Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-04-15
2003-05-13
Seaman, D. Margaret (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S173000
Reexamination Certificate
active
06562976
ABSTRACT:
The present invention relates to tetrahydroquinolines, to processes for their preparation and to their use in medicaments.
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.
The present invention relates to tetrahydroquinolines of the general formula (I),
in 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
in which
R
5
and R
6
together form a carbonyl group (═O), or
R
5
represents hydrogen and
R represents halogen or hydroxyl, or
R
5
and R
6
represent hydrogen,
R
7
and R
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
2
—CH
3
or —NR
9
R
10
,
in which
R
9
and R
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
1
represents hydroxyl, and
R
2
represents hydrogen or represents methyl,
R
3
and R
4
are identical or different and represent straight-chain or branched alkyl having up to 3 carbon atoms, or
R
3
and R
4
together form a spiro-linked alkyl chain having 2 to 4 carbon atoms,
and their salts and N-oxides.
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.
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.
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, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
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.
Preference is given to compounds of the general formula (I) according to the invention
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
in which
R
5
and R
6
together form a carbonyl group (═O), or
R
5
represents hydrogen and
R
6
represents fluorine or hydroxyl, or
R
5
and R
6
represent hydrogen,
R
7
and R
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
1
represents hydroxyl, and
R
2
represents hydrogen or represents methyl,
R
3
and R
4
are identical or different and represent methyl, or
R
3
and R
4
together form a spiro-linked cyclopropyl, cyclobutyl or cyclopentyl ring,
and their salts and N-oxides.
Particular preference is given to compounds of the general formula (I) according to the invention
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
in which
R
5
and R
6
together form a carbonyl group (═O), or
R
5
represents hydrogen and
R
6
represents fluorine or hydroxyl or
R
5
and R
6
represent hydrogen,
R
7
and R
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
1
represents hydroxyl and
R
2
represents hydrogen or represents methyl,
R
3
and R
4
are identical or different and represent methyl, or
R
3
and R
4
together form a spiro-linked cyclopropyl, cyclobutyl or cyclopentyl ring,
and their salts and N-oxides.
Moreover, processes for preparing the compounds of the general formula (I) according to the invention have been found which are characterized in that
[A] in the case that D represents the radical
in compounds of the general formula (I)
in which
A, E, R
1
, R
2
, R
3
and R
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
8
—CH
2
—O—CH
2
, in which R
8
is as defined above,
[B] either compounds of the general formula (III)
in which
A, E, R
1
, R
2
, R
3
and R
4
are as defined above
are reacted with compounds of the general formula (IV)
R
8
—CH
2
—Z (IV),
in which
R
8
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 an auxiliary, or
[C] compounds of the general formula (III) are first converted, by reaction with compounds of the general formula (V)
in which
R
11
represents straight-chain alkyl having up to 4 carbon atoms,
into the compounds of the general formula (VI)
in which
A, E, R
1
, R
2
R
3
, R
4
and R
11
are as defined above,
and subsequently reacted with compounds of the general formula (VII)
R′—CH
2
—OH (VII),
in which
R
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)
in which
A, E, R
3
, R
4
, R
5
and R
6
are as defined above,
compounds of the general formula (VIII)
in which
A, E, R
3
, R
4
and R
7
are as defined above,
are first oxidized to the compounds
Bischoff Hilmar
Brandes Arndt
Bremm Klaus-Dieter
Lögers Michael
Schmeck Carsten
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