed in claim 1 for producing a medicament for the treatment or prophylaxis of disorders of biliary function.

13. The use of a compound 1 as claimed in claim 1 for producing a medicament for the treatment or prophylaxis of ischemic states of the peripheral and central nervous system and of stroke.

14. The use of a compound 1 as claimed in claim 1 for producing a medicament for the treatment or prophylaxis of ischemic states of the peripheral organs and limbs.
15. The use of a compound 1 as claimed in claim 1 for producing a medicament for the treatment of states of shock.

16. The use of a compound 1 as claimed in claim 1 for producing a medicament for use in surgical operations and organ transplantations.

17. The use of a compound 1 as claimed in claim 1 for producing a medicament for the preservation and storage of transplants for surgical procedures.

18. The use of a compound I as claimed in claim 1 for producing a medicament for the treatment of disorders in which cell proliferation represents a primary or secondary cause.

19. The use of a compound 1 as claimed in claim 1 for producing a medicament for the treatment or prophylaxis of disorders of lipid metabolism.

20. The use of a compound 1 as claimed in claim 1 for producing a medicament for the treatment or prophylaxis of infestation by ectoparasites.

21. A medicine comprising an effective amount of a compound I as claimed in

claim 1.