US 6,911,453 B2 · Substituted 4-phenyltetrahydroisoquinolinium, process for their preparation, their use as a medicament, and medicament containing them

Abstract

The invention relates to compounds of the formula I in which R1 to R9 are as defined herein. In one embodiment, these compounds may be used as antihypertensives, for reducing or preventing ischemia-induced damage, as medicaments for surgical intervention for the treatment of ischemias of the nervous system, of stroke and of cerebral edema, of shock, of impaired respiratory drive, for the treatment of snoring, as laxative, as agent against ectoparasites, to prevent the formation of gallstones, as antiatherosclerotics, agents against late complications of diabetes, cancers, fibrotic disorders, endothelial dysfunction, organ hypertrophies and hyperplasias. In one embodiment, the compounds may be inhibitors of the cellular sodium-proton antiporter and influence serum lipoproteins and thus be used for the prophylaxis and for the regression of atherosclerotic lesions.

A compound of the formula I

wherein:
R1, R2, R3 and R4 are independently of one another H, F, Cl, Br, I, CN, NO2, OH, NH2, CaH2a+1, CqqH2qq−1, OCbH2b+1, COOR10, OCOR10, COR10 or Ox—(CH2)y-phenyl;
wherein
a and b are independently of one another 1, 2, 3, 4, 5, 6, 7 or 8, wherein the groups CaH2a+1 and OCbH2b+1 independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms;
qq is 3, 4, 5, 6, 7 or 8, wherein the group CqqH2qq−1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms;
R10 is H or CcH2c+1;
c is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group CcH2c+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms;
x is zero or 1;
y is zero, 1, 2, 3 or 4;
where the phenyl ring in the group Ox—(CH2)y-phenyl is unsubstituted or substituted by 1-3 independently chosen from F, Cl, Br, CN, NO2, OH, NH2 and CdH2d+1,
d is 1, 2, 3 or 4, wherein the group CdH2d+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms;
or
R1, R2, R3 and R4 are independently of one another chosen from a heteroaryl with at least one heteroatom chosen from 1, 2, 3 or 4 N atoms, 1 oxygen atom and 1 S atom, present as ring atoms;
or
R1, R2, R3 and R4 are independently of one another CONR11R12 or NR11R12;
wherein
R11 and R12 are independently of one another H, CeH2e+1, CrrH2rr−1;
e is 1, 2, 3, 4, 5, 6, 7 or 8;
rr is 3, 4, 5, 6, 7, or 8, wherein the groups CeH2e+1 and CrrH2rr−1 independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms and/or one or more CH2 groups are replaced by O or NR13;
R13 is H or CfH2f+1;
f is 1, 2, 3 or 4, wherein the group CfH2f+1 is unsubsitituted or substituted where one or more H atoms are replaced by F atoms;
or
R13 and a CH2 group of R11 or R12 together with the N atom to which they are bonded form a 5- or 6-membered ring;
or
R11 and R12 together with the N atom to which they are bonded form a 5-, 6- or 7-membered ring;
or
R11 and R12 are independently of one another COR14, CSR14 or SO2R14;
wherein
R14 is CgH2g+1;
g is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group CgH2g+1 is unsubsitituted or substituted where one or more H atoms are replaced by F atoms, and/or one or more CH2 groups are replaced by O or NR13;
or
R1, R2, R3 and R4 are independently of one another —Oh—SOj-R15, with
h is zero or 1;
j is zero, 1 or 2;
R15 is CkH2k+1, OH, OClH2l+1 or NR17R18;
k is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group CkH2k+1 is unsubsitituted or substituted where one or more H atoms are replaced by F atoms;
l is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group OClH2l+1 is unsubsitituted or substituted where one or more H atoms are replaced by F atoms;
R17 and R18 are independently of one another H or CmH2m+1;
m is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group CmH2m+1 is unsubstituted or substituted where one or more H atoms is replaced by F atoms and/or one or more CH2 groups are replaced by O, CO, CS or NR19;
R19 is H or CnH2n+1;
n is 1, 2, 3 or 4, wherein the group CnH2n+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms;
or
R19 and a CH2 group of R17 or R18 together with the N atom to which they are bonded form a 5- or 6-membered ring;
or
R17 and R18 together with the N atom to which they are bonded form a 5-, 6- or 7-membered ring;
but where R2 does not equal H in any of the foregoing definitions,
R5 is H, CpH2p+1, CssH2ss−1, COR20 or SO2R20;
wherein
p is 1, 2, 3, 4, 5, 6, 7 or 8,
ss is 3, 4, 5, 6, 7 or 8,
R20 is CqH2q+1;
q is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the groups CpH2p+1, CssH2ss−1 and CqH2q+1 independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms and/or one or more CH2 groups are replaced by O or NR21;
R21 is H or CrH2r+1;
r is 1, 2, 3 or 4;
wherein the group CrH2r+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms;
R6 is H, F, Cl, Br, I, CsH2s+1, CddH2dd−1, OH, OCtH2t+1 or OCOR22;
wherein
s and t are independently of one another 1, 2, 3, 4, 5, 6, 7 or 8;
dd is 3, 4, 5, 6, 7 or 8, wherein the groups CsH2s+1, CddH2dd−1 and OCtH2t+1 independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms;
R22 is CuH2u+1;
u 1, 2, 3 or 4, wherein the group CuH2u+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms;
R7, R8 and R9 are independently of one another —Ov—SOw—R23;
wherein
v is zero or 1;
w is zero, 1 or 2;
R23 is CnnH2nn+1, CmmH2mm−1, OH, OCppH2pp+1 or NR25R26;
nn and pp are independently of one another 1, 2, 3, 4, 5, 6, 7 or 8,
mm is 3, 4, 5, 6, 7 or 8, wherein the groups CnnH2nn+1, CmmH2mm−1 and OCppH2pp+1 independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms;
R25 and R26 are independently of one another H, CN, CzH2z+1, or CzzH2zz−1;
z is 1, 2, 3, 4, 5, 6, 7 or 8;
zz is 3, 4, 5, 6, 7 or 8, wherein the group CzH2z+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms and,
wherein the group CzH2z+1, is unsubstituted or substituted where one or more H atoms are replaced by F atoms and/or one or more CH2 groups are replaced by O, CO, CS or NR27;
R27 is H or CaaH2aa+1;
aa is 1, 2, 3 or 4, wherein the group CaaH2aa+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms;
or
R27 and a CH2 group of R25 or R26 together with the N atom to which they are bonded form a 5- or 6-membered ring;
or
R25 and R26 together with the N atom to which they are bonded form a 5-, 6- or 7-membered ring;
or
R7, R8 and R9 are independently of one another NR32COR30, NR32CSR30 or NR32SObbR30;
R30 is H, CccH2cc+1, CyyH2yy−1, pyrrolidinyl or piperidinyl, wherein the pyrrolidinyl or piperidinyl is unsubstituted or substituted where a CH2 group is replaced by O or NR33;
R32 and R33 are independently of one another H or ChH2h+1;
bb is 2 or 3;
cc is 1, 2, 3, 4, 5, 6, 7 or 8;
yy is 3,4,5,6, 7 or 8;
h is 1, 2, 3, 4, 5, 6, 7 or 8,
wherein the group ChH2h+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms, and
wherein the groups CccH2cc+1 and CyyH2yy−1 independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms and/or one or more CH2 groups are replaced by NR31 and/or one CH2 group are replaced by O;
R31 is H, CkkH2kk+1, COR65 or SO2 R65;
kk is 1, 2, 3, or 4;
wherein the group CkkH2kk+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms,
R65 is H, or CxxH2xx+1;
xx is 1, 2, 3 or 4, wherein the group CxxH2xx+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms;
or
R31 together with a CH2 group of R30 forms a 5-, 6- or 7-membered ring;
or
R30 is a 5- or 6-membered heteroaryl with at least one hetero atom chosen from 1, 2, 3 or 4 N atoms, zero, 1 S atom and 1 O atom, which is unsubstituted or substituted by up to three substituents chosen from F, Cl, Br, I, CooH2oo+1, and NR70R71;
R70 and R71 are independently of one another H, CuuH2uu+1 or COR72;
R72 is H, or CvvH2vv+1;
oo, uu and vv are independently of one another 1, 2, 3, 4, 5, 6, 7 or 8, wherein the groups CooH2oo+1, CuuH2uu+1 and CvvH2vv+1 independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms;
or
R7, R8 and R9 are independently of one another H, F, Cl, Br, I, NO2, CN, OH, NH2, CeeH2ee+1, CwwH2ww−1, OCffH2ff+1, NR40R41, CONR40R41, COOR42, COR42 or OCOR42,
ee and ff are independently of one another 1, 2, 3, 4, 5, 6, 7 or 8;
ww is 3, 4, 5, 6, 7 or 8, wherein the groups CeeH2ee+1, CwwH2ww−1 and OCffH2ff+1 independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms;
R40 and R41 are independently of one another H, CttH2tt+1 or C(NH)NH2;
tt is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group CttH2tt+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms and/or where one or more CH2 groups are replaced by O or NR44;
R44 is H or CggH2gg+1;
gg is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group CggH2gg+1 is unnsubstituted or substituted where one or more H atoms are replaced by F atoms
or
R44 forms a 5- or 6-membered ring together with a (CH2) group of R40 or R41 and the N atom to which they are bound;
or
R40 and R41 with the N atom to which they are bonded form a 5- or 6-membered ring;
R42 is H or ChhH2hh+1;
hh is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group ChhH2hh+1 is unnsubstituted or substituted where one or more H atoms are replaced by F atoms;
with the proviso that two substituents chosen from the group R7, R8 and R9 can not simultaneously be OH and OCH3,
and that at least one of the substituents R7, R8 and R9 is chosen from CONR40R41, —Ov—SOw-R23, NR32COR30, NR32CSR30 and NR32SObbR30;
or a pharmaceutically acceptable salt thereof, or a trifluoroacetate thereof in any stereoisomeric form, or a mixture of any such compounds in any ratio.

114 more elements

Substituted 4-phenyltetrahydroisoquinolinium, process for their preparation, their use as a medicament, and medicament containing them

Life of this patent

Substituted 4-phenyltetrahydroisoquinolinium, process for their preparation, their use as a medicament, and medicament containing them

Life of this patent

Abstract

Claims28