U.S. patent application number 09/873460 was filed with the patent office on 2002-04-11 for tetrahydroquinolines.
Invention is credited to Bischoff, Hilmar, Brandes, Arndt, Bremm, Klaus-Dieter, Logers, Michael, Schmeck, Carsten, Schmidt, Delf, Schmidt, Gunter, Stoltefuss, Jurgen.
Application Number | 20020042515 09/873460 |
Document ID | / |
Family ID | 7842954 |
Filed Date | 2002-04-11 |
United States Patent
Application |
20020042515 |
Kind Code |
A1 |
Schmidt, Gunter ; et
al. |
April 11, 2002 |
Tetrahydroquinolines
Abstract
The tetrahydroquinolines can be prepared by condensing
appropriately substituted tetrahydroquinoline aldehydes with
suitable substances and subsequently varying the substituents
present by customary methods. The tetrahydroquinolines are suitable
as active compounds in medicaments, in particular in medicaments
for the treatment of arteriosclerosis and dyslipidaemias.
Inventors: |
Schmidt, Gunter; (Wuppertal,
DE) ; Stoltefuss, Jurgen; (Haan, DE) ; Logers,
Michael; (Wuppertal, DE) ; Brandes, Arndt;
(Wuppertal, DE) ; Schmeck, Carsten; (Wuppertal,
DE) ; Bremm, Klaus-Dieter; (Recklinghausen, DE)
; Bischoff, Hilmar; (Wuppertal, DE) ; Schmidt,
Delf; (Wuppertal, DE) |
Correspondence
Address: |
KURT BRISCOE
NORRIS, MCLAUGHLIN & MARCUS, P.A.
220 EAST 42ND STREET, 30TH FLOOR
NEW YORK
NY
10017
US
|
Family ID: |
7842954 |
Appl. No.: |
09/873460 |
Filed: |
June 4, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09873460 |
Jun 4, 2001 |
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09508483 |
Mar 10, 2000 |
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09508483 |
Mar 10, 2000 |
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PCT/EP98/05658 |
Sep 7, 1998 |
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Current U.S.
Class: |
546/152 ;
546/168 |
Current CPC
Class: |
A61P 9/10 20180101; C07D
401/06 20130101; A61P 3/06 20180101; C07D 221/20 20130101; C07D
215/20 20130101; C07D 417/06 20130101 |
Class at
Publication: |
546/152 ;
546/168 |
International
Class: |
C07D 215/00; C07D
213/22 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 19, 1997 |
DE |
197 41 399.4 |
Claims
1. Tetrahydroquinolines of the general formula (I) 102in which A
represents phenyl which is optionally substituted up to 2 times by
identical or different substituents from the group consisting of
halogen, trifluoromethyl and straight-chain or branched alkyl or
alkoxy having in each case up to 3 carbon atoms, D represents a
radical of the formula 103or R.sup.8--CH.sub.2--O--CH.sub.2--, in
which R.sup.5 and R.sup.6 together form a carbonyl group (.dbd.O),
or R.sup.5 represents hydrogen and R.sup.6 represents halogen or
hydroxyl, or R.sup.5 and R.sup.6 represent hydrogen, R.sup.7 and
R.sup.8 are identical or different and represent phenyl, naphthyl,
benzothiazolyl, quinolyl, pyrimidyl or pyridyl which are optionally
substituted up to 4 times by identical or different substituents
from the group consisting of halogen, trifluoromethyl, nitro,
cyano, trifluoromethoxy, or by a radical of the formula
--SO.sub.2--CH.sub.3 or --NR.sup.9R.sup.10, in which R.sup.9 and
R.sup.10 are identical or different and represent hydrogen or
straight-chain or branched alkyl having up to 3 carbon atoms, E
represents cycloalkyl having 3 to 6 carbon atoms, or represents
straight-chain or branched alkyl having up to 8 carbon atoms,
R.sup.1 represents hydroxyl, and R.sup.2 represents hydrogen or
represents methyl, R.sup.3 and R.sup.4 are identical or different
and represent straight-chain or branched alkyl having up to 3
carbon atoms, or R.sup.3 and R.sup.4 together form a spiro-linked
alkyl chain having 2 to 4 carbon atoms, and their salts and
N-oxides.
2. Tetrahydroquinolines of the formula according to claim 1 in
which A represents phenyl which is optionally substituted up to 2
times by identical or different substituents from the group
consisting of fluorine, chlorine, trifluoromethyl, methyl, ethyl,
methoxy and ethoxy, D represents a radical of the formula 104or
R.sup.8--CH.sub.2--O--CH.sub.2- --, in which R.sup.5 and R.sup.6
together form a carbonyl group (.dbd.O), or R.sup.5 represents
hydrogen and R.sup.6 represents fluorine or hydroxyl, or R.sup.5
and R.sup.6 represent hydrogen, R.sup.7 and R.sup.8 are identical
or different and represent phenyl, naphthyl, benzothiazolyl,
quinolyl, pyrimidyl or pyridyl, which are optionally substituted up
to 3 times by identical or different substituents from the group
consisting of fluorine, chlorine, bromine, trifluoromethyl, nitro,
cyano, trifluoromethoxy, amino or dimethylamino, E represents
cyclopropyl, cyclobutyl, cyclopentyl or represents straight-chain
or branched alkyl having up to 6 carbon atoms, R.sup.1 represents
hydroxyl, and R.sup.2 represents hydrogen or represents methyl,
R.sup.3 and R.sup.4 are identical or different and represent
methyl, or R.sup.3 and R.sup.4 together form a spiro-linked
cyclopropyl, cyclobutyl or cyclopentyl ring, and their salts and
N-oxides.
3. Tetrahydroquinolines of the formula according to claim 1 in
which A represents phenyl which is optionally substituted up to 2
times by identical or different substituents from the group
consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy
and ethoxy, D represents a radical of the formula 105or
R.sup.8--CH.sub.2--O--CH.sub.2- --, in which R.sup.5 and R.sup.6
together form a carbonyl group (.dbd.O), or R.sup.5 represents
hydrogen and R.sup.6 represents fluorine or hydroxyl, or R.sup.5
and R.sup.6 represent hydrogen, R.sup.7 and R.sup.8 are identical
or different and represent phenyl, naphthyl, benzothiazolyl,
quinolyl, pyrimidyl or pyridyl which are optionally substituted up
to 3 times by identical or different substituents from the group
consisting of fluorine, chlorine, bromine, trifluoromethyl, nitro,
cyano, trifluoromethoxy, amino and dimethylamino, E represents
cyclopropyl or cyclopentyl, or represents straight-chain or
branched alkyl having up to 3 carbon atoms, R.sup.1 represents
hydroxyl, and R.sup.2 represents hydrogen or represents methyl,
R.sup.3 and R.sup.4 are identical or different and represent
methyl, or R.sup.3 and R.sup.4 together form a spiro-linked
cyclopropyl, cyclobutyl or cyclopentyl ring, and their salts and
N-oxides.
4. Tetrahydroquinolines according to claims 1 to 3 as
medicaments.
5. Process for preparing tetrahydroquinolines according to claims 1
to 3, characterized in that [A] in the case D represents the
radical 106in compounds of the general formula (II) 107in which A,
E, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined above, the
substituent D is synthesized in inert solvents using organometallic
reagents in a Grignard, Wittig or organolithium reaction, or, in
the case that D represents the radical of the formula
R.sup.8--CH.sub.2--O--CH.sub.2, in which R.sup.8 is as defined
above, [B] either compounds of the general formula (III) 108in
which A, E, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined
above are reacted with compounds of the general formula (IV)
R.sup.8--CH.sub.2--Z (IV), in which R.sup.5 is 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 first
converted, by reaction with compounds of the general formula (V)
109in which R.sup.11 represents straight-chain alkyl having up to 4
carbon atoms, into the compounds of the general formula (VI) 110in
which A, E, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.11 are as
defined above, and subsequently reacted with compounds of the
general formula (VII) R.sup.8--CH.sub.2--OH (VII), in which R.sup.8
is as defined above and, if appropriate, protective groups are
cleaved off, or [D] in the case of the compounds of the general
formula (Ia) 111in which A, E, R.sup.3, R.sup.4, R.sup.5 and
R.sup.6 are as defined above, compounds of the general formula
(VIII) 112in which A, E, R.sup.3, R.sup.4 and R.sup.7 are as
defined above, are first oxidized to the compounds of the general
formula (I) 113in which R.sup.3, R.sup.4, R.sup.7, A and E are as
defined above, these are, in a next step, converted by asymmetric
reduction into the compounds of the general formula (X) 114in which
R.sup.3, R.sup.4, R.sup.7, A and E are as defined above, these are
then converted, by introduction of a hydroxyl-protective group,
into the compounds of the general formula (XI) 115in which R.sup.3,
R.sup.4, R.sup.7, A and E are as defined above and R.sup.12
represents a hydroxyl-protective group, preferably a radical of the
formula --SiR.sup.13R.sup.14R.sup.15, in which R.sup.13, R.sup.14
and R.sup.15 are identical or different and represent
C.sub.1-C.sub.4-alkyl, from which compound, in a subsequent step,
the compounds of the general formula (XII) 116in which R.sup.3,
R.sup.4, R.sup.7, R.sup.12, A and E are as defined above are
prepared by diastereoselective reduction, and subsequently, by
introducing the fluorine substituent with fluorinating agents, such
as, for example, DAST and SF.sub.4 derivatives, the compounds of
the general formula (XIII) 117in which R.sup.3, R.sup.4, R.sup.7,
R.sup.12, A and E are as defined above, are prepared, and the
hydroxyl-protective group is subsequently cleaved off 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.
6. Medicaments, comprising at least one tetrahydroquinoline
according to claim 1 and pharmacologically acceptable formulation
auxiliaries.
7. Medicament according to claim 6 for treating
hyperlipoproteinaemia.
8. Medicament according to claim 6 or 7 for treating
arteriosclerosis.
9. Use of tetrahydroquinolines according to claim 1 for preparing
medicaments.
10. Use according to claim 9 for preparing medicaments for the
treatment of arteriosclerosis, in particular dyslipidaemias.
Description
[0001] The present invention relates to 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)-quinolones,
3-benzyl-7,8-dihydro-2,7,7-trimethyl-4-phenyl, is known from the
publication Khim, Geterotsikl, Soedin. (1967), (6), 1118-1120.
[0003] The present invention relates to tetrahydroquinolines of the
general formula (I), 1
[0004] in which
[0005] A represents phenyl which is optionally substituted up to 2
times by identical or different substituents from the group
consisting of halogen, trifluoromethyl and straight-chain or
branched alkyl or alkoxy having in each case up to 3 carbon
atoms,
[0006] D represents a radical of the formula 2
[0007] or
R.sup.8--CH.sub.2--O--CH.sub.2--,
[0008] in which
[0009] R.sup.5 and R.sup.6together form a carbonyl group
(.dbd.O),
[0010] or
[0011] R.sup.5 represents hydrogen
[0012] and
[0013] R.sup.6 represents halogen or hydroxyl,
[0014] or
[0015] R.sup.5 and R.sup.6 represent hydrogen,
[0016] R.sup.7 and R.sup.5 are identical or different and represent
phenyl, naphthyl, benzothiazolyl, quinolyl, pyrimidyl or pyridyl
which are optionally substituted up to 4 times by identical or
different substituents from the group consisting of halogen,
trifluoromethyl, nitro, cyano, trifluoromethoxy, or by a radical of
the formula --SO.sub.2--CH.sub.3 or --NR.sup.9R.sup.10,
[0017] in which
[0018] R.sup.9 and R.sup.10 are identical or different and
represent hydrogen or straight-chain or branched alkyl having up to
3 carbon atoms,
[0019] E represents cycloalkyl having 3 to 6 carbon atoms, or
represents straight-chain or branched alkyl having up to 8 carbon
atoms,
[0020] R.sup.1 represents hydroxyl,
[0021] and
[0022] R.sup.2 represents hydrogen or represents methyl,
[0023] R.sup.3 and R.sup.4 are identical or different and represent
straight-chain or branched alkyl having up to 3 carbon atoms,
[0024] or
[0025] R.sup.3 and R.sup.4 together form a spiro-linked alkyl chain
having 2 to 4 carbon atoms,
[0026] and their salts and N-oxides.
[0027] The 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.
[0028] 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.
[0029] 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, potassium, magnesium or calcium salts, and to
ammonium salts, which are derived from ammonia, or organic amines,
such as, for example, ethylamine, di- or triethylamine, di- or
triethanolamine, dicyclo-hexylamine, dimethylaminoethanol,
arginine, lysine, ethylenediamine or 2-phenylethylamine.
[0030] 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
enantiomers and diastereomers can be separated into the
stereoisomerically uniform components in a known manner.
[0031] Preference is given to compounds of the general formula (I)
according to the invention
[0032] in which
[0033] A represents phenyl which is optionally substituted up to 2
times by identical or different substituents from the group
consisting of fluorine, chlorine, trifluoromethyl, methyl, ethyl,
methoxy and ethoxy,
[0034] D represents a radical of the formula 3
[0035] or
R.sup.8--CH.sub.2--O--CH.sub.2--,
[0036] in which
[0037] R.sup.5 and R.sup.6 together form a carbonyl group
(.dbd.O),
[0038] or
[0039] R.sup.5 represents hydrogen
[0040] and
[0041] R.sup.6 represents fluorine or hydroxyl,
[0042] or
[0043] R.sup.5 and R.sup.6 represent hydrogen,
[0044] R.sup.7 and R.sup.8 are identical or different and represent
phenyl, naphthyl, benzothiazolyl, quinolyl, pyrimidyl or pyridyl,
which are optionally substituted up to 3 times by identical or
different substituents from the group consisting of fluorine,
chlorine, bromine, trifluoromethyl, nitro, cyano, trifluoromethoxy,
amino or dimethylamino,
[0045] E represents cyclopropyl, cyclobutyl, cyclopentyl or
represents straight-chain or branched alkyl having up to 6 carbon
atoms,
[0046] R.sup.1 represents hydroxyl,
[0047] and
[0048] R.sup.2 represents hydrogen or represents methyl,
[0049] R.sup.3 and R.sup.4 are identical or different and represent
methyl,
[0050] or
[0051] R.sup.3 and R.sup.4 together form a spiro-linked
cyclopropyl, cyclobutyl or cyclopentyl ring,
[0052] and their salts and N-oxides.
[0053] Particular preference is given to compounds of the general
formula (I) according to the invention
[0054] in which
[0055] A represents phenyl which is optionally substituted up to 2
times by identical or different substituents from the group
consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy
and ethoxy,
[0056] D represents a radical of the formula 4
[0057] or
R.sup.8--CH.sub.2--O--CH.sub.2--,
[0058] in which
[0059] R.sup.5 and R.sup.6 together form a carbonyl group
(.dbd.O),
[0060] or
[0061] R.sup.5 represents hydrogen
[0062] and
[0063] R.sup.6 represents fluorine or hydroxyl
[0064] or
[0065] R.sup.5 and R.sup.6represent hydrogen,
[0066] R.sup.7 and R.sup.8 are identical or different and represent
phenyl, naphthyl, benzothiazolyl, quinolyl, pyrimidyl or pyridyl
which are optionally substituted up to 3 times by identical or
different substituents from the group consisting of fluorine,
chlorine, bromine, trifluoromethyl, nitro, cyano, trifluoromethoxy,
amino and dimethylamino,
[0067] E represents cyclopropyl or cyclopentyl, or represents
straight-chain or branched alkyl having up to 3 carbon atoms,
[0068] R.sup.1 represents hydroxyl
[0069] and
[0070] R.sup.2 represents hydrogen or represents methyl,
[0071] R.sup.3 and R.sup.4 are identical or different and represent
methyl,
[0072] or
[0073] R.sup.3 and R.sup.4 together form a spiro-linked
cyclopropyl, cyclobutyl or cyclopentyl ring,
[0074] and their salts and N-oxides.
[0075] Moreover, processes for preparing the compounds of the
general formula (I) according to the invention have been found
which are characterized in that
[0076] [A] in the case that D represents the radical 5
[0077] in compounds of the general formula (II) 6
[0078] in which
[0079] A, E, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined
above,
[0080] the substituent D is synthesized in inert solvents using
organometallic reagents in a Grignard, Wittig or organolithium
reaction,
[0081] or, in the case that D represents the radical of the formula
R.sup.8--CH.sub.2--O--CH.sub.2, in which R.sup.8 is as defined
above,
[0082] [B] either compounds of the general formula (III) 7
[0083] in which
[0084] A, E, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined
above
[0085] are reacted with compounds of the general formula (IV)
R.sup.8--CH.sub.2--Z (IV),
[0086] in which
[0087] R.sup.8 is as defined above,
[0088] and
[0089] Z represents halogen, preferably chlorine or bromine,
[0090] in inert solvents, if appropriate in the presence of a base
and/or an auxiliary,
[0091] or
[0092] [C] compounds of the general formula (III) are first
converted, by reaction with compounds of the general formula (V)
8
[0093] in which
[0094] R.sup.11 represents straight-chain alkyl having up to 4
carbon atoms,
[0095] into the compounds of the general formula (VI) 9
[0096] in which
[0097] A, E, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.11 are as
defined above,
[0098] and subsequently reacted with compounds of the general
formula (VII)
R.sup.8--CH.sub.2--OH (VII),
[0099] in which
[0100] R.sup.8 is as defined above,
[0101] and, if appropriate, protective groups are cleaved off,
[0102] or
[0103] [D] in the case of the compounds of the general formula (Ia)
10
[0104] in which
[0105] A, E, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined
above,
[0106] compounds of the general formula (VIII) 11
[0107] in which
[0108] A, E, R.sup.3, R.sup.4 and R.sup.7 are as defined above,
[0109] are first oxidized to the compounds of the general formula
(IX) 12
[0110] in which
[0111] R.sup.3, R.sup.4, R.sup.7, A and E are as defined above,
[0112] these are, in a next step, converted by asymmetric reduction
into the compounds of the general formula (X) 13
[0113] in which
[0114] R.sup.3, R.sup.4, R.sup.7, A and E are as defined above,
[0115] these are then converted, by introduction of a
hydroxyl-protective group, into the compounds of the general
formula (XI) 14
[0116] in which
[0117] R.sup.3, R.sup.4, R.sup.7, A and E are as defined above
[0118] and
[0119] R.sup.12 represents a hydroxyl-protective group, preferably
a radical of the formula --SiR.sup.13R.sup.14R.sup.15,
[0120] in which
[0121] R.sup.13, R.sup.14 and R.sup.15 are identical or different
and represent C.sub.1-C.sub.4-alkyl,
[0122] from which compound, in a subsequent step, the compounds of
the general formula (XII) 15
[0123] in which
[0124] R.sup.3, R.sup.4, R.sup.7, R.sup.12, A and E are as defined
above,
[0125] are prepared by diastereoselective reduction,
[0126] and subsequently, by introducing the fluorine substituent
with fluorinating agents, such as, for example, DAST and SF.sub.4
derivatives, the compounds of the general formula (XIII) 16
[0127] in which
[0128] R.sup.3, R.sup.4, R.sup.7, R.sup.12, A and E are as defined
above,
[0129] are prepared,
[0130] and the hydroxyl-protective group is subsequently cleaved
off by customary methods,
[0131] 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.
[0132] The processes according to the invention can be illustrated
in an exemplary manner by the following schemes: 17
[0133] Suitable solvents for all processes are ethers such as
diethyl ether, dioxane, tetra-hydrofuran, glycol dimethyl ether, or
hydrocarbons such as benzene, toluene, xylene, hexane, cylcohexane
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 dichloromethane.
[0134] 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.
[0135] 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.
[0136] Suitable organometallic reagents are, for example, systems
such as the appropriate Wittig reagents, for example
Mg/bromobenzotrifluoride, and the appropriate organolithium
compounds, for example p-trifluoromethylphenyllithium.
[0137] The reductions are generally carried out using reducing
agents, preferably those which are suitable for reducing ketones to
hydroxyl compounds. Particularly suitable here 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 borohydride, sodium borohydride, potassium
borohydride, zinc borohydride, lithium trialkylborohydride,
diisobutylaluminium hydride or lithium aluminium hydride. The
reduction is very particularly preferably carried out using
diisobutylaluminium hydride and sodium borohydride.
[0138] 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. The reduction 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 the case of
DIBAH, from 0.degree. C. to room temperature in the case of
NaBH.sub.4, particularly preferably at -78.degree. C., in each case
depending on the choice of the reducing agent and the solvent.
[0139] The reduction generally proceeds at atmospheric pressure;
however, it is also possible to operate under elevated or reduced
pressure.
[0140] The hydrogenation is carried out by customary methods using
hydrogen in the presence of noble metal catalysts, such as, for
example, Pd/C, Pt/C or Raney nickel in one of the abovementioned
solvents, preferably in alcohols such as, for example, methanol,
ethanol or propanol, in a temperature range of from -20.degree. C.
to +100.degree. C., preferably from 0.degree. C. to +50.degree. C.,
under atmospheric pressure or superatmospheric pressure.
[0141] 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
cleaving off the protective group with tetrabutylammonium fluoride
(TBAF) in THF.
[0142] In the context of the definition given above,
hydroxyl-protective group generally represents a protective group
from the series: trimethylsilyl, triisopropylsilyl, tert
butyl-dimethylsilyl, benzyl, benzyloxycarbonyl, 2-nitrobenzyl,
4-nitrobenzyl, tert butyloxy-carbonyl, 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,
tert-butyldimethylsilyl and triisopropylsilyl. Particular
preference is given to tert-butyldimethylsilyl.
[0143] Suitable solvents for the individual steps are ethers such
as diethyl ether, dioxane, tetra-hydrofuran, 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, dichloroethylene, trichloroethylene or
chlorobenzene. It is also possible to use mixtures of the solvents
mentioned.
[0144] Suitable oxidizing agents for preparing the compounds of the
general formula (IX) are, for example, nitric acid, 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.
[0145] The oxidation is carried out in one of the abovementioned
chlorinated hydrocarbons and water. Preference is given to
dichloromethane and water.
[0146] 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).
[0147] The oxidation generally proceeds at a temperature of from
-50.degree. C. to +100.degree. C., preferably from 0.degree. C. to
room temperature.
[0148] The oxidation generally proceeds at atmospheric pressure.
However, it is also possible to carry out the oxidation under
elevated or reduced pressure.
[0149] 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.
[0150] 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.
[0151] 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.
[0152] 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.
[0153] The reduction generally proceeds at atmospheric pressure;
however, it is also possible to operate under elevated or reduced
pressure.
[0154] 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 atmospheric pressure.
[0155] Reagents for introducing the silyl protective group are, in
general, tert-butyldimethylsilyl chloride or
tert-butyldimethylsilyl trifluoromethanesulphonate. Preference is
given to tert-butyldimethylsilyl trifluoromethansulphonate.
[0156] The reduction to the compounds of the general formula (XII)
proceeds in one of the abovementioned hydrocarbons, preferably
toluene.
[0157] The reduction for preparing 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 are. Particularly suitable for this purpose is
the reduction with metal hydrides or complex metal hydroxides 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 borohydride, sodium
borohydride, potassium borohydride, zinc borohydride, lithium
trialkylborohydride, diisobutylaluminium hydride, sodium
bis-(2-methoxyethoxy)-aluminium hydride or lithium aluminium
hydride. Very particularly preferably, the reduction is carried out
using sodium bis-(2-methoxyethoxy)-aluminium hydride.
[0158] 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.
[0159] The reduction generally proceeds at a temperature of from
-20.degree. C. to +110.degree. C., preferably from 0.degree. C. to
room temperature.
[0160] The reduction generally proceeds at atmospheric pressure;
however, it is also possible to operate under elevated or reduced
pressure.
[0161] 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 protected (XI) and thus be recycled into the
synthesis cycle without loss of yield.
[0162] 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.
[0163] SF.sub.4 derivatives are generally understood to be
diethylaminosulphur trifluoride (DAST) or
2,2'-bisfluoro-substituted amines such as, for example,
diethyl-1,2,3,3,3-hexafluoropropylamine.
[0164] The reaction generally proceeds at a temperature of from
-78.degree. C. to 100.degree. C., preferably, in the case of the
diethylaminosulphur trifluoride, at from -78.degree. C. to RT and,
in the case of the diethyl-1,1,2,3,3,3-hexafluoropropylamine, at
from room temperature to 80.degree. C.
[0165] The protective group is generally cleaved off 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
cleaving off the protective group with tetrabutylammonium fluoride
(TBAF) in THF at room temperature.
[0166] Derivatizations which may be mentioned by way of example are
the following reaction types:
[0167] oxidations, reductions, hydrogenations, halogenation,
Wittig/Grignard reactions and amidations/sulphoamidations.
[0168] 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.
[0169] 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.
[0170] Suitable solvents for the individual reaction steps are also
alcohols such as methanol, ethanol, propanol, butanol or
tertbutanol. Preference is given to tertbutanol.
[0171] If required, it is necessary to carry out some reaction
steps under an atmosphere of protective gas.
[0172] The halogenations are generally carried out in one of the
abovementioned chlorinated hydrocarbons, and preference is given to
methylene chloride.
[0173] Suitable halogenating agents are, for example,
diethylamino-sulphur trifluoride (DAST), morpholino-sulphur
trifluoride or SOCl.sub.2.
[0174] 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 halogenating agent and solvent.
[0175] The halogenation generally proceeds at atmospheric pressure;
however, it is also possible to operate under elevated or reduced
pressure.
[0176] The compounds of the general formulae (II) and (III) are
novel and can be prepared by preparing,
[0177] by reacting the compounds of the general formula (XIV)
18
[0178] in which
[0179] E is as defined above
[0180] and
[0181] R.sup.16 represents C.sub.1-C.sub.4-alkoxycarbonyl or aryl
(D=aryl)
[0182] with aldehydes of the general formula (XV)
A--CHO (XV),
[0183] in which
[0184] A is as defined above,
[0185] and compounds of the general formula (XVI) 19
[0186] in which
[0187] R.sup.17 and R.sup.18 together with a carbonyl group have
the abovementioned scope of R.sup.1 and R.sup.2,
[0188] the compounds of the general formula (XVII) 20
[0189] in which
[0190] A, E, R.sup.16, R.sup.17 and R.sup.18 are as defined
above
[0191] and, in the case of the compounds of the general formula
(III), then carrying out a reduction, as described above, to give
the hydroxymethyl function,
[0192] and, in a last step, converting the alkoxycarbonyl group
(R.sup.16) by a reduction-oxidation sequence into an aldehyde
group.
[0193] Suitable solvents 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.
[0194] 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.
[0195] 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).
[0196] 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.
[0197] The oxidation generally proceeds at atmospheric pressure.
However, it is also possible to carry out the oxidation under
elevated or reduced pressure.
[0198] The compounds of the general formulae (IV), (V), (VII),
(XIV), (XV) and (XVI) are known per se or can be prepared by
customary methods.
[0199] Some of the compounds of the general formulae (VI) and (XV)
are known or novel, in which case they can be prepared as described
above.
[0200] The compounds of the general formulae (IX) and (X) are novel
species and can be prepared as described above.
[0201] The compounds of the general formula (VIII) are novel and
can be prepared by reacting
[0202] compounds of the general formulae (XVa), (XVIII) and
(XIX)
A--CHO (XVa),
[0203] 21
[0204] in which
[0205] A, E, R.sup.3, R.sup.4 and R.sup.7 are as defined above,
[0206] with an acid.
[0207] Suitable solvents for preparing the compounds of the general
formula (VIII) are the abovementioned ethers or alcohols.
Preference is given to diisopropyl ether.
[0208] 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 and oxalic acid.
[0209] 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).
[0210] The reaction is generally carried out at atmospheric
pressure. However, it is also possible to carry out the reaction
under elevated or reduced pressure.
[0211] The reaction is generally carried out at the reflux
temperature of the solvent in question.
[0212] The compounds of the general formulae (XV) and (XIX) are
known per se or can be prepared by customary methods.
[0213] The compounds of the general formula (XVIII) are novel and
can be prepared by first preparing, by reacting the compounds of
the general formula (XX)
E--CO.sub.2--R.sup.19 (XX)
[0214] in which
[0215] E is as defined above
[0216] and
[0217] R.sup.19 represents C.sub.1-C.sub.4-alkyl
[0218] with compounds of the general formula (XXI) 22
[0219] in which
[0220] R.sup.7 is as defined above
[0221] in a solvent in the presence of 18-crown-6 ether, the
compounds of the general formula (XXII) 23
[0222] in which
[0223] R.sup.7 and E are as defined above,
[0224] followed by reaction with ammonium acetate in inert
solvents.
[0225] Suitable solvents for the first step of the process are the
abovementioned ethers and hydrocarbons, and preference is given to
tetrahydrofuran.
[0226] 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.
[0227] All steps of the process are carried out at the respective
reflux temperature of the solvent in question and at atmospheric
pressure.
[0228] Some of the compounds of the general formulae (XX) and (XXI)
are known, or they can be prepared by known methods.
[0229] Some of the compounds of the general formula (XXII) are
novel species, and they can be prepared as described above.
[0230] The compounds of the general formulae (I) and (Ia) according
to the invention have a pharmacological activity spectrum which
could not have been foreseen.
[0231] 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 cholesterol ester transfer protein
(CETP) and they stimulate the reverse cholesterol transport. The
active compounds according to the invention effect a reduction of
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 hyperlipoproteinaemia, dyslipidaemias,
hypertriglyceridaemias, hyperlipidaemias or arteriosclerosis.
[0232] The pharmacological activity of the substances according to
the invention was assessed using the following test:
[0233] CETP Inhibition Test
[0234] Preparation of CETP
[0235] 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).
[0236] Preparation of Radioactively Labelled HDL
[0237] 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 Ty 65 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 ml of .sup.3H-cholesterol
(Dupont NET-725; 1 mC/ml, dissolved in ethanol) are subsequently
added, and the mixture is incubated at 37.degree. C. under N.sub.2
for 72 h.
[0238] 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.
[0239] 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.
[0240] CETP Test
[0241] To assess the CETP activity, the transfer of
.sup.3H-cholesterol ester from human HD-lipoproteins to
biotinylated LD-lipoproteins is measured.
[0242] The reaction is terminated by addition of
Streptavidin-SPA.RTM. beads (Amersham) and the transferred
radioactivity is directly measured in a liquid scintillation
counter.
[0243] In the assay mixture, 10 ml of HDL-.sup.3H-cholesterol ester
(.about.50,000 cpm) with 10 ml of Biotin-LDL (Amersham) in 50 mM
Hepes/0.15 m NaCl/0.1% bovine serum albumin/0.05% NaN.sub.3 pH 7.4
are incubated with 10 ml of CETP (1 mg/ml) and 3 ml of a solution
of the substance to be tested (dissolved in 10% DMSO/1% BSA) at
37.degree. C. for 18 h. 200 ml 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.
[0244] The controls used are corresponding incubations with 10 ml
of buffer, 10 ml of CETP at 4.degree. C. and 10 ml of CETP at
37.degree. C.
[0245] The activity which is transferred in the control experiments
with CETP at 37.degree. C. is taken to be 100% transfer. The
substance concentration at which this transfer is reduced by half
is stated as the IC.sub.50 value.
[0246] In Table A below, the IC.sub.50 values (mol/l) for CETP
inhibitors are given:
1 TABLE A Example No. IC.sub.50 value (mol/l) 1 6 .times. 10.sup.-9
53 1 .times. 10.sup.-8 61 2.3 .times. 10.sup.-8
[0247] Ex Vivo Activity of the Compounds According to the
Invention
[0248] 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.
[0249] 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.
[0250] At different intervals--up to 24 hours after the
administration--blood samples are taken from the animals by
puncture of the retro-orbital venous plexus (approximately 250 ml).
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.
[0251] The reaction is terminated by addition of
Streptavidin-SPA.RTM. beads (Amersham), and the transferred
radioactivity is directly determined in a liquid scintlation
counter.
[0252] The test protocol is carried out as described under "CETP
test". However, to test the serum, 10 ml of CETP are replaced by 10
ml of the appropriate serum samples. Corresponding incubations of
sera of untreated animals serve as controls.
[0253] 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
[0254] In Vivo Activity of the Compounds According to the
Invention
[0255] In experiments for assessing the oral activity on
lipoproteins and triglycerides, test substance, dissolved in DMSO
and suspended in 0.5% tylose, is administered perorally using a
pharyngeal tube to Syrian gold hamsters which have been bred in our
own laboratory. To determine the CETP activity, blood samples
(approximately 250 ml) 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 the administration of the
substances--blood samples are taken by puncture of the
retro-orbital venous plexus.
[0256] 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 assessed using modified
commercially available enzyme tests (cholesterol enzymatic 14366
Merck, triglycerides 14364 Merck). Serum is diluted in a suitable
manner with physiological saline solution.
[0257] 100 ml of serum dilution and 100 ml 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.
[0258] 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.
[0259] In Vivo Activity in Transgenic hCETP Mice
[0260] 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.
[0261] The invention furthermore relates to the combination of
tetrahydroquinolenes of the general formula (I) with a glucosidase
and/or amylase inhibitor for the treatment of familial
hyperlipidaemias, 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,
miglitol, emiglitate, MDL-25637, camiglibose (MDL-73945),
tendamistate, AI-3688, trestatin, pradimicin-Q and salbostatin.
[0262] Preference is given to the combination of acarbose,
miglitol, emiglitate or voglibose with one of the abovementioned
compounds of the general formnula (I) according to the
invention.
[0263] 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.
[0264] The abovementioned combinations can also be used for primary
or secondary prevention of coronary heart diseases (for example
myocardial infarction).
[0265] Vastatins in the context of the present invention are, for
example, lovastatin, simvastatin, pravastatin, fluvastatin,
atorvastatin and cerivastatin. ApoB-lowering agents are, for
example, MTP inhibitors.
[0266] Preference is given to the combination of cerivastatin or
ApoB inhibitors with one of the abovementioned compounds of the
general formula (I) according to the invention.
[0267] 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 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.
[0268] 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.
[0269] Administration is carried out in a customary manner,
intravenously, orally, parenterally or perlingually, in particular
orally.
[0270] In the case of parenteral administration, solutions of the
active compound can be used by employing suitable liquid carrier
materials.
[0271] In general, it has proved advantageous, in the case of
intravenous administration, to administer amounts 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.
[0272] 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 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 amounts, 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.
[0273] Abbreviations Used
2 Cy = cyclohexane EA = ethyl acetate PE = petroleum ether THF =
tetrahydrofuran DAST = dimethylaminosulphur trifluoride PTA =
para-toluenesulphonic acid PDC = pyridinium dichromate PE/EA =
petroleum ether/ethyl acetate Tol = toluene
[0274] Starting Materials
EXAMPLE I
[0275] Methyl
2-cyclopentyl-4-(4-fluorophenyl)-5-oxo-7,7-dimethyl-1,4,5,6,-
7,8-hexahydroquinoline-3-carboxylate 24
[0276] 25.07 g (0.202 mol) of p-fluorobenzaldehyde, 28.32 g (0.202
mol) of 5,5-dimethyl-1,3-cyclohexanedione (dimedone) and 34.18 g
(0.202 mol) of ethyl 3-amino-3-cyclopentylacrylate in 400 ml of
ethanol are boiled under reflux for 24 hours. The mixture is cooled
to room temperature and concentrated to dryness. The residue is
suspended with heating in 180 ml of toluene and, during cooling,
covered with a layer of petroleum ether, whereupon crystallization
begins. The product which has crystallized out is filtered off with
suction.
[0277] Yield: 41.21 g (51% of theory)
[0278] TLC: R.sub.f=0.07 (toluene/ethyl acetate=9:1)
EXAMPLE II
[0279] Methyl
2-cyclopentyl-4-(4-fluorophenyl)-5-oxo-7,7-dimethyl-5,6,7,8--
tetrahydroquinoline-3-carboxylate 25
[0280] 23.6 g (0.104 mol) of
2,3-dichloro-5,6-dicyano-p-benzioquinone (DDQ) are added to a
solution of 41.2 g (0.104 mol) of the compound from Example I in
300 g of dichloromethan p.a., and the mixture is stirred at room
temperature for 2 hours. The mixture is then filtered off with
suction through 500 ml of silica gel 60 (0.04 to 0.063 mm), the
silica gel is washed with 300 g of dichloromethane and the combined
filtrates are concentrated to dryness. The crude product is eluted
over silica gel using toluene in a gradient mode with ethyl
acetate.
[0281] Yield: 38.31 g (94% of theory)
[0282] TLC: R.sub.f=0.6 (toluene/ethyl acetate 9:1)
EXAMPLE III
[0283] Methyl
2-cyclopentyl-4-(4-fluorphenyl)-5-hydroxy-7,7-dimethyl-5,6,7-
,8-tetrahydroquinoline-3-carboxylate 26
[0284] Under argon, 28 g (70.8 mmol) of the compound from Example
II are dissolved in 700 ml of toluene p.a., the mixture is cooled
to -78.degree. C. and 84.96 ml (84.96 mmol; 1.2 eq.) of
diisobutylaluminium hydride (DIBAL-H); 1.0 molar in toluene) are
added dropwise over a period of 20 min. After 5 min of stirring at
-78.degree. C., the cooling bath is removed and the mixture is
stirred for another 15 min. 500 ml of 20% strength potassium sodium
tartrate solution are then added dropwise and the mixture is
admixed with 600 ml of ethyl acetate. After 1 hour of stirring, the
aqueous phase is separated off and reextracted twice with ethyl
acetate, and the combined organic phases are dried over sodium
sulphate, filtered and concentrated.
[0285] Yield: 27.66 g (98.2% of theory)
[0286] TLC: R.sub.f=0.37 (toluene/ethyl acetate, 9:1)
EXAMPLE IV
[0287] Methyl
5-(tertbutyldimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophe-
nyl)-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carboxylate 27
[0288] 25.5 g (64.15 mmol) of the compound from Example III are
dissolved in 300 g of methylene chloride and, under argon, admixed
successively with 28.83 ml (0.2476 mol; 3.8 eq.) of 2,6-lutidine
and 32.56 ml (0.1418 mol, 2.12 eq.) of tert.butyl-dimethylsilyl
trifluoromethanesulphonate (TBS-triflate) at from -10.degree. C. to
0.degree. C. After 1 hour of stirring without cooling, the batch is
stirred with 500 ml of ammonium chloride solution and 800 ml of
ethyl acetate and adjusted to pH 5-6 using 6 molar hydrochloric
acid. The organic phase is separated off, the aqueous phase is
extracted two more times with ethyl acetate and the combined
organic phases are dried over sodium sulphate, filtered and
concentrated. The crude product is dissolved in toluene and
chromatographed over silica gel using toluene.
[0289] Yield: 31.5 g (96% of theory)
[0290] TLC: R.sub.f=0.76 (toluene/ethyl acetate, 9:1)
EXAMPLE V
[0291]
5-(tertButyidimethylsilanyloxy)-2-cyclopentyl-3-hydroxymethyl-4-(4--
fluorophenyl)-7,7-dimethyl-5,6,7,8-tetrahydroquinoline 28
[0292] 41.6 g (81.3 mmol) of the compound from Example IV are
dissolved in 700 g of toluene p.a. and, under argon, cooled to
-78.degree. C. Over a period of 30-40 minutes, 244 ml (0.244 mol; 3
eq.) of DIBAL-H (1.0 molar in toluene) are added dropwise, and the
mixture is subsequently stirred without cooling for 15 minutes. The
reaction solution is stirred into 700 ml of 20% strength potassium
sodium tartrate solution and covered with a layer of 350 ml of
ethyl acetate. After 40 minutes of stirring, the organic phase is
separated off and the aqueous phase is extracted twice with ethyl
acetate. The combined organic phases are dried with
Na.sub.2SO.sub.4, filtered, concentrated and dried under reduced
pressure.
[0293] Yield: 39.42 g (100% of theory)
[0294] TLC: R.sub.f=0.54 (toluene/ethyl acetate, 9:1)
EXAMPLE VI
[0295]
5-(tertButyldimethylsilanyloxy)-2-cyclopentyl)-4-(4-fluorophenyl)-7-
,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde 29
[0296] Under argon and at 0-5.degree. C., 87 ml (1.23 mol, 1.5 eq.)
of DMSO and 56.7 ml (0.407 mol, 5 eq.) of triethylamine are added
to a solution of 39.4 g (81.5 mmol) of the compound from Example V
in 400 ml of dichloromethane. 48.7 g (0.326 mol; 3.75 eq.) of
sulphur trioxide-pyridine complex are then added, and the mixture
is stirred for 2 hours with ice-cooling. The reaction solution is
admixed with stirring with 250 mg of NaHCO.sub.3 solution, the
methylene chloride phase is separated off and the aqueous phase is
washed twice with methylene chloride. The combined organic phases
dried over Na.sub.2SO.sub.4 and concentrated. The
residue--dissolved in toluene--is chromatographed over silica gel
using toluo, toluene/ethyl acetate.
[0297] Yield: 32.61 g (83% of theory)
[0298] TLC: R.sub.f=0.92 (toluene/ethyl acetate, 9:1)
EXAMPLE VII
[0299]
5-(tertButyldimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophenyl)-3--
[hydroxy-(4-trifluoromethylphenyl)-methyl]-7,7-dimethyl-5,6,7,8-tetrahydro-
quinoline 30
[0300] 5.50 g (0.2262 mol, 6 eq.) of magnesium turnings are
initially charged in 230 g of THF p.a., the mixture is, under
argon, heated to reflux and 7.92 ml (0.05655 mol; 1.5 eq.) of
4-bromobenzotrifluoride are added dropwise using a syringe. The
mixture is boiled under reflux for 60 min and then allowed to cool
to room temperature (Grignard reagent). 18.17 g (0.0377 mol) of the
compound from Example VI are dissolved in 115 g of THV p.a. and,
under argon, cooled to approximately -78.degree. C., and the
Grignard reagent is added with stirring. The cooling bath is
removed and the batch is stirred for 1 hour. The reaction solution
is partitioned with stirring in 600 ml of conc. ammonium chloride
solution and 500 ml of ethyl acetate, the organic phases are
separated off, the aqueous phase is extracted once more with ethyl
acetate and the combined organic layers are dried with sodium
sulphate, filtered, concentrated and dried under high vacuum. The
two diastereomers (Dia A and Dia B) are separated by chromatography
over 1 kg of silica gel--conditioned with cyclohexane, by eluting
the crude product in 60 ml of cyclohexane/THF (9:1). Concentration
of the fractions gives the 2 pairs of diastereomers:
[0301] Yields:
3 Dia A: 18.5 g (78.2% of theory) TLC: R.sub.f = 0.54
(cyclohexane/THF, 9:1) Dia B: 6.3 g (26.6% of theory) TLC: R.sub.f
= 0.41 (cyclohexane/THF, 9:1)
EXAMPLE VIII
[0302]
5-(tertButyldimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophenyl)-3--
[fluoro-(4-trifluoromethyl)-methyl]-7,7-dimethyl-5,6,7,8-tetrahydroquinoli-
ne (Dia A) 31
[0303] At -78.degree. C. and under argon, 1.042 ml (7.88 mmol, 1.5
eq.) of diethylaminosulphur trifluoride (DAST) are added with a
syringe to a solution of 3.3 g (5.26 mmol) of the compound Dia A
from Example VII in 150 ml of dichloromethane p.a., and the cooling
bath is then removed and the mixture is stirred for 30 minutes. The
reaction solution is subsequently stirred into ethyl
acetate/ammonium chloride solution, the organic phase is separated
off, the aqueous phase is extracted three times with ethyl acetate,
and the combined organic extract is dried with Na.sub.2SO.sub.4,
filtered, concentrated and dried under high vacuum.
[0304] Yield: 3.1 g (93.7% of theory)
[0305] TLC: R.sub.f=0.79 (toluene/ethyl acetate=9:1)
EXAMPLE IX
[0306]
5-(tertButyldimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophenyl)-3--
[fluoro-(4-trifluoromethyl)-methyl]-7,7-dimethyl-5,6,7,8-tetrahydroquinoli-
ne (Dia B) 32
[0307] Analogously to Example VIII, 6.3 g (10 mmol) of the compound
Dia B from Example VI in 200 g of dichloromethane p.a. are reacted
with 2.0 ml (15 mmol; 1.5 eq.) of DAST at -78.degree. C.
[0308] Yield: 5.9 g (93.6% of theory)
[0309] TLC: R.sub.f=0.75 (cyclohexane/THF 9:1)
EXAMPLE X
[0310]
2-Cyclopentyl-4-(4-fluorophenyl)-3-[fluoro-(4-trifluoromethyl-pheny-
l)-methyl]-7,7-dimethyl-5,6,7,8-tetrahydro-quinolin-5-ol (Dia A)
33
[0311] 60 ml of 6 molar hydrochloric acid are added to 3.1 g (4.92
mmol) of the compound from Example VIII--dissolved in 200 ml of
methanol and 46 ml of THF--and the mixture is stirred at 60.degree.
C. for 1.5 hours. The reaction solution is stirred into saturated
sodium bicarbonate solution which is covered with a layer of ethyl
acetate. The organic phase is separated off and the aqueous phase
is extracted twice with ethyl acetate. The combined organic phases
are washed once with saturated sodium chloride solution, dried over
Na.sub.sSO.sub.4, filtered and concentrated. The residue is
chromatographed over 150 ml of silica gel 60 one another with
toluene and toluene/ethyl acetate (8:2).
[0312] Yield: 2.43 g (95.7% of theory)
[0313] TLC: R.sub.f=0.61 (toluene/ethyl acetate, 9:1)
EXAMPLE XI
[0314]
2-Cyclopentyl-4-(4-fluorophenyl)-3-[fluoro-(4-trifluoromethyl-pheny-
l)-methyl]-5-oxo-7,7-dimethyl-5,6,7,8-tetrahydro-quinoline 34
[0315] At room temperature, 3.0 g (5.819 mmol) of the compound
enantiomer I from
2-cyclopentyl-4-(4-fluoro-phenyl)-3-[fluoro-(4-trifluoromethyl-phe-
nyl)-methyl]-7,7-dimethyl-5,6,7,8-tetrahydro-quinolin-5-ol in 270
ml of dichloromethane p.a. are reacted with 6.57 g (17.452 mmol; 3
eq.) of pyridinium dichromate. After 5 hours, the reaction solution
is applied to 300 ml of silica gel which had been conditioned with
dichloromethane beforehand, and the solution is eluted with
dichloromethane. The fractions containing the pure product are
combined and concentrated.
[0316] Yield. 2.64 g
[0317] TLC: R.sub.f=0.66 (toluene/ethyl acetate, 9:1)
PREPARATION EXAMPLES
Example 1 and 2
[0318]
2-Cyclopentyl-4-(4-fluorophenyl)-3-[fluoro-(4-trifluoromethyl-pheny-
l)-methyl]-5-methyl-7,7-dimethyl-5,6,7,8-tetrahydro-quinolin-5-ol
35
[0319] 514 mg (1 mmol) of the keto compound from Example XI are
dissolved in 50 ml of ether p.a. (which had been dried over a
molecular sieve), and the mixture is cooled under argon to
-78.degree. C. and admixed dropwise with 3.1 ml (5 mmol, 5 eq.) of
methyllithium (1.6 molar solution in ether). The solution is
subsequently stored at -30.degree. C. (deep freezer) for 20 hours.
The solution is then cooled to -78.degree. C. and admixed with 20
ml of ammonium chloride solution and 40 ml of toluene p.a. The
cooling bath is removed and the solution is allowed to warm to room
temperature. The organic phase is separated off, the aqueous phase
is extracted twice with toluene and the combined organic phases are
dried over Na.sub.2SO.sub.4, filtered and concentrated. The
residue--dissolved in toluene--is chromatographed over 500 ml of
silica gel using cyclohexane with a little added ethyl acetate as
eluent.
4 Example 1: Isomer A: Yield: 39 mg TLC: R.sub.f = 0.57
(dichloromethane) Example 2: Isomer B: Yield: 39 mg TLC: R.sub.f =
0.48 (dichloromethane)
Example 3
[0320]
[2-Cyclopentyl-4-(3,4-difluorophenyl)-5-hydroxy-7,7-dimethyl-5,6,7,-
8-tetrahydro-quinolin-3-yl]-(4-trifluoromethylphenyl)-methanone
36
[0321] a)
2-Cyclopentyl-4-(3,4-difluorophenyl)-7,7-dimethyl-3-(4-trifluoro-
methyl-benzoyl)-7,8-dihydro-6H-quinolin-5-one 37
[0322] 0.9 g (1.7 mmol) of
2-cyclopentyl-4-(3,4-difluorophenyl)-7,7-dimeth-
yl-3-(4-trifluoromethylbenzoyl-4,6,7,8-tetrhydro-1H-quinolin-5-one
were oxidized at room temperature within one hour to give the
pyridine, using 4.5 g of manganese dioxide (activated) in 25 ml of
methylene chloride. The manganese dioxide was separated off and the
methylene chloride was distilled off, and the mixture was then
filtered off with suction using petroleum ether. This gave 0.8 g of
crystals of melting point: 210-212.degree. C.
[0323] b) 2.1 g (4 mmol) of
2-cyclopentyl-4-(3,4-difluorophenyl)7,7-dimeth-
yl-3-(4-trifluoromethylbenzoyl)-7,8-dihydro-6H-quinolin-5-one were
dissolved in 20 ml of tetrahydrofuran and, at 0.degree. C., added
dropwise to a solution of 0.2 g (1.2 mmol) of 1R, 2S-aminoindanol
and 2.7 ml (16 mmol) of borane-diethylaniline complex in 2 ml of
THF. The mixture is stirred at RT overnight. After about 20 hours,
the reaction was quenched using 2.4 ml of 1,2-ethanediol. The
tetrahydrofuran was distilled off, the resulting oil was taken up
in ethyl acetate and the organic phase was, after washing with 2N
hydrochloric acid and saturated sodium bicarbonate solution, dried
and concentrated. The residue was recrystallized from hot
cyclohexane. This gave a total of 1.4 g of colourless crystals of
melting point: 166-168.degree. C.
Example 4
[0324]
2-Cyclopentyl4-(3,4-difluorophenyl)-3-[fluoro-(4-trifluoromethylphe-
nyl)-methyl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol 38
[0325] a)
[5-(tert-Butyldimethylsilanyloxy)-2-cyclopentyl-4-(3,4-difluorop-
henyl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphe-
nyl)-methanone 39
[0326] 0.529 g (1 mmol) of
[2-cyclopentyl-4-(3,4-difluorophenyl)-5-hydroxy-
-7,7-dimethyl-5,6,7,8-tetrahydro-quinolin-3-yl]-(4-trifluoromethylphenyl)--
methanone are dissolved in 6 ml of abs. toluene and admixed with
0.465 ml of lutidine at -5.degree. C. At from -5.degree. C. to
-10.degree. C., 0.459 ml (2 mmol) of tert-butyl-dimethylsilyl
trifluoromethanesulphonate is added. The mixture is stirred at
20.degree. C. for 3 hours. The mixture is diluted with toluene, the
reaction is quenched with 10% strength aqueous ammonium chloride
solution and the organic phase is washed with 0.1 N hydrochloric
acid and saturated aqueous sodium bicarbonate solution and dried.
The solvent is distilled off under reduced pressure and the residue
is then purified using a column. This gives 620 mg of colourless
crystals of melting point: 128.degree. C.-129.degree. C.
[0327] b)
[5-(tert-Butyldimethylsilanyloxy)-2-cyclopentyl-4-(3,4-difluorop-
henyl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphe-
nyl)-methanol 40
[0328] At 0.degree. C., 1.15 ml (4 mmol) of sodium
bis-(2-methoxyethoxy)-a- luminium dihydride (65% strength in
toluene) were added dropwise to 600 mg (0.93 mmol) of
[5-(tert-butyldimethylsilanyloxy)-2-cyclopentyl-4-(3,4-dif-
luorophenyl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromet-
hylphenyl)-methanone dissolved in 6 ml of toluene. After 3.5 hours,
the reaction was quenched with methanol, the mixture was extracted
with ethyl acetate and the organic phase was washed with
potassium-sodium tartrate solution and saturated aqueous sodium
bicarbonate solution and dried. The solvent is distilled off under
reduced pressure and the residue is then purified over a silica gel
column using toluene/ethyl acetate. This gives a total of 0.56 g of
a colourless foam.
[0329] c)
5-(tert-Butyldimethylsilanyloxy)-2-cyclopentyl-4-(3,4-difluoroph-
enyl)-3-[fluoro-(4-trifluoromethylphenyl)-methyl]-7,7-dimethyl-5,6,7,8-tet-
rahydroquinoline 41
[0330] At -5.degree. C., 0.06 ml of diethylaminosulphur
trifluoride, dissolved in 10.15 ml of toluene, was added dropwise
to 200 mg (0.3 mmol) of
[5-(tert-butyldimethylsilanyloxy)-2-cyclopentyl-4-(3,4-difluorophenyl)-
-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphenyl)-m-
ethanol dissolved in 2 ml of toluene. After 60 minutes, the
reaction was quenched with saturated aqueous sodium bicarbonate
solution, toluene was added and the organic phase was washed once
more with saturated aqueous sodium bicarbonate solution and dried.
The solvent was distilled off under reduced pressure and the
residue was then purified over a silica gel column. This gave a
total of 190 mg of a colourless oil.
[0331] d) 190 mg of
5-(tert-butyldimethylsilanyloxy)-2-cyclopentyl-4-(3,4--
difluorophenyl)-3-[fluoro-(4-trifluoromethylphenyl)-methyl]-7,7-dimethyl-5-
,6,7,8-tetra-hydroquinoline, in a mixture of 1.6 ml of 5 N
hydrochloric acid, 2.3 ml of methanol and 1.5 ml of
tetrahydrofuran, were stirred at RT for 1 hour and then at
40.degree. C. -45.degree. C. for 2 hours. Some of the compound
precipitated out as a by-product. This gives 80 mg of m.p.
206-207.degree. C. The mother liquor is admixed with saturated
aqueous sodium bicarbonate solution and with ethyl acetate. The
organic phase is once more washed with saturated aqueous sodium
bicarbonate solution and then dried. The solvent is distilled off
under reduced pressure and the residue is then purified over a
silica gel column. Crystallization with heptane gives 40 mg of the
base of m.p. 149-150.degree. C.
Example 5
[0332]
2-Cyclopropyl-4-(3,4-difluorophenyl)-3-(4-trifluoromethylbenzyl)-7,-
7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol 42
[0333] 280 mg (0.52 mmol) of the compound from Example 4 are
dissolved in 40 ml of abs. toluene and, at from -10.degree. C. to
-15.degree. C., admixed dropwise with 3.5 ml of 25% strength
diisobutylaluminium hyride solution. The mixture is stirred for 1
hour, cooled to -70.degree. C. and admixed dropwise with 0.2 ml of
methanol. At 20.degree. C., the mixture is admixed with sodium
chloride solution, the phases are separated and the organic phase
is dried. The evaporation residue is purified over a silica gel
column Crystallization from heptane gives 195 mg of colourless
crystals of m.p. 126-127.degree. C.
[0334] The compounds listed in Table 1 are prepared analogously to
the procedure of Examples 1 to 5:
5TABLE 1 Example No. Structure Isomer R.sub.f value/m.p. (.degree.
C.) 6 43 racemate 0.50 toluene/EA (9:1) 7 44 racemate Lichrosorb Si
60: 2.785 n-heptane/ethanol (95:5) 8 45 diastereomer A 0.32
cyclohexane/EA (9:1) 9 46 diastereomer B 0.58 toluene/EA (9:1) 10
47 enantiomer H Chiral AD: 79.551 n-heptane/2-propanol (99:1) 11 48
enantiomer I 0.2 cyclohexane/EA (9:1) 12 49 enantiomer I KBD 4922C
column: 9.50 (Bayer AG) n-heptane/THF (100:3) 13 50 diastereomer A
0.73 toluene/EA (8:2) 14 51 diastereomer B 0.16 cyclohexane/EA
(8:2) 15 52 diastereomer B 0.50 toluene/EA (8:2) 16 53 diastereomer
A 0.40 cyclohexane/EA (8:2) 17 54 diastereomer A 0.55 toluene/EA
(9:1) 18 55 diastereomer B 0.48 toluene/EA (9:1) 19 56 racemate
0.34 toluene/EA (95:5) 20 57 diastereomer B 0.53 toluene/EA (9:1)
21 58 diastereomer A, B 0.43 and 0.46 toluene/EA (95:5) 22 59
enantiomer I KBD 4922 C column: 4.82 (Bayer AG) n-heptane/THF (9:1)
23 60 enantiomer II KBD 4922 C column: 7.32 (Bayer AG)
n-heptane/THF (9:1) 24 61 0.41 toluene/EA (95:5) 25 62 diastereomer
A 0.16 toluene/EA (95:5) 26 63 diastereomer B 0.66 toluene/EA (9:1)
27 64 0.22 toluene/EA (9:1) 28 65 diatsreomer A 0.44 toluene/EA
(9:1) 29 66 diastereomer A 0.36 toluene/EA (95:5) 30 67
diastereomer B 0.37 toluene/EA (95:5) 31 68 diastereomer A 0.48
toluene/EA (95:5) 32 69 diastereomer B 0.45 toluene/EA (95:5) 33 70
racemate 0.42 toluene/EA (9:1) 34 71 diastereomer B 0.65 toluene/EA
(9:1) 35 72 diastereomer A 0.47 toluene/EA (95:5) 36 73
diastereomer B 0.45 toluene/EA (95:5) 37 74 diastereomer A 0.61
toluene/EA (9:1) 38 75 diastereomer A 0.33 toluene/EA (9:1) 39 76
diastereomer B 0.32 toluene/EA (9:1) 40 77 diastereomer A 0.57
dichloromethane 41 78 diastereomer B 0.48 dichloromethane 42 79
diastereomer A 0.51 cyclohexane/EA (8:2) 43 80 diastereomer B 0.44
cyclohexane/EA (8:2) 44 81 diastereomer A 0.52 methylene chloride
45 82 diastereomer B 0.41 methylene chloride 46 83 m.p.:
166-168.degree. C. 47 84 m.p.: 171-174.degree. C. 48 85 m.p.:
157-162.degree. C. 49 86 m.p.: 167-168.degree. C. 50 87
diastereomer B 0.33 toluene/EA (7:3) 51 88 m.p.: 153-155.degree. C.
52 89 m.p.: 168-169.degree. C. 53 90 m.p.: 156-158.degree. C. 54 91
m.p.: 175-176.degree. C. 55 92 m.p.: 138-139.degree. C. 56 93 m.p.:
136-137.degree. C. 57 94 m.p.: 206-207.degree. C. 58 95 mixture of
diastereomers 0.62 toluene/EA (9:1) 59 96 diastereomer A 0.52
methylene chloride 60 97 diastereomer B 0.41 methylene chloride 61
98 atropisomer m.p.: 129.degree. C. (from 129.degree. C.) 62 99
m.p.: 106-108.degree. C. 63 100 atropisomer 0.19 and 0.39 petroleum
ether/EA (10:1) 64 101 0.37 toluene/EA (20:1)
* * * * *