U.S. patent application number 11/677790 was filed with the patent office on 2007-06-21 for 4-heteroaryl-tetrahydroquinolines and their use as inhibitors of the cholesterin-ester transfer protein.
This patent application is currently assigned to BAYER AKTIENGESELLSCHAFT. Invention is credited to HILMAR BISCHOFF, ARNDT BRANDES, KLAUS DIETER BREMM, MICHAEL LOGERS, CARSTEN SCHMECK, DELF SCHMIDT, GUNTER SCHMIDT, JURGEN STOLTEFUSS.
Application Number | 20070142420 11/677790 |
Document ID | / |
Family ID | 7842737 |
Filed Date | 2007-06-21 |
United States Patent
Application |
20070142420 |
Kind Code |
A1 |
STOLTEFUSS; JURGEN ; et
al. |
June 21, 2007 |
4-HETEROARYL-TETRAHYDROQUINOLINES AND THEIR USE AS INHIBITORS OF
THE CHOLESTERIN-ESTER TRANSFER PROTEIN
Abstract
Hetero-tetrahydroquinolines can be prepared either by condensing
correspondingly substituted hetero-tetrahydroquinoline aldehydes
with the desired substituent or by reducing the corresponding
keto-substituted hetero-tetrahydroquinolines, followed by
introduction of the desired substituent by customary methods. The
hetero-tetrahydroquinolines are suitable for use as active
compounds in medicaments, in particular in medicaments for treating
artheriosclerosis and dyslipidaemias.
Inventors: |
STOLTEFUSS; JURGEN;
(Leverkusen, DE) ; LOGERS; MICHAEL; (Leverkusen,
DE) ; SCHMIDT; GUNTER; (Leverkusen, DE) ;
BRANDES; ARNDT; (Leverkusen, DE) ; SCHMECK;
CARSTEN; (Leverkusen, DE) ; BREMM; KLAUS DIETER;
(Leverkusen, DE) ; BISCHOFF; HILMAR; (Leverkusen,
DE) ; SCHMIDT; DELF; (Leverkusen, DE) |
Correspondence
Address: |
NORRIS, MCLAUGHLIN & MARCUS, PA
875 THIRD AVENUE
18TH FLOOR
NEW YORK
NY
10022
US
|
Assignee: |
BAYER AKTIENGESELLSCHAFT
Leverkusen
DE
D-51368
|
Family ID: |
7842737 |
Appl. No.: |
11/677790 |
Filed: |
February 22, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11257931 |
Oct 25, 2005 |
7192971 |
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11677790 |
Feb 22, 2007 |
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09999233 |
Oct 31, 2001 |
6958346 |
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11257931 |
Oct 25, 2005 |
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09508399 |
Mar 10, 2000 |
6387929 |
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PCT/EP98/05656 |
Sep 7, 1998 |
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09999233 |
Oct 31, 2001 |
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Current U.S.
Class: |
514/278 ;
514/314; 546/15 |
Current CPC
Class: |
C07D 401/04 20130101;
A61P 9/10 20180101; C07D 215/20 20130101; C07D 409/04 20130101;
A61P 3/06 20180101; A61P 31/06 20180101 |
Class at
Publication: |
514/278 ;
514/314; 546/015 |
International
Class: |
A61K 31/4747 20060101
A61K031/4747; C07D 405/02 20060101 C07D405/02 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 18, 1997 |
DE |
19741051.0 |
Claims
1. A hetero-tetrahydroquinoline compound of the formula (I),
##STR55## in which A represents cycloalkyl having 3 to 8 carbon
atoms or represents a 5- to 7-membered saturated, partially
unsaturated or unsaturated, optionally benzo-fused heterocycle
having up to 3 heteroatoms from the group consisting of S, N and O
which, in the case of a saturated heterocycle with a nitrogen
function, is optionally also attached via this function, and where
the abovementioned ring systems are optionally substituted up to 5
times by identical or different substituents from the group
consisting of halogen, nitro, hydroxyl, trifluoromethyl,
trifluoromethoxy and straight-chain or branched alkyl, acyl,
hydroxyalkyl or alkoxy having in each case up to 7 carbon atoms, or
by a group of the formula --NR.sup.3R.sup.4, in which R.sup.3 and
R.sup.4 are identical or different and represent hydrogen, phenyl
or straight-chain or branched alkyl having up to 6 carbon atoms, A
represents a radical of the formula ##STR56## D represents aryl
having 6 to 10 carbon atoms which is optionally substituted by
phenyl, nitro, halogen, trifluoromethyl or trifluoromethoxy, or
represents a radical of the formula ##STR57## which R.sup.5 and
R.sup.9 independently of one another represent cycloalkyl having 3
to 6 carbon atoms, or represent aryl having 6 to 10 carbon atoms or
represent a 5- to 7-membered optionally benzo-fused saturated or
unsaturated mono-, bi- or tricyclic hetreocycle having up to 4
heteroatoms from the group consisting of S, N and O, where the
cycles are optionally substituted, in the case of the
nitrogen-containing rings also via the N function, up to 5 times by
identical or different substituents from the group consisting of
halogen, trifluoromethyl, nitro, hydroxyl, cyano, carboxyl,
trifluoromethoxy, and straight-chain or branched acyl, alkyl,
alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl having in each
case up to 6 carbon atoms, by aryl or trifluoromethyl-substituted
aryl having in each case 6 to 10 carbon atoms or by an optionally
benzo-fused aromatic 5- to 7-membered heterocycle having up to 3
heteroatoms from the group consisting of S, N and O, and/or by a
group of the formula --OR.sup.10, --SR.sup.11, --SO.sub.2R.sup.12
or --NR.sup.13R.sup.14, in which R.sup.10, R.sup.11 and R.sup.12
independently of one another represent aryl having 6 to 10 carbon
atoms which for its part is substituted up to 2 times by identical
or different substituents from the group consisting of phenyl,
halogen and straight-chain or branched alkyl having up to 6 carbon
atoms, R.sup.13 and R.sup.14 are identical or different and have
the meaning of R.sup.3 and R.sup.4 given above, or R.sup.5 and/or
R.sup.6 represent(s) a radical of the formula ##STR58## R.sup.7
represents hydrogen or halogen, and R.sup.8 represents hydrogen,
halogen, azido, trifluoromethyl, hydroxyl, trifluoromethoxy,
straight-chain or branched alkoxy or alkyl having in each case up
to 6 carbon atoms or a radical of the formula --NR.sup.15R.sup.16,
in which R.sup.15 and R.sup.16 are identical or different and have
the meaning of R.sup.3 and R.sup.4 given above, or R.sup.7 and
R.sup.8 together form a radical of the formula .dbd.O or
.dbd.NR.sup.17, in which R.sup.17 represents hydrogen or
straight-chain or branched alkyl, alkoxy or acyl having in each
case up to 6 carbon atoms, L represents a straight-chain or
branched alkylene or alkenylene chain having in each case up to 8
carbon atoms which are optionally substituted up to 2 times by
hydroxyl, T and X are identical or different and represent a
straight-chain or branched alkylene chain having up to 8 carbon
atoms, or T or X represents a bond, V represents an oxygen or
sulphur atom or represents an --NR.sup.18 group, in which R.sup.18
represents hydrogen or straight-chain or branched alkyl having up
to 6 carbon atoms or phenyl, E represents cycloalkyl having 3 to 8
carbon atoms, or represents straight-chain or branched alkyl having
up to 8 carbon atoms which is optionally substituted by cycloalkyl
having 3 to 8 carbon atoms or hydroxyl, or represents phenyl which
is optionally substituted by halogen or trifluoromethyl, R.sup.1
and R.sup.2 together form a straight-chain or branched alkylene
chain having up to 7 carbon atoms which has to be substituted by a
carbonyl group and/or by a radical of the formula ##STR59## in
which a and b are identical or different and represent a number 1,
2 or 3, R.sup.19 represents hydrogen, cycloalkyl having 3 to 7
carbon atoms, straight-chain or branched silylalkyl having up to 8
carbon atoms or straight-chain or branched alkyl having up to 8
carbon atoms which is optionally substituted by hydroxyl,
straight-chain or branched alkoxy having up to 6 carbon atoms or by
phenyl which for its part may be substituted by halogen, nitro,
trifluoromethyl, trifluoromethoxy or by phenyl or
tetrazolesubstituted phenyl, and alkyl is optionally substituted by
a group of the formula --OR.sup.22 in which R.sup.22 represents
straight-chain or branched acyl having up to 4 carbon atoms or
benzyl, or R.sup.19 represents straight-chain or branched acyl
having up to 20 carbon atoms or benzoyl which is optionally
substituted by halogen, trifluoromethyl, nitro or trifluoromethoxy,
or represents straight-chain or branched fluoroacyl having up to 8
carbon atoms and 9 fluorine atoms, R.sup.20 and R.sup.21 are
identical or different, represent hydrogen, phenyl or
straight-chain or branched all having up to 6 carbon atoms, or
R.sup.20 and R.sup.21 together form a 3 to 6-membered carbocycle
and, if appropriate also geminally, the carbocycles formed are
optionally substituted up to 6 times by identical or different
substituents from the group consisting of trifluoromethyl,
hydroxyl, nitrile, halogen, carboxyl, nitro, azido, cyano,
cycloalkyl or cycloalkyloxy having in each case 3 to 7 carbon
atoms, straight-chain or branched alkoxycarbonyl, alkoxy or
alkylthio having in each case up to 6 carbon atoms and
straight-chain or branched all having up to 6 carbon atoms which
for its part is substituted up to 2 times by identical or different
substituents from the group consisting of hydroxyl, benzyloxy,
trifluoromethyl, benzoyl, straight-chain or branched alkoxy,
oxyacyl or carboxyl having in each case up to 4 carbon atoms and
phenyl which for its part may be substituted by halogen,
trifluoromethyl or trifluoromethoxy, and/or the carbocycles formed
are optionally substituted, also seminally, up to 5 times by
identical or different substituents from the group consisting of
phenyl, benzoyl, thiophenyl and sulphonylbenzyl which for their
part are optionally substituted by halogen, trifluoromethyl,
trifluoromethoxy or nitro, and/or are optionally substituted by a
radical of the formula ##STR60## in which c represents a number 1,
2, 3 or 4, d represents a number 0 or I, R.sup.23 and R.sup.24 are
identical or different and represent hydrogen, 30 cycloalkyl having
3 to 6 carbon atoms, straight-chain or branched alkyl having up to
6 carbon atoms, benzyl or phenyl which is optionally substituted up
to 2 times by identical or different substituents from the group
consisting of halogen, trifluoromethyl, cyan, phenyl and nitro,
and/or the carbocycles formed are optionally substituted by a
Spiro-linked radical of the formula ##STR61## in which w represents
either an oxygen or a sulphur atom, Y and Y' together form a 2- to
6-membered straight-chain or branched alkylene chain, e represents
a number 1, 2, 3, 4, 5, 6 or 7, f represents a number 1 or 2,
R.sup.25, R.sup.26, R.sup.27, R.sup.28, R.sup.29, R.sup.30 and
R.sup.31 are identical or different and represent hydrogen,
trifluoromethyl, phenyl, halogen or straight-chain or branched
alkyl or alkoxy having in each case up to 6 carbon atoms, R.sup.25
and R.sup.26 or R.sup.27 and R.sup.28 in each case together form a
straight-chain or branched alkyl chain having up to 6 carbon atoms,
or R.sup.25 and R.sup.26 or R.sup.27 and R.sup.28 in each case
together form a radical of the formula ##STR62## in which W is as
defined above, g represents a number 1, 2, 3, 4, 5, 6 or 7,
R.sup.32 and R.sup.33 together form a 3- to 7-membered heterocycle
which contains an oxygen or sulphur atom or a group of the formula
SO, SO.sub.2 or --NR.sup.34, in which R.sup.34 represents hydrogen,
phenyl, benzyl or straight-chain or branched alkyl having up to 4
carbon atoms, or a salt of said compound or an N-oxide of said
compound or said salt.
2. The hetero-tetrahydroquinoline compound of the formula (1)
according to claim 1, in which A represents cyclopropyl,
cyclobutyl, cyclopentyl, cycloheptyl, cyclobutyl or cyclohexyl, or
represents thienyl, imidazolyl, pyrrole, furryl, pyridyl,
morpholine, pyrimidyl or pyridazinyl, which are optionally
substituted up to 2 times by identical or different substituents
from the group consisting of fluorine, chlorine, bromine, amino,
hydroxyl, trifluoromethyl, trifluoromethoxy and straight-chain or
branched alkyl, and alkoxy having in each case up to 6 carbon
atoms, or A represents a radical of the formula ##STR63## D
represents phenyl which is optionally substituted by nitro,
fluorine, chlorine, bromine, phenyl, trifluoromethyl or
trifluoromethoxy, or represents a radical of the formula ##STR64##
in which R.sup.5, R.sup.6 and R.sup.9 independently of one another
represent cyclopropyl, cyclopentyl or cyclohexyl, or represent
phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl,
pyrrolidinyl, indolyl, morpholinyl, imidazolyl, benzothiazolyl,
phenoxathiin-2-yl, benzoxazolyl, furyl, quinolyl or purin-8-yl,
where the cycles are optionally substituted up to 3 times, in the
case of the nitrogen-containing rings also via the N function, by
identical or different substituents from the group consisting of
fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, cyano,
carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl,
alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl having in each
case up to 4 carbon atoms, triazolyl, tetrazolyl, benzoxathiazolyl,
trifluoromethyl-substituted phenyl and phenyl, or R.sup.7
represents hydrogen, fluorine, chlorine or bromine, and R.sup.8
represents hydrogen, fluorine, chlorine, bromine, azido,
trifluoromethyl, hydroxyl, trifluoromethoxy, straight-chain or
branched alkoxy or alkyl having in each case up to 5 carbon atoms
or a radical of the formula --NR.sup.15R.sup.16, in which R.sup.15
and R.sup.16 are identical or different and represent hydrogen,
phenyl or straight-chain or branched alkyl having up to 4 carbon
atoms, or R.sup.7 and R.sup.8 together form a radical of the
formula .dbd.O or .dbd.NR.sup.17, in which R.sup.17 represents
hydrogen or straight-chain or branched alkyl, alkoxy or acyl having
in each case up to 4 carbon atoms, L represents a straight-chain or
branched alkylene or alkenylene chain having in each case up to 6
carbon atoms which are optionally substituted up to 2 times by
hydroxyl, T and X are identical or different and represent a
straight-chain or branched alkylene chain having up to 6 carbon
atoms, or T or X represents a bond, V represents an oxygen or
sulphur atom or represents a group of the formula --NR.sup.18--, in
which R.sup.18 represents hydrogen or straight-chain or branched
alkyl having up to 4 carbon atoms or phenyl, E represents
cyclopropyl, -butyl, -pentyl, -hexyl or -heptyl, or represents
straight-chain or branched all having up to 6 carbon atoms which is
optionally substituted by cyclopropyl, -butyl, -hexyl, -pentyl,
-heptyl or by hydroxyl, or represents phenyl which is optionally
substituted by fluorine, chlorine or trifluoromethyl, R.sup.1 and
R.sup.2 together form a straight-chain or branched alkylene chain
having up to 6 carbon atoms which has to be substituted by a
carboxyl group and/or by a radical of the formula ##STR65## in
which a and b are identical or different and represent a number 1,
2 or 3, R.sup.19 represents hydrogen, cyclopropyl, cyclopentyl,
cyclohexyl, straight-chain or branched silylalkyl having up to 7
carbon atoms or straight-chain or branched alkyl having up to 6
carbon atoms which is optionally substituted by hydroxyl,
straight-chain or branched alkoxy having up to 4 carbon atoms or by
phenyl which for its part may be substituted by fluorine, chlorine,
bromine, nitro, trifluoromethyl, trifluoromethoxy or by phenyl or
tetrazole-substituted phenyl, and alkyl is optionally substituted
by a group of the formula --OR.sup.22, in which R.sup.22 represents
straight-chain or branched acyl having up to 3 carbon atoms or
benzyl, or R.sup.19 represents straight-chain or branched acyl
having up to 18 carbon atoms or benzoyl which is optionally
substituted by fluorine, chlorine, bromine, trifluoromethyl, nitro
or trifluoromethoxy, or represents straight-chain or branched
fluoroacyl having up to 6 carbon atoms, R.sup.20 and R.sup.21 are
identical or different, represent hydrogen, phenyl or
straight-chain or branched alkyl having up to 4 carbon atoms, or
R.sup.20 and R.sup.21 together form a cyclpropyl, cyclobutyl,
cyclopentyl, cyclohexyl or cycloheptyl ring, and the carbocycles
formed are optionally substituted, if appropriate, also geminally,
up to 5 times by identical or different substituents from the group
consisting of trifluoromethyl, hydroxyl, carboxyl, azido, fluorine,
chlorine, bromine, nitro, cyano, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cyclopropyloxy, cyclopentyloxy,
cyclohexyloxy, straight-chain or branched alkoxycarbonyl, alkoxy or
alkylthio having in each case up to about 5 carbon atoms and
straight-chain or branched alkyl having up to 5 carbon atoms which
for its part is substituted up to 2 times by identical or different
substituents from the group consisting of hydroxyl, benryloxy,
benzoyl, straight-chain or branched alkoxy or oxyacyl having in
each case up to 3 carbon atoms, trifluoromethyl and phenyl which
for its part may be substituted by fluorine, chlorine, bromine,
trifluoromethyl or trifluoromethoxy, and/or the carbocycles formed
are optionally substituted, also geminally, up to 4 times by
identical or different substituents from the group consisting of
phenyl, benzoyl, thiophenyl and sulphonylbenzyl which for their
part are optionally substituted by fluorine, chlorine, bromine,
trifluoromethyl, trifluoromethoxy or nitro, and/or are optionally
substituted by a radical of the formula ##STR66## in which c
represents a number 1, 2, 3 or 4, d represents a number 0 or 1,
R.sup.23 and R.sup.24 are identical or different and represent
hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
straight-chain or branched alkyl having up to 5 carbon atoms,
benzyl or phenyl which is optionally substituted by fluorine,
chlorine, bromine, phenyl or trifluoromethyl, and/or the
carbocycles formed are optionally substituted by a spiro-linked
radical of the formula ##STR67## in which w represents either an
oxygen or a sulphur atom, Y and Y' together form a 2- to 5-membered
straight-chain or branched all chain, e represents a number 1, 2,
3, 4, 5 or 6, f represents a number 1 or 2, R.sup.25, R.sup.26,
R.sup.27 and R.sup.28 are identical or different and represent
hydrogen, trifluoromethyl, phenyl, fluorine, chlorine, bromine or
straight-chain or branched alkyl or alkoxy having in each case up
to 5 carbon atoms, or R.sup.25 and R.sup.26 or R.sup.27 and
R.sup.28 in each case together form a straight-chain or branched
alkyl chain having up to 5 carbon atoms or R.sup.25 and R.sup.26 or
R.sup.27 and R.sup.28 in each case together form a radical of the
formula ##STR68## in which W is as defined above, g represents a
number 1, 2, 3, 4, 5 or 6, or a salt of said compound or an N-oxide
of said compound or said salt.
3. The hetero-tetrahydroquinoline compound of the formula (I)
according to claim 1, in which A represents cyclopropyl,
cyclopentyl or cyclohexyl, or represents thienyl or pyridyl which
are optionally substituted up to 2 times by identical or different
substituents from the group consisting of fluorine, chlorine,
bromine, hydroxyl, trifluoromethyl, trifluoromethoxy and
straight-chain or branched all or alkoxy having in each case up to
5 carbon atoms, or A represents a radical of the formula ##STR69##
D represents phenyl which is optionally substituted by nitro,
trifluoromethyl, phenyl, fluorine, chlorine or bromine, or
represents a radical of the formula ##STR70## in which R.sup.5,
R.sup.6 and R.sup.9 independently of one another represent
cyclopropyl, cyclopentyl or cyclohexyl, or represent phenyl,
naphthyl or pyridyl, where the cycles optionally up to 2 times by
identical or different substituents from the group consisting of
fluorine, chlorine, trifluoromethyl, hydroxyl, cyano, carboxyl,
trifluoromethoxy and straight-chain or branched alkyl, alkylthio,
alkylalkoxy, alkoxy or alkoxycarbonyl having in each case up to 4
carbon atoms, or R.sup.7 represents hydrogen or fluorine, and
R.sup.8 represents hydrogen, fluorine, chlorine, bromine, azido,
trifluoromethyl, hydroxyl, trifluoromethoxy, or straight-chain or
branched alkoxy or alkyl having in each case up to 4 carbon atoms
or a radical of the formula --NR.sup.15R.sup.16, in which R.sup.15
and R.sup.16 are identical or different and represent hydrogen or
straight-chain or branched all having up to 3 carbon atoms, or
R.sup.7 and R.sup.8 together represent a radical of the formula
.dbd.O, L represents a straight-chain or branched alkylene or
alkenylene chain having in each case up to 5 carbon atoms which are
optionally substituted up to 2 times by hydroxyl, T and X are
identical or different and represent a straight-chain or branched
alkylene chain having up to 3 carbon atoms, or T or X represents a
bond, V represents an oxygen or sulphur atom or a group of the
formula --NR.sup.18, in which R.sup.18 represents hydrogen or
straight-chain or branched alkyl having up to 3 carbon atoms, E
represents cyclopropyl, cyclopentyl or cyclohexyl or phenyl which
is optionally substituted by fluorine or trifluoromethyl, or
represents straight chain or branched alkyl having up to 4 carbon
atoms which is optionally substituted by hydroxyl, R.sup.1 and
R.sup.2 together form a straight-chain or branched alkylene chain
having up to 5 carbon atoms which has to be substituted by a
carbonyl group and/or a radical of the formula --OR.sup.19, in
which R.sup.19 represents hydrogen, cyclopropyl, cyclopentyl or
cyclohexyl, or R.sup.19 represents straight-chain or branched acyl
having up to 15 carbon atoms or benzoyl which is optionally
substituted by fluorine, chlorine, bromine, trifluoromethyl, nitro
or trifluoromethoxy, or represents a radical of the formula
--Si(CH.sub.3).sub.2C(CH.sub.3).sub.3, and the carbocycles formed
are optionally substituted, if appropriate also geminally, up to 4
times by identical or different substituents from the group
consisting of fluorine, hydroxyl, trifluoromethyl, carboxyl, azido,
chlorine, bromine, nitro, cyano, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cyclopropyloxy, cyclopentyloxy,
cyclohexyloxy, straight-chain or branched ##STR71## alkoxycarbonyl,
alkoxy or alkylthio having in each case up to 4 carbon atoms and
straight-chain or branched alkyl having up to 4 carbon atoms which
for its part is substituted up to 2 times by identical or different
substituents from the group consisting of hydroxyl, benzyloxy,
trifluoromethyl, benzoyl, methoxy, oxyacetyl and phenyl which for
its part may be substituted by fluorine, chlorine, bromine,
trifluoromethyl or trifluoromethoxy, and/or the carbocycles formed
are optionally substituted, also geminally, up to 4 times by
identical or different substituents from the group consisting of
phenyl, benzoyl, thiophenyl and sulphonylbenzyl which for their
part are optionally substituted by fluorine, trifluoromethyl,
trifluoromethoxy or nitro, and/or are optionally substituted by a
radical of the formula ##STR72## in which c represents a number 1,
2, 3 or 4, and/or the carbocycles formed are optionally substituted
by a spiro-linked radical of the formula in which e represents a
number 1,2,3,4 or 5, R.sup.25, R.sup.26, R.sup.27, and R.sup.28 are
identical or different and represent hydrogen, trifluoromethyl,
phenyl, fluorine, chlorine, bromine or straight-chain or branched
all or alkoxy having in each case up to 4 carbon atoms, or R.sup.25
and R.sup.26 or R.sup.27 and R.sup.28 together form a
straight-chain or branched alkyl chain having up to 4 carbon atoms,
or a salt of said compound or an N-oxide of said compound or said
salt.
4. The hetero-tetrahydroquinoline compound of the formula (I)
according to claim 1, in which A represents cyclopropyl,
cyclopentyl or cyclohexyl, or represents thienyl or pyndyl, or A
represents a radical of the formula ##STR73## D represents phenyl
which is optionally substituted by trifluoromethyl, fluorine, or
represents a radical of the formula ##STR74## in which R.sup.6
represents phenyl which is optionally substituted by fluorine,
chlorine, trifluoromethyl, trifluoromethoxy, straight-chain or
branched alkyl having in each case up to 4 carbon atoms, or R.sup.7
represents hydrogen or fluorine, and R.sup.8 represents hydrogen,
fluorine, chlorine, hydroxyl, methoxy or R.sup.7 and R.sup.8
together represent a radical of the formula .dbd.O, E represents
cyclopropyl, cyclopentyl or cyclohexyl represents straight-chain or
branched all having up to 4 carbon atoms, R.sup.1 and R.sup.2
together form a straight-chain or branched alkylene chain having up
to 5 carbon atoms which has to be substituted by a carbonyl group
and/or a radical of the formula --OR.sup.19, in which R.sup.19
represents hydrogen or represents a radical of the formula
--Si(CH.sub.3).sub.2C(CH.sub.3).sub.3, or a salt of said compound
or an N-oxide of said compound or said salt.
5. (canceled)
6. Process for preparing hetero-tetrahydroquinolines according to
claim 1, characterized in that [A] in the case where D.noteq.aryl,
compounds of the general formula (II) ##STR75## in which A, E,
R.sup.1 and R.sup.2 are as defined above, with organometallic
reagents in a Grignard or Wittig reaction or in a reaction with
organolithium compounds, the substituent D is synthesized in inert
solvents, or in the case where D represents the radical of the
formula R.sup.9-T-V-X in which V is an oxygen atom, [B] either
compounds of the general formula (III) ##STR76## in which A, E, X,
R.sup.1 and R.sup.2 are as defined above, are reacted with
compounds of the general formula (IV) R.sup.9-T-Z (IV), in which
R.sup.9 and T are as defined above and Z represents halogen,
preferably chlorine or bromine, in inert solvents, if appropriate
in the presence of a base and/or auxiliary, or [C] compounds of the
general formula (III) are initially, by reaction with compounds
general formula (V) ##STR77## in which R.sup.35 represents
straight-chain alkyl having up to 4 carbon atoms, to the compounds
of the general formula (VI) ##STR78## in which A, E, X, R.sup.1,
R.sup.2 and R.sup.35 are as defined above, and subsequently reacted
with compounds of the general formula (VII) R.sup.9-T-V-H (VII), in
which R.sup.9, T and V are as defined above, and, if appropriate,
protective groups are removed, or [D] in the case of the compounds
of the general formula (Ia) ##STR79## in which A and R.sup.6 are as
defined above, R.sup.36 and R.sup.37 are identical or different and
represent cycloalkyl or cycloalkyloxy having in each case 3 to 7
carbon atoms, or represent straight-chain or branched alkyl having
up to 6 carbon atoms, or represent phenyl which for its part are
optionally substituted by halogen, trifluoromethyl,
trifluoromethoxy or nitro, or R.sup.16 and R.sup.37 represent one
of the abovementioned spiro-linked radicals of the formula
##STR80## which W, Y, Y', R.sup.25, R.sup.26, R.sup.27, R.sup.28,
e, R.sup.29, R.sup.30, R.sup.31, R.sup.32 and R.sup.33 are as
defined above, pounds of the general formula (VIII) ##STR81## which
R.sup.6, R.sup.36, R.sup.37, A and E are as defined above,
initially oxidized to the compounds of the general formula (IX)
##STR82## which R.sup.6, R.sup.36, R.sup.37, A and E are as defined
above, these are, in a subsequent step, converted by asymmetric
reduction into the compounds of the general formula (X) ##STR83##
which R.sup.6, R.sup.36, R.sup.37, A and E are as defined above,
these are then converted, by the introduction of a hydroxyl
protective group, into compounds of the general formula (XI)
##STR84## which R.sup.6, R.sup.36, R.sup.37, A and E are as defined
above and R.sup.38 represents a hydroxyl protective group,
preferably a radical of the formula --SiR.sup.39R.sup.40R.sup.41
which R and R are identical or different and represent
C.sub.1-C.sub.4-alkyl, which is used to prepare in a subsequent
step, by diastereoselective reduction, the pounds of the general
formula (XII) ##STR85## which R.sup.6, R.sup.36, R.sup.37,
R.sup.38, A and E areas defined above, the compounds of the general
formula (XIII) ##STR86## which R.sup.6, R.sup.36, R.sup.37,
R.sup.38, A and E are as defined above, are subsequently prepared
by introducing the fluorine substituent with fluorinating agents,
such as, for example, DAST and SF.sub.4 derivatives, and the
hydroxyl protective group is then removed by customary methods,
and, if appropriate, the substituents listed under D, E and/or
R.sup.1 and R.sup.2 are varied or introduced by customary
methods.
7.-11. (canceled)
12. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and an effective amount of the
hetero-tetrahydroquinoline compound of the formula (I) according to
claim 1, or a salt or an N-oxide of said compound or said salt.
13. A method of treating hyperlipoproteinanaemia comprising
administering to a patient in need thereof an effective amount
therefor of the composition according to claim 12.
14. A method of treating arteriosclerosis comprising administering
to a patient in need thereof an effective amount therefor of the
composition according to claim 12.
15. A method of treating dislipidaemia comprising administering to
a patient in need thereof an effective amount therefor of the
composition according to claim 12.
Description
[0001] The present invention relates to
hetero-tetrahydroquinolines, to processes for their preparation and
to their use in medicaments.
[0002] The publication U.S. Pat. No. 5,169,857-A2 discloses
7-(polysubstituted pyridyl)-6-heptenoates for treating
arteriosclerosis, lipoproteinaemia and hyperproteinaemia. Moreover,
the preparation of 7-(4-aryl-3-pyridyl)-3,5-dihydroxy-6-heptenoates
is described in the publication EP-325 130-A2. Furthermore, the
compound
5(6H)-quinolone,3-benzyl-7,8-dihydro-2,7,7-trimethyl-4-phenyl is
known from the publication Khim. Geterotsikl.
[0003] Soedin. (1967), (6), 1118-1120.
[0004] The present invention relates to hetero-tetrahydroquinolines
of the general formula (I) ##STR1## in which [0005] A represents
cycloalkyl having 3 to 8 carbon atoms or [0006] represents a 5- to
7-membered saturated, partially unsaturated or unsaturated,
optionally benzo-fused heterocycle having up to 3 heteroatoms from
the group consisting of S, N and O which, in the case of a
saturated heterocycle with a nitrogen function, is optionally also
attached via this function, and where the abovementioned ring
systems are optionally substituted up to 5 times by identical or
different substituents from the group consisting of halogen, nitro,
hydroxyl, trifluoromethyl, trifluoromethoxy and straight-chain or
branched alkyl, acyl, hydroxyalkyl or alkoxy having in each case up
to 7 carbon atoms, or by a group of the formula --NR.sup.3R.sup.4,
[0007] in which [0008] R.sup.3 and R.sup.4 are identical or
different and represent hydrogen, phenyl or straight-chain or
branched alkyl having up to 6 carbon atoms, or [0009] A represents
a radical of the formula ##STR2## [0010] D represents aryl having 6
to 10 carbon atoms which is optionally substituted by phenyl,
nitro, halogen, trifluoromethyl or trifluoromethoxy, or [0011]
represents a radical of the formula ##STR3## [0012] in which [0013]
R.sup.5, R.sup.6 and R.sup.9 independently of one another represent
cycloalkyl having 3 to 6 carbon atoms, or [0014] represent aryl
having 6 to 10 carbon atoms or represent a 5- to 7-membered
optionally benzo-fused saturated or unsaturated mono-, bi- or
tricyclic hetreocycle having up to 4 heteroatoms from the group
consisting of S, N and O, [0015] where the cycles are optionally
substituted, in the case of the nitrogen-containing rings also via
the N function, up to 5 times by identical or different
substituents from the group consisting of halogen, trifluoromethyl,
nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, and
straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy,
alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms,
by aryl or trifluoromethyl-substituted aryl having in each case 6
to 10 carbon atoms or by an optionally benzo-fused aromatic 5- to
7-membered heterocycle having up to 3 heteroatoms from the group
consisting of S, N and O, [0016] and/or by a group of the formula
--OR.sup.10, --SR.sup.11, --SO.sub.2R.sup.2 or --NR.sup.13R.sup.14,
[0017] in which [0018] R.sup.10, R.sup.11 and R.sup.12
independently of one another represent aryl having 6 to 10 carbon
atoms which for its part is substituted up to 2 times by identical
or different substituents from the group consisting of phenyl,
halogen and straight-chain or branched alkyl having up to 6 carbon
atoms, [0019] R.sup.13 and R.sup.14 are identical or different and
have the meaning of R.sup.3 and R.sup.4 given above, [0020] or
[0021] R.sup.5 and/or R.sup.6 represent(s) a radical of the formula
##STR4## [0022] R.sup.7 represents hydrogen or halogen, [0023] and
[0024] R.sup.8 represents hydrogen, halogen, azido,
trifluoromethyl, hydroxyl, trifluoromethoxy, straight-chain or
branched alkoxy or alkyl having in each case up to 6 carbon atoms
or a radical of the formula --NR.sup.15R.sup.16, [0025] in which
[0026] R.sup.15 and R.sup.16 are identical or different and have
the meaning of R.sup.3 and R.sup.4 given above, [0027] or [0028]
R.sup.7 and R.sup.8 together form a radical of the formula .dbd.O
or .dbd.NR.sup.17, [0029] in which [0030] R.sup.17 represents
hydrogen or straight-chain or branched alkyl, alkoxy or acyl having
in each case up to 6 carbon atoms, [0031] L represents a
straight-chain or branched alkylene or alkenylene chain having in
each case up to 8 carbon atoms which are optionally substituted up
to 2 times by hydroxyl, [0032] T and X are identical or different
and represent a straight-chain or branched alkylene chain having up
to 8 carbon atoms, [0033] or [0034] T or X represents a bond,
[0035] V represents an oxygen or sulphur atom or represents an
--NR.sup.18 group, [0036] in which [0037] R.sup.18 represents
hydrogen or straight-chain or branched alkyl having up to 6 carbon
atoms or phenyl, [0038] E represents cycloalkyl having 3 to 8
carbon atoms, or [0039] represents straight-chain or branched alkyl
having up to 8 carbon atoms which is optionally substituted by
cycloalkyl having 3 to 8 carbon atoms or hydroxyl, or represents
phenyl which is optionally substituted by halogen or
trifluoromethyl, [0040] R.sup.1 and R.sup.2 together form a
straight-chain or branched alkylene chain having up to 7 carbon
atoms which has to be substituted by a carbonyl group and/or by a
radical of the formula ##STR5## [0041] in which [0042] a and b are
identical or different and represent a number 1, 2 or 3, [0043]
R.sup.19 represents hydrogen, cycloalkyl having 3 to 7 carbon
atoms, straight-chain or branched silylalkyl having up to 8 carbon
atoms or straight-chain or branched alkyl having up to 8 carbon
atoms which is optionally substituted by hydroxyl, straight-chain
or branched alkoxy having up to 6 carbon atoms or by phenyl which
for its part may be substituted by halogen, nitro, trifluoromethyl,
trifluoromethoxy or by phenyl or tetrazole-substituted phenyl,
[0044] and alkyl is optionally substituted by a group of the
formula --OR.sup.22, [0045] in which [0046] R.sup.22 represents
straight-chain or branched acyl having up to 4 carbon atoms or
benzyl, [0047] or [0048] R.sup.19 represents straight-chain or
branched acyl having up to 20 carbon atoms or benzoyl which is
optionally substituted by halogen, trifluoromethyl, nitro or
trifluoromethoxy, or [0049] represents straight-chain or branched
fluoroacyl having up to 8 carbon atoms and 9 fluorine atoms, [0050]
R.sup.20 and R.sup.21 are identical or different, represent
hydrogen, phenyl or straight-chain or branched alkyl having up to 6
carbon atoms, [0051] or [0052] R.sup.20 and R.sup.21 together form
a 3 to 6-membered carbocycle [0053] and, if appropriate also
geminally, the carbocycles formed are optionally substituted up to
6 times by identical or different substituents from the group
consisting of trifluoromethyl, hydroxyl, nitrile, halogen,
carboxyl, nitro, azido, cyano, cycloalkyl or cycloalkyloxy having
in each case 3 to 7 carbon atoms, straight-chain or branched
alkoxycarbonyl, alkoxy or alkylthio having in each case up to 6
carbon atoms and straight-chain or branched alkyl having up to 6
carbon atoms which for its part is substituted up to 2 times by
identical or different substituents from the group consisting of
hydroxyl, benzyloxy, trifluoromethyl, benzoyl, straight-chain or
branched alkoxy, oxyacyl or carboxyl having in each case up to 4
carbon atoms and phenyl which for its part may be substituted by
halogen, trifluoromethyl or trifluoromethoxy, [0054] and/or the
carbocycles formed are optionally substituted, also geminally, up
to 5 times by identical or different substituents from the group
consisting of phenyl, benzoyl, thiophenyl and sulphonylbenzyl which
for their part are optionally substituted by halogen,
trifluoromethyl, trifluoromethoxy or nitro, [0055] and/or are
optionally substituted by a radical of the formula ##STR6## [0056]
in which [0057] c represents a number 1, 2, 3 or 4, [0058] d
represents a number 0 or 1, [0059] R.sup.23 and R.sup.24 are
identical or different and represent hydrogen, cycloalkyl having 3
to 6 carbon atoms, straight-chain or branched alkyl having up to 6
carbon atoms, benzyl or phenyl which is optionally substituted up
to 2 times by identical or different substituents from the group
consisting of halogen, trifluoromethyl, cyano, phenyl and nitro,
[0060] and/or the carbocycles formed are optionally substituted by
a spiro-linked radical of the formula ##STR7## [0061] in which
[0062] w represents either an oxygen or a sulphur atom, [0063] Y
and Y' together form a 2- to 6-membered straight-chain or branched
alkylene chain, [0064] e represents a number 1, 2, 3, 4, 5, 6 or 7,
[0065] f represents a number 1 or 2, [0066] R.sup.25, R.sup.26,
R.sup.27, R.sup.28, R.sup.29, R.sup.30 and R.sup.31 are identical
or different and represent hydrogen, trifluoromethyl, phenyl,
halogen or straight-chain or branched alkyl or alkoxy having in
each case up to 6 carbon atoms, [0067] or [0068] R.sup.25 and
R.sup.26 or R.sup.27 and R.sup.28 in each case together form a
straight-chain or branched alkyl chain having up. to 6 carbon
atoms, [0069] or [0070] R.sup.25 and R.sup.26 or R.sup.27 and
R.sup.28 in each case together form a radical of the formula
##STR8## [0071] in which [0072] W is as defined above, [0073] g
represents a number 1, 2, 3, 4, 5, 6 or 7, [0074] R.sup.32 and
R.sup.33 together form a 3- to 7-membered heterocycle which
contains an oxygen or sulphur atom or a group of the formula SO,
SO.sub.2 or --NR.sup.34, [0075] in which [0076] R.sup.34 represents
hydrogen, phenyl, benzyl or straight-chain or branched alkyl having
up to 4 carbon atoms, [0077] and their salts and N-oxides.
[0078] The hetero-tetrahydroquinolines according to the invention
can also be present in the form of their salts. In general, salts
with organic or inorganic bases or acids may be mentioned here.
[0079] In the context of the present invention, preference is given
to physiologically acceptable salts. Physiologically acceptable
salts of the compounds according to the invention can be salts of
the substances according to the invention with mineral acids,
carboxylic acids or sulphonic acids. Particular preference is
given, for example, to salts with hydrochloric acid, hydrobromic
acid, sulphuric acid, phosphoric acid, methanesulphonic acid,
ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid,
naphthalenedisulphonic acid, acetic acid, propionic acid, lactic
acid, tartaric acid, citric acid, fumaric acid, maleic acid or
benzoic acid.
[0080] Physiologically acceptable salts can also be metal or
ammonium salts of the compounds according to the invention which
have a free carboxyl group. Particular preference is given, for
example, to sodium salts, potassium salts, magnesium salts or
calcium salts, and also to ammonium salts which are derived from
ammonia or organic amines, such as, for example, ethylamine, di- or
triethylamine, di- or triethanolamine, dicyclohexylamine,
dimethylaminoethanol, arginine, lysine, ethylenediamine or
2-phenylethylamine.
[0081] The compounds according to the invention can exist in
stereoisomeric forms which are either like image and mirror image
(enantiomers), or which are not like image and mirror image
(diastereomers). The invention relates both to the enantiomers or
diastereomers and to their respective mixtures. These mixtures of
the enantiomers and diastereomers can be separated into the
stereoisomerically uniform components in a known manner.
[0082] In the context of the invention, a 3- to 8-membered
saturated carbocyclic ring represents a cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl ring. Preference
is given to a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl
ring. Particular preference is given to cyclobutyl, cyclopentyl or
cyclohexyl.
[0083] In the context of the invention, heterocycle generally
represents a saturated, partially unsaturated or unsaturated,
optionally benzo-fused 5- to 7-membered, preferably 5- to
6-membered, heterocycle which may contain up to 3 heteroatoms from
the group consisting of S, N and O. Examples which may be mentioned
are:. indolyl, isoquinolyl, quinolyl, benzo[b]thiophene,
benzo[b]furanyl, pyridyl, thienyl, furyl, pyrrolyl, thiazolyl,
oxazolyl, inidazolyl, morpholinyl or piperidyl. Preference is given
to quinolyl, furyl, pyridyl and thienyl.
[0084] Preference is given to the compounds of the general formula
(I) according to the invention,
[0085] in which [0086] A represents cyclopropyl, cyclobutyl,
cyclopentyl, cycloheptyl, cyclooctyl or cyclohexyl, or [0087]
represents thienyl, imidazolyl, pyrrole, furryl, pyridyl,
morpholine, pyrimidyl or pyridazinyl, which are optionally
substituted up to 2 times by identical or different substituents
from the group consisting of fluorine, chlorine, bromine, amino,
hydroxyl, trifluoromethyl, trifluoromethoxy and straight-chain or
branched alkyl, and alkoxy having in each case up to 6 carbon
atoms, or [0088] A represents a radical of the formula ##STR9##
[0089] D represents phenyl which is optionally substituted by
nitro, fluorine, chlorine, bromine, phenyl, trifluoromethyl or
trifluoromethoxy, or [0090] represents a radical of the formula
##STR10## in which [0091] R.sup.5, R.sup.6 and R.sup.9
independently of one another represent cyclopropyl, cyclopentyl or
cyclohexyl, or [0092] represent phenyl, naphthyl, pyridyl,
tetrazolyl, pyrimidyl, pyrazinyl, pyrrolidinyl, indolyl,
morpholinyl, imidazolyl, benzothiazolyl, phenoxathiin-2-yl,
benzoxazolyl, furyl, quinolyl or purin-8-yl, [0093] where the
cycles are optionally substituted up to 3 times, in the case of the
nitrogen-containing rings also via the N function, by identical or
different substituents from the group consisting of fluorine,
chlorine, bromine, trifluoromethyl, hydroxyl, cyano, carboxyl,
trifluoromethoxy, straight-chain or branched acyl, alkyl,
alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl having in each
case up to 4 carbon atoms, triazolyl, tetrazolyl, benzoxathiazolyl,
trifluoromethyl-substituted phenyl and phenyl, or [0094] R.sup.7
represents hydrogen, fluorine, chlorine or bromine, and [0095]
R.sup.8 represents hydrogen, fluorine, chlorine, bromine, azido,
trifluoromethyl, hydroxyl, trifluoromethoxy, straight-chain or
branched alkoxy or alkyl having in each case up to 5 carbon atoms
or a radical of the formula --NR.sup.15R.sup.16, [0096] in which
[0097] R.sup.15 and R.sup.16 are identical or different and
represent hydrogen, phenyl or straight-chain or branched alkyl
having up to 4 carbon atoms, or [0098] R.sup.7 and R.sup.8 together
form a radical of the formula .dbd.O or .dbd.NR.sup.17,
[0099] in which [0100] R.sup.17 represents hydrogen or
straight-chain or branched alkyl, alkoxy or acyl having in each
case up to 4 carbon atoms, [0101] L represents a straight-chain or
branched alkylene or alkenylene chain having in each case up to 6
carbon atoms which are optionally substituted up to 2 times by
hydroxyl, [0102] T and X are identical or different and represent a
straight-chain or branched alkylene chain having up to 6 carbon
atoms, or [0103] T or X represents a bond, [0104] V represents an
oxygen or sulphur atom or represents a group of the formula
--NR.sup.18--, [0105] in which [0106] R.sup.18 represents hydrogen
or straight-chain or branched alkyl having up to 4 carbon atoms or
phenyl, [0107] E represents cyclopropyl, -butyl, -pentyl, -hexyl or
-heptyl, or represents straight-chain or branched alkyl having up
to 6 carbon atoms which is optionally substituted by cyclopropyl,
-butyl, -hexyl, -pentyl, -heptyl or by hydroxyl, or represents
phenyl which is optionally substituted by fluorine, chlorine or
trifluoromethyl, [0108] R.sup.1 and R.sup.2 together form a
straight-chain or branched alkylene chain having up to 6 carbon
atoms which has to be substituted by a carboxyl group and/or by a
radical of the formula ##STR11## [0109] in which [0110] a and b are
identical or different and represent a number 1, 2 or 3, [0111]
R.sup.19 represents hydrogen, cyclopropyl, cyclopentyl, cyclohexyl,
straight-chain or branched silylalkyl having up to 7 carbon atoms
or straight-chain or branched alkyl having up to 6 carbon atoms
which is optionally substituted by hydroxyl, straight-chain or
branched alkoxy having up to 4 carbon atoms or by phenyl which for
its part may be substituted by fluorine, chlorine, bromine, nitro,
trifluoromethyl, trifluoromethoxy or by phenyl or
tetrazole-substituted phenyl, [0112] and alkyl is optionally
substituted by a group of the formula --OR.sup.22, [0113] in which
[0114] R.sup.22 represents straight-chain or branched acyl having
up to 3 carbon atoms or benzyl, [0115] or [0116] R.sup.19
represents straight-chain or branched acyl having up to 18 carbon
atoms or benzoyl which is optionally substituted by fluorine,
chlorine, bromine, trifluoromethyl, nitro or trifluoromethoxy, or
[0117] represents straight-chain or branched fluoroacyl having up
to 6 carbon atoms, [0118] R.sup.20 and R.sup.21 are identical or
different, represent hydrogen, phenyl or straight-chain or branched
alkyl having up to 4 carbon atoms, [0119] or [0120] R.sup.20 and
R.sup.21 together form a cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl or cycloheptyl ring, [0121] and the carbocycles formed
are optionally substituted, if appropriate, also geminally, up to 5
times by identical or different substituents from the group
consisting of trifluoromethyl, hydroxyl, carboxyl, azido, fluorine,
chlorine, bromine, nitro, cyano, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cyclopropyloxy, cyclopentyloxy,
cyclohexyloxy, straight-chain or branched alkoxycarbonyl, alkoxy or
alkylthio having in each case up to about 5 carbon atoms and
straight-chain or branched alkyl having up to 5 carbon atoms which
for its part is substituted up to 2 times by identical or different
substituents from the group consisting of hydroxyl, benzyloxy,
benzoyl, straight-chain or branched alkoxy or oxyacyl having in
each case up to 3 carbon atoms, trifluoromethyl and phenyl which
for its part may be substituted by fluorine, chlorine, bromine,
trifluoromethyl or trifluoromethoxy, [0122] and/or the carbocycles
formed are optionally substituted, also geminally, up to 4 times by
identical or different substituents from the group consisting of
phenyl, benzoyl, thiophenyl and sulphonylbenzyl which for their
part are optionally substituted by fluorine, chlorine, bromine,
trifluoromethyl, trifluoromethoxy or nitro, [0123] and/or are
optionally substituted by a radical of the formula ##STR12## [0124]
in which [0125] c represents a number 1, 2, 3 or 4, [0126] d
represents a number 0 or 1, [0127] R.sup.23 and R.sup.24 are
identical or different and represent hydrogen, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, straight-chain or branched
alkyl having up to 5 carbon atoms, benzyl or phenyl which is
optionally substituted by fluorine, chlorine, bromine, phenyl or
trifluoromethyl, [0128] and/or the carbocycles formed are
optionally substituted by a spiro-linked radical of the formula
##STR13## [0129] in which [0130] W represents either an oxygen or a
sulphur atom, [0131] Y and Y' together form a 2- to 5-membered
straight-chain or branched alkyl chain, [0132] e represents a
number 1, 2, 3, 4, 5 or 6, [0133] f represents a number 1 or 2,
[0134] R.sup.25, R.sup.26, R.sup.27 and R.sup.28 are identical or
different and represent hydrogen, trifluoromethyl, phenyl,
fluorine, chlorine, bromine or straight-chain or branched alkyl or
alkoxy having in each case up to 5 carbon atoms, [0135] or [0136]
R.sup.25 and R.sup.26 or R.sup.27 and R.sup.28 in each case
together form a straight-chain or branched alkyl chain having up to
5 carbon atoms or [0137] or [0138] R.sup.25 and R.sup.26 or
R.sup.27 and R.sup.28 in each case together form a radical of the
formula ##STR14## [0139] in which [0140] W is as defined above,
[0141] g represents a number 1, 2, 3, 4, 5 or 6, [0142] and their
salts and N-oxides.
[0143] Particular preference is given to compounds of the general
formula (I) according to the invention,
in which
[0144] A represents cyclopropyl, cyclopentyl or cyclohexyl, or
[0145] represents thienyl or pyridyl which are optionally
substituted up to 2 times by identical or different substituents
from the group consisting of fluorine, chlorine, bromine, hydroxyl,
trifluoromethyl, trifluoromethoxy and straight-chain or branched
alkyl or alkoxy having in each case up to 5 carbon atoms, or [0146]
A represents a radical of the formula ##STR15## [0147] D represents
phenyl which is optionally substituted by nitro, trifluoromethyl,
phenyl, fluorine, chlorine or bromine, or [0148] represents a
radical of the formula ##STR16## [0149] in which [0150] R.sup.5,
R.sup.6 and R.sup.9 independently of one another represent
cyclopropyl, cyclopentyl or cyclohexyl, or [0151] represent phenyl,
naphthyl or pyridyl, [0152] where the cycles optionally up to 2
times by identical or different substituents from the group
consisting of fluorine, chlorine, trifluoromethyl, hydroxyl, cyano,
carboxyl, trifluoromethoxy and straight-chain or branched alkyl,
alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl having in each
case up to 4 carbon atoms, [0153] or [0154] R.sup.7 represents
hydrogen or fluorine, [0155] and [0156] R.sup.8 represents
hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl,
hydroxyl, trifluoromethoxy, or straight-chain or branched alkoxy or
alkyl having in each case up to 4 carbon atoms or a radical of the
formula --NR.sup.15R.sup.16, [0157] in which [0158] R.sup.15and
R.sup.16 are identical or different and represent hydrogen or
straight-chain or branched alkyl having up to 3 carbon atoms,
[0159] or [0160] R.sup.7 and R.sup.8 together represent a radical
of the formula .dbd.O, [0161] L represents a straight-chain or
branched alkylene or alkenylene chain having in each case up to 5
carbon atoms which are optionally substituted up to 2 times by
hydroxyl, [0162] T and X are identical or different and represent a
straight-chain or branched alkylene chain having up to 3 carbon
atoms, [0163] or [0164] T or X represents a bond, [0165] V
represents an oxygen or sulphur atom or a group of the formula
--N.sup.18, [0166] in which [0167] R.sup.18 represents hydrogen or
straight-chain or branched alkyl having up to 3 carbon atoms,
[0168] E represents cyclopropyl, cyclopentyl or cyclohexyl or
phenyl which is optionally substituted by fluorine or
trifluoromethyl, or [0169] represents straight-chain or branched
alkyl having up to 4 carbon atoms which is optionally substituted
by hydroxyl, [0170] R.sup.1 and R.sup.2 together form a
straight-chain or branched alkylene chain having up to 5 carbon
atoms which has to be substituted by a carbonyl group and/or a
radical of the formula --OR.sup.19, [0171] in which [0172] R.sup.19
represents hydrogen, cyclopropyl, cyclopentyl or cyclohexyl, [0173]
or [0174] R.sup.19 represents straight-chain or branched acyl
having up to 15 carbon atoms or benzoyl which is optionally
substituted by fluorine, chlorine, bromine, trifluoromethyl, nitro
or trifluoromethoxy, or [0175] represents a radical of the formula
--Si(CH.sub.3).sub.2C(CH.sub.3).sub.3, [0176] and the carbocycles
formed are optionally substituted, if appropriate also geminally,
up to 4 times by identical or different substituents from the group
consisting of fluorine, hydroxyl, trifluoromethyl, carboxyl, azido,
chlorine, bromine, nitro, cyano, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cyclopropyloxy, cyclopentyloxy,
cyclohexyloxy, straight-chain or branched alkoxycarbonyl, alkoxy or
alkylthio having in each case up to 4 carbon atoms and
straight-chain or branched alkyl having up to 4 carbon atoms which
for its part is substituted up to 2 times by identical or different
substituents from the group consisting of hydroxyl, benzyloxy,
trifluoromethyl, benzoyl, methoxy, oxyacetyl and phenyl which for
its part may be substituted by fluorine, chlorine, bromine,
trifluoromethyl or trifluoromethoxy, [0177] and/or the carbocycles
formed are optionally substituted, also geminally, up to 4 times by
identical or different substituents from the group consisting of
phenyl, benzoyl, thiophenyl and sulphonylbenzyl which for their
part are optionally substituted by fluorine, trifluoromethyl,
trifluoromethoxy or nitro, [0178] and/or are optionally substituted
by a radical of the formula ##STR17## [0179] in which [0180] c
represents a number 1, 2, 3 or 4, [0181] and/or the carbocycles
formed are optionally substituted by a spiro-linked radical of the
formula ##STR18## [0182] in which [0183] e represents a number 1,
2, 3, 4 or 5, [0184] R.sup.25 , R.sup.26, R.sup.27 and R.sup.28 are
identical or different and represent hydrogen, trifluoromethyl,
phenyl, fluorine, chlorine, bromine or straight-chain or branched
alkyl or alkoxy having in each case up to 4 carbon atoms, [0185] or
[0186] R.sup.25 and R.sup.26 or R.sup.27 and R.sup.28 together form
a straight-chain or branched alkyl chain having up to 4 carbon
atoms, and their salts and N-oxides.
[0187] Very particular preference is given to compounds of the
general formula (I) according to the invention,
in which
[0188] A represents cyclopropyl, cyclopentyl or cyclohexyl, or
[0189] represents thienyl or pyridyl, or A represents a radical of
the formula ##STR19## [0190] D represents phenyl which is
optionally substituted by trifluoromethyl, fluorine, or [0191]
represents a radical of the formula ##STR20## [0192] in which
[0193] R.sup.6 represents phenyl which is optionally substituted by
fluorine, chlorine, trifluoromethyl, trifluoromethoxy,
straight-chain or branched alkyl having in each case up to 4 carbon
atoms, [0194] or [0195] R.sup.7 represents hydrogen or fluorine,
[0196] and [0197] R.sup.8 represents hydrogen, fluorine, chlorine,
hydroxyl, methoxy or [0198] R.sup.7 and R.sup.8 together represent
a radical of the formula .dbd.O, [0199] E represents cyclopropyl,
cyclopentyl or cyclohexyl [0200] represents straight-chain or
branched alkyl having up to 4 carbon atoms, [0201] R.sup.1 and
R.sup.2 together form a straight-chain or branched alkylene chain
having up to 5 carbon atoms which has to be substituted by a
carbonyl group and/or a radical of the formula --OR.sup.19, [0202]
in which [0203] R.sup.19 represents hydrogen [0204] or represents a
radical of the formula --Si(CH.sub.3).sub.2C(CH.sub.3).sub.3, and
their salts and N-oxides.
[0205] Moreover, processes for preparing the compounds of the
general formula (I) according to the invention have been found,
characterized in that [0206] [A] in the case where D.noteq.aryl,
compounds of the general formula (II) ##STR21## in which [0207] A,
E, R.sup.1 and R.sup.2 are as defined above, [0208] with
organometallic reagents in a Grignard or Wittig reaction or in a
reaction with organolithium compounds, the substituent D is
synthesized in inert solvents, or in the case where D represents
the radical of the formula R.sup.9-T-V-X in which V is an oxygen
atom, [0209] [B] either compounds of the general formula (III)
##STR22## in which [0210] A, E, X, R.sup.1 and R.sup.2 are as
defined above, [0211] are reacted with compounds of the general
formula (IV) R.sup.9-T-Z (IV), in which [0212] R.sup.9 and T are as
defined above and [0213] Z represents halogen, preferably chlorine
or bromine, [0214] in inert solvents, if appropriate in the
presence of a base and/or auxiliary, or [0215] [C] compounds of the
general formula (III) are initially, by reaction with compounds of
the general formula (V) ##STR23## in which [0216] R.sup.35
represents straight-chain alkyl having up to 4 carbon atoms, [0217]
converted into the compounds of the general formula (VI) ##STR24##
in which [0218] A, E, X, R.sup.1, R.sup.2 and R.sup.35 are as
defined above, [0219] and subsequently reacted with compounds of
the general formula (VII) R.sup.9-T-V-H (VII), in which [0220]
R.sup.9, T and V are as defined above, [0221] and, if appropriate,
protective groups are removed, or [0222] [D] in the case of the
compounds of the general formula (Ia) ##STR25## in which [0223] A
and R.sup.6 are as defined above, [0224] R.sup.36 and R.sup.37 are
identical or different and [0225] represent cycloalkyl or
cycloalkyloxy having in each case 3 to 7 carbon atoms, [0226] or
[0227] represent straight-chain or branched alkyl having up to 6
carbon atoms, or [0228] represent phenyl which for its part are
optionally substituted by halogen, trifluoromethyl,
trifluoromethoxy or nitro, or [0229] R.sup.36 and R.sup.37
represent one of the abovementioned spiro-linked radicals of the
formula ##STR26## in which [0230] W, Y, Y', R.sup.25, R.sup.26,
R.sup.27, R.sup.28, e, R.sup.29, R.sup.30, R.sup.31, R.sup.32 and
R.sup.33 are as defined above,
[0231] compounds of the general formula (VIII) ##STR27## in which
[0232] R.sup.6, R.sup.36, R.sup.37, A and E are as defined above,
[0233] are initially oxidized to the compounds of the general
formula (IX) ##STR28## in which [0234] R.sup.6, R.sup.36, R.sup.37,
A and E are as defined above, [0235] these are, in a subsequent
step, converted by asymmetric reduction into the compounds of the
general formula (X) ##STR29## in which [0236] R.sup.6 , R.sup.36,
R.sup.37, A and E are as defined above, [0237] these are then
converted, by the introduction of a hydroxyl protective group, into
the compounds of the general formula (XI) ##STR30## in which [0238]
R.sup.6, R.sup.36, R.sup.37, A and E are as defined above and
[0239] R.sup.38 represents a hydroxyl protective group, preferably
a radical of the formula --SiR.sup.39R.sup.40R.sup.41, [0240] in
which [0241] R.sup.39, R.sup.40 and R.sup.41 are identical or
different and represent C.sub.1-C.sub.4-alkyl,
[0242] which is used to prepare in a subsequent step, by
diastereoselective reduction, the compounds of the general formula
(XII) ##STR31## in which [0243] R.sup.6, R.sup.36, R.sup.37,
R.sup.38, A and E are as defined above, [0244] and the compounds of
the general formula (XIII) ##STR32## in which [0245] R.sup.6,
R.sup.36, R.sup.37, R.sup.38, A and E are as defined above, [0246]
are subsequently prepared by introducing the fluorine substituent
with fluorinating agents, such as, for example, DAST and SF.sub.4
derivatives, [0247] and the hydroxyl protective group is then
removed by customary methods, [0248] and, if appropriate, the
substituents listed under D, E and/or R.sub.1 and R.sup.2 are
varied or introduced by customary methods.
[0249] By way of example, the processes according to the invention
can be illustrated by the following schemes: ##STR33##
##STR34##
[0250] Suitable solvents for all processes are ethers such as
diethyl ether, dioxane, tetrahydrofuiran, glycol dimethyl ether, or
hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane
or mineral oil fractions, or halogenated hydrocarbons such as
dichloromethane, trichloromethane, carbon tetrachloride,
dichloroethylene, trichlorbethylene or chlorobenzene, or ethyl
acetate, or triethylamine, pyridine, dimethyl sulphoxide,
dimethylformamide, hexamethylphosphoric triamide, acetonitrile,
acetone or nitromethane. It is also possible to use mixtures of the
solvents mentioned. Preference is given to dichloromethane.
[0251] Suitable bases for the individual steps are the customary
strongly basic compounds. These preferably include organolithium
compounds such as, for example, N-butyllithium, sec-butyllithium,
tertbutyllithium or phenyllithium, or amides such as, for example,
lithium diisopropylamide, sodium amide or potassium amide, or
lithium hexamethylsilylamide, or alkali metal hydrides such as
sodium hydride or potassium hydride. Particular preference is given
to using N-butyllithium, sodium hydride or lithium
diisopropylamide.
[0252] Suitable for the processes [B] and [C] are furthermore the
customary inorganic bases. These preferably include alkali metal
hydroxides or alkaline earth metal hydroxides, such as, for
example, sodium hydroxide, potassium hydroxide or barium hydroxide,
or alkali metal carbonates such as sodium carbonate or potassium
carbonate or sodium bicarbonate. Particular preference is given to
using sodium hydride or potassium hydroxide.
[0253] Suitable organometallic reagents are, for example, systems
such as Mg/bromobenzotrifluoride and
p-trifluoromethylphenyllithium.
[0254] The reductions are generally carried out with reducing
agents, preferably those which are suitable for reducing ketones to
hydroxyl compounds are. Particularly suitable for this purpose is
the reduction with metal hydrides or complex metal hydrides in
inert solvents, if appropriate in the presence of a trialkylborane.
The reduction is preferably carried out using complex metal
hydrides such as, for example, lithium borohydrides, sodium
borohydrides, potassium borohydrides, zinc borohydrides, lithium
trialkylborohydride, diisobutylaluminium hydride or lithium
aluminium hydride. The reaction is very particularly preferably
carried out using diisobutylaluminium hydride and sodium
borohydride.
[0255] The reducing agent is generally employed in an amount of
from 1 mol to 6 mol, preferably from 1 mol to 4 mol, based on 1 mol
of the compounds to be reduced.
[0256] The reduction generally proceeds in a temperature range of
from -78.degree. C. to +50.degree. C., preferably of from
-78.degree. C. to 0.degree. C. in the case of DIBAH, of from
0.degree. C. to room temperature in the case of NaBH, particularly
preferably at -78.degree. C., in each case depending on the choice
of reducing agent and solvent.
[0257] The reduction generally proceeds at atmospheric pressure;
however, it is also possible to carry out the reduction at elevated
or reduced pressure.
[0258] In the case [A], the process is preferably carried out using
initially compounds of the general formula (II) in which the
carbocycle R.sup.1/R.sup.2 is initially only substituted by a group
--OSiR.sup.IR.sup.IIR.sup.III in which R.sup.I, R.sup.II and
R.sup.III are identical or different and represent phenyl or
straight-chain or branched alkyl having up to 5 carbon atoms, and
the substituent mentioned above under R.sup.19/R.sup.20 is
introduced by customary methods after the protective group has been
removed.
[0259] Removal of the protective group is generally carried out in
one of the abovementioned alcohols and THF, preferably
methanol/THF, in the presence of hydrochloric acid in a temperature
range of from 0.degree. C. to 50.degree. C., preferably at room
temperature, and at atmospheric pressure. In particular cases,
preference is given to removing the protective group with
tetrabutylarunonium fluoride (TBAF) in THF.
[0260] In the context of the definition given above, hydroxyl
protective group generally represents a protective group from the
group trimethylsilyl, triisopropylsilyl, tert-butyl-dimethylsilyl,
benzyl, benzyloxycarbonyl, 2-nitrobenzyl, 4-nitrobenzyl,
tert-butyloxycarbonyl, allyloxycarbonyl, 4-methoxybenzyl,
4-methoxybenzyloxycarbonyl, tetrahydropyranyl, formyl, acetyl,
trichloroacetyl, 2,2,2-trichloroethoxycarbonyl,
methoxyethoxymethyl, [2-(trimethylsilyl)ethoxy]methyl, benzoyl,
4-methylbenzoyl, 4-nitrobenzoyl, 4-fluorobenzoyl, 4-chlorobenzoyl
or 4-methoxybenzoyl. Preference is given to tetrahydropyranyl,
tertbutyldimethylsilyl and triisopropylsilyl. Particular preference
is given to tertbutyldimethylsilyl.
[0261] Suitable solvents for the individual steps are ethers such
as diethyl, ether, dioxane, tetrahydrofuran, glycol dimethyl ether,
diisopropyl ether or hydrocarbons such as benzene, toluene, xylene,
hexane, cyclohexane or mineral oil fractions, or halogenated
hydrocarbons such as dichloromethane, trichloromethane, carbon
tetrachloride,. dichlocroethylene, trichloroethylene or
chlorobenzene. It is also possible to use mixtures of the solvents
mentioned.
[0262] Suitable oxidizing agents for preparing the compounds of the
general formula (IX) are, for example, nitric acid, cerium (IV)
ammonium nitrate, 2,3-dichloro-5,6-dicyano-benzoquinone, pyridinium
chlorochromate (PCC), pyridinium chlorochromate on basic alumina,
osmium tetroxide and manganese dioxide. Preference is given to
manganese dioxide and nitric acid.
[0263] The oxidation is carried out in one of the abovementioned
chlorinated hydrocarbons and water. Preference is given to
dichloromethane and water.
[0264] The oxidizing agent is employed in an amount of from 1 mol
to 10 mol, preferably from 2 mol to 5 mol, based on 1 mol of the
compounds of the general formula (VIII).
[0265] The oxidation generally proceeds at a temperature of from
-50.degree. C. to +100.degree. C., preferably from 0.degree. C. to
room temperature.
[0266] The oxidation generally proceeds at atmospheric pressure.
However, it is also possible to carry out the oxidation at elevated
or reduced pressure.
[0267] The asymmetric reduction to the compounds of the general
formula (X) is generally carried out in one of the abovementioned
ethers or toluene, preferably tetrahydrofuran and toluene.
[0268] The reduction is generally carried out using
enantiomerically pure 1R,2S-aminoindanol and borane complexes such
as BH.sub.3.times.THF, BH.sub.3.times.DMS and
BH.sub.3.times.(C.sub.2H.sub.5).sub.2NC.sub.6H.sub.5. Preference is
given to the system borane-diethylaniline/1R,2S-aminoindanol.
[0269] The reducing agent is generally employed in an amount of
from 1 mol to 6 mol, preferably from 1 mol to 4 mol, based on 1 mol
of the compounds to be reduced.
[0270] The reduction generally proceeds at a temperature of from
-78.degree. C. to +50.degree. C., preferably from 0.degree. C. to
30.degree. C.
[0271] The reduction generally proceeds at atmospheric pressure;
however, it is also possible to carry out the reduction at elevated
or reduced pressure.
[0272] The hydroxyl protective group is introduced in one of the
abovementioned hydrocarbons, dimethylformamide or THF, preferably
in toluene in the presence of lutidine in a temperature range of
from -20.degree. C. to +50.degree. C., preferably from -5.degree.
C. to room temperature and at atmospheric pressure.
[0273] General reagents for introducing the silyl protective group
are tert-butyldimethylsilyl chloride or tert-butyldimethylsilyl
trifluoromethanesulphonate. Preference is given to
tert-butylimethylsilyl trifluoromethanesulphonate.
[0274] The reduction to the compounds of the general formula (XII)
proceeds in one of the abovementioned hydrocarbons, preferably
toluene.
[0275] The reduction to prepare the compounds of the general
formula (XII) is generally carried out using customary reducing
agents, preferably those which are suitable for reducing ketones to
hydroxyl compounds. Particularly suitable for this purpose is the
reduction with metal hydrides or complex metal hydrides in the
abovementioned inert solvents, such as, for example, toluene, if
appropriate in the presence of a trialkylborane. The reduction is
preferably carried out using complex metal hydrides such as, for
example, lithium borohydride, sodium borohydride, potassium
borohydride, zinc borohydride, lithium trialkylborohydride,
diisobutylaluminium hydride, sodium bis-(2-methoxyethoxy)aluminium
hydride or lithium aluminium hydride. The reduction is very
particularly preferably carried out using sodium
bis-(2-methoxyethoxy)aluminium hydride.
[0276] The reducing agent is generally employed in an amount of
from 1 mol to 6 mol, preferably from 1 mol to 3 mol, based on 1 mol
of the compounds to be reduced.
[0277] The reduction generally proceeds at a temperature of from
-20.degree. C. to +110.degree. C., preferably from 0.degree. C. to
room temperature.
[0278] The reduction generally proceeds at atmospheric pressure;
however, it is also possible to carry out the reduction at elevated
or reduced pressure.
[0279] In the reduction to the compounds of the general formula
(XII), small residues of the wrong diastereomer remain in the
mother liquor. These residues can be reoxidized with customary
oxidizing agents such as, for example, pyridinium chlorochromate
(PCC) or activated manganese dioxide, in particular with activated
manganese dioxide, to give protected (XI) and thus be recycled into
the synthesis cycle without any loss in yield.
[0280] The fluorine substituent is generally introduced in one of
the abovementioned hydrocarbons or methylene chloride, preferably
in toluene and under an atmosphere of protective gas.
[0281] Under SF.sub.4 derivatives, in general diethylamino sulphur
trifluoride or 2,2'-bisfluoro-substituted amines such as, for
example, diethyl-1,2,3,3,3-hexafluoropropylamine are prepared.
[0282] The reaction generally proceeds at a temperature of from
-78.degree. C. to 100.degree. C., in the case of dimethylamino
sulphur trifluoride preferably at from -78.degree. C. to RT and in
the case of diethyl-1,1,2,3,3,3-hexafluoropropylamine preferably at
from room temperature to 80.degree. C.
[0283] The protective group is generally removed in one of the
abovementioned alcohols and THF, preferably methanol/THF in the
presence of hydrochloric acid in a temperature range of from
0.degree. C. to 50.degree. C., preferably at room temperature, and
atmospheric pressure. In particular cases, preference is given to
removing the protective group with tetrabutylammonium fluoride
(TBAF) in THF at room temperature.
[0284] The following types of reaction may be mentioned by way of
example for derivatizations:
[0285] oxidations, reductions, hydrogenations, halogenation,
Wittig/Grignard reactions and amidations/sulphoamidations.
[0286] Suitable bases for the individual steps are the customary
strongly basic compounds. These preferably include organolithium
compounds such as, for example, n-butyllithium, sec-butyllithium,
tertbutyllithium or phenyllithium, or amides such as, for example,
lithium diusopropylamide, sodium amide or potassium amide, or
lithium hexamethylsilylamide, or alkali metal hydrides such as
sodium hydride or potassium hydride. Particular preference is given
to using N-butyllithium, sodium hydride or lithium
diisopropylamide.
[0287] Suitable bases are furthermore the customary inorganic
bases. These preferably include alkali metal hydroxides or alkaline
earth metal hydroxides such as, for example, sodium hydroxide,
potassium hydroxide or barium hydroxide, or alkali metal carbonates
such as sodium carbonate or potassium carbonate or sodium
bicarbonate. Particular preference is given to using sodium
hydroxide or potassium hydroxide.
[0288] Suitable solvents for the individual reaction steps are also
alcohols such as methanol, ethanol, propanol, butanol or
tertbutanol. Preference is given to tertbutanol.
[0289] If required, it may be necessary to carry out some reaction
steps under an atmosphere of protective gas.
[0290] The halogenations are generally carried out in one of the
abovementioned chlorinated hydrocarbons, preference being given to
methylene chloride.
[0291] Suitable halogenating agents are, for example, diethylamino
sulphur trifluoride (DAST), morpholino sulphur trifluoride or
SOCl.sub.2.
[0292] The halogenation generally proceeds in a temperature range
of from -78.degree. C. to +50.degree. C., preferably from
-78.degree. C. to 0.degree. C., in each case depending on the
choice of the halogenating agent and the solvent.
[0293] The halogenation generally proceeds at atmospheric pressure;
however, it is also possible to carry out the halogenation at
elevated or reduced pressure.
[0294] The compounds of the general formulae (II) and (III) are
novel, and they can be prepared by preparing, [0295] by reaction of
the compounds of the general formula (XIV) ##STR35## in which
[0296] E is as defined above and [0297] R.sup.42 represents
C.sub.1-C.sub.4-alkoxycarbonyl or aryl (D=aryl) [0298] with
aldehydes of the general formula (XV) A-CHO (XV), in which [0299] A
is as defined above
[0300] and compounds of the general formula (XVI) ##STR36## in
which [0301] R.sup.43 and R.sup.44, together with a carbonyl group,
embrace the scope of the meaning of R.sup.1 and R.sup.2 mentioned
above, [0302] the compounds of the general formula (XVII) ##STR37##
in which [0303] A, E, R.sup.42, R.sup.43 and R.sup.44 are as
defined above
[0304] and, in the case of the compounds of the general formula
(III), carrying out a reduction, as described above, to furnish the
hydroxymethyl function
[0305] and, in a last step, converting the alkoxycarbonyl group
(R.sup.42) by a reduction-oxidation sequence into an aldehyde
group.
[0306] Solvents which are suitable for the oxidation are ethers
such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl
ether, or hydrocarbons such as benzene, toluene, xylene, hexane,
cyclohexane or mineral oil fractions, or halogenated hydrocarbons
such as dichloromethane, trichloromethane, carbon tetrachloride,
dichloroethylene, trichloroethylene or chlorobenzene, or ethyl
acetate, or triethylamine, pyridine, dimethyl sulphoxide,
dimethylformamide, hexamethylphosphoric triamide, acetonitrile,
acetone or nitromethane. It is also possible to use mixtures of the
solvents mentioned. Preference is given to methylene chloride.
[0307] Suitable oxidizing agents are, for example, cerium (IV)
ammonium nitrate, 2,3-dichloro-5,6-dicyano-benzoquinone, pyridinium
chlorochromate (PCC), pyridinium chlorochromate on basic alumina,
osmium tetroxide and manganese dioxide. Preference is given to
sulphur trioxide-pyridine complex in DMSO/methylene chloride and
pyridinium chlorochromate on basic alumina.
[0308] The oxidizing agent is employed in an amount of from 1 mol
to 10 mol, preferably from 2 mol to 5 mol, based on 1 mol of the
compounds of the general formula (XVII).
[0309] The oxidation generally proceeds in a temperature range of
from -50.degree. C. to +100.degree. C., preferably from 0.degree.
C. to room temperature.
[0310] The oxidation generally proceeds at atmospheric pressure.
However, it is also possible to carry out the oxidation at elevated
or reduced pressure.
[0311] The compounds of the general formulae (IV), (V), (VII),
(XIV), (XV) and (XVI) are known per se or can be prepared by
customary methods.
[0312] Some of the compounds of the general formulae (VI) and (XV)
are known, or they are novel, in which case they can be prepared as
described above.
[0313] The compounds of the general formulae (IX) and (X) are novel
species and can be prepared as described above.
[0314] The compounds of the general formula (VIII) are novel and
can be prepared by reacting
[0315] compounds of the general formulae (XVa), (XVIII) and (XIX)
##STR38## in which [0316] A, E, R.sup.6, R.sup.36 and R.sup.37 are
as defined above [0317] in the presence of an acid.
[0318] Suitable solvents for preparing the compounds of the general
formula (VIII) are the abovementioned ethers or alcohols.
Preference is given to dilsopropyl ether.
[0319] Suitable acids for preparing the compounds of the general
formula (VIII) are, in general, organic carboxylic acids and
inorganic acids, such as, for example, oxalic acid, maleic acid,
phosphoric acid, fumaric acid and trifluoroacetic acid. Preference
is given to trifluoroacetic acid.
[0320] The acid is generally employed in an amount of from 0.1 mol
to 5 mol, preferably 1 mol, based on 1 mol of the compounds of the
general formula (XIX).
[0321] The reaction is generally carried out at atmospheric
pressure. However, it is also possible to carry out the reaction at
elevated or reduced pressure.
[0322] The reaction is generally carried out at the reflux
temperature of the solvent in question.
[0323] The compounds of the general formulae (XV) and (XIX) are
known per se or can be prepared by customary methods.
[0324] The compounds of the general formula (XVIII) are novel and
can be prepared by initially preparing, by reaction of the
compounds of the general formula (XX) E-CO.sub.2-R.sup.45 (XX), in
which [0325] E is as defined above and [0326] R.sup.45 represents
C.sub.1-C.sub.4-alkyl [0327] with compounds of the general formula
(XXI) ##STR39## in which [0328] R.sup.6 is as defined above [0329]
in a solvent in the presence of 18-crown-6 ether, the compounds of
the general formula (XXII) ##STR40## in which [0330] R.sup.6 and E
are as defined above, [0331] followed by reaction with ammonium
acetate in inert solvents.
[0332] Suitable solvents for the first step of the process are the
abovementioned ethers and hydrocarbons, preference being given to
tetrahydrofuiran.
[0333] Suitable solvents for the reaction with the compounds of the
general formula (XXII) are alcohols, such as, for example,
methanol, ethanol, propanol or isopropanol. Preference is given to
ethanol.
[0334] All steps of the process are carried out at the respective
reflux temperature of the solvent in question and at atmospheric
pressure.
[0335] Some of the compounds of the general formulae (XX) and (XXI)
are known, or they can be prepared by known methods.
[0336] Some of the compounds of the general formula (XXII) are
novel species, and they can be prepared as described above.
[0337] The compounds of the general formulae (I) and (Ia) according
to the invention have a pharmacological activity spectrum which
could not have been foreseen.
[0338] The compounds of the general formulae (I) and (Ia) according
to the invention have useful pharmacological properties which are
superior when compared to the prior art, in particular, they are
highly effective inhibitors of the cholesterol ester transfer
protein (CETP) and they stimulate the reverse cholesterol
transport. The active compounds according to the invention effect a
reduction in the LDL cholesterol level in the blood and
simultaneously increase the HDL cholesterol level. They can
therefore be used for the treatment and prevention of
hypolipoproteinaemia, dyslipidaemias, hypertriglyceridaemias,
hyperlipidaemias or arteriosclerosis.
[0339] The pharmacological activity of the substances according to
the invention was determined in the following test:
CETP inhibition test
Preparation of CETP
[0340] CETP is obtained in partially purified form from human
plasma by differential centrifugation and column chromatography and
used for the test. For this purpose, human plasma is adjusted to a
density of 1.21 g per ml using NaBr and centrifuged at 50,000 rpm
at 4.degree. C. for 18 h. The bottom fraction (d>1.21 g/ml) is
applied to a Sephadex.RTM.Phenyl-Sepharose 4B (Pharmacia) column,
washed with 0.15 m NaCl/0.001 m TrisHCl pH 7.4 and subsequently
eluted using dist. water. The CETP-active fractions are pooled,
dialysed against 50 mM Na-acetate pH 4.5 and applied to a
CM-Sepharose.RTM. (Pharmacia) column. Elution is subsequently
carried out using a linear gradient (0-1 M NaCl). The pooled CETP
fractions are dialysed against 10 mM TrisHCl pH 7.4 and
subsequently purified further by chromatography over a Mono Q.RTM.
column (Pharmacia).
Preparation of Radioactively Labelled HDL
[0341] 50 ml of fresh human EDTA plasma are adjusted to a density
of 1.12 using NaBr and centrifuged at 4.degree. C. in a Ty65 rotor
at 50,000 rpm for 18 h. The upper phase is used to obtain cold LDL.
The lower phase is dialysed against 3*4 l of PDB buffer (10 mM
Tris/HCl pH 7.4, 0.15 mM NaCl, 1 mM EDTA, 0.02% NaN.sub.3). Per 10
ml volume of retained material, 20 .mu.l of 3H-cholesterol (Dupont
NET-725; 1 .mu.C/.mu.l, dissolved in ethanol!) are subsequently
added, and the mixture is incubated at 37.degree. C. under N.sub.2
for 72 h.
[0342] The mixture is then adjusted to a density of 1.21 using NaBr
and centrifuged in a Ty 65 rotor at 20.degree. C. and 50,000 rpm
for 18 h. The upper phase is collected and the lipoprotein
fractions are purified by gradient centrifugation. To this end, the
isolated labelled lipoprotein fraction is adjusted to a density of
1.26 using NaBr. In each case 4 ml of this solution are covered in
centrifuge tubes (SW 40 rotor) with 4 ml of a solution of a density
of 1.21 and 4.5 ml of a solution of 1.063 (density solutions of PDB
buffer and NaBr), and the tubes are subsequently centrifuged in an
SW 40 rotor at 38,000 rpm and 20.degree. C. for 24 h. The
intermediate layer which is found between a density of 1.063 and a
density of 1.21 and which contains the labelled HDL is dialysed
against 3*100 volume of PDB buffer at 4.degree. C.
[0343] The retained material contains radioactively labelled
.sup.3H-CE-HDL, which is used for the test adjusted to
approximately 5.times.10.sup.6 cmp per ml.
CETP test
[0344] To test the CETP activity, the transfer of
.sup.3H-cholesterol ester from human HD-lipoproteins to
biotinylated LD-lipoproteins is measured.
[0345] The reaction is terminated by addition of
Streptavidin-SPA.RTM. beads (Amersham) and the transferred
radioactivity is directly determined in a liquid scintillation
counter.
[0346] In the assay mixture, 10 .rho.l of HDL-.sup.3H-cholesterol
ester (.about.50,000 cpm) with 10 .mu.l of Biotin-LDL (Amersham) in
50 mM Hepes/0.15 m NaCl0.1% bovine serum albumin/0.05% NaN.sub.3 pH
7.4 are incubated with 10 .mu.l of CETP (1 mg/ml) and 3 .mu.l of a
solution of the substance to be tested (dissolved in 10% DMSO/1%
BSA) at 37.degree. C. for 18 h. 200 .mu.l of the SPA streptavidin
bead solution (TRKQ 7005) are subsequently added, the mixture is
incubated with shaking for another 1 h and subsequently measured in
a scintillation counter. The controls used are corresponding
incubations with 10 .mu.l of buffer, 10 .mu.l of CETP at 4.degree.
C. and 10 .mu.l of CETP at 37.degree. C.
[0347] The activity which is transferred in the control experiments
with CETP at 37.degree. C. is classified as 100% transfer. The
substance concentration at which this transfer is reduced by half
is stated as the IC.sub.50 value.
[0348] In Table A below, the IC.sub.50 values (mol/l) for CETP
inhibitors are given: TABLE-US-00001 TABLE A Example No. IC.sub.50
value (mol/l) 1 1 .times. 10.sup.-8
Ex Vivo Activity of the Compounds According to the Invention
[0349] Syrian gold hamsters, which have been bred in our own
laboratory, are anaesthetized after 24 hours of fasting (0.8 mg/kg
of atropine, 0.8 mg/kg of Ketavet.RTM. s.c., 30' later 50 mg/kg of
Nembutal i.p.). The jugular vein is subsequently exposed and
cannulated. The test substance is dissolved in a suitable solvent
(usually adalate placebo solution: 60 g of glycerol, 100 ml of
H.sub.2O, ad 1000 ml PEG-400) and administered to the animals via a
PE catheter, which is introduced into the jugular vein. The same
volume of solvent without test substance is administered to the
control animals. The vein is subsequently tied off and the wound is
closed.
[0350] The test substances can also be administered p.o. by
dissolving the substances in DMSO and suspending them in 0.5%
tylose and administering them perorally using a pharyngeal tube.
Identical volumes of solvent without test substance are
administered to the control animals
[0351] At different intervals--up to 24 hours after
administration--blood samples are taken from the animals by
puncture of the retro-orbital venous plexus (approximately 250
.mu.l). Coagulation is completed by incubation at 4.degree. C.
overnight, and the samples are subsequently centrifuged at
6000.times.g for 10 minutes. The CETP activity is determined in the
resulting serum using the modified CETP test. The transfer of
.sup.3H-cholesterol ester from HD-lipoproteins to biotinylated
LD-lipoproteins is measured as described above for the CETP
test.
[0352] The reaction is terminated by addition of
Streptavidin-SPA.sup.R beads (Amersham), and the transferred
radioactivity is directly determined in a liquid scintillation
counter. The test protocol is carried out as described under "CETP
test". However, to test the serum, only 10 .mu.l of CETP are
replaced by 10 .mu.l of the appropriate serum samples.
Corresponding incubations of sera of untreated animals serve as
controls.
[0353] The activity that is transferred in the control experiments
using control sera is classified as 100% transfer. The substance
concentration at which this transfer is reduced by half is stated
as the ED.sub.50 value.
In Vivo Activity of the Compounds According to the Invention
[0354] In experiments for determining the oral activity on
lipoproteins and triglycerides, test substance, dissolved in DMSO
and suspended in 0.5% tylose, is administered perorally by means of
a pharyngeal tube to Syrian gold hamsters which have been bred in
our own laboratory. To determine the CETP activity, blood samples
(approximately 250 .mu.l) are taken by retro-orbital puncture prior
to the start of the experiment. The test substances are
subsequently administered perorally using a pharyngeal tube.
Identical volumes of solvent without test substance are
administered to the control animals. Subsequently, the animals have
to fast and at different intervals--up to 24 hours after
administration of the substances--blood samples are taken by
puncture of the retro-orbital venous plexus.
[0355] Coagulation is completed by incubation at 4.degree. C.
overnight, and the samples are subsequently centrifuged at
6000.times.g for 10 minutes. The content of cholesterol and
triglycerides in the resulting serum is determined using modified
commercially available enzyme tests (cholesterol enzymatic 14366
Merck, triglycerides 14364 Merck). Serum is diluted in a suitable
manner with normal saline solution.
[0356] 100 .mu.l of serum dilution and 100 .mu.l of test substance
are transferred into 96-well plates and incubated at room
temperature for 10 minutes. The optical density is subsequently
determined at a wavelength of 492 nm using an automatic plate
reader. The triglyceride and cholesterol concentrations of the
samples are determined with the aid of a standard curve measured in
parallel.
[0357] The determination of the HDL-cholesterol content is carried
out after precipitation of the ApoB-containing lipoproteins using a
reagent mixture (Sigma 352-4 HDL cholesterol reagent) in accordance
with the instructions of the manufacturer.
In Vivo Activity in Transgenic HCETP Mice
[0358] The substances to be tested were administered to transgenic
mice, which were bred in our own laboratory (Dinchuck, Hart,
Gonzalez, Karmann, Schmidt, Wirak; BBA (1995), 1295, 301), via the
feed. Prior to the beginning of the experiment, blood samples were
taken retro-orbitally from the mice to determine cholesterol and
triglycerides in the serum. The serum was obtained as described
above for hamsters by incubation at 4.degree. C. overnight and
subsequent centrifugation at 6000.times.g. After one week, blood
samples were again taken from the mice to determine lipoproteins
and triglycerides. The change of the measured parameters are
expressed as a change in per cent based on the initial value.
[0359] The invention furthermore relates to the combination of
hetero-tetrahydroquinolines of the general formula (I) with a
glucosidase and/or amylase inhibitor for the treatnent of familial
hyperlipidaernias, of obesity (adipositas) and of diabetes
mellitus. Glucosidase and/or amylase inhibitors in the context of
the present invention are, for example, acarbose, adiposine,
voglibose, mniglitol, emiglitate, MDL-25637, camiglibose
(MDL-73945), tendamistate, AI-3688, trestatin, pradimicin-Q and
salbostatin.
[0360] Preference is given to the combination of acarbose.,
miglitol, emiglitate or voglibose with one of the abovementioned
compounds of the general formula (I) according to the
invention.
[0361] Furthermore, the compounds according to the invention can be
combined with cholesterol-lowering vastatines or ApoB-lowering
principles, in order to treat dyslipidaemias., combined
hyperlipidaemias, hypercholesterolaemias or
hypertriglyceridaemias.
[0362] The abovementioned combinations can also be used for primary
or secondary prevention of coronary heart diseases (for example
myocardial infarction).
[0363] Vastatines in the context of the present invention are, for
example, lovastatill, sinvastatin, pravastatin, fluvastatin,
atorvastatin and cerivastatin. ApoB-lowering agents are, for
example, MTP inhibitors.
[0364] Preference is given to the combination of cerivastatin or
ApoB inhibitors with one of the aboverxientioned compounds of the
general formula (I) according to the invention.
[0365] The novel active compounds can be converted in a known
manner into the customary formulations, such as tablets, coated
tablets, pills, granules, aerosols, syrups, emulsions, suspensions
and solutions, Using inert, non-toxic, pharmaceutically suitable
carriers or solvents. In this case the therapeutically active
compound should in each case be present in a concentration of from
approximately 0.5 to 90% by weight of the total mixture, i.e. in
amounts which are sufficient in order to achieve the dosage range
indicated.
[0366] The formulations are prepared, for example, by extending the
active compounds using solvents and/or carriers, if appropriate
using emulsifiers and/or dispersants, it optionally being possible,
for example, to use organic solvents as auxiliary solvents if the
diluent used is water.
[0367] Administration is carried out in a customary manner,
intravenously, orally, parenterally or perlingually, in particular
orally.
[0368] In the case of parenteral administration, solutions of the
active compound can be used by employing suitable liquid carrier
materials.
[0369] In general, it has proved advantageous, in the case of
intravenous administration, to administer amounts of from
approximately 0.001 to 1 mg/kg, preferably approximately 0.01 to
0.5 mg/kg, of body weight to achieve effective results, and in the
case of oral administration the dosage is approximately 0.01 to 20
mg/kg, preferably 0.1 to 10 mg/kg, of body weight.
[0370] In spite of this, if appropriate it may be necessary to
depart from the amounts mentioned, namely depending on the body
weight or on the type of administration route, on the individual
reaction towards the medicament, the manner of its formulation and
the time at or interval during which administration takes place.
Thus, in some cases it may be adequate to manage with less than the
abovementioned minimum amount, while in other cases the upper limit
mentioned has to be exceeded. In the case of the administration of
relatively large amounts, it may be advisable to divide these into
several individual doses over the course of the day
Abbreviations Used:
[0371] Cy=Cyclohexane [0372] EA=Ethyl acetate [0373] PE=Petroleum
ether [0374] THF=Tetrahydrofuran [0375] DAST=Dimethylaminosulphur
trifluoride [0376] PTA=para-toluenesulphonic acid [0377]
PDC=Pyridinium dichromate [0378] PE/EA=Petroleum ether/ethyl
acetate [0379] Tol=Toluene Starting materials
EXAMPLE I
2-Cyclopentyl-7,7-dimethyl-4-(3-thienyl)-3-(4-trifluoromethylbenzoyl)-1,4,-
5,6,7,8-hexahydro-quinolin-5-one
[0380] ##STR41## 1.425 g (5.03 mol) of
3-amino-3-cyclopentyl-1-(4-trifluoromethylphenyl)-propenone are
suspended in 25 ml of diisopropyl ether. 740 mg (5.28 mol) of
dimedone, 0.39 ml (5.03 mol) of trifluoroacetic acid and then 592
mg (5.28 mol) of thiophen-3-aldehyde are added. The mixture is
heated at reflux for 2 hours, which immediately gives a yellow
solution from which, after 30 minutes, product precipitates out.
The mixture is cooled and the product is filtered off with suction
and washed with diusopropyl ether. The product is recrystallized
from acetonitrile.
[0381] Yield: 741 mg, m.p. 228-229.degree. C.
[0382] The mother liquor gives another 230 mg of pure product.
[0383] The compounds listed in Table 1 are prepared analogously to
the procedure of Example I: TABLE-US-00002 TABLE I m.p.: Ex. No.
Structure (.degree. C.) II ##STR42## 144- 47 III ##STR43##
200-206
PREPARATION EXAMPLES
Example 1
2-Cyclopentyl-7,7-dimethyl-4-(3-thienyl)-3-(4-trifluoromethylbenzoyl)-5,6,-
7,8-tetrahydro-quinolin-5-one
[0384] ##STR44## 1.21 g (2.42 mmol) of the compound from Example 1
are dissolved in 35 ml of dichloromethane and, after addition of
6.8 g of manganese dioxide, stirred for 2 hours. The mixture is
filtered off with suction using Celite as a filtration aid and is
concentrated. The evaporation residue is stirred with acetonitrile,
filtered off with suction and washed with acetonitrile. This gives
1.045 g of crystals of m.p.: 236-238.degree. C.
[0385] The compounds listed in Table 1 are prepared analogously to
the procedure of Example 1: TABLE-US-00003 TABLE 1 m.p. Ex. No.
Structure (.degree. C.) 2 ##STR45## 221-224 3 ##STR46## 185-186
Example 4
2-Cyclopentyl-5-hydroxy-7,7-dimethyl-4-(3-thienyl)-3-(4-trifluoromethylben-
zoyl)-5,6,7,8-tetrahydroquinoline
[0386] ##STR47## (1R,2S)-Aminoindan-2-ol are suspended in 0.4 ml of
THF. At RT, N,N-boranediethylaniline complex (Aldrich) are added
dropwise. All is dissolved and stirred at RT for 1 hour. The
mixture is then stirred at 0.degree. C. for 15 minutes. The
compound from Example 1 is dissolved in 16 ml of THF and added
dropwise at from 0 to 5.degree. C. over a period of 10 minutes. The
mixture is then stirred at 0.degree. C. for 30 min and at RT for 4
hours. At from -10.degree. C. to 0.degree. C., 35 ml of 1,2
ethanediol are carefully added dropwise, the mixture is stirred for
30 minutes and concentrated, the residue is dissolved in ethyl
acetate, the solution is washed with 1 N HCl, then with sat. sodium
bicarbonate solution, then with sat. sodium chloride solution,
dried over sodium sulphate, filtered and concentrated. This gives
1.17 g of a crystalline compound. The compound is dissolved in hot
cyclohexane and the mixture is filtered off. On cooling, the
compound crystallizes out. The mixture is filtered off with suction
and the compound is washed and dried at 70.degree. C. under reduced
pressure.
[0387] Yield: 0.7 g
[0388] Concentration of the mother liquor (column: toluene: ethyl
acetate 20.1), dissolving the residue in methylene chloride and
reconcentrating the solution gives a further 0.27 g of
crystals.
[0389] Overall yield: 970 mg (87.3%) of m.p.: 179-182.degree.
C.
Example 5
5-tertButyldimethylsilyloxy-2-cyclopentyl-7,7-dimethyl-4-(3-thienyl)-3-(4--
trifluoro-methylbenzoyl)-5,6,7,8-tetrahydroquinoline
[0390] ##STR48## Under argon, 0.8 g (1.6 mmol) of the compound from
Example 4 is dissolved in 6.4 ml of toluene and, at from -5.degree.
to -10.degree. C. admixed dropwise with 0.69 g (6.4 mmol) of
2,6-lutidine. The-mixture is stirred for 15 minutes. At the same
temperature, 0.86 g (3.2 mmol) of tertbutyl-dimethylsilyl
trifluoromethanesulphonate in 1.2 ml of toluene is then added
dropwise. The mixture is stirred at from -5.degree. C. to
-10.degree. C. for 15 minutes and then at room temperature for 2
hours.
[0391] The mixture is diluted with toluene and washed successively
with 2.6 ml of 10% ammonium chloride solution, 7 times with in each
case 3.5 ml of 0.1 N HCl, once with 1.5 ml of sat. sodium
bicarbonate solution and once with 3.5 ml of sat. sodium chloride
solution. The mixture is then dried and concentrated and
concentrated once with ethanol.
[0392] This gives 1.0 g The product is recrystallized from a little
ethanol, filtered off with suction, washed and dried at 60.degree.
C. under reduced pressure.
[0393] Yield: 716 mg, m.p. 147-148.degree. C.
[0394] The mother liquor is concentrated and the residue is treated
with ethanol and filtered off with suction. This gives another 60
mg.
Example 6
5-(S)-tertButyldimethylsilyloxy-2-cyclopentyl-7,7-dimethyl-4-(3-thienyl)-3-
-[(R)-hydroxy-(4-trifluoromethylphenyl)]methyl-5,6,7,8-tetrahydroquinoline
[0395] ##STR49## 0.69 g (1.124 mmol) of the compound from Example 5
is dissolved in 5 ml of toluene; at 0.degree. C., 1.40 g (4.496
mmol) of RED-A1 are added dropwise and the mixture is stirred at
0.degree. C. for 30 minutes and at RT for 1 hour. At 0.degree. C.,
0.85 ml of methanol is slowly added dropwise, and the yellow
solution is stirred at 0.degree. C. for 30 minutes. 0.73 ml of a
20% strength potassium sodium tartrate solution is then added
dropwise, the mixture is filtered off with suction, the filtrate is
washed with toluene and a little 20% strength potassium sodium
tartrate solution, separated off, washed once with sat. sodium
bicarbonate solution and twice with sat. sodium chloride solution,
dried over sodium sulphate and concentrated. This gives 850 mg of
an oil which comprises the two possible diastereomers which are
separated on a 400 ml silica gel column. The product is eluted with
petroleum ether, petroleum ether/ethyl acetate 20:1, 10:1.
[0396] This gives 86.2 mg of the wrong diastereomer and 356.2 mg of
the right diastereomer.
Example 7
5-(S)-tertButyldimethylsilyloxy-2-cyclopentyl-7,7-dimethyl-3-[5-fluoro-(4--
trifluoro-methylphenyl)-methyl]-4-(3-thienyl)-5,6,7,8-tetrahydroquinoline
[0397] ##STR50## 320 mg (0.52 mmol) of the compound from Example 6
are dissolved in 7 ml of dichloromethane and, at -15.degree. C.,
treated with 140 mg (0.86 mmol) of DAST. After 30 minutes, the
reaction is carried out at from -15.degree. C. to -10.degree. C.,
in ethylene chloride and water are added, the phases are separated,
the aqueous phases extracted once with methylene chloride, and the
organic phases are washed once with sat. sodium chloride solution
and with a little sat. sodium bicarbonate solution, dried and
concentrated.
[0398] Crystallization is carried out using methanol. The product
is filtered off with suction and washed.
[0399] Yield: 57.8 mg of m.p.: 171-172.degree. C.
Example 8
2-Cyclopentyl-3-[fluoro-(4-trifluoromethylphenyl)methyl]-5-hydroxy-7,7-dim-
ethyl-4-(3-thienyl)-5,6,7,8-tetrahydroquinoline
[0400] ##STR51## 111 mg (0.18 mmol) of the compound from Example 7
are dissolved in 1.4 ml of methanol and admixed with 0.9 ml of THF
and 0.98 ml of 5 N hydrochloric acid. The mixture is stirred at
40.degree. C. for 4 hours. The mixture is concentrated, admixed
with water, ammonia solution and ethyl acetate, the phases are
separated and the aqueous phases extracted once with ethyl acetate.
The organic phases are washed once with sodium chloride solution,
dried and concentrated this gives 82 mg as an oil.
[0401] The product is dissolved in petroleum ether and a little
methylene chloride and applied to a column, eluted with petroleum
ether: ethyl acetate 30.1, 20.1, 10.1, and 2 fractions are
concentrated.
[0402] The crystalline solid is filtered off with suction with a
little n-heptane and dried under reduced pressure.
[0403] This gives 37.1 mg (41% of theory) of a colourless substance
of m.p.: 157-159.degree. C.
Example 9
2-Cyclopentyl-5-hydroxy-7,7-dimethyl-4-(3-thienyl)-3-(trifluoromethylbenzy-
l)-5,6,7,8-tetrahydroquinoline
[0404] ##STR52## 20 mg (0.04 mmol) of the compound from Example 8
are dissolved in 3 ml of toluene and, at -20.degree. C., admixed
with 0.27 ml of Dibal-H in tolol. The mixture is stirred at
-20.degree. C. for 2 hours. The mixture is admixed with 10 ml of
20% potassium sodium tartrate solution and ethyl acetate and
stirred for some time, the phases are separated, the aqueous phase
is extracted 2.times. with ethyl acetate, and the organic phases
are dried and concentrated.
[0405] 17 mg of the title compound are dissolved in methylene
chloride, applied to a column and eluted with toluene.
[0406] FR 1-1:5.5 mg NMR
[0407] R.sub.f value: TLC aluminium foil silica gel 60 F.sub.254,
layer thickness 0.2 mm=0.40 (mobile phase:petroleum ether/ethyl
acetate 10:1)
[0408] R.sub.f=0.45; mobile phase toluene/ethyl acetate 10:1.
[0409] The compounds listed in Table 1 are prepared analogously to
the procedures given above: TABLE-US-00004 Ex. No. Structure Isomer
R.sub.f 10 ##STR53## isomer 1 0.67 .sup.a) 11 ##STR54## isomer 2
0.52 .sup.a) .sup.a) EtOAc/petroleum ether 1:1
* * * * *