U.S. patent application number 12/036635 was filed with the patent office on 2008-06-26 for multiply-substituted tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents.
Invention is credited to Stefan Baeurle, Markus Berger, Stefan Jaroch, Konrad Krolikiewicz, Anne Mengel, Duy Nguyen, Hartmut Rehwinkel, Heike Schaecke, Norbert Schmees, Werner Skuballa.
Application Number | 20080153859 12/036635 |
Document ID | / |
Family ID | 39543775 |
Filed Date | 2008-06-26 |
United States Patent
Application |
20080153859 |
Kind Code |
A1 |
Rehwinkel; Hartmut ; et
al. |
June 26, 2008 |
MULTIPLY-SUBSTITUTED TETRAHYDRONAPHTHALENE DERIVATIVES, PROCESS FOR
THEIR PRODUCTION AND THEIR USE AS ANTI-INFLAMMATORY AGENTS
Abstract
The invention relates to multiply-substituted
tetrahydronaphthalene derivatives of formula (I) ##STR00001##
process for their production and their use as anti-inflammatory
agents.
Inventors: |
Rehwinkel; Hartmut; (Berlin,
DE) ; Baeurle; Stefan; (Berlin, DE) ; Berger;
Markus; (Berlin, DE) ; Schmees; Norbert;
(Berlin, DE) ; Schaecke; Heike; (Berlin, DE)
; Krolikiewicz; Konrad; (Berlin, DE) ; Mengel;
Anne; (Berlin, DE) ; Nguyen; Duy; (Berlin,
DE) ; Jaroch; Stefan; (Berlin, DE) ; Skuballa;
Werner; (Berlin, DE) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD., SUITE 1400
ARLINGTON
VA
22201
US
|
Family ID: |
39543775 |
Appl. No.: |
12/036635 |
Filed: |
February 25, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10961375 |
Oct 12, 2004 |
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12036635 |
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10960754 |
Oct 8, 2004 |
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10961375 |
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60560414 |
Apr 7, 2004 |
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Current U.S.
Class: |
514/266.1 ;
514/311; 514/765; 544/283; 546/152; 585/26 |
Current CPC
Class: |
C07D 209/34 20130101;
C07D 215/38 20130101; C07D 307/88 20130101; C07D 209/46 20130101;
C07D 215/48 20130101; C07D 231/56 20130101; C07D 239/76 20130101;
C07D 277/64 20130101; C07C 255/58 20130101; A61K 31/517 20130101;
C07D 215/227 20130101; A61K 31/472 20130101; C07D 317/70 20130101;
A61K 31/47 20130101; C07D 405/12 20130101; C07C 2602/10 20170501;
C07D 237/32 20130101; C07D 239/74 20130101; C07D 215/04 20130101;
C07D 215/58 20130101; C07D 215/22 20130101; C07D 471/04 20130101;
A61P 29/00 20180101; C07D 213/74 20130101; C07D 217/24 20130101;
C07C 215/44 20130101 |
Class at
Publication: |
514/266.1 ;
546/152; 585/26; 514/311; 514/765; 544/283 |
International
Class: |
A61K 31/015 20060101
A61K031/015; C07C 13/48 20060101 C07C013/48; C07D 215/00 20060101
C07D215/00; C07D 239/72 20060101 C07D239/72; A61P 29/00 20060101
A61P029/00; A61K 31/517 20060101 A61K031/517; A61K 31/47 20060101
A61K031/47 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 5, 2004 |
DE |
102004017662.0 |
Claims
1. Stereoisomers of general formula (I) ##STR00013## in which
R.sup.1 and R.sup.2, independently of one another, mean a hydrogen
atom, a hydroxy group, a halogen atom, an optionally substituted
(C.sub.1-C.sub.10)-alkyl group, an optionally substituted
(C.sub.1-C.sub.1)-alkoxy group, a (C.sub.1-C.sub.10)-alkylthio
group, a (C.sub.1-C.sub.5)-perfluoroalkyl group, a cyano group, or
a nitro group, or R.sup.1 and R.sup.2 together mean a group that is
selected from the groups --O--(CH.sub.2).sub.n--O--,
--O--(CH.sub.2).sub.n--CH.sub.2--, --O--CH.dbd.CH--,
--(CH.sub.2).sub.n+2--, --NH--(CH.sub.2).sub.n+1,
N(C.sub.1-C.sub.3-alkyl)-(CH.sub.2).sub.n+1, or --NH--N.dbd.CH--,
whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms
and/or nitrogen atoms are linked to directly adjacent ring-carbon
atoms, or NR.sup.8R.sup.9, whereby R.sup.8 and R.sup.9,
independently of one another, can be hydrogen,
C.sub.1-C.sub.5-alkyl or (CO)--C.sub.1-C.sub.5-alkyl, R.sup.11
means a hydrogen atom, a hydroxy group, a halogen atom, a cyano
group, an optionally substituted (C.sub.1-C.sub.10)-alkyl group, a
(C.sub.1-C.sub.10)-alkoxy group, a (C.sub.1-C.sub.10)-alkylthio
group, or a (C.sub.1-C.sub.5)-perfluoroalkyl group, R.sup.12 means
a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an
optionally substituted (C.sub.1-C.sub.10)-alkyl group, or a
(C.sub.1-C.sub.10)-alkoxy group, R.sup.3 means a
C.sub.1-C.sub.10-alkyl group that optionally is substituted by 1-3
hydroxy groups, halogen atoms, 1-3 (C.sub.1-C.sub.5)-alkoxy groups;
an optionally substituted (C.sub.3-C.sub.7)-cycloalkyl group, an
optionally substituted heterocyclyl group, an optionally
substituted aryl group, a monocyclic or bicyclic heteroaryl group
that optionally contains 1-4 nitrogen atoms and/or 1-2 oxygen atoms
and/or 1-2 sulfur atoms and/or 1-2 keto groups and that optionally
is substituted, independently of one another, by one or more groups
selected from (C.sub.1-C.sub.5)-alkyl groups (which optionally can
be substituted by 1-3 hydroxy groups or 1-3 COOR.sup.13 groups,
whereby R.sup.13 means hydrogen or (C.sub.1-C.sub.5)-alkyl);
(C.sub.1-C.sub.5)-alkoxy groups, halogen atoms, hydroxy groups,
NR.sup.8R.sup.9 groups, exomethylene groups, or oxygen, whereby
this group can be linked via any position to the amine of the
tetrahydronaphthalene system and optionally can be hydrogenated at
one or more locations, R.sup.4 means a hydroxy group, a group
OR.sup.10 or an O(CO)R.sup.10 group, whereby R.sup.10 means any
hydroxy protective group or a C.sub.1-C.sub.10-alkyl group, R.sup.5
means a (C.sub.1-C.sub.10)-alkyl group or an optionally partially
or completely fluorinated (C.sub.1-C.sub.10)-alkyl group, a
(C.sub.3-C.sub.7)cycloalkyl group, a
(C.sub.1-C.sub.8)alkyl(C.sub.3-C.sub.7)cycloalkyl group, a
(C.sub.2-C.sub.8)alkenyl(C.sub.3-C.sub.7)cycloalkyl group, a
heterocyclyl group, a (C.sub.1-C.sub.8)alkylheterocyclyl group, a
(C.sub.2-C.sub.8)-alkenylheterocyclyl group, an aryl group, a
(C.sub.1-C.sub.8)alkylaryl group, a (C.sub.2-C.sub.8)alkenylaryl
group, (C.sub.2-C.sub.8)alkinylaryl groups, a monocyclic or
bicyclic heteroaryl group that contains 1-3 nitrogen atoms and/or
1-2 oxygen atoms and/or 1-2 sulfur atoms and that optionally is
substituted by 1-2 keto groups, 1-2 (C.sub.1-C.sub.5)-alkyl groups,
1-2 (C.sub.1-C.sub.5)-alkoxy groups, 1-3 halogen atoms or 1-2
exomethylene groups; a (C.sub.1-C.sub.8)alkylheteroaryl group or a
(C.sub.2-C.sub.8)alkenylheteroaryl group, or a
(C.sub.2-C.sub.8)alkinylheteroaryl group, whereby these groups can
be linked via any position to the tetrahydronaphthalene system and
optionally can be hydrogenated at one or more locations, R.sup.6
and R.sup.7, independently of one another, mean a hydrogen atom, a
methyl or ethyl group or together with the carbon atom of the
tetrahydronaphthalene system mean a (C.sub.3-C.sub.6)-cycloalkyl
ring, provided that at least three of radicals R.sup.1, R.sup.2,
R.sup.11 and R.sup.12 are not hydrogen.
2. Stereoisomers of general formula (I) according to claim 1, in
which R.sup.1 and R.sup.2, independently of one another, mean a
hydrogen atom, a hydroxy group, a halogen atom, an optionally
substituted (C.sub.1-C.sub.10)-alkyl group, a
(C.sub.1-C.sub.10)-alkoxy group, a (C.sub.1-C.sub.10)-alkylthio
group, a (C.sub.1-C.sub.5)-perfluoroalkyl group, a cyano group, or
a nitro group, or R.sup.1 and R.sup.2 together mean a group that is
selected from the groups --O--(CH.sub.2).sub.n--O--,
--O--(CH.sub.2).sub.n--CH.sub.2--, --O--CH.dbd.CH--,
--(CH.sub.2).sub.n+2--, --NH--(CH.sub.2).sub.n+1,
--N(C.sub.1-C.sub.3-alkyl)-(CH.sub.2).sub.n+1--, and
--NH--N.dbd.CH--, whereby n=1 or 2, and the terminal oxygen atoms
and/or carbon atoms and/or nitrogen atoms are linked to directly
adjacent ring-carbon atoms, or NR.sup.8R.sup.9, whereby R.sup.8 and
R.sup.9, independently of one another, can be hydrogen,
C.sub.1-C.sub.5-alkyl or (CO)--C.sub.1-C.sub.5-alkyl, R.sup.11
means a hydrogen atom, a hydroxy group, a halogen atom, a cyano
group, an optionally substituted (C.sub.1-C.sub.10)-alkyl group, a
(C.sub.1-C.sub.10)-alkoxy group, a (C.sub.1-C.sub.10)-alkylthio
group, or a (C.sub.1-C.sub.5)-perfluoroalkyl group, R.sup.12 means
a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an
optionally substituted (C.sub.1-C.sub.10)-alkyl group, or a
(C.sub.1-C.sub.10)-alkoxy group, R.sup.3 means a
C.sub.1-C.sub.10-alkyl group that optionally is substituted by 1-3
hydroxy groups, halogen atoms, or 1-3 (C.sub.1-C.sub.5)-alkoxy
groups; an optionally substituted (C.sub.3-C.sub.7)-cycloalkyl
group, an optionally substituted heterocyclyl group, an optionally
substituted aryl group, a monocyclic or bicyclic heteroaryl group
that optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms
and/or 1-2 sulfur atoms and/or 1-2 keto groups and that optionally
is substituted by one or more groups that are selected from
(C.sub.1-C.sub.5)-alkyl groups (which optionally can be substituted
by 1-3 hydroxy groups or 1-3 COOR.sup.13 groups, whereby R.sup.13
means hydrogen or (C.sub.1-C.sub.5)-alkyl);
(C.sub.1-C.sub.5)-alkoxy groups, halogen atoms, or exomethylene
groups, whereby this group can be linked via any position to the
amine of the tetrahydronaphthalene system and optionally can be
hydrogenated at one or more locations, R.sup.4 means a hydroxy
group, a group OR.sup.10 or an O(CO)R.sup.10 group, whereby
R.sup.10 means any hydroxy protective group or a
C.sub.1-C.sub.10-alkyl group, R.sup.5 means a
(C.sub.1-C.sub.5)-alkyl group or an optionally partially or
completely fluorinated (C.sub.1-C.sub.5)-alkyl group, a
(C.sub.3-C.sub.7)cycloalkyl group, a
(C.sub.1-C.sub.8)alkyl(C.sub.3-C.sub.7)cycloalkyl group, a
(C.sub.2-C.sub.8)alkenyl(C.sub.3-C.sub.7)cycloalkyl group, a
heterocyclyl group, a (C.sub.1-C.sub.8)alkylheterocyclyl group, a
(C.sub.2-C.sub.8)-alkenylheterocyclyl group,
(C.sub.2-C.sub.8)alkinylaryl groups, an aryl group, a
(C.sub.1-C.sub.8)alkylaryl group, a (C.sub.2-C.sub.8)alkenylaryl
group, a monocyclic or bicyclic heteroaryl group that contains 1-3
nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and
that optionally is substituted by 1-2 keto groups, 1-2
(C.sub.1-C.sub.5)-alkyl groups, 1-2 (C.sub.1-C.sub.5)-alkoxy
groups, 1-3 halogen atoms, or 1-2 exomethylene groups; a
(C.sub.1-C.sub.8)alkylheteroaryl group or a
(C.sub.2-C.sub.8)alkenylheteroaryl group, whereby these groups can
be linked via any position to the tetrahydronaphthalene system and
optionally can be hydrogenated at one or more locations, R.sup.6
and R.sup.7, independently of one another, mean a hydrogen atom, a
methyl or ethyl group or together with the carbon atom of the
tetrahydronaphthalene system mean a (C.sub.3-C.sub.6)-cycloalkyl
ring, provided that at least three of radicals R.sup.1, R.sup.2,
R.sup.11 and R.sup.12 are not hydrogen.
3. Stereoisomers of general formula (I) according to claim 2, in
which R.sup.1 and R.sup.2, independently of one another, mean a
hydrogen atom, a hydroxy group, a halogen atom, an optionally
substituted (C.sub.1-C.sub.10)-alkyl group, an optionally
substituted (C.sub.1-C.sub.10)-alkoxy group, a
(C.sub.1-C.sub.10)-alkylthio group, a
(C.sub.1-C.sub.5)-perfluoroalkyl group, a cyano group, or a nitro
group, or R.sup.1 and R.sup.2 together mean a group that is
selected from the groups --O--(CH.sub.2).sub.n--O--,
--O--(CH.sub.2).sub.n--CH.sub.2--, --O--CH.dbd.CH--,
--(CH.sub.2).sub.n+2--, --NH--(CH.sub.2).sub.n+1,
--N(C.sub.1-C.sub.3-alkyl)-(CH.sub.2).sub.n+1, and
--NH--N.dbd.CH--, whereby n=1 or 2, and the terminal oxygen atoms
and/or carbon atoms and/or nitrogen atoms are linked to directly
adjacent ring-carbon atoms, or NR.sup.8R.sup.9, whereby R.sup.8 and
R.sup.9, independently of one another, can be hydrogen,
C.sub.1-C.sub.5-alkyl, or (CO)--C.sub.1-C.sub.5-alkyl, R.sup.11
means a hydrogen atom, a hydroxy group, a halogen atom, a cyano
group, an optionally substituted (C.sub.1-C.sub.10)-alkyl group, a
(C.sub.1-C.sub.10)-alkoxy group, a (C.sub.1-C.sub.10)-alkylthio
group, or a (C.sub.1-C.sub.5)-perfluoroalkyl group, R.sup.12 means
a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an
optionally substituted (C.sub.1-C.sub.10)-alkyl group, or a
(C.sub.1-C.sub.10)-alkoxy group, R.sup.3 means a
C.sub.1-C.sub.10-alkyl group that optionally is substituted by 1-3
hydroxy groups, halogen atoms, 1-3 (C.sub.1-C.sub.5)-alkoxy groups,
an optionally substituted (C.sub.3-C.sub.7)-cycloalkyl group, an
optionally substituted heterocyclyl group, an optionally
substituted aryl group, a monocyclic or bicyclic heteroaryl group
that optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms
and/or 1-2 sulfur atoms and/or 1-2 keto groups and that optionally
is substituted, independently of one another, by one or more groups
selected from (C.sub.1-C.sub.5)-alkyl groups (which optionally can
be substituted by 1-3 hydroxy groups or 1-3 COOR.sup.13 groups,
whereby R.sup.13 means hydrogen or (C.sub.1-C.sub.5)-alkyl);
(C.sub.1-C.sub.5)-alkoxy groups, halogen atoms, hydroxy groups,
NR.sup.8R.sup.9 groups, exomethylene groups, or oxygen, whereby
this group can be linked via any position to the amine of the
tetrahydronaphthalene system and optionally can be hydrogenated at
one or more locations, R.sup.4 means a hydroxy group, a group
OR.sup.10 or an O(CO)R.sup.10 group, whereby R.sup.10 means any
hydroxy protective group or a C.sub.1-C.sub.10-alkyl group, R.sup.5
means a (C.sub.1-C.sub.10)-alkyl group or an optionally partially
or completely fluorinated (C.sub.1-C.sub.10)-alkyl group, R.sup.6
and R.sup.7, independently of one another, mean a hydrogen atom, a
methyl or ethyl group, or together with the carbon atom of the
tetrahydronaphthalene system mean a (C.sub.3-C.sub.6)-cycloalkyl
ring, provided that at least three of radicals R.sup.1, R.sup.2,
R.sup.11 and R.sup.12 are not hydrogen.
4. Stereoisomers of general formula (I), ##STR00014## in which
R.sup.1 and R.sup.2, independently of one another, mean a hydrogen
atom, a hydroxy group, a halogen atom, an optionally substituted
(C.sub.1-C.sub.10)-alkyl group, a (C.sub.1-C.sub.10)-alkoxy group,
a (C.sub.1-C.sub.10)-alkylthio group, a
(C.sub.1-C.sub.5)-perfluoroalkyl group, a cyano group, or a nitro
group, or R.sup.1 and R.sup.2 together mean a group that is
selected from the groups --O--(CH.sub.2).sub.n--O--,
--O--(CH.sub.2).sub.n--CH.sub.2--, --O--CH.dbd.CH--,
--(CH.sub.2).sub.n+2--, --NH--(CH.sub.2).sub.n+1,
--N(C.sub.1-C.sub.3-alkyl)-(CH.sub.2).sub.n+1, and
--NH--N.dbd.CH--, whereby n=1 or 2, and the terminal oxygen atoms
and/or carbon atoms and/or nitrogen atoms are linked to directly
adjacent ring-carbon atoms, or NR.sup.8R.sup.9, whereby R.sup.8 and
R.sup.9, independently of one another, can be hydrogen,
C.sub.1-C.sub.5-alkyl, or (CO)--C.sub.1-C.sub.5-alkyl, R.sup.11
means a hydrogen atom, a hydroxy group, a halogen atom, a cyano
group, an optionally substituted (C.sub.1-C.sub.10)-alkyl group, a
(C.sub.1-C.sub.10)-alkoxy group, a (C.sub.1-C.sub.10)-alkylthio
group, or a (C.sub.1-C.sub.5)-perfluoroalkyl group, R.sup.12 means
a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an
optionally substituted (C.sub.1-C.sub.10)-alkyl group, or a
(C.sub.1-C.sub.10)-alkoxy group, R.sup.3 means a
C.sub.1-C.sub.10-alkyl group that optionally can be substituted by
a group that is selected from 1-3 hydroxy groups, halogen atoms,
1-3 (C.sub.1-C.sub.5)-alkoxy groups, an optionally substituted
(C.sub.3-C.sub.7)-cycloalkyl group, an optionally substituted
heterocyclyl group, an optionally substituted aryl group, a
monocyclic or bicyclic heteroaryl group that optionally contains
1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms
and/or 1-2 keto groups and that optionally is substituted by one or
more groups selected from (C.sub.1-C.sub.5)-alkyl groups (which
optionally can be substituted by 1-3 hydroxy groups or 1-3
COOR.sup.13 groups); (C.sub.1-C.sub.5)-alkoxy groups, halogen
atoms, or exomethylene groups, whereby this group can be linked via
any position to the amine of the tetrahydronaphthalene system and
optionally can be hydrogenated at one or more locations, R.sup.4
means a hydroxy group, a group OR.sup.10 or an O(CO)R.sup.10 group,
whereby R.sup.10 means any hydroxy protective group or a
C.sub.1-C.sub.10-alkyl group, R.sup.5 means a
(C.sub.1-C.sub.10)-alkyl group or an optionally partially or
completely fluorinated (C.sub.1-C.sub.5)-alkyl group, a
(C.sub.3-C.sub.7)cycloalkyl group, a
(C.sub.1-C.sub.8)alkyl(C.sub.3-C.sub.7)cycloalkyl group, a
(C.sub.2-C.sub.8)alkenyl(C.sub.3-C.sub.7)cycloalkyl group, a
heterocyclyl group, a (C.sub.1-C.sub.8)alkylheterocyclyl group, a
(C.sub.2-C.sub.8)-alkenylheterocyclyl group, an aryl group, a
(C.sub.1-C.sub.8)alkylaryl group, a (C.sub.2-C.sub.8)alkenylaryl
group, (C.sub.2-C.sub.8)alkinylaryl groups, a monocyclic or
bicyclic heteroaryl group that contains 1-3 nitrogen atoms and/or
1-2 oxygen atoms and/or 1-2 sulfur atoms and that optionally is
substituted by 1-2 keto groups, 1-2 (C.sub.1-C.sub.5)-alkyl groups,
1-2 (C.sub.1-C.sub.5)-alkoxy groups, 1-3 halogen atoms, or 1-2
exomethylene groups; a (C.sub.1-C.sub.8)alkylheteroaryl group or a
(C.sub.2-C.sub.8)alkenylheteroaryl group, whereby these groups can
be linked via any position to the tetrahydronaphthalene system and
optionally can be hydrogenated at one or more locations, R.sup.6
and R.sup.7, independently of one another, mean a hydrogen atom, a
methyl or ethyl group, or together with the carbon atom of the
tetrahydronaphthalene system mean a (C.sub.3-C.sub.6)-cycloalkyl
ring, provided that at least three of radicals R.sup.1, R.sup.2,
R.sup.11 and R.sup.12 are not hydrogen.
5. Stereoisomers of general formula (I) according to claim 4,
##STR00015## in which R.sup.1 and R.sup.2, independently of one
another, mean a hydrogen atom, a hydroxy group, a halogen atom, a
(C.sub.1-C.sub.10)-alkyl group, a (C.sub.1-C.sub.10)-alkoxy group,
a (C.sub.1-C.sub.10)-alkylthio group, a
(C.sub.1-C.sub.5)-perfluoroalkyl group, a cyano group, a nitro
group, or R.sup.1 and R.sup.2 together mean a group that is
selected from the groups --O--(CH.sub.2).sub.n--O--,
--O--(CH.sub.2).sub.n--CH.sub.2--, --O--CH.dbd.CH--, or
--(CH.sub.2).sub.n+2--, whereby n=1 or 2, and the terminal oxygen
atoms and/or carbon atoms are linked to directly adjacent
ring-carbon atoms, or NR.sup.8R.sup.9, whereby R.sup.8 and R.sup.9,
independently of one another, can be hydrogen,
C.sub.1-C.sub.5-alkyl or (CO)--C.sub.1-C.sub.5-alkyl, R.sup.11
means a hydrogen atom, a hydroxy group, a halogen atom, a cyano
group, an optionally substituted (C.sub.1-C.sub.10)-alkyl group, a
(C.sub.1-C.sub.10)-alkoxy group, a (C.sub.1-C.sub.10)-alkylthio
group, or a (C.sub.1-C.sub.5)-perfluoroalkyl group, R.sup.12 means
a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an
optionally substituted (C.sub.1-C.sub.10)-alkyl group, or a
(C.sub.1-C.sub.10)-alkoxy group, R.sup.3 means a
C.sub.1-C.sub.10-alkyl group, which optionally can be substituted
by a group that is selected from 1-3 hydroxy groups, halogen atoms
or 1-3 (C.sub.1-C.sub.5)-alkoxy groups, an optionally substituted
phenyl group or a naphthyl group, a monocyclic or bicyclic
heteroaryl group that contains 1-3 nitrogen atoms and/or 1-2 oxygen
atoms and/or 1-2 sulfur atoms and that optionally is substituted by
1-2 keto groups, 1-2 (C.sub.1-C.sub.5)-alkyl groups, 1-2
(C.sub.1-C.sub.5)-alkoxy groups, 1-3 halogen atoms, or 1-2
exomethylene groups, whereby these groups can be linked via any
position to the amine of the tetrahydronaphthalene system and
optionally can be hydrogenated at one or more locations, R.sup.4
means a hydroxy group, R.sup.5 means a (C.sub.1-C.sub.5)-alkyl
group or an optionally partially or completely fluorinated
(C.sub.1-C.sub.5)-alkyl group, an aryl group, a
(C.sub.1-C.sub.8)alkylaryl group, a (C.sub.2-C.sub.8)alkenylaryl
group, a (C.sub.3-C.sub.7)cycloalkyl group, a
(C.sub.1-C.sub.8)alkyl(C.sub.3-C.sub.7)cycloalkyl group, or a
(C.sub.2-C.sub.8)alkenyl(C.sub.3-C.sub.7)cycloalkyl group, R.sup.6
and R.sup.7, independently of one another, mean a hydrogen atom, a
methyl or ethyl group, or together with the carbon atom of the
tetrahydronaphthalene system mean a (C.sub.3-C.sub.6)-cycloalkyl
ring, provided that at least three of radicals R.sup.1, R.sup.7,
R.sup.11 and R.sup.12 are not hydrogen.
6. Stereoisomers of general formula (I) according to claim 4,
##STR00016## in which R.sup.1 and R.sup.2, independently of one
another, mean a hydrogen atom, a hydroxy group, a halogen atom, a
(C.sub.1-C.sub.10)-alkyl group, a (C.sub.1-C.sub.10)-alkoxy group,
a (C.sub.1-C.sub.10)-alkylthio group, a
(C.sub.1-C.sub.5)-perfluoroalkyl group, a cyano group, a nitro
group, or R.sup.1 and R.sup.2 together mean a group that is
selected from the groups --O--(CH.sub.2).sub.n--O,
--O--(CH.sub.2).sub.n--CH.sub.2--, --O--CH.dbd.CH--, or
--(CH.sub.2).sub.n+2--, whereby n=1 or 2, and the terminal oxygen
atoms and/or carbon atoms are linked to directly adjacent
ring-carbon atoms, or NR.sup.8R.sup.9, whereby R.sup.8 and R.sup.9,
independently of one another, can be hydrogen,
C.sub.1-C.sub.5-alkyl or (CO)--C.sub.1-C.sub.5-alkyl, R.sup.11
means a hydrogen atom, a hydroxy group, a halogen atom, a cyano
group, an optionally substituted (C.sub.1-C.sub.10)-alkyl group, a
(C.sub.1-C.sub.10)-alkoxy group, a (C.sub.1-C.sub.10)-alkylthio
group, or a (C.sub.1-C.sub.5)-perfluoroalkyl group, R.sup.12 means
a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an
optionally substituted (C.sub.1-C.sub.10)-alkyl group, or a
(C.sub.1-C.sub.10)-alkoxy group, R.sup.3 means a
C.sub.1-C.sub.10-alkyl group that optionally can be substituted by
a group that is selected from 1-3 hydroxy groups, halogen atoms, or
1-3 (C.sub.1-C.sub.5)-alkoxy groups, an optionally substituted
phenyl group, a monocyclic or bicyclic heteroaryl group that
contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2
sulfur atoms and that optionally is substituted by 1-2 keto groups,
1-2 (C.sub.1-C.sub.5)-alkyl groups, 1-2 (C.sub.1-C.sub.5)-alkoxy
groups, 1-3 halogen atoms, or 1-2 exomethylene groups, whereby
these groups can be linked via any position to the amine of the
tetrahydronaphthalene system and optionally can be hydrogenated at
one or more locations, R.sup.4 means a hydroxy group, R.sup.5 means
a (C.sub.1-C.sub.5)-alkyl group or an optionally partially or
completely fluorinated (C.sub.1-C.sub.5)-alkyl group, an aryl
group, a (C.sub.1-C.sub.8)alkylaryl group, a
(C.sub.2-C.sub.8)alkenylaryl group, a (C.sub.3-C.sub.7)cycloalkyl
group, a (C.sub.1-C.sub.8)alkyl(C.sub.3-C.sub.7)cycloalkyl group,
or a (C.sub.2-C.sub.8)alkenyl(C.sub.3-C.sub.7)cycloalkyl group,
R.sup.6 and R.sup.7, independently of one another, mean a hydrogen
atom, a methyl or ethyl group, or together with the carbon atom of
the tetrahydronaphthalene system mean a
(C.sub.3-C.sub.6)-cycloalkyl ring, provided that at least three of
radicals R.sup.1, R.sup.2, R.sup.11 and R.sup.12 are not
hydrogen.
7. Stereoisomers of general formula (I) according to claim 4,
##STR00017## in which R.sup.1 and R.sup.2, independently of one
another, mean a hydrogen atom, a hydroxy group, a halogen atom, a
(C.sub.1-C.sub.10)-alkyl group, a (C.sub.1-C.sub.10)-alkoxy group,
a (C.sub.1-C.sub.10)-alkylthio group, a
(C.sub.1-C.sub.5)-perfluoroalkyl group, a cyano group, or a nitro
group, or R.sup.1 and R.sup.2 together mean a group that is
selected from the groups --O--(CH.sub.2).sub.n--O--,
O--(CH.sub.2).sub.n--CH.sub.2--, --O--CH.dbd.CH--, or
--(CH.sub.2).sub.n+2--, whereby n=1 or 2, and the terminal oxygen
atoms and/or carbon atoms are linked to directly adjacent
ring-carbon atoms, or NR.sup.8R.sup.9, whereby R.sup.8 and R.sup.9,
independently of one another, can be hydrogen,
C.sub.1-C.sub.5-alkyl or (CO)--C.sub.1-C.sub.5-alkyl, R.sup.11
means a hydrogen atom, a hydroxy group, a halogen atom, a cyano
group, an optionally substituted (C.sub.1-C.sub.10)-alkyl group, a
(C.sub.1-C.sub.10)-alkoxy group, a (C.sub.1-C.sub.10)-alkylthio
group, or a (C.sub.1-C.sub.5)-perfluoroalkyl group, R.sup.12 means
a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an
optionally substituted (C.sub.1-C.sub.10)-alkyl group, or a
(C.sub.1-C.sub.10)-alkoxy group, R.sup.3 means a
C.sub.1-C.sub.10-alkyl group, which optionally can be substituted
by a group that is selected from 1-3 hydroxy groups, halogen atoms,
or 1-3 (C.sub.1-C.sub.5)-alkoxy groups, an optionally substituted
phenyl group, a monocyclic or bicyclic heteroaryl group that
contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2
sulfur atoms and that optionally is substituted by 1-2 keto groups,
1-2 (C.sub.1-C.sub.5)-alkyl groups, 1-2 (C.sub.1-C.sub.5)-alkoxy
groups, 1-3 halogen atoms, or 1-2 exomethylene groups, whereby
these groups can be linked via any position to the amine of the
tetrahydronaphthalene system and optionally can be hydrogenated at
one or more locations, R.sup.4 means a hydroxy group, R.sup.5 means
a (C.sub.1-C.sub.5)-alkyl group or an optionally partially or
completely fluorinated (C.sub.1-C.sub.5)-alkyl group, an aryl
group, a (C.sub.1-C.sub.8)alkylaryl group, a
(C.sub.2-C.sub.8)alkenylaryl group, a (C.sub.3-C.sub.7)cycloalkyl
group, a (C.sub.1-C.sub.8)alkyl(C.sub.3-C.sub.7)cycloalkyl group,
or a (C.sub.2-C.sub.8)alkenyl(C.sub.3-C.sub.7)cycloalkyl group,
R.sup.6 and R.sup.7, independently of one another, mean a hydrogen
atom, a methyl or ethyl group, or together with the carbon atom of
the tetrahydronaphthalene system mean a
(C.sub.3-C.sub.6)-cycloalkyl ring, provided that at least three of
radicals R.sup.1, R.sup.2, R.sup.11 and R.sup.12 are not
hydrogen.
8. Stereoisomers of general formula (I) according to claim 4,
##STR00018## in which R.sup.1 and R.sup.2, independently of one
another, mean a hydrogen atom, a hydroxy group, a halogen atom, a
(C.sub.1-C.sub.5)-alkyl group, a (C.sub.1-C.sub.5)-alkoxy group, a
(C.sub.1-C.sub.5)-perfluoroalkyl group, a cyano group, or R.sup.1
and R.sup.2 together mean a group that is selected from the groups
O--(CH.sub.2).sub.n--O--, --O--(CH.sub.2).sub.n--CH.sub.2--,
--O--CH.dbd.CH--, or --(CH.sub.2).sub.n+2--, whereby n=1 or 2, and
the terminal oxygen atoms and/or carbon atoms are linked to
directly adjacent ring-carbon atoms, R.sup.11 means a hydrogen
atom, a hydroxy group, a halogen atom, a cyano group, an optionally
substituted (C.sub.1-C.sub.10)-alkyl group, a
(C.sub.1-C.sub.10)-alkoxy group, a (C.sub.1-C.sub.10)-alkylthio
group, or a (C.sub.1-C.sub.5)-perfluoroalkyl group, R.sup.12 means
a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an
optionally substituted (C.sub.1-C.sub.10)-alkyl group, or a
(C.sub.1-C.sub.10)-alkoxy group, R.sup.3 means a
C.sub.1-C.sub.10-alkyl group, which optionally can be substituted
by 1-3 hydroxy groups, halogen atoms, a phenyl, phthalidyl,
isoindolyl, dihydroindolyl, dihydroisoindolyl,
dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl,
phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl,
isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl,
quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl,
dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl
group that optionally is substituted with C.sub.1-C.sub.5alkyl,
halogen, hydroxy, or C.sub.1-C.sub.5-alkoxy, whereby these groups
can be linked via any position to the amine of the
tetrahydronaphthalene system and optionally can be substituted in
one or more places with 1-2 keto groups, 1-2
(C.sub.1-C.sub.3)-alkyl groups, 1-2 (C.sub.1-C.sub.3)-alkoxy
groups, 1-3 halogen atoms, or 1-2 exomethylene groups, and
optionally can be hydrogenated at one or more locations, R.sup.4
means a hydroxy group, R.sup.5 means a (C.sub.1-C.sub.5)-alkyl
group or an optionally partially or completely fluorinated
(C.sub.1-C.sub.5)-alkyl group, R.sup.6 and R.sup.7, independently
of one another, mean a hydrogen atom, a methyl or ethyl group or
together with the carbon atom of the tetrahydronaphthalene system
mean a (C.sub.3-C.sub.6)-cycloalkyl ring, provided that at least
three of radicals R.sup.1, R.sup.2, R.sup.11 and R.sup.12 are not
hydrogen.
9. Stereoisomers of general formula (I) according to claim 4,
##STR00019## in which R.sup.1 and R.sup.2, independently of one
another, mean a hydrogen atom, a hydroxy group, a halogen atom, a
(C.sub.1-C.sub.5)-alkyl group, a (C.sub.1-C.sub.5)-perfluoroalkyl
group, a cyano group, a (C.sub.1-C.sub.5)-alkoxy group, or together
mean a (C.sub.1-C.sub.2)-alkylenedioxy group, whereby then R.sup.1
and R.sup.2 must be directly adjacent, R.sup.11 means a hydrogen
atom, a hydroxy group, a halogen atom, a cyano group, an optionally
substituted (C.sub.1-C.sub.10)-alkyl group, a
(C.sub.1-C.sub.10)-alkoxy group, a (C.sub.1-C.sub.10)-alkylthio
group, or a (C.sub.1-C.sub.5)-perfluoroalkyl group, R.sup.12 means
a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an
optionally substituted (C.sub.1-C.sub.10)-alkyl group, or a
(C.sub.1-C.sub.10)-alkoxy group, R.sup.3 means a phenyl,
phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl,
dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl,
phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl,
isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl,
quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl,
dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl
group that optionally is substituted with C.sub.1-C.sub.5-alkyl,
halogen, hydroxy, or C.sub.1-C.sub.5-alkoxy, whereby these groups
can be linked via any position to the amine of the
tetrahydronaphthalene system and optionally can be substituted in
one or more places with 1-2 keto groups, 1-2
(C.sub.1-C.sub.3)-alkyl groups, or 1-2 exomethylene groups, and
optionally can be hydrogenated at one or more locations, R.sup.4
means a hydroxy group, R.sup.5 means a (C.sub.1-C.sub.5)-alkyl
group or an optionally partially or completely fluorinated
(C.sub.1-C.sub.5)-alkyl group, R.sup.6 and R.sup.7, independently
of one another, mean a hydrogen atom, a methyl or ethyl group or
together with the carbon atom of the tetrahydronaphthalene system
mean a (C.sub.3-C.sub.6)-cycloalkyl ring, provided that at least
three of radicals R.sup.1, R.sup.2, R.sup.11 and R.sup.12 are not
hydrogen.
10. Use of the stereoisomers according to claim 1 for the
production of a pharmaceutical agent.
11. Use of the stereoisomers of claim 1 for the production of a
pharmaceutical agent for treating inflammatory diseases.
12. Pharmaceutical preparations that contain at least one
stereoisomer according to claim 1 or mixtures thereof as well as
pharmaceutically compatible vehicles.
13. Process for the production of the stereoisomers of general
formula I, characterized in that stereoisomers of general formula
II ##STR00020## in which radicals R.sup.1, R.sup.11, R.sup.12,
R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 have the
above-indicated meanings, optionally are cyclized with the addition
of inorganic or organic aids or Lewis acids to compounds of general
formula I.
14. Stereoisomers of general formula I, according to claim 1, in
the form of the salts with physiologically compatible anions.
15. Stereoisomers of general formula II, in which radicals R.sup.1,
R.sup.11, R.sup.12, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7
have the meanings that are defined in claim 1, provided that at
least three of radicals R.sup.1, R.sup.2, R.sup.11 and R.sup.12 are
not hydrogen.
Description
[0001] This application claims the benefit of the filing date of
U.S. application Ser. No. (not yet assigned), Attorney Docket No.
SCH-1982 filed Oct. 8, 2004, which claims the benefit of U.S. Ser.
No. 60/560,014 filed Apr. 7, 2004, all of which are incorporated by
reference herein.
[0002] The invention relates to multiply-substituted
tetrahydronaphthalene derivatives, process for their production and
their use as anti-inflammatory agents.
[0003] Open-chain, non-steroidal anti-inflammatory agents are known
from the prior art (DE 100 38 639 and WO02/10143). In the
experiment, these compounds show dissociations of action between
anti-inflammatory and undesirable metabolic actions and are
superior to the previously described nonsteroidal glucocorticoids
or exhibit at least just as good an action.
[0004] The selectivity as well as the pharmacokinetic parameters of
the compounds of the prior art are still in need of improvement,
however.
[0005] It was therefore the object of this invention to make
available compounds whose selectivity compared to the other steroid
receptors as well as their pharmacokinetic properties are at least
just as good or better than the compounds of the prior art.
[0006] This object is achieved by the compounds of this invention,
explained in the claims.
[0007] This invention therefore relates to stereoisomers of general
formula (I)
##STR00002##
in which [0008] R.sup.1 and R.sup.2, independently of one another,
mean a hydrogen atom, a hydroxy group, a halogen atom, an
optionally substituted (C.sub.1-C.sub.10)-alkyl group, an
optionally substituted (C.sub.1-C.sub.1)-alkoxy group, a
(C.sub.1-C.sub.10)-alkylthio group, a
(C.sub.1-C.sub.5)-perfluoroalkyl group, a cyano group, or a nitro
group, or R.sup.1 and R.sup.2 together mean a group that is
selected from the groups --O--(CH.sub.2).sub.n--O--,
--O--(CH.sub.2).sub.n--CH.sub.2--, --O--CH.dbd.CH--,
--(CH.sub.2).sub.n+2--, --NH--(CH.sub.2).sub.n+1,
N(C.sub.1-C.sub.3-alkyl)-(CH.sub.2).sub.n+1, or --NH--N.dbd.CH--,
whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms
and/or nitrogen atoms are linked to directly adjacent ring-carbon
atoms, or NR.sup.8R.sup.9, whereby R.sup.8 and R.sup.9,
independently of one another, can be hydrogen,
C.sub.1-C.sub.5-alkyl or (CO)--C.sub.1-C.sub.5-alkyl, [0009]
R.sup.11 means a hydrogen atom, a hydroxy group, a halogen atom, a
cyano group, an optionally substituted (C.sub.1-C.sub.10)-alkyl
group, a (C.sub.1-C.sub.10)-alkoxy group, a
(C.sub.1-C.sub.10)-alkylthio group, or a
(C.sub.1-C.sub.5)-perfluoroalkyl group, [0010] R.sup.12 means a
hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an
optionally substituted (C.sub.1-C.sub.10)-alkyl group, or a
(C.sub.1-C.sub.10)-alkoxy group, [0011] R.sup.3 means a
C.sub.1-C.sub.10-alkyl group that optionally is substituted by 1-3
hydroxy groups, halogen atoms, 1-3 (C.sub.1-C.sub.5)-alkoxy groups,
an optionally substituted (C.sub.3-C.sub.7)-cycloalkyl group, an
optionally substituted heterocyclyl group, an optionally
substituted aryl group, a monocyclic or bicyclic heteroaryl group
that optionally contains 1-4 nitrogen atoms and/or 1-2 oxygen atoms
and/or 1-2 sulfur atoms and/or 1-2 keto groups and that optionally
is substituted, independently of one another, by one or more groups
selected from (C.sub.1-C.sub.5)-alkyl groups (which optionally can
be substituted by 1-3 hydroxy groups or 1-3 COOR.sup.13 groups,
whereby R.sup.13 means hydrogen or (C.sub.1-C.sub.5)-alkyl);
(C.sub.1-C.sub.5)-alkoxy groups, halogen atoms, hydroxy groups,
NR.sup.8R.sup.9 groups, exomethylene groups, or oxygen, whereby
this group can be linked via any position to the amine of the
tetrahydronaphthalene system and optionally can be hydrogenated at
one or more locations, [0012] R.sup.4 means a hydroxy group, a
group OR.sup.10, or an O(CO)R.sup.10 group, whereby R.sup.10 means
any hydroxy protective group or a C.sub.1-C.sub.10-alkyl group,
[0013] R.sup.5 means a (C.sub.1-C.sub.10)-alkyl group or an
optionally partially or completely fluorinated
(C.sub.1-C.sub.10)-alkyl group, a (C.sub.3-C.sub.7)cycloalkyl
group, a (C.sub.1-C.sub.8)alkyl(C.sub.3-C.sub.7)cycloalkyl group, a
(C.sub.2-C.sub.8)alkenyl(C.sub.3-C.sub.7)cycloalkyl group, a
heterocyclyl group, a (C.sub.1-C.sub.8)alkylheterocyclyl group, a
(C.sub.2-C.sub.8)-alkenylheterocyclyl group, an aryl group, a
(C.sub.1-C.sub.8)alkylaryl group, a (C.sub.2-C.sub.8)alkenylaryl
group, (C.sub.2-C.sub.8)alkinylaryl groups, a monocyclic or
bicyclic heteroaryl group that contains 1-3 nitrogen atoms and/or
1-2 oxygen atoms and/or 1-2 sulfur atoms and that optionally is
substituted by 1-2 keto groups, 1-2 (C.sub.1-C.sub.5)-alkyl groups,
1-2 (C.sub.1-C.sub.5)-alkoxy groups, 1-3 halogen atoms or 1-2
exomethylene groups; a (C.sub.1-C.sub.8)alkylheteroaryl group or a
(C.sub.2-C.sub.8)alkenylheteroaryl group, or a
(C.sub.2-C.sub.8)alkinylheteroaryl group, whereby these groups can
be linked via any position to the tetrahydronaphthalene system and
optionally can be hydrogenated at one or more locations, [0014]
R.sup.6 and R.sup.7, independently of one another, mean a hydrogen
atom, a methyl or ethyl group or together with the carbon atom of
the tetrahydronaphthalene system mean a
(C.sub.3-C.sub.6)-cycloalkyl ring, provided that at least three of
radicals R.sup.1, R.sup.2, R.sup.11 and R.sup.12 are not
hydrogen.
[0015] Stereoisomers of general formula (I), in which [0016]
R.sup.1 and R.sup.2, independently of one another, mean a hydrogen
atom, a hydroxy group, a halogen atom, an optionally substituted
(C.sub.1-C.sub.10)-alkyl group, a (C.sub.1-C.sub.10)-alkoxy group,
a (C.sub.1-C.sub.10)-alkylthio group, a
(C.sub.1-C.sub.5)-perfluoroalkyl group, a cyano group, or a nitro
group, or R.sup.1 and R.sup.2 together mean a group that is
selected from the groups --O--(CH.sub.2).sub.n--O--,
--O--(CH.sub.2).sub.n--CH.sub.2--, --O--CH.dbd.CH--,
--(CH.sub.2).sub.n+2--, --NH--(CH.sub.2).sub.n+1,
--N(C.sub.1-C.sub.3-alkyl)-(CH.sub.2).sub.n+1--, and
--NH--N.dbd.CH--, whereby n=1 or 2, and the terminal oxygen atoms
and/or carbon atoms and/or nitrogen atoms are linked to directly
adjacent ring-carbon atoms, or NR.sup.8R.sup.9, whereby R.sup.8 and
R.sup.9, independently of one another, can be hydrogen,
C.sub.1-C.sub.5-alkyl or (CO)--C.sub.1-C.sub.5-alkyl, [0017]
R.sup.11 means a hydrogen atom, a hydroxy group, a halogen atom, a
cyano group, an optionally substituted (C.sub.1-C.sub.10)-alkyl
group, a (C.sub.1-C.sub.10)-alkoxy group, a
(C.sub.1-C.sub.10)-alkylthio group, or a
(C.sub.1-C.sub.5)-perfluoroalkyl group, [0018] R.sup.12 means a
hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an
optionally substituted (C.sub.1-C.sub.10)-alkyl group, or a
(C.sub.1-C.sub.10)-alkoxy group, [0019] R.sup.3 means a
C.sub.1-C.sub.10-alkyl group that optionally is substituted by 1-3
hydroxy groups, halogen atoms, or 1-3 (C.sub.1-C.sub.5)-alkoxy
groups, an optionally substituted (C.sub.3-C.sub.7)-cycloalkyl
group, an optionally substituted heterocyclyl group, an optionally
substituted aryl group, a monocyclic or bicyclic heteroaryl group
that optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms
and/or 1-2 sulfur atoms and/or 1-2 keto groups and that optionally
is substituted by one or more groups that are selected from
(C.sub.1-C.sub.5)-alkyl groups (which optionally can be substituted
by 1-3 hydroxy groups or 1-3 COOR.sup.13 groups, whereby R.sup.13
means hydrogen or (C.sub.1-C.sub.5)-alkyl),
(C.sub.1-C.sub.5)-alkoxy groups, halogen atoms, or exomethylene
groups, whereby this group can be linked via any position to the
amine of the tetrahydronaphthalene system and optionally can be
hydrogenated at one or more locations, [0020] R.sup.4 means a
hydroxy group, a group OR.sup.10 or an O(CO)R.sup.10 group, whereby
R.sup.10 means any hydroxy protective group or a
C.sub.1-C.sub.10-alkyl group, [0021] R.sup.5 means a
(C.sub.1-C.sub.5)-alkyl group or an optionally partially or
completely fluorinated (C.sub.1-C.sub.5)-alkyl group, a
(C.sub.3-C.sub.7)cycloalkyl group, a
(C.sub.1-C.sub.8)alkyl(C.sub.3-C.sub.7)cycloalkyl group, a
(C.sub.2-C.sub.8)alkenyl(C.sub.3-C.sub.7)cycloalkyl group, a
heterocyclyl group, a (C.sub.1-C.sub.8)alkylheterocyclyl group, a
(C.sub.2-C.sub.8)-alkenylheterocyclyl group,
(C.sub.2-C.sub.8)alkinylaryl groups, an aryl group, a
(C.sub.1-C.sub.8)alkylaryl group, a (C.sub.2-C.sub.8)alkenylaryl
group, a monocyclic or bicyclic heteroaryl group that contains 1-3
nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and
that optionally is substituted by 1-2 keto groups, 1-2
(C.sub.1-C.sub.5)-alkyl groups, 1-2 (C.sub.1-C.sub.5)-alkoxy
groups, 1-3 halogen atoms, or 1-2 exomethylene groups; a
(C.sub.1-C.sub.8)alkylheteroaryl group or a
(C.sub.2-C.sub.8)alkenylheteroaryl group, whereby these groups can
be linked via any position to the tetrahydronaphthalene system and
optionally can be hydrogenated at one or more locations, [0022]
R.sup.6 and R.sup.7, independently of one another, mean a hydrogen
atom, a methyl or ethyl group or together with the carbon atom of
the tetrahydronaphthalene system mean a
(C.sub.3-C.sub.6)-cycloalkyl ring, provided that at least three of
radicals R.sup.1, R.sup.2, R.sup.11 and R.sup.12 are not hydrogen,
are another subject of this invention.
[0023] In addition, this invention relates to compounds of general
formula (I),
##STR00003##
in which [0024] R.sup.1 and R.sup.2, independently of one another,
mean a hydrogen atom, a hydroxy group, a halogen atom, an
optionally substituted (C.sub.1-C.sub.10)-alkyl group, a
(C.sub.1-C.sub.10)-alkoxy group, a (C.sub.1-C.sub.10)-alkylthio
group, a (C.sub.1-C.sub.5)-perfluoroalkyl group, a cyano group, or
a nitro group, or R.sup.1 and R.sup.2 together mean a group that is
selected from the groups --O--(CH.sub.2).sub.n--O--,
--O--(CH.sub.2).sub.n--CH.sub.2--, --O--CH.dbd.CH--,
--(CH.sub.2).sub.n+2--, --NH--(CH.sub.2).sub.n+1,
N(C.sub.1-C.sub.3-alkyl)-(CH.sub.2).sub.n+1, and --NH--N.dbd.CH--,
whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms
and/or nitrogen atoms are linked to directly adjacent ring-carbon
atoms, or NR.sup.8R.sup.9, [0025] whereby R.sup.8 and R.sup.9,
independently of one another, can be hydrogen,
C.sub.1-C.sub.5-alkyl or (CO)--C.sub.1-C.sub.5-alkyl, [0026]
R.sup.11 means a hydrogen atom, a hydroxy group, a halogen atom, a
cyano group, an optionally substituted (C.sub.1-C.sub.1)-alkyl
group, a (C.sub.1-C.sub.10)-alkoxy group, a
(C.sub.1-C.sub.10)-alkylthio group, or a
(C.sub.1-C.sub.5)-perfluoroalkyl group, [0027] R.sup.12 means a
hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an
optionally substituted (C.sub.1-C.sub.10)-alkyl group, or a
(C.sub.1-C.sub.10)-alkoxy group, [0028] R.sup.3 means a
C.sub.1-C.sub.10-alkyl group, which optionally can be substituted
by a group that is selected from 1-3 hydroxy groups, halogen atoms,
or 1-3 (C.sub.1-C.sub.5)-alkoxy groups, an optionally substituted
(C.sub.3-C.sub.7)-cycloalkyl group, an optionally substituted
heterocyclyl group, an optionally substituted aryl group, a
monocyclic or bicyclic heteroaryl group that optionally contains
1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms
and/or 1-2 keto groups and that optionally is substituted by one or
more groups that are selected from (C.sub.1-C.sub.5)-alkyl groups
(which optionally can be substituted by 1-3 hydroxy groups or 1-3
COOR.sup.13 groups, whereby R.sup.13 means hydrogen or
(C.sub.1-C.sub.5)-alkyl), (C.sub.1-C.sub.5)-alkoxy groups, halogen
atoms, or exomethylene groups, whereby this group can be linked via
any position to the amine of the tetrahydronaphthalene system and
optionally can be hydrogenated at one or more locations, [0029]
R.sup.4 means a hydroxy group, a group OR.sup.10 or an
O(CO)R.sup.10 group, whereby R.sup.10 means any hydroxy protective
group or a C.sub.1-C.sub.10-alkyl group, [0030] R.sup.5 means a
(C.sub.1-C.sub.5)-alkyl group or an optionally partially or
completely fluorinated (C.sub.1-C.sub.5)-alkyl group, a
(C.sub.3-C.sub.7)cycloalkyl group, a
(C.sub.1-C.sub.8)alkyl(C.sub.3-C.sub.7)cycloalkyl group, a
(C.sub.2-C.sub.8)alkenyl(C.sub.3-C.sub.7)cycloalkyl group, a
heterocyclyl group, a (C.sub.1-C.sub.8)alkylheterocyclyl group, a
(C.sub.2-C.sub.8)-alkenylheterocyclyl group, an aryl group, a
(C.sub.1-C.sub.8)alkylaryl group, a (C.sub.2-C.sub.8)alkenylaryl
group, (C.sub.2-C.sub.8)alkinylaryl groups, a monocyclic or
bicyclic heteroaryl group that contains 1-3 nitrogen atoms and/or
1-2 oxygen atoms and/or 1-2 sulfur atoms and that optionally is
substituted by 1-2 keto groups, 1-2 (C.sub.1-C.sub.5)-alkyl groups,
1-2 (C.sub.1-C.sub.5)-alkoxy groups, 1-3 halogen atoms, or 1-2
exomethylene groups; a (C.sub.1-C.sub.8)alkylheteroaryl group or a
(C.sub.2-C.sub.8)alkenylheteroaryl group, whereby these groups can
be linked via any position to the tetrahydronaphthalene system and
optionally can be hydrogenated at one or more locations, [0031]
R.sup.6 and R.sup.7, independently of one another, mean a hydrogen
atom, a methyl or ethyl group or together with the carbon atom of
the tetrahydronaphthalene system mean a
(C.sub.3-C.sub.6)-cycloalkyl ring, provided that at least three of
radicals R.sup.1, R.sup.2, R.sup.11 and R.sup.12 are not
hydrogen.
[0032] Stereoisomers of general formula (I), in which [0033]
R.sup.1 and R.sup.2, independently of one another, mean a hydrogen
atom, a hydroxy group, a halogen atom, an optionally substituted
(C.sub.1-C.sub.10)-alkyl group, an optionally substituted
(C.sub.1-C.sub.10)-alkoxy group, a (C.sub.1-C.sub.10)-alkylthio
group, a (C.sub.1-C.sub.5)-perfluoroalkyl group, a cyano group, or
a nitro group, or R.sup.1 and R.sup.2 together mean a group that is
selected from the groups --O--(CH.sub.2).sub.n--O--, --O--,
--O--(CH.sub.2).sub.n--CH.sub.2--, --O--CH.dbd.CH--,
--(CH.sub.2).sub.n+2--, --NH--(CH.sub.2).sub.n+1,
--N(C.sub.1-C.sub.3-alkyl)-(CH.sub.2).sub.n+1, and
--NH--N.dbd.CH--, whereby n=1 or 2, and the terminal oxygen atoms
and/or carbon atoms and/or nitrogen atoms are linked to directly
adjacent ring-carbon atoms, or NR.sup.8R.sup.9, whereby R.sup.8 and
R.sup.9, independently of one another, can be hydrogen,
C.sub.1-C.sub.5-alkyl, or (CO)--C.sub.1-C.sub.5-alkyl, [0034]
R.sup.11 means a hydrogen atom, a hydroxy group, a halogen atom, a
cyano group, an optionally substituted (C.sub.1-C.sub.10)-alkyl
group, a (C.sub.1-C.sub.10)-alkoxy group, a
(C.sub.1-C.sub.10)-alkylthio group, or a
(C.sub.1-C.sub.5)-perfluoroalkyl group, [0035] R.sup.12 means a
hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an
optionally substituted (C.sub.1-C.sub.10)-alkyl group, or a
(C.sub.1-C.sub.10)-alkoxy group, [0036] R.sup.3 means a
C.sub.1-C.sub.10-alkyl group that optionally is substituted by 1-3
hydroxy groups, halogen atoms, 1-3 (C.sub.1-C.sub.5)-alkoxy groups,
an optionally substituted (C.sub.3-C.sub.7)-cycloalkyl group, an
optionally substituted heterocyclyl group, an optionally
substituted aryl group, a monocyclic or bicyclic heteroaryl group
that optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms
and/or 1-2 sulfur atoms and/or 1-2 keto groups and that optionally
is substituted, independently of one another, by one or more groups
selected from (C.sub.1-C.sub.5)-alkyl groups (which optionally can
be substituted by 1-3 hydroxy groups or 1-3 COOR.sup.3 groups,
whereby R.sup.13 means hydrogen or (C.sub.1-C.sub.5)-alkyl),
(C.sub.1-C.sub.5)-alkoxy groups, halogen atoms, hydroxy groups,
NR.sup.8R.sup.9 groups, exomethylene groups, or oxygen, whereby
this group can be linked via any position to the amine of the
tetrahydronaphthalene system and optionally can be hydrogenated at
one or more locations, [0037] R.sup.4 means a hydroxy group, a
group OR.sup.10 or an O(CO)R.sup.10 group, whereby R.sup.10 means
any hydroxy protective group or a C.sub.1-C.sub.10-alkyl group,
[0038] R.sup.5 means a (C.sub.1-C.sub.10)-alkyl group or an
optionally partially or completely fluorinated
(C.sub.1-C.sub.10)-alkyl group, [0039] R.sup.6 and R.sup.7,
independently of one another, mean a hydrogen atom, a methyl or
ethyl group, or together with the carbon atom of the
tetrahydronaphthalene system mean a (C.sub.3-C.sub.6)-cycloalkyl
ring,
[0040] provided that at least three of radicals R.sup.1, R.sup.2,
R.sup.11 and R.sup.12 are not hydrogen, are another subject of this
invention.
[0041] Stereoisomers of general formula (I) according to claim
1,
##STR00004##
in which [0042] R.sup.1 and R.sup.2, independently of one another,
mean a hydrogen atom, a hydroxy group, a halogen atom, a
(C.sub.1-C.sub.10)-alkyl group, a (C.sub.1-C.sub.10)-alkoxy group,
a (C.sub.1-C.sub.10)-alkylthio group, a
(C.sub.1-C.sub.5)-perfluoroalkyl group, a cyano group, a nitro
group, or R.sup.1 and R.sup.2 together mean a group that is
selected from the groups --O--(CH.sub.2).sub.n--O--,
--O--(CH.sub.2).sub.n--CH.sub.2--, --O--CH.dbd.CH--, or
--(CH.sub.2).sub.n+2--, whereby n=1 or 2, and the terminal oxygen
atoms and/or carbon atoms are linked to directly adjacent
ring-carbon atoms, or NR.sup.8R.sup.9, whereby R.sup.8 and R.sup.9,
independently of one another, can be hydrogen,
C.sub.1-C.sub.5-alkyl or (CO)--C.sub.1-C.sub.5-alkyl, [0043]
R.sup.11 means a hydrogen atom, a hydroxy group, a halogen atom, a
cyano group, an optionally substituted (C.sub.1-C.sub.10)-alkyl
group, a (C.sub.1-C.sub.10)-alkoxy group, a
(C.sub.1-C.sub.10)-alkylthio group, or a
(C.sub.1-C.sub.5)-perfluoroalkyl group, [0044] R.sup.12 means a
hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an
optionally substituted (C.sub.1-C.sub.10)-alkyl group, or a
(C.sub.1-C.sub.10)-alkoxy group, [0045] R.sup.3 means a
C.sub.1-C.sub.10-alkyl group, which optionally can be substituted
by a group that is selected from 1-3 hydroxy groups, halogen atoms
or 1-3 (C.sub.1-C.sub.5)-alkoxy groups, an optionally substituted
phenyl group or a naphthyl group, a monocyclic or bicyclic
heteroaryl group that contains 1-3 nitrogen atoms and/or 1-2 oxygen
atoms and/or 1-2 sulfur atoms and that optionally is substituted by
1-2 keto groups, 1-2 (C.sub.1-C.sub.5)-alkyl groups, 1-2
(C.sub.1-C.sub.5)-alkoxy groups, 1-3 halogen atoms, or 1-2
exomethylene groups, whereby these groups can be linked via any
position to the amine of the tetrahydronaphthalene system and
optionally can be hydrogenated at one or more locations, [0046]
R.sup.4 means a hydroxy group, [0047] R.sup.5 means a
(C.sub.1-C.sub.5)-alkyl group or an optionally partially or
completely fluorinated (C.sub.1-C.sub.5)-alkyl group, an aryl
group, a (C.sub.1-C.sub.8)alkylaryl group, a
(C.sub.2-C.sub.8)alkenylaryl group, a (C.sub.3-C.sub.7)cycloalkyl
group, a (C.sub.1-C.sub.8)alkyl(C.sub.3-C.sub.7)cycloalkyl group,
or a (C.sub.2-C.sub.8)alkenyl(C.sub.3-C.sub.7)cycloalkyl group,
[0048] R.sup.6 and R.sup.7, independently of one another, mean a
hydrogen atom, a methyl or ethyl group, or together with the carbon
atom of the tetrahydronaphthalene system mean a
(C.sub.3-C.sub.6)-cycloalkyl ring, provided that at least three of
radicals R.sup.1, R.sup.2, R.sup.11 and R.sup.12 are not hydrogen,
are another subject.
[0049] Compounds of general formula (I)
##STR00005##
in which [0050] R.sup.1 and R.sup.2, independently of one another,
mean a hydrogen atom, a hydroxy group, a halogen atom, a
(C.sub.1-C.sub.10)-alkyl group, a (C.sub.1-C.sub.10)-alkoxy group,
a (C.sub.1-C.sub.10)-alkylthio group, a
(C.sub.1-C.sub.5)-perfluoroalkyl group, a cyano group, a nitro
group, or R.sup.1 and R.sup.2 together mean a group that is
selected from the groups --O--(CH.sub.2).sub.n--O,
--O--(CH.sub.2).sub.n--CH.sub.2--, --O--CH.dbd.CH--, or
(CH.sub.2).sub.n+2--, whereby n=1 or 2, and the terminal oxygen
atoms and/or carbon atoms are linked to directly adjacent
ring-carbon atoms, or NR.sup.8R.sup.9, whereby R.sup.8 and R.sup.9,
independently of one another, can be hydrogen,
C.sub.1-C.sub.5-alkyl or (CO)--C.sub.1-C.sub.5-alkyl, [0051]
R.sup.11 means a hydrogen atom, a hydroxy group, a halogen atom, a
cyano group, an optionally substituted (C.sub.1-C.sub.10)-alkyl
group, a (C.sub.1-C.sub.10)-alkoxy group, a
(C.sub.1-C.sub.10)-alkylthio group, or a
(C.sub.1-C.sub.5)-perfluoroalkyl group, [0052] R.sup.12 means a
hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an
optionally substituted (C.sub.1-C.sub.10)-alkyl group, or a
(C.sub.1-C.sub.10)-alkoxy group, [0053] R.sup.3 means a
C.sub.1-C.sub.10-alkyl group that optionally can be substituted by
a group that is selected from 1-3 hydroxy groups, halogen atoms, or
1-3 (C.sub.1-C.sub.5)-alkoxy groups, an optionally substituted
phenyl group, a monocyclic or bicyclic heteroaryl group that
contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2
sulfur atoms and that optionally is substituted by 1-2 keto groups,
1-2 (C.sub.1-C.sub.5)-alkyl groups, 1-2 (C.sub.1-C.sub.5)-alkoxy
groups, 1-3 halogen atoms, or 1-2 exomethylene groups, whereby
these groups can be linked via any position to the amine of the
tetrahydronaphthalene system and optionally can be hydrogenated at
one or more locations, [0054] R.sup.4 means a hydroxy group, [0055]
R.sup.5 means a (C.sub.1-C.sub.5)-alkyl group or an optionally
partially or completely fluorinated (C.sub.1-C.sub.5)-alkyl group,
an aryl group, a (C.sub.1-C.sub.8)alkylaryl group, a
(C.sub.2-C.sub.8)alkenylaryl group, a (C.sub.3-C.sub.7)cycloalkyl
group, a (C.sub.1-C.sub.8)alkyl(C.sub.3-C.sub.7)cycloalkyl group,
or a (C.sub.2-C.sub.8)alkenyl(C.sub.3-C.sub.7)cycloalkyl group,
[0056] R.sup.6 and R.sup.7, independently of one another, mean a
hydrogen atom, a methyl or ethyl group, or together with the carbon
atom of the tetrahydronaphthalene system mean a
(C.sub.3-C.sub.6)-cycloalkyl ring, provided that at least three of
radicals R.sup.1, R.sup.2, R.sup.11 and R.sup.12 are not hydrogen,
are another subject of the invention.
[0057] Compounds of general formula (I) according to claim 4,
##STR00006##
in which [0058] R.sup.1 and R.sup.2, independently of one another,
mean a hydrogen atom, a hydroxy group, a halogen atom, a
(C.sub.1-C.sub.10)-alkyl group, a (C.sub.1-C.sub.10)-alkoxy group,
a (C.sub.1-C.sub.10)-alkylthio group, a
(C.sub.1-C.sub.5)-perfluoroalkyl group, a cyano group, or a nitro
group, or R.sup.1 and R.sup.2 together mean a group that is
selected from the groups --O--(CH.sub.2).sub.n--O--,
--O--(CH.sub.2).sub.n--CH.sub.2--, --O--CH.dbd.CH--, or
--(CH.sub.2).sub.n+2--, whereby n=1 or 2, and the terminal oxygen
atoms and/or carbon atoms are linked to directly adjacent
ring-carbon atoms, or NR.sup.8R.sup.9, whereby R.sup.8 and R.sup.9,
independently of one another, can be hydrogen,
C.sub.1-C.sub.5-alkyl or (CO)--C.sub.1-C.sub.5-alkyl, [0059]
R.sup.3 means a C.sub.1-C.sub.10-alkyl group, which optionally can
be substituted by a group that is selected from 1-3 hydroxy groups,
halogen atoms, or 1-3 (C.sub.1-C.sub.5)-alkoxy groups, an
optionally substituted phenyl group or a naphthyl group, a
monocyclic or bicyclic heteroaryl group that contains 1-3 nitrogen
atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and that
optionally is substituted by 1-2 keto groups, 1-2
(C.sub.1-C.sub.5)-alkyl groups, 1-2 (C.sub.1-C.sub.5)-alkoxy
groups, 1-3 halogen atoms, or 1-2 exomethylene groups, whereby
these groups can be linked via any position to the amine of the
tetrahydronaphthalene system and optionally can be hydrogenated at
one or more locations, [0060] R.sup.4 means a hydroxy group, [0061]
R.sup.5 means a (C.sub.1-C.sub.5)-alkyl group or an optionally
partially or completely fluorinated (C.sub.1-C.sub.5)-alkyl group,
an aryl group, a (C.sub.1-C.sub.8)alkylaryl group, a
(C.sub.2-C.sub.8)alkenylaryl group, a (C.sub.3-C.sub.7)cycloalkyl
group, a (C.sub.1-C.sub.8)alkyl(C.sub.3-C.sub.7)cycloalkyl group,
or a (C.sub.2-C.sub.8)alkenyl(C.sub.3-C.sub.7)cycloalkyl group,
[0062] R.sup.6 and R.sup.7, independently of one another, mean a
hydrogen atom, a methyl or ethyl group, or together with the carbon
atom of the tetrahydronaphthalene system mean a
(C.sub.3-C.sub.6)-cycloalkyl ring, provided that at least three of
radicals R.sup.1, R.sup.2, R.sup.11 and R.sup.12 are not hydrogen,
are another subject of the invention.
[0063] Compounds of general formula (I) according to claim 4,
##STR00007##
in which [0064] R.sup.1 and R.sup.2, independently of one another,
mean a hydrogen atom, a hydroxy group, a halogen atom, a
(C.sub.1-C.sub.10)-alkyl group, a (C.sub.1-C.sub.10)-alkoxy group,
a (C.sub.1-C.sub.10)-alkylthio group, a
(C.sub.1-C.sub.5)-perfluoroalkyl group, a cyano group, a nitro
group, or R.sup.1 and R.sup.2 together mean a group that is
selected from the groups --O--(CH.sub.2).sub.n--O--,
--O--(CH.sub.2).sub.n--CH.sub.2--, --O--CH.dbd.CH--, or
--(CH.sub.2).sub.n+2--, whereby n=1 or 2, and the terminal oxygen
atoms and/or carbon atoms are linked to directly adjacent
ring-carbon atoms, or NR.sup.8R.sup.9, whereby R.sup.8 and R.sup.9,
independently of one another, can be hydrogen,
C.sub.1-C.sub.5-alkyl or (CO)--C.sub.1-C.sub.5-alkyl, [0065]
R.sup.3 means a C.sub.1-C.sub.10-alkyl group, which optionally can
be substituted by a group that is selected from 1-3 hydroxy groups,
halogen atoms, or 1-3 (C.sub.1-C.sub.5)-alkoxy groups, an
optionally substituted phenyl group, a monocyclic or bicyclic
heteroaryl group that contains 1-3 nitrogen atoms and/or 1-2 oxygen
atoms and/or 1-2 sulfur atoms and that optionally is substituted by
1-2 keto groups, 1-2 (C.sub.1-C.sub.5)-alkyl groups, 1-2
(C.sub.1-C.sub.5)-alkoxy groups, 1-3 halogen atoms or 1-2
exomethylene groups, whereby these groups can be linked via any
position to the amine of the tetrahydronaphthalene system and
optionally can be hydrogenated at one or more locations, [0066]
R.sup.4 means a hydroxy group, [0067] R.sup.5 means a
(C.sub.1-C.sub.5)-alkyl group or an optionally partially or
completely fluorinated (C.sub.1-C.sub.5)-alkyl group, an aryl
group, a (C.sub.1-C.sub.8)alkylaryl group, a
(C.sub.2-C.sub.8)alkenylaryl group, a (C.sub.3-C.sub.7)cycloalkyl
group, a (C.sub.1-C.sub.8)alkyl(C.sub.3-C.sub.7)cycloalkyl group,
or a (C.sub.2-C.sub.8)alkenyl(C.sub.3-C.sub.7)cycloalkyl group,
[0068] R.sup.6 and R.sup.7, independently of one another, mean a
hydrogen atom, a methyl or ethyl group, or together with the carbon
atom of the tetrahydronaphthalene system, mean a
(C.sub.3-C.sub.6)-cycloalkyl ring, provided that at least three of
radicals R.sup.1, R.sup.2, R.sup.11 and R.sup.12 are not hydrogen,
are another subject of the invention.
[0069] Compounds of general formula (I)
##STR00008##
in which [0070] R.sup.1 and R.sup.2, independently of one another,
mean a hydrogen atom, a hydroxy group, a halogen atom, a
(C.sub.1-C.sub.5)-alkyl group, a (C.sub.1-C.sub.5)-alkoxy group, a
(C.sub.1-C.sub.5)-perfluoroalkyl group, a cyano group, or R.sup.1
and R.sup.2 together mean a group that is selected from the groups
--O--(CH.sub.2).sub.n--O--, --O--(CH.sub.2).sub.n--CH.sub.2--,
--O--CH.dbd.CH--, or --(CH.sub.2).sub.n+2--, whereby n=1 or 2, and
the terminal oxygen atoms and/or carbon atoms are linked to
directly adjacent ring-carbon atoms, [0071] R.sup.11 means a
hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an
optionally substituted (C.sub.1-C.sub.10)-alkyl group, a
(C.sub.1-C.sub.10)-alkoxy group, a (C.sub.1-C.sub.10)-alkylthio
group, or a (C.sub.1-C.sub.5)-perfluoroalkyl group, [0072] R.sup.12
means a hydrogen atom, a hydroxy group, a halogen atom, a cyano
group, an optionally substituted (C.sub.1-C.sub.10)-alkyl group, or
a (C.sub.1-C.sub.10)-alkoxy group, [0073] R.sup.3 means a
C.sub.1-C.sub.10-alkyl group, which optionally can be substituted
by 1-3 hydroxy groups, halogen atoms, a phenyl, phthalidyl,
isoindolyl, dihydroindolyl, dihydroisoindolyl,
dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl,
phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl,
isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl,
quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl,
dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl
group that optionally is substituted with C.sub.1-C.sub.5-alkyl,
halogen, hydroxy, or C.sub.1-C.sub.5-alkoxy, whereby these groups
can be linked via any position to the amine of the
tetrahydronaphthalene system and optionally can be substituted in
one or more places with 1-2 keto groups, 1-2
(C.sub.1-C.sub.3)-alkyl groups, 1-2 (C.sub.1-C.sub.3)-alkoxy
groups, 1-3 halogen atoms, or 1-2 exomethylene groups, and
optionally can be hydrogenated at one or more locations, [0074]
R.sup.4 means a hydroxy group, [0075] R.sup.5 means a
(C.sub.1-C.sub.5)-alkyl group or an optionally partially or
completely fluorinated (C.sub.1-C.sub.5)-alkyl group, [0076]
R.sup.6 and R.sup.7, independently of one another, mean a hydrogen
atom, a methyl or ethyl group or together with the carbon atom of
the tetrahydronaphthalene system mean a
(C.sub.3-C.sub.6)-cycloalkyl ring, provided that at least three of
radicals R.sup.1, R.sup.2, R.sup.11 and R.sup.12 are not hydrogen,
are another subject of the invention.
[0077] Compounds of general formula (I)
##STR00009##
in which [0078] R.sup.1 and R.sup.2, independently of one another,
mean a hydrogen atom, a hydroxy group, a halogen atom, a
(C.sub.1-C.sub.5)-alkyl group, a (C.sub.1-C.sub.5)-perfluoroalkyl
group, a cyano group, a (C.sub.1-C.sub.5)-alkoxy group, or together
mean a (C.sub.1-C.sub.2)-alkylenedioxy group, whereby then R.sup.1
and R.sup.2 must be directly adjacent, [0079] R.sup.11 means a
hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an
optionally substituted (C.sub.1-C.sub.10)-alkyl group, a
(C.sub.1-C.sub.10)-alkoxy group, a (C.sub.1-C.sub.10)-alkylthio
group, or a (C.sub.1-C.sub.5)-perfluoroalkyl group, [0080] R.sup.12
means a hydrogen atom, a hydroxy group, a halogen atom, a cyano
group, an optionally substituted (C.sub.1-C.sub.10)-alkyl group, or
a (C.sub.1-C.sub.10)-alkoxy group, [0081] R.sup.3 means a phenyl,
phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl,
dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl,
phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl,
isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl,
quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl,
dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl
group that optionally is substituted with C.sub.1-C.sub.5-alkyl,
halogen, hydroxy, or C.sub.1-C.sub.5-alkoxy, whereby these groups
can be linked via any position to the amine of the
tetrahydronaphthalene system and optionally can be substituted in
one or more places with 1-2 keto groups, 1-2
(C.sub.1-C.sub.3)-alkyl groups, or 1-2 exomethylene groups, and
optionally can be hydrogenated at one or more locations, [0082]
R.sup.4 means a hydroxy group, [0083] R.sup.5 means a
(C.sub.1-C.sub.5)-alkyl group or an optionally partially or
completely fluorinated (C.sub.1-C.sub.5)-alkyl group, [0084]
R.sup.6 and R.sup.7, independently of one another, mean a hydrogen
atom, a methyl or ethyl group or together with the carbon atom of
the tetrahydronaphthalene system mean a
(C.sub.3-C.sub.6)-cycloalkyl ring, provided that at least three of
radicals R.sup.1, R.sup.2, R.sup.11 and R.sup.12 are not hydrogen,
are another subject of the invention.
[0085] Compounds of general formula (I) according to claim 4,
##STR00010##
in which [0086] R.sup.1 and R.sup.2, independently of one another,
mean a hydrogen atom, a hydroxy group, a halogen atom, a
(C.sub.1-C.sub.5)-alkyl group, a (C.sub.1-C.sub.5)-alkoxy group, a
(C.sub.1-C.sub.5)-perfluoroalkyl group, a cyano group, or R.sup.1
and R.sup.2 together mean a group that is selected from the groups
--O--(CH.sub.2).sub.n--O--, --O--(CH.sub.2).sub.n--CH.sub.2--,
--O--CH.dbd.CH--, or --(CH.sub.2).sub.n+2--, whereby n=1 or 2, and
the terminal oxygen atoms and/or carbon atoms are linked to
directly adjacent ring-carbon atoms, [0087] R.sup.3 means a
C.sub.1-C.sub.10-alkyl group, which optionally can be substituted
by 1-3 hydroxy groups, halogen atoms; a phenyl, phthalidyl,
isoindolyl, dihydroindolyl, dihydroisoindolyl,
dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl,
phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl,
isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl,
quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl,
dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl
group that optionally is substituted with C.sub.1-C.sub.5-alkyl,
halogen, hydroxy, or C.sub.1-C.sub.5-alkoxy, whereby these groups
can be linked via any position to the amine of the
tetrahydronaphthalene system and optionally can be substituted in
one or more places with 1-2 keto groups, 1-2
(C.sub.1-C.sub.3)-alkyl groups, 1-2 (C.sub.1-C.sub.3)-alkoxy
groups, 1-3 halogen atoms, or 1-2 exomethylene groups, and
optionally can be hydrogenated at one or more locations, [0088]
R.sup.4 means a hydroxy group, [0089] R.sup.5 means a
(C.sub.1-C.sub.5)-alkyl group or an optionally partially or
completely fluorinated (C.sub.1-C.sub.5)-alkyl group, [0090]
R.sup.6 and R.sup.7, independently of one another, mean a hydrogen
atom, a methyl or ethyl group or together with the carbon atom of
the tetrahydronaphthalene system mean a
(C.sub.3-C.sub.6)-cycloalkyl ring, provided that at least three of
radicals R.sup.1, R.sup.2, R.sup.11 and R.sup.12 are not hydrogen,
are another subject of the invention.
[0091] Compounds of general formula (I) according to claim 4,
##STR00011##
in which [0092] R.sup.1 and R.sup.2, independently of one another,
mean a hydrogen atom, a hydroxy group, a halogen atom, a
(C.sub.1-C.sub.5)-alkyl group, a (C.sub.1-C.sub.5)-perfluoroalkyl
group, a cyano group, a (C.sub.1-C.sub.5)-alkoxy group, or together
mean a (C.sub.1-C.sub.2)-alkylenedioxy group, whereby then R.sup.1
and R.sup.2 must be directly adjacent, [0093] R.sup.3 means a
phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl,
dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl,
phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl,
isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl,
quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl,
dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl
group that optionally is substituted with C.sub.1-C.sub.5-alkyl,
halogen, hydroxy, or C.sub.1-C.sub.5-alkoxy, whereby these groups
can be linked via any position to the amine of the
tetrahydronaphthalene system and optionally can be substituted in
one or more places with 1-2 keto groups, 1-2
(C.sub.1-C.sub.3)-alkyl groups, or 1-2 exomethylene groups, and
optionally can be hydrogenated at one or more locations, [0094]
R.sup.4 means a hydroxy group, [0095] R.sup.5 means a
(C.sub.1-C.sub.5)-alkyl group or an optionally partially or
completely fluorinated (C.sub.1-C.sub.5)-alkyl group, [0096]
R.sup.6 and R.sup.7, independently of one another, mean a hydrogen
atom, a methyl or ethyl group or together with the carbon atom of
the tetrahydronaphthalene system mean a
(C.sub.3-C.sub.6)-cycloalkyl ring, provided that at least three of
radicals R.sup.1, R.sup.2, R.sup.11 and R.sup.12 are not hydrogen,
are another subject of the invention.
[0097] Stereoisomers according to claims 1 to 9 that on the
aromatic ring of the tetrahydronaphthalene system carry
substituents, selected from the group C.sub.1-C.sub.5-alkyl,
C.sub.1-C.sub.5-alkoxy, COOR.sup.13, NR.sup.8R.sup.9,
C1-C.sub.5-perfluoroalkyl, halogen, hydroxy, cyano, nitro,
--O--(CH.sub.2).sub.n--O--, --O--(CH.sub.2).sub.n--CH.sub.2--,
--O--CH.dbd.CH--, --(CH.sub.2).sub.n+2--, --NH--(CH.sub.2).sub.n+1,
N(C.sub.1-C.sub.3-alkyl)-(CH.sub.2).sub.n+1, or
--NH--N.dbd.CH--,
[0098] whereby n=1 or 2, and the terminal oxygen atoms and/or
carbon atoms and/or nitrogen atoms are linked to directly adjacent
ring-carbon atoms, are a special subject of the invention. Then,
the divalent radicals can be counted as two substituents in terms
of the invention.
[0099] Compounds according to claims 1 to 9 that on the aromatic
ring of the tetrahydronaphthalene system carry three substituents,
selected from the group C.sub.1-C.sub.5-alkyl,
C.sub.1-C.sub.5-alkoxy, C.sub.1-C.sub.5-perfluoroalkyl, halogen,
hydroxy, cyano, nitro, --O--(CH.sub.2).sub.n--O--,
--O--(CH.sub.2).sub.n--CH.sub.2--, --O--CH.dbd.CH--,
--(CH.sub.2).sub.n+2--, --NH--(CH.sub.2).sub.n+1--,
--N(C.sub.1-C.sub.3-alkyl)-(CH.sub.2).sub.n+1--, or
--NH--N.dbd.CH--,
[0100] whereby n=1 or 2, and the terminal oxygen atoms and/or
carbon atoms and/or nitrogen atoms are linked to directly adjacent
ring-carbon atoms, are a special subject of the invention. Then,
the divalent radicals can be counted as two substituents in terms
of the invention.
[0101] Another subject of the invention is if R.sup.3 is formed by
a radical that contains COOR.sup.13 as a substituent, whereby
R.sup.13 means C.sub.1-C.sub.10-alkyl or C.sub.1-C.sub.5-alkyl.
[0102] The compounds according to claim 1, in which R.sup.1 and
R.sup.2 together mean the radicals --O--(CH.sub.2).sub.n--O--,
--O--(CH.sub.2).sub.n--CH.sub.2--, --O--CH.dbd.CH--,
--(CH.sub.2).sub.n+2--, --NH--(CH.sub.2).sub.n+1--,
N(C.sub.1-C.sub.3-alkyl)-(CH.sub.2).sub.n+1--, and
--NH--N.dbd.CH--, are a subgroup of these compounds. The respective
terminal atoms of the above-indicated divalent groups are linked to
directly adjacent carbon atoms of the tetrahydronaphthalene
system.
[0103] The stereoisomers according to claims 1 to 9, in which
R.sup.1, R.sup.2, R.sup.11 or R.sup.12 are selected from the group
that consist of optionally substituted C.sub.1-C.sub.5-alkyl,
optionally substituted C.sub.1-C.sub.5-alkoxy, halogen, hydroxy, or
cyano, are another subgroup.
[0104] The compounds according to claim 4, in which R.sup.1,
R.sup.2, R.sup.11 or R.sup.12 are selected from the group that
consists of C.sub.1-C.sub.5-alkyl, C.sub.1-C.sub.5-alkoxy,
C.sub.1-C.sub.5-perfluoroalkyl, halogen, hydroxy, cyano, or nitro,
are a subgroup.
[0105] The compounds according to claim 1, in which alkyl radicals
R.sup.1 and R.sup.2 have the meaning --(CH.sub.2).sub.n+2-- and
thus form a 5- to 6-membered ring together with the carbon atom of
the chain, represent another subgroup.
[0106] Compounds of general formula I according to claim 1, in
which R.sup.3 means a C.sub.1-C.sub.10-alkyl group, which
optionally can be substituted by 1-3 hydroxy groups, halogen atoms,
1-3 (C.sub.1-C.sub.5)-alkoxy groups, an optionally substituted
(C.sub.3-C.sub.7)-cycloalkyl group, an optionally substituted
heterocyclyl group, a monocyclic or bicyclic heteroaryl group that
optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms
and/or 1-2 sulfur atoms and/or 1-2 keto groups and that optionally
is substituted by one or more groups that are selected from
(C.sub.1-C.sub.5)-alkyl groups, (C.sub.1-C.sub.5)-alkoxy groups,
halogen atoms, or exomethylene groups, whereby these groups can be
linked via any position to the amine of the tetrahydronaphthalene
system and optionally can be hydrogenated at one or more locations,
are another subject of the invention.
[0107] Compounds of formula I, in which R.sup.3 means a
C.sub.1-C.sub.10-alkyl group, which optionally can be substituted
by 1-3 hydroxy groups, halogen atoms, an optionally substituted
phenyl group, a monocyclic or bicyclic heteroaryl group that
contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2
sulfur atoms and that optionally is substituted by 1-2 keto groups,
1-2 (C.sub.1-C.sub.5)-alkyl groups, 1-2 (C.sub.1-C.sub.5)-alkoxy
groups, 1-3 halogen atoms, or 1-2 exomethylene groups, whereby
these groups can be linked via any position to the nitrogen atom
and optionally can be hydrogenated at one or more locations, are
another subject of the invention.
[0108] Stereoisomers of general formula I, in which R.sup.3 means a
phenyl group or a naphthyl group that optionally is substituted
with one or more radicals from the group C.sub.1-C.sub.5-alkyl,
C.sub.1-C.sub.5-alkoxy, hydroxy, halogen, cyano, CF.sub.3, nitro,
COOR.sup.13, or NR.sup.8R.sup.9, are a subject of the
invention.
[0109] Compounds of general formula I according to claims 1-9, in
which R.sup.3 means a monocyclic or bicyclic heteroaryl group that
optionally contains 1-4 nitrogen atoms and/or 1-2 oxygen atoms
and/or 1-2 sulfur atoms and/or 1-2 keto groups and that optionally
is substituted by one or more groups, independently of one another,
selected from (C.sub.1-C.sub.5)-alkyl groups, which themselves
optionally can be substituted by 1-3 hydroxy groups or 1-3
COOR.sup.13 groups, whereby R.sup.13 means hydrogen or
(C.sub.1-C.sub.5)-alkyl; (C.sub.1-C.sub.5)-alkoxy groups, halogen
atoms, hydroxy groups, NR.sup.8R.sup.9 groups, exomethylene groups,
or oxygen, whereby this group can be linked via any position to the
amine of the tetrahydronaphthalene system and optionally can be
hydrogenated at one or more locations,
are a preferred subject of this invention.
[0110] Compounds of general formula I or II according to claims
1-6, in which R.sup.3 means a monocyclic or bicyclic heteroaryl
group that optionally contains 1-4 nitrogen atoms and/or 1-2 oxygen
atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups and that
optionally is substituted by one or more groups, independently of
one another, selected from (C.sub.1-C.sub.5)-alkyl groups, which
themselves optionally can be substituted by 1-3 hydroxy groups or
1-3 COOR.sup.13 groups, whereby R.sup.13 means hydrogen or
(C.sub.1-C.sub.5)-alkyl; (C.sub.1-C.sub.5)-alkoxy groups, halogen
atoms, hydroxy groups, NR.sup.8R.sup.9 groups, exomethylene groups,
or oxygen, whereby this group can be linked via any position to the
amine of the tetrahydronaphthalene system and optionally can be
hydrogenated at one or more locations, and R.sup.5 means an
optionally partially or completely fluorinated
(C.sub.1-C.sub.5)-alkyl group, are another preferred subject of
this invention.
[0111] Compounds of general formula I, in which R.sup.3 means a
C.sub.1-C.sub.10-alkyl group, which optionally can be substituted
by 1-3 hydroxy groups, halogen atoms, a phenyl, naphthyl,
phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl,
dihydroisoquinolinyl, dihydroquinolinyl, thiophthalidyl,
benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl,
quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl,
quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl,
dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl
group that optionally is substituted with C.sub.1-C.sub.5-alkyl,
halogen, hydroxy, or C.sub.1-C.sub.5-alkoxy, are a preferred
subject of the invention.
[0112] Compounds of general formula I, in which R.sup.3 a phenyl or
naphthyl that optionally is substituted with C.sub.1-C.sub.5-alkyl,
halogen, hydroxy or C.sub.1-C.sub.5-alkoxy; phthalidyl,
thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl,
isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl,
benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl,
phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl,
dihydroisoindolonyl, benzimidazolyl or indolyl group, are an also
preferred subject.
[0113] Compounds of general formula I, in which R.sup.3 a phenyl,
phthalidyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl,
quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl,
benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl,
phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl,
dihydroisoindolonyl, benzimidazolyl or indolyl group that
optionally is substituted with C.sub.1-C.sub.5-alkyl, halogen,
hydroxy or C.sub.1-C.sub.5-alkoxy are an especially preferred
subject.
[0114] Compounds of formula (I), in which R.sup.3 means phthalidyl,
isoindolyl, dihydroindolyl, dihydroisoindolyl, thiophthalidyl,
indazolyl, benzothiazolyl, dihydroindolonyl, dihydroisoindolonyl,
benzimidazolyl or indolyl group, are another subject of the
invention.
[0115] Compounds of formula (I), in which R.sup.3 means
dihydroisoquinolinyl, dihydroquinolinyl, benzoxazinonyl,
phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl,
isoquinolonyl, quinazolinyl, quinoxalinyl, cinnolinyl,
phthalazinyl, 1,7- or 1,8-naphthyridinyl, are another subject of
the invention.
[0116] Compounds of general formula I, in which R.sup.3 means an
isoquinolonyl, quinolonyl, quinazolinyl or phthalazinyl group, are
another subject of the invention.
[0117] Stereoisomers of general formula I, in which R.sup.3 means
an optionally substituted isoquinolonyl, quinolonyl, quinazolinyl,
phthalazinyl, indazolyl, quinolinyl, isoquinolinyl, isoquinolonyl,
dihydroindolonyl, dihydroindolyl, dihydroindolonyl, naphthyl,
pyridyl, or phthalidyl group, especially preferably if R.sup.3
means an optionally substituted isoquinolonyl, quinolonyl,
quinolinyl, quinazolinyl, phthalazinyl, phthalazinonyl,
dihydrophthalazinyl, dihydrophthalazinonyl, dihydroindolonyl,
dihydroquinolinyl, or dihydroquinolonyl, are a special subject of
the invention.
[0118] The meanings of R.sup.3 that are mentioned in the paragraph
above combined with the usual radicals, as they are defined in
claims 1-9, are a special subject of the invention.
[0119] Compounds of general formula I in which R.sup.3 means
isoquinolin-1(2H)on-5yl, quinolin-2(1H)-on-5yl-, 8- or
7-fluoro-2-methyl-quinazoline, 7,8-difluoro-4-methyl-quinazoline,
7,8-difluoro-2-methyl-quinazoline or 2-methyl-phthalazin-1-one are
another subject of the invention.
[0120] Radical R.sup.3 is bonded via the amine to the
tetrahydronaphthalene system. If radical R.sup.3 exhibits several
positions that are chemically possible to be bonded to the ring
system, then this invention comprises all these possibilities.
[0121] Radical R.sup.3 is also part of this invention when it is
hydrogenated at one or more locations.
[0122] As substituents of the monocyclic or bicyclic heteroaryl
groups (heterocyclic groups) R.sup.3, just as it was first defined,
for example, hydroxy, halogen atoms, in particular fluorine and
chlorine, (C.sub.1-C.sub.5)-alkyl groups (which themselves
optionally can be substituted by hydroxy groups,
(C.sub.1-C.sub.5)-alkoxy groups or COOR.sup.13 groups, whereby
R.sup.13 means hydrogen or (C.sub.1-C.sub.5)-alkyl), in particular
methyl, (C.sub.2-C.sub.5)-alkenyl groups, completely or partially
fluorinated (C.sub.1-C.sub.5)-alkyl groups, in particular CF.sub.3,
CFH.sub.2 or C.sub.2F.sub.5, (C.sub.1-C.sub.5)-alkoxy groups, in
particular methoxy and ethoxy, NR.sup.8R.sup.9 groups, in
particular NH.sub.2, N(CH.sub.3).sub.2 or NH(CH.sub.3), cyano
groups as well as keto groups, which are formed with a carbon atom
of a ring of the heteroaryl group, and oxygen, which forms an
N-oxide with an optionally present nitrogen atom of the ring, are
suitable at chemically suitable positions. The group that consists
of fluorine, chlorine, OH, CH.sub.3, CF.sub.3, CFH.sub.2, or
C.sub.2F.sub.5, OCH.sub.3, OC.sub.2H.sub.5, NH.sub.2,
N(CH.sub.3).sub.2 and NH(CH.sub.3), cyano, keto and oxygen follows
from the above as a preferred group of substituents for radical
R.sup.3 as it is defined in claim 1 and for all additional claims.
Especially preferred are halogen, in particular fluorine and
chlorine, hydroxy, C.sub.1-C.sub.5-alkyl, in particular CH.sub.3,
C.sub.2H.sub.5 or keto-oxygen.
[0123] As a subgroup of the substituents of the heterocyclic group
R.sup.3, as it was first defined in the above-mentioned subjects of
the invention, for example, halogen atoms, (C.sub.1-C.sub.5)-alkyl
groups (which themselves are substituted by hydroxy groups or COOH
groups or COOR.sup.13 groups, whereby R.sup.13 means hydrogen or
(C.sub.1-C.sub.5)-alkyl), (C.sub.2-C.sub.5)-alkenyl groups,
fluorinated (C.sub.1-C.sub.5)-alkyl groups,
(C.sub.1-C.sub.5)-alkoxy groups or cyano groups are suitable at
suitable positions.
[0124] Heterocyclyl group R.sup.3 is not aromatic and can be, for
example, pyrrolidine, imidazolidine, pyrazolidine, or
piperidine.
[0125] The hydroxy group in R.sup.4 can be protected by one of the
common hydroxy protective groups that are known to one skilled in
the art, such as, for example, silyl ether or ester of organic
C.sub.1-C.sub.10 acids or can be present as C.sub.1-C.sub.5-ether
or benzyl ether, preferably as one of the common hydroxy protective
groups or as C.sub.1-C.sub.5-ether. The hydroxy group is preferred
as radical R.sup.4.
[0126] The common hydroxy protective groups are described in detail
in T. W. Greene, P. G. M. Wuts "Protective Groups in Organic
Synthesis," 2.sup.nd Edition, John Wiley & Sons, 1991).
[0127] The protective groups are preferably alkyl-, aryl- or mixed
alkylaryl-substituted silyl groups, e.g., the trimethylsilyl (TMS),
triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS),
tert-butyldiphenylsilyl (TBDPS) or triisopropylsilyl groups (TIPS)
or another conventional hydroxy protective group (methoxymethyl,
methoxyethoxymethyl, ethoxyethyl, tetrahydrofuranyl, and
tetrahydropyranyl groups).
[0128] Radical R.sup.5 is bonded directly to the
tetrahydronaphthalene system. If radical R.sup.5 has several
positions that are chemically possible to be bonded to the ring
system, this invention then encompasses all these
possibilities.
[0129] Stereoisomers of general formula I according to claim 1, in
which R.sup.5 means a (C.sub.3-C.sub.7)cycloalkyl group, a
(C.sub.1-C.sub.8)alkyl(C.sub.3-C.sub.7)cycloalkyl group, a
(C.sub.2-C.sub.8)alkenyl(C.sub.3-C.sub.7)cycloalkyl group, a
heterocyclyl group, a (C.sub.1-C.sub.8)alkylheterocyclyl group, a
(C.sub.2-C.sub.8)alkenylheterocyclyl group, an aryl group, a
(C.sub.1-C.sub.8)alkylaryl group, a (C.sub.2-C.sub.8)alkenylaryl
group, a monocyclic or bicyclic heteroaryl group that contains 1-3
nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and
that optionally is substituted by 1-2 keto groups, 1-2
(C.sub.1-C.sub.5)-alkyl groups, 1-2 (C.sub.1-C.sub.5)-alkoxy
groups, 1-3 halogen atoms, 1-2 exomethylene groups; a
(C.sub.1-C.sub.8)alkylheteroaryl group or a
(C.sub.2-C.sub.8)alkenylheteroaryl group, or a
(C.sub.2-C.sub.8)alkinylheteroaryl group, whereby these groups can
be linked via any position to the tetrahydronaphthalene system and
optionally can be hydrogenated at one or more locations, are
another subgroup of the invention.
[0130] Compounds of general formula I in which R.sup.5 means a
(C.sub.1-C.sub.5)-alkyl group or an optionally partially or
completely fluorinated (C.sub.1-C.sub.5)-alkyl group, a
(C.sub.3-C.sub.7)cycloalkyl group, a
(C.sub.1-C.sub.8)alkyl(C.sub.3-C.sub.7)cycloalkyl group, a
(C.sub.2-C.sub.8)alkenyl(C.sub.3-C.sub.7)cycloalkyl group, a
heterocyclyl group, a (C.sub.1-C.sub.8)alkylheterocyclyl group, a
(C.sub.2-C.sub.8)alkenylheterocyclyl group, an aryl group, a
(C.sub.1-C.sub.8)alkylaryl group, or a (C.sub.2-C.sub.8)alkenylaryl
group are another subject of the invention.
[0131] Compounds of general formula I in which R.sup.5 means a
(C.sub.1-C.sub.5)-alkyl group or an optionally partially or
completely fluorinated (C.sub.1-C.sub.5)-alkyl group, an aryl
group, a (C.sub.1-C.sub.8)alkylaryl group, a
(C.sub.2-C.sub.8)alkenylaryl group, a (C.sub.3-C.sub.7)cycloalkyl
group, a (C.sub.1-C.sub.8)alkyl(C.sub.3-C.sub.7)cycloalkyl group,
or a (C.sub.2-C.sub.8)alkenyl(C.sub.3-C.sub.7)cycloalkyl group are
a special subject of the invention.
[0132] Stereoisomers of general formula I according to claims 1 to
6, in which R.sup.5 represents a (C.sub.1-C.sub.10)-alkyl group or
an optionally partially or completely fluorinated
(C.sub.1-C.sub.10)-alkyl group, preferably represents a
(C.sub.1-C.sub.5)-alkyl group or an optionally partially or
completely fluorinated (C.sub.1-C.sub.5)-alkyl group, especially
preferably represents a (C.sub.1-C.sub.3)-alkyl group or an
optionally partially or completely fluorinated
(C.sub.1-C.sub.3)-alkyl group, in particular an optionally or
partially or completely fluorinated (C.sub.1-C.sub.3)-alkyl group,
or quite especially represents CF.sub.3 or C.sub.2F.sub.5, are
another subject of the invention.
[0133] Preferred are stereoisomers according to claims 1 to 9 whose
radical R.sup.5 means an optionally partially or completely
fluorinated (C.sub.1-C.sub.5)-alkyl group, in particular an
optionally partially or completely fluorinated
(C.sub.1-C.sub.3)-alkyl group.
[0134] The radicals and all their subcombinations, which are
confirmed by the examples, represent an especially preferred
subgroup, as it was disclosed for this invention.
[0135] The designation halogen atom or halogen means a fluorine,
chlorine, bromine or iodine atom. A fluorine, chlorine or bromine
atom is preferred.
[0136] The C.sub.1-C.sub.10- or C.sub.1-C.sub.5-alkyl groups
R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.11 and
R.sup.12 can be straight-chain or branched and stand for, for
example, a methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
tert.-butyl or n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl or
3-methylbutyl group, as well as hexyl, heptyl, nonyl, or decyl
group, and any of their branched derivatives. A methyl or ethyl
group is preferred.
[0137] The above-mentioned alkyl groups optionally can be
substituted by 1-5 groups, independently of one another, selected
from hydroxy, cyano, nitro, COOR.sup.13, C.sub.1-C.sub.5-alkoxy
groups, halogen, NR.sup.8R.sup.9, a partially or completely
fluorinated C.sub.1-C.sub.3-alkyl group; the substituents 1-3
halogen atoms and/or 1-3 hydroxy groups and/or 1-3 cyano groups
and/or 1-3 COOR.sup.13 groups represent a subgroup. Fluorine atom,
hydroxy, methoxy and/or cyano groups represent a preferred
subgroup.
[0138] They can optionally also only be substituted by 1-3 hydroxy
groups and/or 1-3 COOR.sup.13 groups. Hydroxy groups are
preferred.
[0139] For a partially or completely fluorinated
C.sub.1-C.sub.3-alkyl group, for example, the following partially
or completely fluorinated groups are considered: fluoromethyl,
difluoromethyl, trifluoromethyl, fluoroethyl, 1,1-difluoroethyl,
1,2-difluoroethyl, 1,1,1-trifluoroethyl, tetrafluoroethyl, and
pentafluoroethyl. Of the latter, the trifluoromethyl group or the
pentafluoroethyl group is preferred, and the completely fluorinated
group is also named perfluoroalkyl group.
[0140] The reagents, which optionally are used during the
synthesis, are commercially available, or the published syntheses
of the corresponding reagents are part of the prior art, or
published syntheses can be used analogously.
[0141] The C.sub.1-C.sub.10- or C.sub.1-C.sub.5-alkoxy groups can
be straight-chain or branched and stand for, for example, a
methoxy, ethoxy, n-propoxy, iso-propoxy-, n-butoxy, iso-butoxy,
tert.-butoxy or n-pentoxy, 2,2-dimethylpropoxy, 2-methylbutoxy or
3-methylbutoxy group. C.sub.1-C.sub.5-Alkoxy groups are preferred.
A methoxy or ethoxy group is especially preferred.
[0142] The above-mentioned alkoxy groups optionally can be
substituted with 1-3 groups that are selected from halogen, in
particular fluorine, chlorine, hydroxy and cyano.
[0143] The C.sub.1-C.sub.5-alkylthio groups can be straight-chain
or branched and stand for, for example, a methylthio, ethylthio,
n-propylthio, iso-propylthio, n-butylthio, iso-butylthio,
tert.-butylthio or n-pentylthio, 2,2-dimethylpropylthio,
2-methylbutylthio or 3-methylbutylthio group. A methylthio or
ethylthio group is preferred.
[0144] Substituent NR.sup.8R.sup.9 means, for example, NH.sub.2,
NH(CH.sub.3), N(CH.sub.3).sub.2, NH(C.sub.2H.sub.5),
N(C.sub.2H.sub.5).sub.2, NH(C.sub.3H.sub.7),
N(C.sub.3H.sub.7).sub.2, NH(C.sub.4H.sub.9),
N(C.sub.4H.sub.9).sub.2, NH(C.sub.5H.sub.11),
N(C.sub.5H.sub.11).sub.2, NH(CO)CH.sub.3, NH(CO)C.sub.2H.sub.5,
NH(CO)C.sub.3H.sub.7, NH(CO)C.sub.4H.sub.9, or
NH(CO)C.sub.5H.sub.11.
[0145] The cycloalkyl group means a saturated cyclic group that
optionally is substituted by one or more groups selected from
hydroxy groups, halogen atoms, (C.sub.1-C.sub.5)-alkyl groups,
(C.sub.1-C.sub.5)-alkoxy groups, NR.sup.8R.sup.9 groups, COOR.sup.3
groups, CHO, and cyano, and said group has 3 to 7 ring-carbon
atoms, such as, for example, cyclopropyl, methylcyclopropyl,
cyclobutyl, methylcyclobutyl, cyclopentyl, methylcyclopentyl,
cyclohexyl, methylcyclohexyl, cycloheptyl, and
methylcycloheptyl.
[0146] A (C.sub.1-C.sub.8)alkyl(C.sub.3-C.sub.7)cycloalkyl group
R.sup.5 is defined as a cycloalkyl group that is linked to the ring
system via a straight-chain or branched (C.sub.1-C.sub.8)-alkyl
unit.
[0147] A (C.sub.2-C.sub.8)alkenyl(C.sub.3-C.sub.7)cycloalkyl group
R.sup.5 is defined as a cycloalkyl group that is linked to the ring
system via a straight-chain or branched (C.sub.2-C.sub.8)-alkenyl
unit.
[0148] The heterocyclyl group is not aromatic and can be, for
example, pyrrolidine, imidazolidine, pyrazolidine, or piperidine.
Perhydroquinoline and perhydroisoquinoline are also part of the
included heterocyclyl groups. As substituents for heterocyclyl and
heteroaryl groups, for example, substituents from the group
optionally substituted C.sub.1-C.sub.5-alkyl group, hydroxy-,
C.sub.1-C.sub.5-alkoxy-, NR.sup.8R.sup.9--, halogen, cyano-,
COOR.sup.13--, and CHO-- are suitable. The substituents can
optionally also be bonded to the nitrogen atom; then N-oxides are
also included in the definition.
[0149] Aryl groups in terms of the invention are the aromatic
carbocyclic groups with 6 to 14 carbon atoms, which exhibit a ring,
such as, e.g., phenyl or phenylene, or several condensed rings,
such as, e.g., naphthyl or anthranyl. By way of example, phenyl,
naphthyl, anthranyl, indanyl, tetralinyl and indenyl can be
mentioned.
[0150] The aryl groups can be substituted at any suitable position
that results in a stable compound by one or more radicals from the
group hydroxy, halogen; C.sub.1-C.sub.5-alkyl that optionally is
substituted by 1-3 hydroxy groups or COR.sup.13 groups;
C.sub.1-C.sub.5-alkoxy, cyano, CF.sub.3, and nitro. The optionally
substituted phenyl group and the naphthyl group are preferred.
[0151] A (C.sub.1-C.sub.8)alkylaryl group is an aryl group, as it
is already described above, that is linked to the ring system via a
straight-chain or branched (C.sub.1-C.sub.8)-alkyl unit.
[0152] A (C.sub.2-C.sub.8)alkenylaryl group is an aryl group, as it
is already described above, that is linked to the ring system via a
straight-chain or branched (C.sub.2-C.sub.8)-alkenyl unit.
[0153] A (C.sub.2-C.sub.8)alkinylaryl group is an aryl group, as it
is already described above, that is linked to the ring system via a
straight-chain or branched (C.sub.2-C.sub.8)-alkinyl unit.
[0154] The monocyclic or bicyclic heteroaryl group can optionally
be substituted by one or more substituents that are selected from
C.sub.1-C.sub.5-alkyl group, C.sub.1-C.sub.5-alkoxy group, halogen
or exomethylene that optionally are substituted by 1-3 hydroxy
groups or 1-3 COOR.sup.13 groups. The substituents optionally also
can be directly bonded to the heteroatom. N-oxides are also
included in this invention.
[0155] The monocyclic or bicyclic heteroaryl group optionally can
contain 0-9 groups from the group nitrogen atoms, oxygen atoms,
sulfur atoms or keto groups, of which at most 4 nitrogen atoms, at
most 2 oxygen atoms, at most 2 sulfur atoms and at most 2 keto
groups can be contained. Any subcombination of these groups is
possible. The heteroaryl group can be hydrogenated at one or more
locations.
[0156] Monocyclic heteroaryl groups can be, for example, pyridine,
pyrazine, pyrimidine, pyridazine, triazine, azaindolizine, 2H- and
4H-pyran, 2H- and 4H-thiopyran, furan, thiophene, 1H- and
4H-pyrazole, 1H- and 2H-pyrrole, oxazole, thiazole, furazan, 1H-
and 4H-imidazole, isoxazole, isothiazole, oxadiazole, triazole,
tetrazole, or thiadiazole.
[0157] Bicyclic heteroaryl groups can be, for example, a
phthalidyl, thiophthalidyl, indolyl, isoindolyl, dihydroindolyl,
dihydroisoindolyl, indazolyl, benzothiazolyl, indolonyl,
dihydroindolonyl, isoindolonyl, dihydroisoindolonyl, benzofuranyl,
benzimidazolyl, dihydroisoquinolinyl, dihydroquinolinyl,
benzoxazinonyl, phthalazinonyl, dihydrophthalazinonyl, quinolinyl,
isoquinolinyl, quinolonyl, isoquinolonyl, quinazolinyl,
quinoxalinyl, cinnolinyl, phthalazinyl, dihydrophthalazinyl, 1,7-
or 1,8-naphthyridinyl, cumarinyl, isocumarinyl, indolizinyl,
isobenzofuranyl, azaindolyl, azaisoindolyl, furanopyridyl,
furanopyrimidinyl, furanopyrazinyl, furanopyridazinyl,
dihydrobenzofuranyl, dihydrofuranopyridyl,
dihydrofuranopyrimidinyl, dihydrofuranopyrazinyl,
dihydrofuranopyridazinyl, or dihydrobenzofuranyl group.
[0158] If the heteroaryl groups are partially or completely
hydrogenated, stereoisomers of formula I or II, in which R.sup.3
means tetrahydropyranyl, 2H-pyranyl, 4H-pyranyl, piperidyl,
tetrahydropyridyl, dihydropyridyl, 1H-pyridin-2-onyl,
1H-pyridin-4-onyl, 4-aminopyridyl, 1H-pyridin-4-ylidenaminyl,
chromanyl, isochromanyl, thiochromanyl, decahydroquinolinyl,
tetrahydroquinolinyl, dihydroquinolinyl,
5,6,7,8-tetrahydro-1H-quinolin-4-onyl, decahydroisoquinolinyl,
tetrahydroisoquinolinyl, dihydroisoquinolinyl,
3,4-dihydro-2H-benz[1,4]oxazinyl,
1,2-dihydro[1,3]benzoxazin-4-onyl,
3,4-dihydrobenz[1,4]oxazin-4-only,
3,4-dihydro-2H-benzo[1,4]thiazinyl, 4H-benzo[1,4]thiazinyl,
1,2,3,4-tetrahydroquinoxalinyl, 1H-cinnolin-4-onyl,
3H-quinazolin-4-onyl, 1H-quinazolin-4-onyl,
3,4-dihydro-1H-quinoxalin-2-onyl,
2,3-1,2,3,4-tetrahydro[1,5]naphthyridinyl,
dihydro-1H-[1,5]naphthyridyl, 1H-[1,5]naphthyrid-4-onyl,
5,6,7,8-tetrahydro-1H-naphthyridin-4-onyl,
1,2-dihydropyrido[3,2-d][1,3]oxazin-4-onyl, octahydro-1H-indolyl,
2,3-dihydro-1H-indolyl, octahydro-2H-isoindolyl,
1,3-dihydro-2H-isoindolyl, 1,2-dihydroindazolyl,
1H-pyrrolo[2,3-b]pyridyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridyl,
2,2-dihydro-1H-pyrrolo[2,3-b]pyridin-3-onyl, are part of this
invention.
[0159] A (C.sub.1-C.sub.8)alkylheteroaryl group is a heteroaryl
group, as it is already described above, which is linked to the
ring system via a straight-chain or branched
(C.sub.1-C.sub.8)-alkyl unit.
[0160] A (C.sub.2-C.sub.8)alkenylheteroaryl group is a heteroaryl
group, as it is already described above, which is linked to the
ring system via a straight-chain or branched
(C.sub.2-C.sub.8)-alkenyl unit.
[0161] A (C.sub.2-C.sub.8)alkinylheteroaryl group is a heteroaryl
group, as it is already described above, which is linked to the
ring system via a straight-chain or branched
(C.sub.2-C.sub.8)-alkinyl unit.
[0162] A (C.sub.1-C.sub.8)alkylheterocyclyl group is a heterocyclyl
group, as it is already described above, which is linked to the
ring system via a straight-chain or branched
(C.sub.1-C.sub.8)-alkyl unit.
[0163] A (C.sub.2-C.sub.8)alkenylheterocyclyl group is a
heterocyclyl group, as it is already described above, which is
linked to the ring system via a straight-chain or branched
(C.sub.2-C.sub.8)-alkenyl unit.
[0164] The compounds of general formula I according to the
invention can be present as stereoisomers because of the presence
of asymmetry centers. All possible diastereomers (e.g.: RR, RS, SR,
SS) both as racemates and in enantiomer-pure form are subjects of
this invention. The term stereoisomers also comprises all possible
diastereomers and regioisomers and tautomers (e.g., keto-enol
tautomers), in which the stereoisomers according to the invention
can be present, which thus are also the subject of the
invention.
[0165] The compounds according to the invention can also be present
in the form of salts with physiologically compatible anions, for
example in the form of hydrochloride, sulfate, nitrate, phosphate,
pivalate, maleate, fumarate, tartrate, benzoate, mesylate, citrate
or succinate.
[0166] The compounds according to the invention are produced by the
open-chain precursors of general formula II, in which radicals
R.sup.1, R.sup.11, R.sup.12, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and
R.sup.7 have the above-indicated meanings,
##STR00012##
being generated according to methods that are known in the prior
art, and then being cyclized to the compounds of general formula I
either without additional reagent with a solvent, preferably
chlorinated hydrocarbons, such as, e.g., methylene chloride or
dichloroethane or concentrated organic acids, preferably glacial
acetic acid, or by adding inorganic or organic acids or Lewis acids
under temperatures in the range of -70.degree. C. to +80.degree. C.
(preferably in the range of -30.degree. C. to +80.degree. C.).
[0167] A method for the production of stereoisomers of general
formula I, which is characterized in that imines of general formula
II are cyclized to the stereoisomers of general formula I either
without additional reagent in a solvent or concentrated organic
acids, or by adding inorganic or organic acids or Lewis acids under
temperatures in the range of -70.degree. C. to +80.degree. C.
(preferably in the range of -30.degree. C. to +80.degree. C.), as
well as their direct precursors of formula II, is thus also a
subject of this invention.
[0168] The new imines for the cyclization are also subjects of this
invention, in particular the compounds of general formula II, in
which R.sup.1, R.sup.11, R.sup.12, R.sup.3, R.sup.4, R.sup.5,
R.sup.6 and R.sup.7 in each case have the radicals that are defined
in claims 1 to 9, quite especially those that have been disclosed
by the examples.
[0169] The binding of the substances to the glucocorticoid receptor
(GR) and other steroid-hormone receptors (mineral corticoid
receptor (MR), progesterone receptor (PR) and androgen receptor
(AR)) is examined with the aid of recombinantly produced receptors.
Cytosol preparations of Sf9 cells, which had been infected with
recombinant baculoviruses that code for the GR, are used for the
binding studies. In comparison to the reference substance
[.sup.3H]-dexamethasone, the substances show a high affinity to the
GR. IC.sub.50(GR)=86 nM and IC.sub.50(PR)=>1000 were thus
measured for the compound from Example 3.
[0170] The GR-mediated inhibition of the transcription of
cytokines, adhesion molecules, enzymes and other pro-inflammatory
factors is considered to be an essential, molecular mechanism for
the anti-inflammatory action of glucocorticoids. This inhibition is
produced by an interaction of the OR with other transcription
factors, e.g., AP-1 and NF-kappa-B (for a survey, see Cato, A. C.
B. and Wade, E., BioEssays 18, 371-378, 1996).
[0171] The compounds of general formula I according to the
invention inhibit the secretion of cytokine IL-8 into the human
monocyte cell line THP-1 that is triggered by lipopolysaccharide
(LPS). The concentration of the cytokines was determined in the
supernatant by means of commercially available ELISA kits. The
compound of Example 3 showed an inhibition IC.sub.50(IL8)=40 nm
(79% eff).
[0172] The anti-inflammatory action of the compounds of general
formula I was tested in the animal experiment by tests in the
croton oil-induced inflammation in rats and mice (J. Exp. Med.
(1995), 182, 99-108). To this end, croton oil in ethanolic solution
was applied topically to the animals' ears. The test substances
were also applied topically or systemically at the same time or two
hours before the croton oil. After 16-24 hours, the ear weight was
measured as a yardstick for inflammatory edema, the peroxidase
activity as a yardstick for the invasions of granulocytes, and the
elastase activity as a yardstick for the invasion of neutrophilic
granulocytes. In this test, the compounds of general formula I
inhibit the three above-mentioned inflammation parameters both
after topical administration and after systemic administration.
[0173] One of the most frequent undesirable actions of a
glucocorticoid therapy is the so-called "steroid diabetes" [cf.,
Hatz, H. J., Glucocorticoide: Immunologische Grundlagen,
Pharmakologie und Therapierichtlinien, [Glucocorticoids:
Immunological Bases, Pharmacology and Therapy Guidelines],
Wissenschaftliche Verlagsgesellsch aft mbH, Stuttgart, 1998]. The
reason for this is the stimulation of gluconeogenesis in the liver
by induction of the enzymes responsible in this respect and by free
amino acids, which are produced from the degradation of proteins
(catabolic action of glucocorticoids). A key enzyme of the
catabolic metabolism in the liver is tyrosinamino transferase
(TAT). The activity of this enzyme can be determined from liver
homogenates by photometry and represents a good measurement of the
undesirable metabolic actions of glucocorticoids. To measure the
TAT induction, the animals are sacrificed 8 hours after the test
substances are administered, the livers are removed, and the TAT
activity is measured in the homogenate. In this test, at doses in
which they have an anti-inflammatory action, the compounds of
general formula I induce little or no tyrosinamino transferase.
[0174] Because of their anti-inflammatory action, and, in addition,
anti-allergic, immunosuppressive and antiproliferative action, the
compounds of general formula I according to the invention can be
used as medications for treatment or prophylaxis of the following
pathologic conditions in mammals and humans: In this case, the term
"DISEASE" stands for the following indications:
(i) Lung diseases that are accompanied by inflammatory, allergic
and/or proliferative processes: [0175] Chronic, obstructive lung
diseases of any origin, primarily bronchial asthma [0176]
Bronchitis of different origins [0177] All forms of restrictive
lung diseases, primarily allergic alveolitis,
[0178] All forms of pulmonary edema, primarily toxic pulmonary
edema [0179] Sarcoidoses and granulomatoses, especially Boeck's
disease (ii) Rheumatic diseases/autoimmune diseases/joint diseases
that are accompanied by inflammatory, allergic and/or proliferative
processes: [0180] All forms of rheumatic diseases, especially
rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica
[0181] Reactive arthritis [0182] Inflammatory soft-tissue diseases
of other origins [0183] Arthritic symptoms in the case of
degenerative joint diseases (arthroses) [0184] Traumatic
arthritides [0185] Collagenoses of any origin, e.g., systemic lupus
erythematodes, sclerodermia, polymyositis, dermatomyositis,
Sjogren's syndrome, Still's syndrome, Felty's syndrome (iii)
Allergies that are accompanied by inflammatory and/or proliferative
processes: [0186] All forms of allergic reactions, e.g., Quincke's
edema, hay fever, insect bites, allergic reactions to
pharmaceutical agents, blood derivatives, contrast media, etc.,
anaphylactic shock, urticaria, contact dermatitis (iv) Vascular
inflammations (vasculitides) [0187] Panarteritis nodosa, temporal
arteritis, erythema nodosum (v) Dermatological diseases that are
accompanied by inflammatory, allergic and/or proliferative
processes: [0188] Atopic dermatitis (primarily in children) [0189]
Psoriasis [0190] Pityriasis rubra pilaris [0191] Erythematous
diseases, triggered by different noxae, e.g., radiation, chemicals,
burns, etc. [0192] Bullous dermatoses [0193] Diseases of the
lichenoid group, [0194] Pruritis (e.g., of allergic origin) [0195]
Seborrheal eczema [0196] Rosacea [0197] Pemphigus vulgaris [0198]
Erythema exudativum multiforme [0199] Balanitis [0200] Vulvitis
[0201] Hair loss such as alopecia greata [0202] Cutaneous T-cell
lymphoma (vi) Kidney diseases that are accompanied by inflammatory,
allergic and/or proliferative processes, [0203] Nephrotic syndrome
[0204] All nephritides (vii) Liver diseases that are accompanied by
inflammatory, allergic and/or proliferative processes: [0205] Acute
liver cell decomposition [0206] Acute hepatitis of different
origins, e.g., viral, toxic, pharmaceutical agent-induced [0207]
Chronic aggressive hepatitis and/or chronic intermittent hepatitis
(viii) Gastrointestinal diseases that are accompanied by
inflammatory, allergic and/or proliferative processes: [0208]
Regional enteritis (Crohn's disease) [0209] Colitis ulcerosa [0210]
Gastritis [0211] Reflux esophagitis [0212] Ulcerative colitis of
other origins, e.g., native sprue (ix) Proctologic diseases that
are accompanied by inflammatory, allergic and/or proliferative
processes: [0213] Anal eczema [0214] Fissures [0215] Hemorrhoids
[0216] Idiopathic proctitis (x) Eye diseases that are accompanied
by inflammatory, allergic and/or proliferative processes: [0217]
Allergic keratitis, uveitis, iritis [0218] Conjunctivitis [0219]
Blepharitis [0220] Optic neuritis [0221] Chorioiditis [0222]
Sympathetic ophthalmia (xi) Diseases of the ear-nose-throat area
that are accompanied by inflammatory, allergic and/or proliferative
processes: [0223] Allergic rhinitis, hay fever [0224] Otitis
external e.g., caused by contact dermatitis, infection, etc. [0225]
Otitis media (xii) Neurological diseases that are accompanied by
inflammatory, allergic and/or proliferative processes: [0226]
Cerebral edema, primarily tumor-induced cerebral edema [0227]
Multiple sclerosis [0228] Acute encephalomyelitis [0229] Meningitis
[0230] Various forms of convulsions, e.g., infantile nodding spasms
(xiii) Blood diseases that are accompanied by inflammatory,
allergic and/or proliferative processes: [0231] Acquired hemolytic
anemia [0232] Idiopathic thrombocytopenia (xiv) Tumor diseases that
are accompanied by inflammatory, allergic and/or proliferative
processes: [0233] Acute lymphatic leukemia [0234] Malignant
lymphoma [0235] Lymphogranulomatoses [0236] Lymphosarcoma [0237]
Extensive metastases, mainly in breast, bronchial and prostate
cancers (xv) Endocrine diseases that are accompanied by
inflammatory, allergic and/or proliferative processes: [0238]
Endocrine orbitopathy [0239] Thyreotoxic crisis [0240] De
Quervain's thyroiditis [0241] Hashimoto's thyroiditis [0242]
Basedow's disease (xvi) Organ and tissue transplants,
graft-versus-host disease (xvii) Severe shock conditions, e.g.,
anaphylactic shock, systemic inflammatory response syndrome (SIRS)
(xviii) Substitution therapy in. [0243] Innate primary suprarenal
insufficiency, e.g., congenital adrenogenital syndrome [0244]
Acquired primary suprarenal insufficiency, e.g., Addison's disease,
autoimmune adrenalitis, meta-infective tumors, metastases, etc.
[0245] Innate secondary suprarenal insufficiency, e.g., congenital
hypopituitarism [0246] Acquired secondary suprarenal insufficiency,
e.g., meta-infective tumors, etc. (xix) Vomiting that is
accompanied by inflammatory, allergic and/or proliferative
processes: [0247] e.g., in combination with a 5-HT3 antagonist in
cytostatic-agent-induced vomiting (xx) Pains of inflammatory
origins, e.g., lumbago.
[0248] Moreover, the compounds of general formula I according to
the invention can be used for treatment and prophylaxis of
additional pathologic conditions that are not mentioned above, for
which synthetic glucocorticoids are now used (see in this respect
Hatz, H. J., Glucocorticoide: Immunologische Grundlagen,
Pharmakologie und Therapierichtlinien, Wissenschaftliche
Verlagsgesellschaft mbH, Stuttgart, 1998).
[0249] All previously mentioned indications (i) to (xx) are
described in more detail in Hatz, H. J., Glucocorticoide:
Immunologische Grundlagen, Pharmakologie und Therapierichtlinien,
Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1998.
[0250] For the therapeutic actions in the above-mentioned
pathologic conditions, the suitable dose varies and depends on, for
example, the active strength of the compound of general formula I,
the host, the type of administration, and the type and severity of
the conditions that are to be treated, as well as the use as a
prophylactic agent or therapeutic agent.
[0251] The invention relates to the use of the claimed compounds
for the production of a pharmaceutical agent.
[0252] In addition, the invention provides: [0253] (i) The use of
one of the compounds of general formula I according to the
invention or mixture thereof for the production of a medication for
treating a DISEASE; [0254] (ii) A process for treating a DISEASE,
said process comprises an administration of an amount of the
compound according to the invention, whereby the amount suppresses
the disease and whereby the amount of compound is given to a
patient who requires such a medication; [0255] (iii) A
pharmaceutical composition for treating a DISEASE, said treatment
comprises one of the compounds according to the invention or
mixture thereof and at least one pharmaceutical adjuvant and/or
vehicle.
[0256] In general, satisfactory results can be expected in animals
when the daily doses comprise a range of 1 .mu.g to 100,000 .mu.g
of the compound according to the invention per kg of body weight.
In the case of larger mammals, for example the human, a recommended
daily dose lies in the range of 1 .mu.g to 100,000 .mu.g per kg of
body weight. Preferred is a dose of 10 to 30,000 .mu.g per kg of
body weight, and more preferred is a dose of 10 to 10,000 .mu.g per
kg of body weight. For example, this dose is suitably administered
several times daily. For treating acute shock (e.g., anaphylactic
shock), individual doses can be given that are significantly above
the above-mentioned doses.
[0257] The formulation of the pharmaceutical preparations based on
the new compounds is carried out in a way that is known in the art
by the active ingredient being processed with the vehicles,
fillers, substances that influence decomposition, binding agents,
moisturizers, lubricants, absorbents, diluents, flavoring
correctives, coloring agents, etc., that are commonly used in
galenicals and converted into the desired form of administration.
In this case, reference is made to Remington's Pharmaceutical
Science, 15.sup.th Edition, Mack Publishing Company, East
Pennsylvania (1980).
[0258] For oral administration, especially tablets, coated tablets,
capsules, pills, powders, granulates, lozenges, suspensions,
emulsions or solutions are suitable.
[0259] For parenteral administration, injection and infusion
preparations are possible.
[0260] For intra-articular injection, correspondingly prepared
crystal suspensions can be used.
[0261] For intramuscular injection, aqueous and oily injection
solutions or suspensions and corresponding depot preparations can
be used.
[0262] For rectal administration, the new compounds can be used in
the form of suppositories, capsules, solutions (e.g., in the form
of enemas) and ointments both for systemic and for local
treatment.
[0263] For pulmonary administration of the new compounds, the
latter can be used in the form of aerosols and inhalants.
[0264] For local application to eyes, outer ear channels, middle
ears, nasal cavities, and paranasal sinuses, the new compounds can
be used as drops, ointments and tinctures in corresponding
pharmaceutical preparations.
[0265] For topical application, formulations in gels, ointments,
fatty ointments, creams, pastes, powders, milk and tinctures are
possible. The dosage of the compounds of general formula I should
be 0.01%-20% in these preparations to achieve a sufficient
pharmacological action.
[0266] The invention also comprises the compounds of general
formula I according to the invention as therapeutic active
ingredients. In addition, the compounds of general formula I
according to the invention are part of the invention as therapeutic
active ingredients together with pharmaceutically compatible and
acceptable adjuvants and vehicles.
[0267] The invention also comprises a pharmaceutical composition
that contains one of the pharmaceutically active compounds
according to the invention or mixtures thereof or a
pharmaceutically compatible salt thereof and a pharmaceutically
compatible salt or pharmaceutically compatible adjuvants and
vehicles.
EXPERIMENTS
Example 1
(rac.)
5-{[6-Fluoro-2,5-dihydroxy-4,4,7-dimethyl-2-(trifluoromethyl)-1,2,3-
,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one
5-Amino-isoquinolin-1(2H)-one
2-Methyl-3-nitrobenzoic acid methyl ester
[0268] 30 g (165.6 mmol) of 2-methyl-3-nitrobenzoic acid is added
to 150 ml of methanol, and it is refluxed for two days after 2.9 ml
of concentrated sulfuric acid is added. After cooling, the
crystallizate (25.55 g=79%) is suctioned off and used in the next
stage.
[0269] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta.=2.50 (3H), 3.85
(3H), 7.56 (1H), 8.00 (1H), 8.05 (1H).
2-(Bromomethyl)-3-nitrobenzoic acid methyl ester
[0270] 25.55 g (130.9 mmol) of 2-methyl-3-nitrobenzoic acid methyl
ester is added to 300 ml of carbon tetrachloride, and mixed with
25.6 g (141.7 mmol) of N-bromosuccinimide and 62.8 mg of benzoyl
peroxide. After seven days of refluxing, the succinimide is
suctioned off after cooling, and then the filtrate is spun in until
a dry state is reached. The desired compound that is incorporated
in crude form into the next stage remains.
[0271] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=4.00 (3H), 5.66
(2H), 7.55 (1H), 7.95 (1H), 8.10 (1H).
5-Nitroisocoumarin
[0272] 16.4 g (84.03 mmol) of 2-methyl-3-nitrobenzoic acid methyl
ester is stirred with 26.8 g (225.1 mmol) of N,N-dimethylformamide
dimethylacetal in 85 ml of dimethylformamide for 12 hours at
130.degree. C. The solvent is drawn off in a rotary evaporator, the
residue is taken up in methyl-tert-butyl ether and washed three
times with water. After washing with saturated NaCl solution, the
organic phase is dried. After the desiccant is filtered off and the
solvent is spun off, the remaining residue is chromatographed on
silica gel (mobile solvent ethyl acetate/hexane). 8.73 g (54.4%) of
the desired compound is isolated.
[0273] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=7.39 (H), 7.45
(1H), 7.68 (1H), 8.49 (1H), 8.65 (1H).
5-Nitroisoquinolin-1(2H)-one
[0274] 2.51 g (13.13 mmol) of 5-nitroisocoumarin is added in 100 ml
of ethanol. Ammonia is pressure-forced in an autoclave. The product
precipitates and is suctioned off. 1.98 g (79.7%) of the desired
compound is isolated.
[0275] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta.=6.97 (1H), 7.45
(1H), 7.65 (1H), 8.43 (1H), 8.57 (1H), 11.5 (1H).
5-Aminoisoquinolin-1(2H)-one
[0276] 268.3 mg (1.51 mmol) of 5-nitroisoquinolin-1(2H)-one is
added with 376.5 mg of ammonium chloride and 2.6 ml of water in 14
ml of ethanol and 5.4 ml of tetrahydrofuran. After addition in
portions of 1.23 g of zinc powder (heating to 30 to 35.degree. C.),
it is stirred for two hours. The reaction mixture is suctioned off
through a gas fiber filter and rewashed with ethyl acetate. After
the filtrate is washed with water and saturated sodium chloride
solution, the organic phase is dried as usual. Filtering off the
desiccant and spinning off the solvent produce 196.5 mg (88.1%) of
the desired amine.
[0277] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta.=5.6 (2H), 6.68
(1H), 6.87.45 (1H), 7.00 (1H), 7.17 (1H), 7.39 (1H), 11.7 (1H).
2-(3-Fluoro-2-methoxy-4-methylphenyl)-2-methylpropanenitrile
[0278] 14.48 g (91.56 mmol) of 2,6-difluoro-3-methylanisole is
dissolved in 800 ml of toluene. After 272.2 ml (137.35 mmol) of a
0.5 molar solution of potassium hexamethyl disilazide in toluene is
added, 25.31 g (366.26 mmol) of isobutyronitrile is added in drops.
The batch is stirred for 10 days at room temperature and then added
to a 1 M HCl solution. After being extracted three times with
methyl-tert-butyl ether, the combined organic extracts are washed
with saturated NaCl solution and dried. After spinning-in and
chromatography on silica gel (mobile solvent ethyl acetate/hexane),
10.32 g (49.5%) of the desired compound is obtained.
[0279] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=1.77 (6H), 2.29
(3H), 4.09 (3H), 6.86 (1H), 6.95 (1H).
2-(3-Fluoro-2-methoxy-4-methylphenyl)-2-methylpropanal
[0280] 10.32 g (45.33 mmol) of the above-described nitrite is
dissolved in 138 ml of toluene. 37.4 ml of a 1.2 molar solution of
DIBAH in toluene is added in drops under a cover gas at -70.degree.
C. After three hours of stirring, 7.92 ml of isopropanol is added
in drops, and after a brief stirring, 516 ml of a 10%
L-(+)-tartaric acid solution is added in drops. The temperature
increases, and the batch is vigorously stirred overnight at room
temperature. The reaction mixture is shaken twice with
methyl-tert-butyl ether. The combined organic extracts are shaken
with brine, dried, and the solvent is spun off. Since the residue
that is obtained (11.61 g>100%) still contains approximately 30%
starting material, it is subjected one more time to the reduction
conditions with the difference that during working-up, the
isopropanol is eliminated. 9.94 g of a product, which in addition
to the desired aldehyde also contains the starting material and the
corresponding alcohol, is isolated. This mixture is mixed again
with a 1.2 M DIBAH solution in toluene, but this time at
-20.degree. C. and with subsequent stirring at -10 to 0.degree. C.
to obtain a uniform compound. After the usual working-up and
chromatography on silica gel (mobile solvent ethyl acetate/hexane),
5.82 g of the corresponding alcohol and 1.50 g of the aldehyde are
ultimately obtained. The alcohol (5.82 g=27.42 mmol) is oxidized to
aldehyde according to Swern at -78.degree. C. After the usual
working-up and chromatography on silica gel (mobile solvent ethyl
acetate/hexane), 5.22 g (90.6%) of the desired aldehyde is
isolated.
[0281] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=1.38 (6H), 2.29
(3H), 3.85 (3H), 6.83-6.98 (2H), 9.59 (1H).
(E/Z)-4-(3-Fluoro-2-methoxy-4-methylphenyl)-4-methylpent-2-enoic
acid ethyl ester
[0282] 17.1 ml of a 2 molar LDA solution in THF is added in drops
to a solution of 8.62 g (32.96 mmol) of 2-ethoxy-phosphonoacetic
acid triethyl ester in 20 ml of absolute THF at 0.degree. C. After
40 minutes of stirring at 0.degree. C., 6.72 g (31.96 mmol) of
2-(3-fluoro-2-methoxy-4-methylphenyl)-2-methylpropanal, dissolved
in 20 ml of THF, is added in drops at 0.degree. C. After stirring
overnight at room temperature, the reaction mixture is carefully
mixed with 80 ml of water and extracted three times with
methyl-tert-butyl ether. The combined organic extracts are washed
with brine, dried, and the solvent is spun off after desiccant is
filtered off. The residue is chromatographed on silica gel (mobile
solvent ethyl acetate/hexane). 8.74 g (84.3%) of a mixture that in
addition to the desired compound also contains starting material
(aldehyde), which is separated in the next stage, is isolated.
(E/Z)-4-(3-Fluoro-2-methoxy-4-methylphenyl)-4-methylpent-2-enoic
acid
[0283] 8.74 g (26.95 mmol) of
(E/Z)-4-(3-fluoro-2-methoxy-4-methylphenyl)-4-methylpent-2-enoic
acid ethyl ester is mixed with 245 ml of 1N NaOH in ethanol/water
(2:1) and stirred overnight at room temperature. The ethanol is
drawn off in a rotary evaporator, and the residue is diluted with
water and extracted twice with methyl-tert-butyl ether. The
combined organic extracts contain the unreacted aldehyde from the
previously described reaction. While being cooled in an ice bath,
the aqueous phases are carefully acidified with concentrated
hydrochloric acid to a pH of 3 and extracted three times with 300
ml each of methyl-tert-butyl ether. These ether extracts are washed
with brine, dried, the solvent is spun off, and the residue (6.41
g=80.3%) is incorporated in crude form into the next stage. The
recovered aldehyde is again subjected to the sequence of
Horner-Wittig reaction and subsequent saponification. As a result,
another 2.29 g of the desired compound
(E/Z)-4-(3-fluoro-2-methoxy-4-methylphenyl)-4-methylpent-2-enoic
acid is obtained. Since the compound is an E/Z mixture (no 1:1
ratio), only the location of signals is indicated in the NMR
spectrum.
[0284] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.98, 1.40, 1.53,
2.21, 3.38, 3.75-3.88, 6.72-6.85, 7.00.
4-(3-Fluoro-2-methoxy-4-methylphenyl)-4-methyl-2-oxo-pentanoic
acid
[0285] 8.70 g (29.36 mmol) of the
(E/Z)-4-(3-fluoro-2-methoxy-4-methylphenyl)-4-methylpent-2-enoic
acid that is obtained from the previous batch is mixed with 139 ml
of a 1 molar sulfuric acid and 13.9 ml of glacial acetic acid, and
it is stirred for two days at a bath temperature of 90.degree. C.
After cooling, the batch is made basic with solid potassium
carbonate (caution, foaming). It is extracted three times with
methyl-tert-butyl ether, and the combined organic extracts are
discarded while being monitored by TLC. The aqueous phase is
acidified with concentrated hydrochloric acid and shaken three
times with methyl-tert-butyl ether. The ether extracts are washed
with brine, dried, and the solvent is spun off. The remaining
residue (6.04 g=76.6%) is incorporated in crude form into the next
stage.
[0286] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=1.48 (6H), 2.25
(3H), 3.50 (2H), 3.93 (3H), 6.82 (1H), 6.95 (1H).
4-(3-Fluoro-2-methoxy-4-methylphenyl)-4-methyl-2-oxo-pentanoic acid
ethyl ester
[0287] 6.04 g (22.52 mmol) of
4-(3-fluoro-2-methoxy-4-methylphenyl)-4-methyl-2-oxo-pentanoic acid
is dissolved in 140 ml of ethanol, mixed with 2.5 ml of sulfuric
acid, and refluxed for six hours. The ethanol is drawn off in a
rotary evaporator, and the residue is carefully mixed with 300 ml
of saturated sodium bicarbonate solution. It is extracted three
times with ethyl acetate. The combined organic extracts are washed
once with saturated sodium bicarbonate solution and once with
brine. After drying, and after the desiccant is filtered off and
the solvent is spun in, the residue is chromatographed on silica
gel (mobile solvent ethyl acetate/hexane). 5.58 g (83.7%) of the
desired compound is isolated.
[0288] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=1.29 (3H), 1.47
(6H), 2.23 (3H), 3.40 (2H), 3.95 (3H), 4.17 (2H), 6.79 (1H), 6.90
(1H).
4-(3-Fluoro-2-methoxy-4-methylphenyl)-4-methyl-2-trifluoromethyl-2-trimeth-
ylsilyloxy-pentanoic acid ethyl ester
[0289] 5.58 g (18.83 mmol) of
4-(3-fluoro-2-methoxy-4-methylphenyl)-4-methyl-2-oxo-pentanoic acid
ethyl ester is dissolved in 30 ml of THF and mixed at 0.degree. C.
with 3.21 g (22.6 mmol) of (trifluoromethyl)-trimethylsilane and
46.1 mg of tetrabutylammonium fluoride. After six hours of stirring
between 0 and 5.degree. C., the batch is added to ice water. It is
extracted three times with methyl-tert-butyl ether, and the
combined organic extracts are washed with brine. After
chromatography on silica gel (mobile solvent ethyl acetate/hexane),
7.5 g (90.8%) of the desired compound is obtained.
4-(3-Fluoro-2-methoxy-4-methylphenyl)-4-methyl-2-trifluoromethyl)-pentane--
1,2-diol
[0290] 7.5 g (17.1 mmol) of
4-(3-fluoro-2-methoxy-4-methylphenyl)-4-methyl-2-(trifluoromethyl)-2-trim-
ethylsilyloxy-pentanoic acid ethyl ester is dissolved in 60 ml of
diethyl ether, and it is mixed at 0 to 5.degree. C. in portions
with 1.3 g (34.2 mmol) of LiAlH.sub.4. After five hours of stirring
at room temperature, 60 ml of saturated NaHCO.sub.3 is carefully
added in drops to the reaction mixture while being cooled in an ice
bath. It is stirred vigorously for one hour at room temperature.
After extraction with methyl-tert-butyl ether, the organic phases
are shaken with brine, dried, and the solvent is spun off. After
chromatography on silica gel (mobile solvent ethyl acetate/hexane),
3.65 g (65.8%) of the desired diol is obtained.
[0291] MS (Cl): 342 (100%), 181 (18%).
4-(3-Fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-
)pentanal
[0292] 1.57 g (12.31 mmol) of oxalyl chloride is introduced into 27
ml of dichloromethane and cooled to -78.degree. C. After 1.93 g of
DMSO, dissolved in 5.2 ml of dichloromethane, is added in drops,
the batch is stirred for five more minutes. Then, 3.65 (11.26 mmol)
of
4-(3-fluoro-2-methoxy-4-methylphenyl)-4-methyl-2-(trifluoromethyl)-pentan-
e-1,2-diol, dissolved in 11.5 milliliters of dichloromethane, is
added in drops. After two hours of stirring, the batch is carefully
mixed with 6.61 ml (56.28 mmol) of triethylamine. After one and
one-half hours of vigorous stirring at room temperature, water is
added, and the batch is shaken twice with dichloromethane. The
combined organic extracts are washed with 1% sulfuric acid,
saturated sodium bicarbonate solution and brine. After the organic
phase is dried, the solvent is spun off. 2.79 g (76.9%) of the
aldehyde, which is further used in crude form, remains.
[0293] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=1.41 (3H), 1.45
(3H), 2.15-2.30 (5H), 3.29 (1H), 3.60 (1H), 4.02 (3H), 6.70-6.82
(2H), 9.10 (1H).
(rac.)-5-{[4-(3-Fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-trif-
luoromethyl)pentylidene]amino}isoquinolin-1(2H)-one
[0294] 150 mg (0.465 mmol) of
4-(3-fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluorometh-
yl)pentanal, 74.5 mg (0.465 mmol) of 5-amino-isoquinolin-1(2H)-one
and 264.4 mg (0.930 mmol) of titanium tetraisopropylate are stirred
in 2.5 ml of xylene for five hours at 120.degree. C. The mixture is
diluted with ethyl acetate and washed once with brine. The solvent
is spun off; and the residue is chromatographed on a Flashmaster.
98.6 mg (45.6%) of the desired compound is isolated.
[0295] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=1.40 (3H), 1.58
(3H), 1.89 (3H), 2.29 (1H), 3.30 (1H), 4.00 (3H), 4.79 (1H), 6.38
(1H), 6.67-6.78 (2H), 6.80 (1H), 7.20 (1H), 7.38 (1H), 7.55 (1H),
8.32 (1H), 11.0 (1H).
(rac.)
5-{[6-Fluoro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl-
)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one)
[0296] 1.39 ml (1.27 mmol) of titanium tetrachloride is carefully
added in drops at 0.degree. C. to 98.6 mg (0.212 mmol) of the
compound
rac-5-{[4-(3-fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-triflu-
oromethyl)pentylidene]amino}isoquinolin-1-(2H)-one that is
described in the previous paragraph, and then it is stirred for
three hours at room temperature. The reaction mixture is carefully
mixed at 0.degree. C. with saturated sodium bicarbonate solution.
After being extracted three times with ethyl acetate, the combined
organic extracts are washed with saturated NaCl solution. After
drying on sodium sulfate, the solvent is spun off, and the
remaining residue is chromatographed on a Flashmaster. 63.3 mg
(64.2%) of the desired compound is isolated.
[0297] .sup.1H-NMR (300 MHz, CD.sub.3OD): .delta.=1.52 (3H), 1.67
(3H), 2.05-2.20 (5H), 3.98 (3H), 5.10 (1H), 6.80-6.95 (2H), 7.08
(1H), 7.19 (1H), 7.40 (1H), 7.70 (1H).
(rac.) 5-{[6-Fluoro-2-,
5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphtha-
len-1-yl]amino}-isoquinolin-1(2H)-one
[0298] 59.7 mg (0.128 mmol) of (rac.)
5-{[6-fluoro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,-
3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1-(2H)-one is
mixed at 0.degree. C. with 1.3 ml of a 1 molar solution of boron
tribromide in dichloromethane, and it is stirred for one hour at 0
to 5.degree. C. At -10.degree. C., saturated sodium bicarbonate
solution is now carefully added in drops. After 10 minutes of
vigorous stirring at room temperature, the batch is extracted three
times with methyl-tert-butyl ether. The organic phases are dried,
and the residue is chromatographed on a Flashmaster after the
solvent is spun off. 46.5 mg (80.3%) of the desired compound is
isolated.
[0299] .sup.1H-NMR (300 MHz, CD.sub.3OD): .delta.=1.56 (3H), 1.70
(3H), 2.00-2.20 (5H), 5.09 (1H), 6.65 (1H), 6.85 (1H), 7.05 (1H),
7.18 (1H), 7.39 (1H), 7.68 (1H).
Example 2
(rac.)
5-{[6-Fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,-
3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
5-Amino quinolin-2(1H)-one
[0300] 4.5 g of 5-nitroquinolin-2(1H)-one (Chem. Pharm. Bull. 29,
651 (1981)) is hydrogenated in 200 ml of ethyl acetate and 500 ml
of methanol in the presence of 450 mg of palladium on activated
carbon as a catalyst under normal pressure with hydrogen until the
reaction is completed. The catalyst is removed by filtration
through diatomaceous earth, and the reaction solution is
concentrated by evaporation in a vacuum. 3.8 g of the title
compound is obtained as a yellow solid.
[0301] .sup.1H-NMR (DMSO): .delta.=5.85 (bs, 2H), 6.27 (d, 1H),
6.33 (d, 1H), 6.43 (d, 1H), 7.10 (t, 1H), 8.07 (d, 1H), 11.39 (bs,
1H)
rac-5-{[4-(3-Fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluo-
romethyl)pentylidene]amino}isoquinolin-2(1H)-one
[0302] 150 mg (0.465 mmol) of
4-(3-fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluorometh-
yl)pentanal (described in Example 1), 74.5 mg (0.465 mmol) of
5-amino-isoquinolin-2(1H)-one and 264.4 mg (0.930 mmol) of titanium
tetraisopropylate are stirred in 2.5 ml of xylene for five hours at
120.degree. C. The mixture is diluted with ethyl acetate and washed
once with brine. The solvent is spun off, and the residue is
chromatographed on a Flashmaster. 132.2 mg (61.2%) of the desired
compound is isolated.
[0303] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=1.40 (3H), 1.56
(3H), 1.82 (3H), 2.29 (1H), 3.28 (1H), 3.98 (3H), 4.70 (1H),
6.30-6.45 (2H), 6.70-6.80 (2H), 7.30 (1H), 7.40 (1H), 7.63 (1H),
8.07 (1H), 12.27 (1H).
(rac.)
5-{[6-Fluoro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl-
)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-2(1H)-one
[0304] 1.86 ml (1.708 mmol) of titanium tetrachloride is carefully
added in drops at 0.degree. C. to 132.2 mg (0.285 mmol) of the
compound
rac-5-{[4-(3-fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifl-
uoromethyl)pentylidene]amino}isoquinolin-2(1H)-one that is
described in the preceding paragraph, and then it is stirred for
three hours at room temperature. The reaction mixture is carefully
mixed with saturated sodium bicarbonate solution at 0.degree. C.
After being extracted three times with ethyl acetate, the combined
organic extracts are washed with saturated NaCl solution. After
drying on sodium sulfate, the solvent is spun off, and the
remaining residue is chromatographed on a Flashmaster. 106.7 mg
(80.7%) of the desired compound is isolated.
[0305] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=1.52 (3H), 1.68
(3H), 1.98-2.25 (5H), 3.95 (3H), 4.60 (1H), 4.99 (1H), 5.49 (1H),
6.49-6.62 (3H), 6.80 (1H), 7.35 (1H), 8.16 (1H), 10.40 (1H).
(rac.)
5-{[6-Fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,-
3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-2(1H)-one)
[0306] 101.4 mg (0.218 mmol) of (rac.)
5-{[6-fluoro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,-
3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-2(1H)-one is mixed
at 0.degree. C. with 2.2 ml of a 1 molar solution of boron
tribromide in dichloromethane, and it is stirred for one hour at 0
to 5.degree. C. At -10.degree. C., saturated sodium bicarbonate
solution is now carefully added in drops. After 10 minutes of
vigorous stirring at room temperature, the batch is extracted three
times with methyl-tert-butyl ether. The organic phases are dried,
and the residue is chromatographed on a Flashmaster after the
solvent is spun off. 93.7 mg (95.3%) of the desired compound is
isolated.
[0307] .sup.1H-NMR (300 MHz, CD.sub.3OD): .delta.=1.58 (3H), 1.69
(3H), 2.00-2.20 (5H), 5.10 (1H), 6.51 (1H), 6.55-6.74 (3H), 7.39
(1H), 8.22 (1H).
Example 3
(rac.)
6-Fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-4,4,7-trimethy-
l-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
5-Amino-8-fluoro-2-methylquinazoline
[0308] A solution of 2.4 g (18.6 mmol) of 2,5-difluoroaniline in 11
ml of water and 1.6 ml of concentrated hydrochloric acid (37%) that
is 50.degree. C. and that was previously stirred for one hour at
this temperature is added to a solution of 3.35 g (20.25 mmol) of
chloral hydrate and 21.27 g (149.7 mmol) of sodium sulfate in 72 ml
of water. It is stirred for another 30 minutes at room temperature,
and after 4.09 g (58.9 mmol) of hydroxylammonium chloride in 19 ml
of water is added over 45 minutes, it is heated to 125.degree. C.
and kept at this temperature for 5 minutes. After cooling and after
another hour, the deposited light brown precipitate is filtered
off, washed with water and dried. 3.0 g (15.0 mmol) of the
hydroxylimine is obtained as an intermediate product that is
dissolved in portions in 15 ml of concentrated sulfuric acid at
60.degree. C. After addition is completed, it is heated for 2 hours
to 80.degree. C. and for 4 hours to 90.degree. C. It is allowed to
cool, and the solution is poured onto 100 g of ice. It is extracted
with ethyl acetate, the organic phase is washed with water, dried
on sodium sulfate and concentrated by evaporation. After
chromatography on silica gel with hexane-ethyl acetate (0-45%), 1.2
g (7.1 mmol) of the 4,7-difluorisatin is obtained. 1.8 ml of a 30%
hydrogen peroxide solution is added in drops to isatin in 30 ml of
a 1 molar sodium hydroxide solution over 10 minutes. After 2 hours
of stirring at room temperature, it is cooled to 0.degree. C., and
5 ml of a 4 molar hydrochloric acid is added and diluted with 50 ml
of water. It is extracted with ethyl acetate, dried on sodium
sulfate, concentrated by evaporation, and 1.27 g of
3,6-difluoroanthranilic acid, which is reacted without further
purification, is thus quantitatively obtained. The
3,6-difluoroanthranilic acid is heated in 8 ml of acetic acid
anhydride for 45 minutes to 100.degree. C. After cooling, the
acetic acid that is produced and excess acetic acid anhydride are
removed azeotropically with toluene in a vacuum. The residue is
mixed with 40 ml of a 25% ammonia solution while being cooled with
ice, and it is stirred for 72 hours. It is diluted with water and
acidified with acetic acid. It is extracted with ethyl acetate, the
organic phase is washed with water, dried on sodium sulfate and
concentrated by evaporation. The thus obtained 1.03 g (5.25 mmol)
of 5,8-difluoro-2-methyl-3H-quinazolin-4-one and 6 g of phosphorus
pentachloride are heated in 20 ml of phosphoryl chloride over 12
hours to 125.degree. C. After cooling, it is poured into saturated
NaHCO.sub.3 solution and extracted with ethyl acetate. The organic
phase is dried, and the solvent is removed. 1.7 g of
4-chloro-5,8-difluoro-2-methylquinazoline, which is dissolved in 60
ml of ethyl acetate and 5 ml of triethylamine, is obtained
quantitatively. 600 mg of palladium on carbon is added and shaken
for 2 hours (480 ml of hydrogen absorption) under a hydrogen
atmosphere at normal pressure. Catalyst is removed from the
solution by means of filtration on Celite, whereby it is rewashed
with 100 ml of ethanol and concentrated by evaporation. After
chromatography on silica gel with hexane-ethyl acetate-ethanol
(0-40%), 550 mg of 5,8-difluoro-2-methylquinazoline is obtained.
890 mg (13.7 mmol) of sodium azide is added to 240 mg (1.3 mmol) of
5,8-difluoro-2-methylquinazoline, 300 mg (1.13 mmol) of 18-crown-6
in 10 ml of DMF, and the mixture is heated over 8 hours to
125.degree. C. The solvent is removed in a vacuum, and it is
chromatographed on silica gel with ethyl acetate, and 52 mg of
product is obtained.
[0309] .sup.1H-NMR (300 MHz, CDCl.sub.3); .delta.=2.92 (s, 3H),
4.31 (br., 2H), 6.67 (dd, 1H), 7.38 (dd, 1H), 9.37 (s, 1H).
1,1,1-Trifluoro-4-(3-fluoro-2-methoxy-3-methylphenyl)-2-[(8-fluoro-2-methy-
l-quinazolyl-5-yl)iminomethyl]-4-methylpentan-2-ol
[0310] 150 mg (0.465 mmol) of
4-(3-fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluorometh-
yl)pentanal (described in Example 1), 83.7 mg (0.465 mmol) of
5-amino-8-fluoro-2-methylquinazoline and 264.4 mg (0.930 mmol) of
titanium tetraisopropylate are stirred in 2.5 ml of xylene for five
hours at 120.degree. C. The mixture is diluted with ethyl acetate
and washed once with brine. The solvent is spun off, and the
residue is chromatographed on a Flashmaster. 152.8 mg (68.2%) of
the desired compound is isolated.
[0311] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=1.40 (3H),
1.55-1.66 (6H), 2.29 (1H), 3.00 (3H), 3.30 (1H), 3.98 (3H), 4.60
(1H), 6.29 (1H), 6.67 (1H), 6.78 (1H), 7.43 (1H), 7.71 (1H), 9.49
(1H).
(rac.)
6-Fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-5-methoxy-4,4,-
7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
[0312] 2.1 ml (1.902 mmol) of titanium tetrachloride is carefully
added in drops at 0.degree. C. to 152.8 mg (0.317 mmol) of the
compound
1,1,1-trifluoro-4-(3-fluoro-2-methoxy-3-methylphenyl)-2-[(8-fluoro-2-meth-
yl-quinazolyl-5-yl)iminomethyl]-4-methylpentan-2-ol that is
described in the preceding paragraph, and then it is stirred for
three hours at room temperature. The reaction mixture is carefully
mixed at 0.degree. C. with saturated sodium bicarbonate solution.
After being extracted three times with ethyl acetate, the combined
organic extracts are washed with saturated NaCl solution. After
drying on sodium sulfate, the solvent is spun off, and the
remaining residue is chromatographed on a Flashmaster. 121.8 mg
(79.7%) of the desired compound is isolated.
[0313] .sup.1H-NMR (300 MHz, CDCl.sub.3): .quadrature.=1.57 (3H),
1.72 (3H), 2.05-2.29 (5H), 2.95 (3H), 3.97 (3H), 4.93 (1H), 5.63
(1H), 5.90 (1H), 6.68 (1H), 6.90 (1H), 7.50 (1H), 9.35 (1H).
(rac.)
6-Fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-4,4,7-trimethy-
l-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
[0314] 111.2 mg (0.231 mmol) of
(rac.)6-fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)-amino]-5-methoxy-4,4-
,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
is mixed at 0.degree. C. with 3.2 ml of a 1 molar solution of boron
tribromide in dichloromethane, and it is stirred for one and
one-half hours at 0 to 5.degree. C. At 0.degree. C., the now
carefully saturated sodium bicarbonate solution is added in drops.
After 10 minutes of vigorous stirring at room temperature, the
batch is extracted three times with ethyl acetate. The organic
phases are dried, and the residue is chromatographed on a
Flashmaster after the solvent is spun off, 66.4 mg (61.5%) of the
desired compound is isolated.
[0315] .sup.1H-NMR (300 MHz, CD.sub.3OD): .delta.=1.59 (3H), 1.70
(3H), 2.00-2.20 (5H), 2.88 (3H), 5.20 (1H), 6.68 (1H), 6.85 (1H),
7.58 (1H), 9.65 (1H).
Example 4
(rac.)
5-{[6-Fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,-
3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
5-Amino-2-methyl-phthalazin-1-one
3-Bromo-4-nitro-phthalide
[0316] 5.37 g of 4-nitrophthalide (Tetrahedron Lett. (2001), 42,
pp. 1647-50), 8.04 g of N-bromosuccinimide, and 196 mg of benzoyl
peroxide are refluxed in 80 ml of benzotrifluoride and exposed to
light until the reaction is completed. It is added to water,
extracted with dichloromethane, washed several times with water,
dried, and the solvent is removed in a vacuum. 7.24 g of
3-bromo-4-nitro-phthalide is obtained as a solid.
[0317] .sup.1H-NMR (300 MHz, CDCl.sub.3), .delta.=7.26 (s, 1H),
7.88 (t, 1H), 8.30 (d, 1H), 8.56 (d, 1H)
5-Nitro-phthalazin-1-one
[0318] 18.25 g of hydrazine sulfate and 14.88 g of sodium carbonate
are stirred in 300 ml of DMF at 100.degree. C. for one hour. Then,
7.24 g of 3-bromo-4-nitro-phthalide in 100 ml of DMF is added, and
it is stirred for another 4 hours at 100.degree. C. It is added to
water, extracted several times with ethyl acetate, and the organic
phase is washed with water and brine. It is dried, and the solvent
is removed in a vacuum. After recrystallization from ethyl acetate,
2.35 g of 5-nitro-phthalazin-1-one is obtained as a solid.
[0319] .sup.1H-NMR (300 MHz, DMSO-d.sub.6), .delta.=8.05 (t, 1H),
8.57-8.66 (m, 2H), 8.73 (s, 1H), 13.13 (bs, 1H)
2-Methyl-5-nitro-phthalazin-1-one
[0320] 1.6 g of 5-nitro-phthalazin-1-one and 2.31 g of potassium
carbonate are stirred for 10 minutes at room temperature in 60 ml
of DMF. 1.1 ml of methyl iodide is added, and it is stirred
overnight. It is added to water, extracted several times with ethyl
acetate, and the organic phase is washed with water and brine. It
is dried, and the solvent is removed in a vacuum. 1.57 g of
2-methyl-5-nitro-phthalazin-1-one is obtained as a yellow
solid.
[0321] .sup.1H-NMR (300 MHz, DMSO-d.sub.6), .delta.=3.73 (s, 3H),
8.05 (t, 1H), 8.62 (d, 2H), 8.75 (s, 1H)
5-Amino-2-methyl-phthalazin-1-one
[0322] 1.57 g of 2-methyl-5-nitro-phthalazin-1-one and 130 mg of
palladium on activated carbon are suspended in 45 ml of ethyl
acetate and hydrogenated with hydrogen under normal pressure. It is
filtered through diatomaceous earth, and the solvent is removed in
a vacuum. 1.26 g of 5-amino-2-methyl-phthalazin-1-one is obtained
as a yellow solid.
[0323] .sup.1H-NMR (300 MHz, CDCl.sub.3), .delta.=3.81 (s, 3H),
7.00 (d, 1H), 7.50 (t, 1H), 7.80 (d, 1H), 8.16 (s, 1H)
(rac.)-5-{[4-(3-Fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-trif-
luoromethyl)pentylidene]amino}2-methyl-phthalazinon-1-one
[0324] 400 mg (1.241 mmol) of (rac.)
4-(3-fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluorometh-
yl)pentanal, 271.4 mg (1.241 mmol) of
5-amino-2-methyl-phthalazin-1-one and 705.5 mg (2.482 mmol) of
titanium tetraisopropylate are stirred in seven ml of xylene for
five hours at 120.degree. C. After cooling, the mixture is diluted
with ethyl acetate and washed once with brine. The aqueous phase is
extracted twice with ethyl acetate. The combined organic extracts
are dried, and the solvent is spun off. The residue is
chromatographed on a Flashmaster. 40.9 mg (68.5%) of the desired
compound is isolated.
[0325] .sup.1H-NMR (300 MHz, CDCl.sub.3), .delta.=1.39 (3H), 1.60
(3H), 1.78 (3H), 2.28 (1H), 3.31 (1H), 3.90 (3H), 3.99 (3H), 4.58
(1H), 6.38 (1H), 6.78 (1H), 6.89 (1H), 7.58-7.68 (2H), 8.27-8.35
(2H).
(rac.)
5-{[6-Fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,-
3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one and
(rac.)
5-{[6-fluoro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,-
3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
[0326] 100 mg (0.208 mmol) of
(rac.)-5-{[4-(3-fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-tri-
fluoromethyl)pentylidene]amino}2-methyl-phthalazinon-1-one is mixed
at 0.degree. C. with 2.1 ml of a 1 M solution of boron tribromide
in dichloromethane, and it is stirred for two hours at 0 to
5.degree. C. After careful mixing with saturated sodium bicarbonate
solution, the batch is extracted three times with ethyl acetate.
The combined organic extracts are washed with brine, dried, and the
residue that remains after spinning-in is chromatographed on a
Flashmaster. 38.1 mg of a mixture that consists of the desired
compound and the corresponding ether is isolated. First, a
separation of the ether from phenol is carried out, namely by means
of HPLC (Chiralcel OD 20.mu., eluants: hexane/ethanol). The
respective racemates are then separated by means of chiral HPLC
(Chiralpak AD 20.mu., eluants: hexane/2-propanol or hexane/ethanol)
into their respective enantiomers, so that the following four
compounds result: [0327]
(+)-5-{[6-Fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,-
4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one [0328]
(-)-5-{[6-Fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,-
4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
[0329] .sup.1H-NMR (300 MHz, CD.sub.3OD), .delta.=1.59 (3H), 1.70
(3H), 2.03-2.20 (5H), 3.86 (3H), 5.20 (1H), 6.63 (1H), 7.23 (1H),
7.60-7.72 (2H), 8.58 (1H). [0330]
(+)-5-{[6-Fluoro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)--
1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
[0331] .sup.1H-NMR (300 MHz, CD.sub.3OD), .delta.=1.40 (3H), 1.59
(3H), 2.09 (1H), 2.20-2.35 (4H), 3.52 (3H), 3.80 (3H), 5.34 (1H),
7.08 (1H), 7.52 (1H), 7.62-7.78 (2H), 8.60 (1H). [0332]
(-)-5-{[6-Fluoro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)--
1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
Example 5
(rac.)
5-{[6-Chloro-2,5-dihydroxy-4,4,7-methyl-2-(trifluoromethyl)-1,2,3,4-
-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one
2-(3-Chloro-2-methoxy-4-methylphenyl)-2-methylpropanenitrile
[0333] 17.6 g (100.8 mmol) of 2-chloro-6-fluoro-3-methylanisole is
dissolved in 880 ml of toluene. After 27.8 g (403.2 mmol) of
isobutyric acid nitrile is added, 302.4 ml (151.2 mmol) of a 0.5
molar solution of potassium hexamethyl disilazide in toluene is
added in drops within 40 minutes (temperature increase to
27.degree. C.). After 19 days of stirring at room temperature, the
batch is mixed with 300 ml of water and 400 ml of ethyl acetate,
and then acidified with 10% sulfuric acid until a pH of 4 is
reached. The aqueous phase is shaken with 200 ml of ethyl acetate.
The combined organic extracts are washed with water and twice with
saturated NaCl solution ad then dried. After spinning-in and
chromatography on silica gel (mobile solvent ethyl acetate/hexane),
12.01 g (53.4%) of the desired compound is obtained.
[0334] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=1.75 (6H), 2.40
(3H), 4.09 (3H), 6.99 (1H), 7.09 (1H).
2-(3-Chloro-2-methoxy-4-methylphenyl)-2-methylpropanal
[0335] 11 g (49.17 mmol) of the above-described nitrile is
dissolved in 196 ml of toluene. At -65.degree. C. to -60.degree.
C., 61.5 ml of a 1.2 molar solution of DIBAH in toluene is added in
drops under nitrogen. After two hours of stirring at -65.degree.
C., 280 ml of a 20% L-(+)-tartaric acid solution is added in drops.
The temperature increases to 0.degree. C. The cold bath is removed,
and the batch is vigorously stirred for two hours at room
temperature. The reaction mixture is shaken twice with diethyl
ether. The combined organic extracts are shaken with water and with
brine, dried, and the solvent is spun off. Chromatography on silica
gel (mobile solvent ethyl acetate/hexane) yields 6.12 g of the
desired compound.
[0336] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=1.38 (6H), 2.39
(3H), 3.79 (3H), 7.03 (1H), 7.13 (1H), 9.59 (1H).
(E/Z)-4-(3-Chloro-2-methoxy-4-methylphenyl)-2-ethoxy-4-methylpent-2-enoic
acid ethyl ester
[0337] 14.9 ml of a 2 molar LDA solution in THF is added in drops
at 0.degree. C. within 20 minutes to a solution of 7.45 g (27.79
mmol) of 2-ethoxy-phosphonoacetic acid triethyl ester, dissolved in
30 ml of absolute THF. After 45 minutes of stirring at 0.degree.
C., 6.3 g (27.79 mmol) of
2-(3-chloro-2-methoxy-4-methylphenyl)-2-methylpropanal, dissolved
in 18 ml of THF, is quickly added in drops at 0.degree. C. After
stirring overnight at room temperature, the reaction mixture is
poured into 100 ml of water and extracted twice with 250 ml each of
diethyl ether. The combined organic extracts are washed with water
and brine, dried, and the solvent is spun off after the desiccant
is filtered off. The residue is chromatographed on silica gel
(mobile solvent ethyl acetate/hexane). 8.4 g, which in addition to
the desired compound also contains starting material (aldehyde),
which is separated in the next stage, is isolated.
(E/Z)-4-(3-Chloro-2-methoxy-4-methylphenyl)-2-ethoxy-4-methylpent-2-enoic
acid
[0338] 8.4 g (24.65 mmol) of
(E/Z)-4-(3-chloro-2-methoxy-4-methylphenyl)-2-ethoxy-4-methylpent-2-enoic
acid ethyl ester is mixed with 246 ml of 1N NaoH in ethanol/water
(2:1), and it is stirred for 19 hours at room temperature. The
ethanol is drawn off in a rotary evaporator, and the residue is
extracted twice with diethyl ether. The combined organic extracts
are washed once with 50 ml of water. After drying, the solvent is
spun off. The residue (unreacted aldehyde from the previously
described reaction) is 2 g and is used again in the Horner-Wittig
reaction with subsequent saponification. The combined aqueous
phases are carefully acidified with concentrated hydrochloric acid
to pH 3 while being cooled in an ice bath and extracted twice with
300 ml each of diethyl ether. These ether extracts are washed with
water and brine, dried, the solvent is spun off, and the residue
(5.62=72.9%) is incorporated in crude form into the next stage.
Since the compound is an E/Z mixture in a ratio that is not 1:1,
only the position of the signals is indicated in the NMR
spectrum.
[0339] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.98, 1.40, 1.57,
2.31, 2.38, 3.39, 3.78, 3.80-3.90, 5.79, 6.79, 6.88-6.98, 7.18.
4-(3-Chloro-2-methoxy-4-methylphenyl)-4-methyl-2-oxo-pentanoic
acid
[0340] 7.30 g (23.34 mmol) of the
(E/Z)-4-(3-chloro-2-methoxy-4-methylphenyl)-2-ethoxy-4-methylpent-2-enoic
acid obtained from the previous batch is mixed at room temperature
with 143 ml of a 1 molar sulfuric acid and 20 ml of glacial acetic
acid, and it is stirred for thirty hours at a bath temperature of
90.degree. C. After three days of stirring at room temperature, it
is vigorously stirred for another two days at 90.degree. C. While
being cooled in an ice bath, the batch is made basic (pH 9) with
solid potassium carbonate (caution, foaming). It is extracted twice
with diethyl ether, and the combined organic extracts are discarded
after TLC monitoring. While being cooled in an ice bath, the
aqueous phase is acidified to pH 4 with concentrated hydrochloric
acid and shaken twice with diethyl ether. The ether extracts are
washed with water and brine, dried, and the solvent is spun off.
The remaining residue (5.37 g=80.8%) is incorporated in crude form
into the next stage.
[0341] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=1.50 (6H), 2.34
(3H), 3.50 (2H), 3.89 (3H), 6.97 (1H), 7.15 (1H).
4-(3-Chloro-2-methoxy-4-methylphenyl)-4-methyl-2-oxo-pentanoic acid
ethyl ester
[0342] 5.37 g (18.86 mmol) of
4-(3-chloro-2-methoxy-4-methylphenyl)-4-methyl-2-oxo-pentanoic acid
is dissolved in 112 ml of ethanol, mixed with 2 ml of concentrated
sulfuric acid and refluxed for five hours. The ethanol is drawn off
in a rotary evaporator, and the residue is carefully mixed with
saturated sodium bicarbonate solution after 50 ml of water is
added. It is extracted twice with ethyl acetate. The combined
organic extracts are washed with water and with brine. After
drying, and after the desiccant is filtered off and the solvent is
spun in, the residue is chromatographed on silica gel (mobile
solvent ethyl acetate/hexane). 4.81 g (81.6%) of the desired
compound is isolated.
[0343] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=1.30 (3H), 1.48
(6H), 2.36 (3H), 3.40 (2H), 3.90 (3H), 4.18 (2H), 6.92 (1H), 7.10
(1H).
(rac.)
4-(3-Chloro-2-methoxy-4-methylphenyl)-4-methyl-2-(trifluoromethyl)--
2-trimethylsilyloxy-pentanoic acid ethyl ester
[0344] 4.8 g (15.35 mmol) of
4-(3-chloro-2-methoxy-4-methylphenyl)-4-methyl-2-oxo-pentanoic acid
ethyl ester is dissolved in 25 ml of THF, mixed at 0.degree. C.
with 2.62 g (18.41 mmol) of (trifluoromethyl)-trimethylsilane and
37.6 mg of tetrabutylammonium fluoride, and stirred for one and
one-half hours between 0 and 5.degree. C. The batch is added to 50
ml of ice water and extracted twice with diethyl ether. The
combined organic extracts are washed with water and with brine.
After chromatography on silica gel (mobile solvent ethyl
acetate/hexane), 4.4 g (63%) of the desired compound is
obtained.
[0345] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.03 (9H), 1.22
(3H), 1.38 (3H), 1.42 (3H), 2.35 (3H), 2.52 (1H), 2.69 (1H), 3.78
(1H), 3.99 (3H), 4.03 (1H), 6.90 (1H), 7.00 (1H).
(rac.)
4-(3-Chloro-2-methoxy-4-methylphenyl)-4-methyl-2-(trifluoromethyl)--
2-hydroxy-pentanoic acid ethyl ester
[0346] 4.4 g (9.67 mmol) of (rac.)
4-(3-chloro-2-methoxy-4-methylphenyl)-4-methyl-2-(trifluoromethyl)-2-trim-
ethylsilyloxy-pentanoic acid ethyl ester is dissolved in 56 ml of
tetrahydrofuran and mixed with 3.05 g (9.67 mmol) of
tetrabutylammonium fluoride trihydrate and stirred for one and
one-half hours at room temperature. The reaction mixture is diluted
with water and extracted twice with diethyl ether. The organic
phases are washed with water and with brine. After drying, the
solvent is spun off and the remaining residue is chromatographed on
silica gel (mobile solvent ethyl acetate/hexane). 1.26 g of the
desired compound is isolated.
[0347] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=1.20 (3H), 1.40
(3H), 1.49 (3H), 2.29-2.40 (4H), 2.82 (1H), 3.55 (1H), 3.65 (1H),
3.98 (3H), 4.08 (1H), 6.90 (1H), 7.02 (1H).
(rac.)
4-(3-Chloro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluo-
romethyl)pentanal and (rac.)
4-(3-chloro-2-methoxy-4-methylphenyl)-4-methyl-2-(trifluoromethyl)-pentan-
e-1,2-diol
[0348] 1.05 g (2.74 mmol) of (rac.)
4-(3-chloro-2-methoxy-4-methylphenyl)-4-methyl-2-(trifluoromethyl)-2-hydr-
oxy-pentanoic acid ethyl ester is dissolved in 10 ml of diethyl
ether and mixed at 0.degree. C. in portions with 78 mg (2.06 mmol)
of LiAlH.sub.4. After one hour of stirring at 0.degree. C. and
another hour of stirring between 0 and 10.degree. C., the reaction
mixture is mixed drop by drop with 2.4 ml of saturated NaHCO.sub.3
solution while being cooled in an ice bath. It is stirred for 30
minutes while being cooled in an ice bath and vigorously stirred at
room temperature for one and one-half hours. The precipitate is
suctioned off, washed with ethyl acetate, and the filtrate is
concentrated by evaporation in a rotary evaporator. After the
residue is chromatographed on silica gel (mobile solvent ethyl
acetate/hexane), 425 mg (45.8%) of the aldehyde and 420.4 mg
(44.9%) of the diol are obtained.
[0349] Aldehyde: .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 1.46
(3H), 1.49 (3H), 2.28 (1H), 2.39 (3H), 3.30 (1H), 3.59 (1H), 4.00
(3H), 6.89-7.00 (2H), 9.06 (1H)
[0350] Alcohol: .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=1.48
(3H), 1.57 (3H), 1.82 (1H), 2.20 (1H), 2.38 (3H), 2.55 (1H), 2.91
(1H), 3.29-3.46 (2H), 4.00 (3H), 6.96 (1H), 7.16 (1H).
(rac.)-5-{[4-(3-Chloro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(tri-
fluoromethyl)pentylidene]amino}isoquinolin-1(2H)-one
[0351] 225 mg (0.664 mmol) of (rac.)
4-(3-chloro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluorometh-
yl)-pentanal, 106.3 mg (0.664 mmol) of
5-amino-isoquinolin-1(2H)-one, and 0.39 ml (1.328 mmol) of titanium
tetraisopropylate are stirred in 3.6 ml of o-xylene for two and
one-half hours at 120.degree. C. After cooling, the batch is poured
onto 15 ml of saturated brine and diluted with ethyl acetate. After
20 minutes of vigorous stirring at room temperature, it is filtered
via a column, filled with Extrelute. The residue is on silica gel
(mobile solvent ethyl acetate/hexane). 224.7 mg (70.3%) of the
desired compound is isolated.
[0352] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta.=1.49 (3H), 1.52
(3H), 1.89 (3H), 2.25 (1H), 3.04 (1H), 3.89 (3H), 6.15 (1H), 6.65
(1H), 6.72 (1H), 6.79 (1H), 6.99 (1H), 7.20 (1H), 7.37 (1H), 7.57
(1H), 8.06 (1H), 11.35 (1H).
(rac.)
5-{[6-Chloro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl-
)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one
[0353] 130 mg (0.27 mmol) of the compound
(rac.)-5-{[4-(3-chloro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-tri-
fluoromethyl)pentylidene]amino}-isoquinolin-1(2H)-one, described in
the preceding paragraph, is dissolved in 1.6 ml of dichloromethane
and mixed drop by drop at 0.degree. C. with 0.8 ml (0.81 mmol) of
titanium tetrachloride and then stirred for two and one-half hours
at room temperature. The reaction mixture is mixed carefully with
saturated sodium bicarbonate solution (pH 8) at 0.degree. C. It is
diluted with ethyl acetate, the cold bath is removed, and it is
stirred vigorously for 15 minutes at room temperature. After being
extracted twice with ethyl acetate, the combined organic extracts
are washed with brine. After drying on sodium sulfate, the solvent
is spun off, and the remaining residue is chromatographed on silica
gel. 71.3 mg (54.8%) of the desired compound is isolated.
[0354] .sup.1H-NMR (300 MHz, CD.sub.3OD): .delta.=1.55 (3H), 1.65
(3H), 2.05-2.28 (5H), 3.95 (3H), 5.14 (1H), 6.85 (1H), 7.00-7.12
(2H), 7.19 (1H), 7.40 (1H), 7.70 (1H).
(rac.)
5-{[6-Chloro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,-
3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one
[0355] 40 mg (0.083 mmol) of (rac.)
5-{[6-chloro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,-
3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one is mixed
at room temperature with 0.8 ml of a 1 molar solution of boron
tribromide in dichloromethane, and it is stirred for four hours at
room temperature. Since starting material is still present, another
0.8 ml of boron tribromide solution is added, and it is stirred for
16 hours at room temperature. The reaction mixture is mixed drop by
drop with saturated sodium bicarbonate solution (pH 8) at
-30.degree. C. The batch is mixed with ethyl acetate, and the cold
bath is removed. After 10 minutes of vigorous stirring at room
temperature, the batch is extracted twice with ethyl acetate. The
organic phases are washed with water and with brine, dried, and the
residue is chromatographed on silica gel (mobile solvent
methanol/dichloromethane) after the solvent is spun off. 19.9 mg
(51.2%) of the desired compound is isolated.
[0356] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta.=1.50 (3H), 1.65
(3H), 1.92-2.20 (5H), 5.28 (1H), 5.90 (1H), 6.09 (in), 6.69 (1H),
6.80 (1H), 7.03 (1H), 7.18 (1H), 7.25 (1H), 7.50 (1H), 8.90 (1H),
11.24 (1H).
Example 6
(rac.)
5-{[6-Chloro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,-
3,4-tetrahydronaphthalen-1-yl]amino}-4-quinolin-2(1H)-one
(rac.)-5-{[4-(3-Chloro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-trif-
luoromethyl)pentylidene]amino}isoquinolin-2(1H)-one
[0357] 225 mg (0.664 mmol) of (rac.)
4-(3-chloro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluorometh-
yl)pentanal (described in Example 5) and 106.3 mg (0.664 mmol) of
5-amino-isoquinolin-2-(1H)-one (described in Example 2) are mixed
with 3.6 ml of xylene. After 0.39 ml (1.328 mmol) of titanium
tetraisopropylate is added, the batch is stirred for two and
one-half hours at 120.degree. C. The mixture is added to 15 ml of
saturated brine and diluted with 20 ml of ethyl acetate. The
reaction mixture is filtered over Extrelute and washed with 300 ml
of a mixture that consists of ethyl acetate/dichloromethane. The
solution that is obtained is spun in, and the residue is
chromatographed on silica gel (mobile solvent ethyl
acetate/hexane). 248.5 mg (77.8%) of the desired compound is
isolated.
[0358] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta.=1.38 (3H), 1.53
(3H), 1.85 (3H), 2.20 (1H), 3.05 (1H), 3.85 (3H), 6.18 (1H), 6.32
(1H), 6.52 (1H), 6.65 (1H), 7.00 (1H), 7.18 (1H), 7.39 (1H), 7.58
(1H), 8.09 (1H), 11.78 (1H).
(rac.)
5-{[6-Chloro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl-
)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-2(1H)-one
[0359] 0.8 ml (0.81 mmol) of titanium tetrachloride is added drop
by drop at 0.degree. C. to 130 mg (0.270 mmol) of the compound
(rac.)-5-{[4-(3-chloro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-tri-
fluoromethyl)pentylidene]amino}isoquinolin-2(1H)-one, dissolved in
1.6 ml of dichloromethane, that is described in the preceding
paragraph, and the batch is then stirred for two hours at 0.degree.
C. and for two hours at room temperature. The reaction mixture is
mixed drop by drop at 0.degree. C. with saturated sodium
bicarbonate solution and with ethyl acetate. After the cold bath is
removed, it is vigorously stirred for another 15 minutes at room
temperature. After being extracted twice with ethyl acetate, the
combined organic extracts are washed with saturated NaCl solution.
After drying on sodium sulfate, the solvent is spun off, and the
remaining residue is chromatographed on silica gel (mobile solvent
ethyl acetate/hexane). 82 mg (63.1%) of the desired compound is
isolated.
[0360] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=1.53 (3H), 1.66
(3H), 2.00-2.25 (5H), 3.96 (3H), 4.80 (1H), 5.01 (1H), 5.58 (1H),
6.49-6.62 (3H), 6.92 (1H), 7.35 (1H), 8.19 (1H), 10.25 (1H).
(rac.)
5-{[6-Chloro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,-
3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-2(1H)-one
[0361] 43 mg (0.089 mmol) of (rac.)
5-{[6-chloro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,-
3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-2(1H)-one is mixed
at room temperature with 0.9 ml of a 1 molar solution of boron
tribromide in dichloromethane, and it is stirred for two and
one-fourth hours at room temperature. Saturated sodium bicarbonate
solution is now added drop by drop at -30.degree. C. After dilution
with ethyl acetate, the cold bath is removed, and the batch is
extracted twice with ethyl acetate after 10 minutes of vigorous
stirring at room temperature. The combined organic phases are
washed with water and brine, dried, and the residue is
chromatographed on silica gel after the solvent is spun off (mobile
solvent methanol/dichloromethane). 37.8 mg (90.6%) of the desired
compound is isolated.
[0362] .sup.1H-NMR (300 MHz, CD.sub.3OD): .delta.=1.58 (3H), 1.70
(3H), 2.00-2.24 (5H), 5.12 (1H), 6.51 (1H), 6.62 (1H), 6.70 (1H),
6.80 (1H), 7.39 (1H), 8.22 (1H).
Example 7
(rac.)
6-Chloro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-4,4,7-trimethy-
l-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
(rac.)
1,1,1-Trifluoro-4-(3-chloro-2-methoxy-4-methylphenyl)-2-[(8-fluoro--
2-methyl-quinazolyl-5-yl)iminomethyl]-4-methylpentan-2-ol
[0363] 225 mg (0.664 mmol) of (rac.)
4-(3-chloro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluorometh-
yl)pentanal (described in Example 5) and 117.6 mg (0.664 mmol) of
5-amino-8-fluoro-2-methylquinazoline are mixed with 3.6 ml of
o-xylene. After 0.39 ml (1.328 mmol) of titanium tetraisopropylate
is added, the batch is stirred for two hours at 120.degree. C. The
mixture is added to 15 ml of saturated brine and diluted with 20 ml
of ethyl acetate. The reaction mixture is filtered through
Extrelute and washed with 300 m of a mixture that consists of ethyl
acetate/dichloromethane. The solution that is obtained is spun in,
and the residue is chromatographed on silica gel (mobile solvent
ethyl acetate/hexane). 217.5 mg (65.7%) of the desired compound is
isolated.
[0364] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=1.40 (3H), 1.52
(3H), 1.65 (3H), 2.29 (1H), 3.00 (3H), 3.35 (1H), 3.92 (3H), 4.59
(1H), 6.48 (1H), 6.77 (1H), 7.00 (1H), 7.44 (1H), 7.78 (1H), 9.39
(1H).
(rac.)
6-Chloro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-5-methoxy-4,4,-
7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
[0365] 110 mg (0.221 mmol) of the compound (rac.)
1,1,1-trifluoro-4-(3-chloro-2-methoxy-3-methylphenyl)-2-[(8-fluoro-2-meth-
yl-quinazolyl-5-yl)iminomethyl]-4-methylpentan-2-ol, described in
the preceding paragraph, is dissolved in 1.3 ml of dichloromethane
and carefully mixed at 0.degree. C. with 0.66 ml (0.663 mmol) of
titanium tetrachloride. Then, it is stirred for two hours at
0.degree. C. and for two more hours at room temperature. The
reaction mixture is mixed drop by drop with saturated sodium
bicarbonate solution at 0.degree. C. After dilution with ethyl
acetate, the cold bath is removed, and the batch is stirred
vigorously at room temperature. After being extracted twice with
ethyl acetate, the combined organic extracts are washed with
saturated NaCl solution. After drying on sodium sulfate, the
solvent is spun off, and the remaining residue is chromatographed
on silica gel (mobile solvent methanol/dichloromethane). 76.5 mg
(69.5%) of the desired compound is isolated as a diastereomer
mixture 9:1. The signals of the main diastereomers are
indicated.
[0366] .sup.1H-NMR (300 MHz, CD.sub.3OD). .delta.=1.57 (3H), 1.69
(3H), 2.08-2.29 (5H), 2.89 (3H), 3.95 (3H), 5.28 (1H), 6.87 (1H),
7.05 (1H), 7.59 (1H), 9.65 (1H).
(rac.)
6-Chloro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-4,4,7-trimethy-
l-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
[0367] 40 mg (0.08 mmol) of (rac.)
6-chloro-1-[(8-fluoro-2-methylquinazolin-5-yl)-amino]-5-methoxy-4,4,7-tri-
methyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol is
mixed at room temperature with 0.8 ml of a 1 molar solution of
boron tribromide in dichloromethane, and it is stirred for four
hours at room temperature. Since no reaction was carried out,
another 0.8 ml of the boron tribromide solution was added. After 16
hours of stirring at room temperature, the reaction was complete.
At -30.degree. C., saturated sodium bicarbonate solution is now
carefully added in drops, and the batch is diluted with ethyl
acetate. After the cold bath is removed, it is stirred vigorously
at room temperature for 10 minutes. The batch is extracted twice
with ethyl acetate. The combined organic phases are washed with
water and with brine, dried, and the residue is chromatographed on
silica gel (mobile solvent methanol/dichloromethane) after the
solvent is spun off. 38.2 mg (98.4%) of the desired compound is
isolated.
[0368] .sup.1H-NMR (300 MHz, CD.sub.3OD): .delta.=1.60 (3H), 1.72
(3H), 2.05-2.25 (5H), 2.88 (3H), 5.22 (1H), 6.80-6.90 (2H), 7.59
(1H), 9.68 (1H).
Example 8
(rac.)
5-{[7-Chloro-6-fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl-
)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one
2-(4-Chloro-3-fluoro-2-methoxyphenyl)-2-methylpropanenitrile
[0369] 16.78 g (93.97 mmol) of 3-chloro-2,6-difluoroanisole is
dissolved in 800 ml of toluene. After 25.97 g (375.88 mmol) of
isobutyronitrile is added, 283.97 ml (140.95 mmol) of a 0.5 molar
solution of potassium hexamethyl disilazide in toluene is added in
drops. The temperature in this case increases to 28.degree. C. The
batch is stirred for seven days at 60.degree. C. After mixing with
water and ethyl acetate, the reaction mixture is brought to a pH of
4 with 1 M sulfuric acid. After being extracted twice with ethyl
acetate, the combined organic extracts are washed with water and
with saturated NaCl solution and dried. After spinning-in and
chromatography on silica gel (mobile solvent ethyl acetate/hexane),
7.46 g (21.4%) of the desired compound is obtained.
[0370] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=1.75 (6H), 4.10
(3H), 6.95-7.14 (2H).
2-(4-Chloro-3-fluoro-2-methoxyphenyl)-2-methylpropanal
[0371] 7.46 g (32.78 mmol) of the above-described nitrile is
dissolved in 131 ml of toluene. 41.1 ml of a 1.2 molar solution of
DIBAH in toluene is added in drops at -65.degree. C. to -60.degree.
C. under nitrogen. After two hours of stirring at -65.degree. C.,
374 ml of a 10% L-(+)-tartaric acid solution is added in drops. The
batch is stirred overnight at room temperature. The reaction
mixture is extracted three times with diethyl ether. The combined
organic extracts are shaken with water and with brine, dried, and
the solvent is spun off. 7.35 g (97.2%) of the desired compound is
obtained, which is used as a crude product in the next stage.
(E/Z)-4-(4-Chloro-3-fluoro-2-methoxyphenyl)-2-ethoxy-4-methylpent-2-enoic
acid ethyl ester
[0372] 19.9 ml of a 2 molar LDA solution in THF (1.25 equivalents)
is added in drops to a solution of 10.3 g (38.83 mmol) of
2-ethoxy-phosphonoacetic acid triethyl ester, dissolved in 34 ml of
absolute THF, at 0.degree. C. After 45 minutes of stirring at
0.degree. C., 7.35 g (31.86 mmol) of
2-(4-chloro-3-fluoro-2-methoxyphenyl)-2-methylpropanal, dissolved
in 21 ml of THF, is quickly added in drops at 0.degree. C. After
stirring over the weekend at room temperature, the reaction mixture
is added to water and extracted three times with diethyl ether. The
combined organic extracts are washed with water and brine, dried,
and the solvent is spun off after the desiccant is filtered off.
The residue is chromatographed on silica gel (mobile solvent ethyl
acetate/hexane). 8.41 g, which in addition to the desired compound
also contains the starting material (aldehyde) and which is
separated in the next stage, is isolated.
(E/Z)-4-Chloro-3-fluoro-2-methoxyphenyl)-2-methoxy-4-methylpent-2-enoic
acid
[0373] 8.41 g (24.39 mmol) of
(E/Z)-4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-ethoxy-4-methylpent-2-enoic
acid ethyl ester is mixed with 222 ml of 1N NaOH in ethanol/water
(2:1) and stirred overnight at room temperature. The ethanol is
drawn off in a rotary evaporator, and the residue is extracted
three times with methyl-tert-butyl ether after mixing with water.
Since the organic extracts, in addition to unreacted aldehyde, also
contain the desired acid, it is extracted with 1 M NaOH. After the
organic extracts are dried, the solvent is spun off. The residue
(unreacted aldehyde from the previously described reaction) is 1.59
g and is used again in the Horner-Wittig reaction with subsequent
saponification. The combined aqueous phases are carefully acidified
with concentrated hydrochloric acid while being cooled in an ice
bath and extracted three times with methyl-tert-butyl ether. These
ether extracts are washed with brine, dried, the solvent is spun
off, and the residue (5.99=77.5%) is incorporated in crude form
into the next stage. Since the compound is an E/Z mixture in a
non-1:1 ratio, only the position of the signals is indicated in the
NMR spectrum.
[0374] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.98, 1.40,
1.49-1.59, 3.40, 3.78-3.90, 5.72, 6.70, 6.92-7.09.
4-(4-Chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic
acid
[0375] 6.06 g (19.13 mmol) of the
(E/Z)-4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-ethoxy-4-methylpent-2-enoic
acid that is obtained from the preceding paragraph is mixed at room
temperature with 126 ml of a 1 molar sulfuric acid and 12.6 ml of
glacial acetic acid, and it is stirred for nine days at a bath
temperature of 90.degree. C. While being cooled in an ice bath, the
batch is made basic (pH 9) with solid potassium carbonate (caution,
foaming) and extracted three times with methyl-tert-butyl ether.
While being cooled in an ice bath, the aqueous phase is acidified
to pH 4 with concentrated hydrochloric acid and shaken three times
with methyl-tert-butyl ether. The ether extracts are washed with
water and brine, dried, and the solvent is spun off. The remaining
residue is 2.23 g. Since the first ether phase still contains
product, the latter is concentrated by evaporation, and the solid
residue is taken up in water and methyl-tert-butyl ether. After
acidification, the aqueous phase is extracted twice more with
methyl-tert-butyl ether. After the usual working-up, the combined
organic extracts produce another 3.21 g of the desired product.
Altogether, 5.44 g (98.5%) of acid, which is incorporated in crude
form into the next stage, is obtained.
[0376] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=1.45 (6H), 3.55
(2H), 3.97 (3H), 6.95-7.10 (2H).
4-(4-Chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid
ethyl ester
[0377] 5.44 g (18.84 mmol) of
4-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid
is dissolved in 117 ml of ethanol, mixed with 2.1 ml of
concentrated sulfuric acid and refluxed for six hours. The reaction
mixture is added to 250 ml of saturated sodium bicarbonate solution
and extracted three times with ethyl acetate. The combined organic
extracts are washed with saturated sodium bicarbonate solution and
with brine. After drying and after the desiccant is filtered off
and the solvent is spun in, 5.19 g (87%) of the desired compound is
obtained.
[0378] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=1.30 (3H), 1.45
(6H), 3.40 (2H), 3.98 (3H), 4.20 (2H), 6.92-7.50 (2H).
(rac.)
4-(4-Chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)--
2-trimethylsilyloxy-pentanoic acid ethyl ester
[0379] 5.19 g (16.38 mmol) of
4-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid
ethyl ester is dissolved in 26 ml of THF, mixed at room temperature
with 2.79 g (19.66 mmol) of (trifluoromethyl)-trimethylsilane and
40.1 mg of tetrabutylammonium fluoride, and it is stirred for two
days. The reaction mixture is mixed with methyl-tert-butyl ether
and washed with water and brine. The organic phase is dried, and
the residue is chromatographed on silica gel (mobile solvent ethyl
acetate/hexane) after the solvent is spun off. 4.71 g (62.6%) of
the desired compound is obtained.
(rac.) 4-(4-Chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoro
ethyl)-2-hydroxy-pentanoic acid ethyl ester
[0380] 4.71 g (10.26 mmol) of (rac.)
4-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-trim-
ethylsilyloxy-pentanoic acid ethyl ester is dissolved in 57 ml of
tetrahydrofuran and mixed with 3.24 g (10.26 mmol) of
tetrabutylammonium fluoride trihydrate: after stirring over the
weekend at room temperature, the reaction mixture is mixed with
water and extracted three times with methyl-tert-butyl ether. The
combined organic extracts are washed with brine. After drying, the
solvent is spun off, and the remaining residue is chromatographed
on silica gel (mobile solvent ethyl acetate/hexane). 3.07 g (77.4%)
of the desired compound is isolated.
[0381] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=1.25 (3H), 1.38
(3H), 1.47 (3H), 2.45 (1H), 2.75 (1H), 3.50 (1H), 3.75 (1H), 4.03
(3H), 4.13 (1H), 6.89 (1H), 7.00 (1H).
(rac.)
4-(4-Chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluo-
romethyl)pentanal
[0382] 1.00 g (2.59 mmol) of (rac.)
4-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-hydr-
oxy-pentanoic acid ethyl ester is dissolved in 9.5 ml of diethyl
ether and mixed in portions with 73.7 mg (1.94 mmol) of LiAlH.sub.4
at 0.degree. C. Stirring is continued at 0.degree. C. and a TLC is
drawn off every one-quarter hour. After forty minutes of stirring
at 0.degree. C., the reaction mixture is mixed drop by drop with
2.4 ml of saturated NaHCO.sub.3 solution while being cooled in an
ice bath. It is vigorously stirred for 30 minutes while being
cooled in an ice bath and overnight at room temperature. The
precipitate is suctioned off, washed with ethyl acetate, and the
filtrate is concentrated by evaporation in a rotary evaporator.
After chromatography of the residue on a Flashmaster, 560.2 mg is
obtained. This is a 3:2 mixture of the aldehyde with the starting
ester.
(rac.)-5-{[4-(4-Chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(tri-
fluoromethyl)pentylidene]amino}isoquinolin-1(2H)-one
[0383] 560 mg of the mixture that consists of (rac.)
4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluorometh-
yl)pentanal and (rac.)
4-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-hydr-
oxy-pentanoic acid ethyl ester (since the aldehyde constitutes two
thirds in the mixture, the 560.2 mg mixture corresponds to 336.1 mg
(0.981 mmol) of aldehyde) is heated for two hours to 120.degree. C.
with 157.1 mg (0.981 mmol) of 5-amino-isoquinolin-1(2H)-one and
0.557 mg (1.962 mmol) of titanium tetraisopropylate in 6 ml of
o-xylene. After cooling, the batch is diluted with ethyl acetate
and mixed with brine. The organic phase is separated and worked up
as usual. After chromatography on a Flashmaster, 144.7 mg (30.4%)
of the desired compound is obtained (relative to the aldehyde
portion in the mixture).
[0384] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=1.40 (3H), 1.58
(3H), 2.38 (1H), 3.19 (1H), 4.03 (3H), 4.78 (1H), 6.65 (1H),
6.70-6.83 (3H), 7.20 (1H), 7.44 (1H), 7.62 (1H), 8.35 (1H), 10.95
(1H).
(rac.)
5-{[7-Chloro-6-fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl-
)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1-one
[0385] 80.3 mg (0.166 mmol) of (rac.)
5-{[4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoro-
methyl)pentylidene]amino}isoquinolin-[1(2H)-one is mixed at room
temperature with 1.7 ml of a 1 molar solution of boron tribromide
in dichloromethane, and it is stirred for two and one-half hours at
room temperature. The reaction mixture is mixed with ice, and then
saturated sodium bicarbonate solution is added in drops (pH 8).
After the ethyl acetate is added and after ten minutes of vigorous
stirring at room temperature, the aqueous phase is extracted twice
with ethyl acetate. The combined organic phases are washed with
water and with brine, dried, and the residue is chromatographed on
a Flashmaster after the solvent is spun off. 24.6 mg (31.6%) of the
desired compound is isolated.
[0386] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta.=1.50 (3H), 1.60
(3H), 1.90-2.14 (2H), 5.31 (1H), 5.92 (1H), 6.18 (1H), 6.70 (1H),
6.80 (1H), 7.05 (1H), 7.19 (1H), 7.27 (1H), 7.52 (1H), 10.05 (1H),
11.25 (1H).
Example 9
(rac.)
7-Chloro-6-fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-4,4-d-
imethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
(rac.)
1,1,1-Trifluoro-4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-[(8-fluoro--
2-methyl-quinazolyl-5-yl)iminomethyl]-4-methylpentan-2-ol
[0387] 457 mg of the mixture that consists of (rac.)
4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluorometh-
yl)pentanal and (rac.)
4-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-hydr-
oxy-pentanoic acid ethyl ester (described in Example 8) (since the
aldehyde in the mixture constitutes two thirds, the 457 mg mixture
corresponds to 305.3 (0.891 mmol) of aldehyde) and 158 mg (0.891
mmol) of 5-amino-8-fluoro-2-methylquinazoline are mixed with 5.5 ml
of o-xylene. After 506.6 mg (1.782 mmol) of titanium
tetraisopropylate is added, the batch is stirred for two hours at
120.degree. C. The mixture is diluted with ethyl acetate and mixed
with brine. After ten minutes of vigorous stirring, the reaction
mixture is filtered on Extrelute and eluted with dichloromethane.
The solution that is obtained is spun in, and the residue is
chromatographed on a Flashmaster. 295.8 mg (66.1%) of the desired
compound is isolated.
[0388] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=1.40 (3H), 1.52
(3H), 2.34 (1H), 3.00 (3H), 3.21 (1H), 4.00 (3H), 4.59 (1H), 6.58
(1H), 6.70 (1H), 6.85 (1H), 7.49 (1H), 7.78 (1H), 9.49 (1H).
(rac.)
7-Chloro-6-fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-4,4,7-
-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
[0389] 295.8 mg (0.589 mmol) of (rac.)
1,1,1-trifluoro-4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-[(8-fluoro-2-meth-
yl-quinazolyl-5-yl)iminomethyl]-4-methylpentan-2-ol is mixed at
0.degree. C. with 6.1 ml of a 1 molar solution of boron tribromide
in dichloromethane, and it is stirred for two hours at 0 to
5.degree. C. The reaction mixture is mixed with ice. After
saturated sodium bicarbonate solution is carefully added in drops,
it is diluted with ethyl acetate and stirred vigorously for ten
minutes. The aqueous phase is extracted twice with ethyl acetate.
The organic phases are washed with water and brine, dried, and the
residue is chromatographed several times on a Flashmaster after the
solvent is spun off. 38 mg (13.2%) of the desired compound is
isolated.
[0390] .sup.1H-NMR (300 MHz, CD.sub.3OD): .delta.=1.60 (3H), 1.70
(3H), 2.05-2.21 (2H), 2.83 (3H), 5.23 (1H), 6.80-6.92 (2H), 7.59
(1H), 9.68 (1H).
Example 10
(rac.)
7-Chloro-6-fluoro-1-[(7-fluoro-2-methylquinazolin-5-yl)amino]-4,4,--
dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
5-Amino-7-fluoro-2-methylquinazoline
[0391] 17 g (70.5 mmol) of
3,6-difluoro-2-N-pivaloylaminobenzaldehyde (L. Florvall, I.
Fagervall, L. G. Larsson, S. B. Ross, Eur. J. Med. Chem. 34 (1999)
137-151), 9.2 g of acetamidine hydrochloride, 13.4 g of potassium
carbonate and 10.4 g of molecular sieve (4A) are added together in
70 ml of butyronitrile. While being stirred vigorously, it is
heated for 17 hours to 145.degree. C., and the solvent is removed
in a vacuum. After chromatography of the residue on silica gel with
hexane/ethyl acetate (0-70%), 4.5 g of
7-fluoro-5-N-pivaloylamino-2-methylquinazoline is obtained. 1 g
(3.82 mmol) of 7-fluoro-5-N-pivaloylamino-2-methylquinazoline is
dissolved in 74 ml of toluene and cooled to -70.degree. C. Over 30
minutes, 9.5 ml (11.4 mmol) of a 1.2 M diisobutylaluminum hydride
solution in toluene is added in drops. The reaction mixture is
allowed to heat to -40.degree. C., and it is stirred for four hours
at -40.degree. C. Water is slowly added, and it is stirred for 30
minutes at room temperature until a precipitate forms, which is
removed by means of filtration through Celite. The phases are
separated, washed with saturated sodium chloride solution and dried
on sodium sulfate. After chromatography on silica gel (mobile
solvent ethyl acetate/hexane), 64 mg of the product is
obtained.
[0392] .sup.1H-NMR (CDCl.sub.3): .delta.=2.83 (s, 3H), 4.67 (br.,
2H), 6.50 (dd, 1H), 6.93 (dd, 1H), 9.23 (s, 1H).
(rac.)
1,1,1-Trifluoro-4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-[(7-fluoro--
2-methyl-quinazolyl-5-yl)iminomethyl]-4-methylpentan-2-ol
[0393] 400 mg of the mixture that consists of (rac.)
4-(4-chloro-3-fluoro-2-methoxyphenyl-2-hydroxy-4-methyl-2-(trifluoromethy-
lpentanal and (rac.)
4-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-hydr-
oxy-pentanoic acid ethyl ester (described in Example 8) (since the
aldehyde in the mixture constitutes two thirds, the 400 mg mixture
corresponds to 266.6 (0.778 mmol) of aldehyde) and 137.8 mg (0.778
mmol) of 5-amino-7-fluoro-2-methylquinazoline are mixed with five
ml of o-xylene. After 442.3 mg (1.56 mmol) of titanium
tetraisopropylate is added, the batch is stirred for two hours at
120.degree. C. The mixture is diluted with ethyl acetate and mixed
with brine. After ten minutes of vigorous stirring, the reaction
mixture is filtered through Extrelute and eluted with
dichloromethane. The solution that is obtained is spun in, and the
residue is chromatographed on a Flashmaster. 312.4 mg (80%) of the
desired compound is isolated. The yield relates to the aldehyde
that is contained in the mixture.
[0394] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=1.40 (3H), 1.60
(3H), 2.36 (1H), 2.92 (3H), 3.23 (1H), 4.01 (3H), 4.49 (1H), 6.49
(1H), 6.65 (1H), 6.89 (1H), 7.45 (1H), 7.79 (1H), 9.32 (1H).
(rac.)
7-Chloro-6-fluoro-1-[(7-fluoro-2-methylquinazolin-5-yl)amino]-4,4,7-
-trimethyl-2-(trifluoromethyl)-1,2,34-tetrahydronaphthalene-2,5-diol
[0395] 312.4 mg (0.622 mmol) of (rac.)
1,1,1-trifluoro-4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-[(7-fluoro-2-meth-
yl-quinazolyl-5-yl)iminomethyl]-4-methylpentan-2-ol is mixed at
0.degree. C. with 6.4 ml of a 1 molar solution of boron tribromide
in dichloromethane, and it is stirred for two hours at 0 to
5.degree. C. The reaction mixture is mixed with ice. After
saturated sodium bicarbonate solution is carefully added in drops,
it is diluted with ethyl acetate and stirred vigorously for ten
minutes. The aqueous phase is extracted twice with ethyl acetate.
The organic phases are washed with water and brine, dried, and the
residue is chromatographed several times on a Flashmaster after the
solvent is spun off. 51 mg (16.7%) of the desired compound is
isolated.
[0396] .sup.1H-NMR (300 MHz, CD.sub.3OD): .delta.=1.60 (3H), 1.70
(3H), 2.15 (2H), 2.79 (3H), 5.31 (1H), 6.70-6.88 (3H), 9.58
(1H).
[0397] Analogously to the compounds of Examples 1-10 that are
described in detail, the following structures were synthesized with
use of the corresponding starting materials.
Example 11
1-(7,8-Difluoro-2-methylquinazolin-5-ylamino)-6-fluoro-5-methoxy-4,4,7-tri-
methyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
Example 12
5-(7,8-Difluoro-2-methylquinazolin-5-ylamino)-2-fluoro-3,8,8-trimethyl-6-(-
trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
Examples 13 and 14
1-(2-Ethylquinazolin-5-ylamino)-6-fluoro-5-methoxy-4,4,7-trimethyl-2-(trif-
luoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol, Diastereomer A and
1-(2-Ethylquinazolin-5-ylamino)-6-fluoro-5-methoxy-4,4,7-trimethyl-2-(tri-
fluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol, Diastereomer B
Example 15
5-(2-Ethylquinazolin-5-ylamino)-2-fluoro-3,8,8-trimethyl-6-(trifluoromethy-
l)-5,6,7,8-tetrahydronaphthalene-1,6-diol, Diastereomer A
Example 16
5-(2-Ethylquinazolin-5-ylamino)-2-fluoro-3,8,8-methyl-6-(trifluoromethyl)--
5,6,7,8-tetrahydronaphthalene-1,6-diol, Diastereomer B
Examples 17 and 18
5-(2-Methylquinazolin-5-ylamino)-2-fluoro-3,8,8-trimethyl-6-(trifluorometh-
yl)-5,6,7,8-tetrahydronaphthalene-1,6-diol, Diastereomer A and
5-(2-Methylquinazolin-5-ylamino)-2-fluoro-3,8,8-trimethyl-6-(trifluoromet-
hyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol, Diastereomer B
Examples 19 and 20
(+)-5-{[6-Fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-
-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one and
(-)-5-{[6-Fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,-
4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
[0398] 83 mg of racemic
5-{[6-fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-te-
trahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one is separated into
its enantiomers on a chiral column (Chiralpak AD-H 5.mu., eluants:
hexane/ethanol). 34 mg of the (+)-enantiomer and 33 mg of the
(-)-enantiomer are obtained.
[0399] [a].sub.D=+41.1.+-.0.5 (c=0.51, methanol)
[0400] [a].sub.D=-41.8.+-.0.4 (c=0.505, methanol)
Examples 21 and 22
(+)-6-Fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-4,4,7-trimethyl-2-
-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol and
(-)-6-Fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-4,4,7-methyl-2-(-
trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
[0401] 50.8 mg of racemic
6-fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-4,4,7-trimethyl-2-(t-
rifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol is separated
into its enantiomers on a chiral column (Chiralpak AD-H 5.mu.,
eluants: hexane/ethanol). 25.3 mg of the (+)-enantiomer and 23.8 mg
of the (-)-enantiomer are isolated.
[0402] [a].sub.D=+57.8.+-.1.1 (c=0.50, methanol)
[0403] [a].sub.D=-53.3.+-.0.3 (c=0.50, methanol)
Example 23
5-[7-Chloro-6-fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,-
4-tetrahydronaphthalen-1-ylamino]-1H-quinolin-2-one
Example 24
5-[7-Chloro-6-fluoro-2-hydroxy
tetrahydronaphthalen-1-ylamino]-1,3-dihydroindol-2-one
Example 25
5-[7-Chloro-6-fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,-
4-tetrahydronaphthalen-1-ylamino]-1,3 dihydroindol-2-one
Example 26
7-Chloro-1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-6-fluoro-5-methoxy--
4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
Example 27
3-Chloro-5-(7,8-difluoro-2-methylquinazolin-5-ylamino)-2-fluoro-8,8-dimeth-
yl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
Examples 28 and 29
7-Chloro-1-(2-ethylquinazolin-5-ylamino)-6-fluoro-5-methoxy-4,4-dimethyl-2-
-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol, Diastereomer
A and
7-Chloro-1-(2-ethylquinazolin-5-ylamino)-6-fluoro-5-methoxy-4,4-dimethyl--
2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol, Diastereomer
B
Example 30
3-Chloro-5-(2-ethylquinazolin-5-ylamino)-2-fluoro-8,8-dimethyl-6-(trifluor-
omethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
Examples 31 and 32
3-Chloro-5-(7-fluoro-2-methylquinazolin-5-ylamino)-2-fluoro-8,8-dimethyl-6-
-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol,
Enantiomer A and
3-Chloro-5-(7-fluoro-2-methylquinazolin-5-ylamino)-2-fluoro-8,8-dimet-
hyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol,
Enantiomer B
[0404] 22.5 mg of the racemic compound
3-chloro-5-(7-fluoro-2-methylquinazolin-5-ylamino)-2-fluoro-8,8-dimethyl--
6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol is
separated into its enantiomers on a chiral column (Chiralpak AD-H
5.mu., eluants: hexane/ethanol). 10.5 mg of Enantiomer A (retention
time 5.28 minutes) and 9.9 mg of Enantiomer B (retention time 10.79
minutes) are isolated.
Examples 33 and 34
(+)-3-Chloro-5-(8-fluoro-2-methylquinazolin-5-ylamino)-2-fluoro-8,8-dimeth-
yl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol,
Enantiomer A and
(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol,
Enantiomer B
[0405] 40 mg of the racemic compound
(+)-3-chloro-5-(8-fluoro-2-methylquinazolin-5-ylamino)-2-fluoro-8,8-dimet-
hyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol is
separated into its enantiomers on a chiral column (Chiralpak AD
10.mu., eluants: hexane/ethanol). In each case, 16 mg of the two
enantiomers is obtained.
[0406] [a].sub.D=+53.1.+-.0.6 (c=0.555, methanol)
[0407] [a].sub.D=-46.0.+-.0.6 (c=0.58, methanol)
Example 35
3-Fluoro-4,7-dihydroxy-5,5-dimethyl-8-(2-oxo-1,2-dihydroquinolin-5-ylamino-
)-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
[0408] IR (Microscope, matrix: diamond): 2232
Example 36
3-Fluoro-4,7-dihydroxy-5,5-dimethyl-8-(2-oxo-1,3-dihydroindol-4-ylamino)-7-
-trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
[0409] IR (Microscope, matrix: diamond): 2238
Example 37
6-Chloro-1-(7-fluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,7-trimeth-
yl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
Example 38
2-Chloro-5-(7-fluoro-2-methylquinazolin-5-ylamino)-3,8,8-trimethyl-6-(trif-
luoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
Example 39
6-Chloro-1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,7-tri-
methyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
Example 40
2-Chloro-5-(7,8-difluoro-2-methylquinazolin-5-ylamino)-3,8,8-trimethyl-6-(-
trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
Example 41
4-[6-Chloro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,-
4-tetrahydronaphthalen-1-ylamino]-1,3-dihydroindol-2-one
Example 42
4-[6-Chloro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetr-
ahydronaphthalen-1-v amino]-1,3-dihydroindol-2-one
Example 43
6-Chloro-5-methoxy-4,4,7-trimethyl-1-(2-methylquinazolin-5-ylamino)-2-(tri-
fluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
Example 44
2-Chloro-3,88-trimethyl-5-(2-methylquinazolin-5-ylamino)-6-(trifluoromethy-
l)-5,6,7,8-tetrahydronaphthalene-1,6-diol
Examples 45 and 46
(+)-6-Chloro-1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,7-
-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
and
(-)-6-Chloro-1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,-
7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
[0410] 88 mg of racemic
6-chloro-1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,7-tr-
imethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol is
separated on a chiral column (Chiralpak AD-H 5.mu., eluants:
hexane/ethanol). 42.6 mg of the (+)-enantiomer and 41.3 mg of the
(-)-enantiomer are obtained.
[0411] [a].sub.D=+36.9.+-.0.6 (c=0.50, methanol)
[0412] [a].sub.D=-32.8.+-.0.3 (c=0.51, methanol)
Example 47
(+)-2-Chloro-5-(7,8-difluoro-2-methylquinazolin-5-ylamino)-3,8,8-trimethyl-
-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
[0413] 33.9 mg of the ether ((+)-enantiomer) that is described in
Example 45 is treated as usual with boron tribromide. 30.1 mg
(91.4%) of the enantiomer-pure phenol is isolated.
[0414] [a].sub.D=+49.1.+-.0.3 (c=0.55, methanol)
Example 48
(-)-2-Chloro-5-(7,8-difluoro-2-methylquinazolin-5-ylamino-3,8,8-trimethyl--
6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
[0415] 37.2 mg of the ether ((-)-enantiomer) that is described in
Example 45 is treated as usual with boron tribromide. 30.9 mg
(85.6%) of the enantiomer-pure phenol is isolated.
[0416] [a].sub.D=-44.7.+-.0.4 (c=0.55, methanol)
Examples 49 and 50
(+)-6-Chloro-1-(7-fluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,7-tri-
methyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol and
(-)-6-Chloro-1-(7-fluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,7-tr-
imethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
[0417] 143 mg of racemic
6-chloro-1-(7-fluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,7-trimet-
hyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol is
separated on a chiral column (Chiralcel OD-5.mu., eluants:
hexane/ethanol). 58.4 mg of the (+)-enantiomer and 51.2 mg of the
(-)-enantiomer are obtained.
[0418] [a].sub.D=+30.5.+-.0.7 (c=0.50, methanol) [0419]
[a].sub.D=-27.3.+-.0.8 (c=0.51, methanol)
Example 51
(+)-2-Chloro-5-(7-fluoro-2-methylquinazolin-5-ylamino)-3,8,8-trimethyl-6-(-
trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
[0420] 51 mg of the ether ((+)-enantiomer) that is described in
Example 49 is treated as usual with boron tribromide. 47.3 mg
(95.5%) of the enantiomer-pure phenol is isolated.
[0421] [a].sub.D=+41.6.+-.0.8 (c=0.55, methanol)
Example 52
(-)-2-Chloro-5-(7-fluoro-2-methylquinazolin-5-ylamino)-3,8,8-trimethyl-6-(-
trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
[0422] 44.5 mg of the ether ((-)-enantiomer) that is described in
Example 49 is treated as usual with boron tribromide. 41.4 mg
(95.8%) of the enantiomer-pure phenol is isolated.
[0423] [a].sub.D=-40.2.+-.0.6 (c=0.57, methanol)
Examples 53 and 54
(+)-5-[6-Chloro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,-
2,3,4-tetrahydronaphthalen-1-ylamino]1H-quinolin-2-one and
(-)-5-[6-Chloro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1-
,2,3,4-tetrahydronaphthalen-1-ylamino]-1H-quinolin-2-one
[0424] 124 mg of racemic
5-[6-chloro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3-
,4-tetrahydronaphthalen-1-ylamino]-1H-quinolin-2-one is separated
on a chiral column (Chiralcel OJ-H 5.mu., eluants: hexane/ethanol).
54.7 mg of the (+)-enantiomer and 47.8 mg of the (-)-enantiomer are
obtained.
[0425] [a].sub.D=+37.0.+-.0.6 (c=0.57, methanol)
[0426] [a].sub.D=-46.6.+-.0.4 (c=0.54, methanol)
Example 55
(+)-5-[6-Chloro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4--
tetrahydronaphthalen-1-ylamino]-1H-quinolin-2-one
[0427] 47.3 mg of the ether ((+)-enantiomer) that is described in
Example 53 is treated as usual with boron tribromide. 42.6 mg
(92.8%) of the enantiomer-pure phenol is isolated.
[0428] [a].sub.D=+53.3.+-.0.4 (c=0.52, methanol)
Example 56
(-)-5-[6-Chloro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4--
tetrahydronaphthalen-1-ylamino]-1H-quinolin-2-one
[0429] 42.4 mg of the ether ((-)-enantiomer) that is described in
Example 53 is treated as usual with boron tribromide. 39.4 mg
(95.8%) of the enantiomer-pure phenol is isolated.
[0430] [a].sub.D=-56.3.+-.0.4 (c=0.54, methanol)
Example 57
1,6-Dihydroxy-3,8,8-trimethyl-5-(2-oxo-2,3-dihydroindol-4-ylamino)-6-(trif-
luoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
[0431] IR (Microscope, matrix: diamond): 2235
Example 58
5-(7-Fluoro-2-methylquinazolin-5-ylamino)-1,6-dihydroxy-3,8,8-trimethyl-6--
(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
[0432] IR (Microscope, matrix: diamond): 2228
[0433] Analogously to the described compounds, the following
structures can be synthesized with use of the corresponding
starting materials. [0434]
3-Fluoro-4,7-dihydroxy-5,5-dimethyl-8-(1-oxo-1,2-dihydroisoquinoli-
n-5-ylamino)-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitr-
ile [0435]
3-Fluoro-4,7-dihydroxy-5,5-dimethyl-8-(2-methyl-1-oxo-1,2-dihyd-
roisoquinolin-5-ylamino)-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-
-2-carbonitrile [0436]
3-Fluoro-4,7-dihydroxy-5,5-dimethyl-8-(2-methyl-1-oxo-1,2-dihydrophthalaz-
in-5-ylamino)-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonit-
rile [0437]
3-Fluoro-4,7-dihydroxy-5,5-dimethyl-8-(1-oxo-1,2-dihydrophthalazin-5-ylam-
ino)-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
[0438]
3-Fluoro-8-(7-fluoro-2-methylquinazolin-5-ylamino)-4,7-dihydroxy-5-
,5-dimethyl-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitri-
le [0439]
3-Fluoro-8-(8-fluoro-2-methylquinazolin-5-ylamino)-4,7-dihydroxy-
-5,5-dimethyl-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonit-
rile [0440]
3-Fluoro-8-(7,8-difluoro-2-methylquinazolin-5-ylamino)-4,7-dihydroxy-5,5--
dimethyl-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
[0441]
3-Fluoro-8-(2-methylquinazolin-5-ylamino)-4,7-dihydroxy-5,5-dimeth-
yl-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
[0442]
3-Fluoro-8-(2-ethylquinazolin-5-ylamino)-4,7-dihydroxy-5,5-dimethyl-7-(tr-
ifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [0443]
3-Fluoro-8-(2-methylquinolin-5-ylamino)-4,7-dihydroxy-5,5-dimethyl-7-(tri-
fluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [0444]
3-Fluoro-8-(2,6-dimethyl
quinolin-5-ylamino)-4,7-dihydroxy-5,5-dimethyl-7-(trifluoromethyl)-5,6,7,-
8-tetrahydronaphthalene-2-carbonitrile [0445]
3-Fluoro-8-(6-chloro-2-methylquinolin-5-ylamino)-4,7-dihydroxy-5,5-dimeth-
yl-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
[0446]
3-Fluoro-8-(6-fluoro-2-methylquinolin-5-ylamino)-4,7-dihydroxy-5,5-dimeth-
yl-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
[0447]
3-Fluoro-4,7-dihydroxy-8-(1H-indazol-4-ylamino)-5,5-dimethyl-7-(trifluoro-
methyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [0448]
3-Fluoro-4,7-dihydroxy-5,5-dimethyl-8-(naphthalen-1-ylamino)-7-(trifluoro-
methyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [0449]
3-Fluoro-4,7-dihydroxy-5,5-dimethyl-8-(naphthalen-2-ylamino)-7-(trifluoro-
methyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [0450]
3-Fluoro-4,7-dihydroxy-5,5-dimethyl-8-(6-hydroxynaphthalen-1-ylamino)-7-(-
trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
[0451]
3-Fluoro-4,7-dihydroxy-5,5-dimethyl-8-(5-hydroxynaphthalen-1-ylamino)-7-(-
trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
[0452]
3-Chloro-2-fluoro-5-(6-hydroxynaphthalen-1-ylamino)-8,8-dimethyl-6-(trifl-
uoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol [0453]
3-Chloro-2-fluoro-5-(5-hydroxynaphthalen-1-ylamino)-8,8-dimethyl-6-(trifl-
uoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol [0454]
3-Chloro-2-fluoro-5-(naphthalen-1-ylamino)-8,8-dimethyl-6-(trifluoromethy-
l)-5,6,7,8-tetrahydronaphthalene-1,6-diol [0455]
3-Chloro-2-fluoro-5-(naphthalene-2-ylamino)-8,8-dimethyl-6-(trifluorometh-
yl)-5,6,7,8-tetrahydronaphthalene-1,6-diol [0456]
3-Chloro-2-fluoro-5-(1H-indazol-4-ylamino)-8,8-dimethyl-6-(trifluoromethy-
l)-5,6,7,8-tetrahydronaphthalene-1,6-diol [0457]
3-Chloro-2-fluoro-5-(5-chloro-1H-indazol-4-ylamino)-8,8-dimethyl-6-(trifl-
uoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol [0458]
5-(7,8-Difluoro-2-methylquinazolin-5-ylamino)-1,6-dihydroxy-3,8,8-trimeth-
yl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
[0459]
5-(8-Fluoro-2-methylquinazolin-5-ylamino)-1,6-dihydroxy-3,8,8-trimethyl-6-
-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
[0460]
5-(2-Methylquinazolin-5-ylamino)-1,6-dihydroxy-3,8,8-trimethyl-6-(trifluo-
romethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [0461]
5-(2-Ethylquinazolin-5-ylamino)-1,6-dihydroxy-3,8,8-trimethyl-6-(trifluor-
omethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [0462]
1,6-Dihydroxy-3,8,8-trimethyl-5-(2-oxo-1,2-dihydroquinolin-5-ylamino)-6-(-
trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
[0463]
1,6-Dihydroxy-3,8,8-trimethyl-5-(1-oxo-1,2-dihydroisoquinolin-5-ylamino)--
6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
[0464]
1,6-Dihydroxy-3,8,8-trimethyl-5-(2-methyl-1-oxo-1,2-dihydroisoquinolin-5--
ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
[0465]
1,6-Dihydroxy-3,8,8-trimethyl-5-(1-oxo-1,2-dihydrophthalazin-5-yla-
mino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
[0466]
1,6-Dihydroxy-3,8,8-trimethyl-5-(2-methyl-1-oxo-1,2-dihydrophthala-
zin-5-ylamino)-6-(trifluoromethyl)
5,6,7,8-tetrahydronaphthalene-2-carbonitrile [0467]
1,6-Dihydroxy-3,8,8-trimethyl-5-(2-methylquinolin-5-ylamino)-6-(trifluoro-
methyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [0468]
1,6-Dihydroxy-3,8,8-trimethyl-5-(2,6-dimethylquinolin-5-ylamino)-6-(trifl-
uoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [0469]
1,6-dihydroxy-3,8,8-trimethyl-5-(6-chloro-2-methylquinolin-5-ylamino)-6-(-
trifluoromethyl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [0470]
1,6-Dihydroxy-3,8,8-trimethyl-5-(6-fluoro-2-methylquinolin-5-ylamino)-6-(-
trifluoromethyl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [0471]
1,6-Dihydroxy-5-(1H-indazolyl-4-ylamino)-3,8,8-trimethyl-6-(trifluorometh-
yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [0472]
1,6-Dihydroxy-5-(5-chloro-1H-indazolyl-4-ylamino)-3,8,8-trimethyl-6-(trif-
luoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [0473]
1,6-Dihydroxy-3,8,8-trimethyl-5-(naphthalen-1-ylamino)-6-(trifluoromethyl-
)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [0474]
1,6-Dihydroxy-3,8,8-trimethyl-5-(naphthalen-2-ylamino)-6-(trifluoromethyl-
)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [0475]
1,6-Dihydroxy-3,8,8-trimethyl-5-(6-hydroxy-naphthalen-1-ylamino)-6-(trifl-
uoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [0476]
1,6-Dihydroxy-3,8,8-trimethyl-5-(5-hydroxy-naphthalen-1-ylamino)-6-(trifl-
uoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [0477]
2-Chloro-5-(1H-indazol-4-ylamino)-3,8,8-trimethyl-6-(trifluoromethyl)-5,6-
,7,8-tetrahydronaphthalene-1,6-diol [0478]
2-Fluoro-5-(1H-indazol-4-ylamino)-3,8,8-trimethyl-6-(trifluoromethyl)-5,6-
,7,8-tetrahydronaphthalene-1,6-diol [0479]
2-Chloro-3,8,8-trimethyl-5-(naphthalen-1-ylamino
6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol [0480]
2-Fluoro-3,8,8-trimethyl-5-(naphthalen-1-ylamino
6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol [0481]
2-Chloro-3,8,8-trimethyl-5-(6-hydroxynaphthalen-1-ylamino)-6-(trifluorome-
thyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol [0482]
2-Fluoro-3,8,8-trimethyl-5-(6-hydroxynaphthalen-1-ylamino)-6-(trifluorome-
thyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol [0483]
2-Chloro-3,8,8-trimethyl-5-(5-hydroxynaphthalen-1-ylamino)-6-(trifluorome-
thyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol [0484]
2-Fluoro-3,8,8-trimethyl-5-(5-hydroxynaphthalen-1-ylamino)-6-(trifluorome-
thyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol [0485]
1,6-Dihydroxy-8,8-dimethyl-5-(2-methylquinazolin-5-ylamino)-6-(trifluorom-
ethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [0486]
1,6-Dihydroxy-8,8-dimethyl-5-(2-ethylquinazolin-5-ylamino)-6-(trifluorome-
thyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [0487]
1,6-Dihydroxy-8,8-dimethyl-5-(7-fluoro-2-methylquinazolin-5-ylamino)-6-(t-
rifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [0488]
1,6-Dihydroxy-8,8-dimethyl-5-(7,8-difluoro-2-methylquinazolin-5-ylamino)--
6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
[0489]
1,6-Dihydroxy-8,8-dimethyl-5-(8-fluoro-2-methylquinazolin-5-ylamino)-6-(t-
rifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [0490]
1,6-Dihydroxy-8,8-dimethyl-5-(2-oxo-1,2-dihydroquinolin-5-ylamino)-6-(tri-
fluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
[0491] The entire disclosures of all applications, patents and
publications, cited herein and of corresponding German Application
No. 10 2004 017 662.0, filed Oct. 8, 2003 are incorporated by
reference herein.
* * * * *