Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
1998-09-24
2001-08-21
Shah, Mukund J. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S091000, C514S415000, C514S419000, C514S422000, C514S427000, C514S438000, C514S444000, C514S452000, C514S461000, C548S413000, C548S414000, C548S468000, C548S494000, C548S509000, C548S562000, C549S006000, C549S060000, C549S078000, C549S370000, C549S498000, C549S502000, C549S218000
Reexamination Certificate
active
06277833
ABSTRACT:
The invention relates to substituted triols, to a process for their preparation, and to their use in medicaments.
It has been disclosed that lactone derivatives isolated from fungal cultures are inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoA reductase) [mevinolin, EP 22 478; U.S. Pat. No. 4,231,938].
It has additionally been disclosed that pyridine-substituted dihydroxyheptenoic acids are inhibitors of HMG-CoA reductase [EP 325 130; EP 307 342; EP 306 929].
The present invention relates to substituted triols of the general formula (I)
D—R (I)
in which
D represents a hetero- or carbocyclic radical of the formula
wherein
R
1
, R
2
, R
3
and R
4
are identical or different and denote hydrogen or methyl, or R
4
denotes hydroxyl,
R
5
denotes 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 having up to 8 carbon atoms,
R
6
, R
7
, R
8
and R
9
are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 6 carbon atoms, or in each case R
6
and R
7
and/or R
8
and R
9
each together form a saturated or partially unsaturated carbocycle having 3 to 6 carbon atoms
R
10
denotes cycloalkyl having 3 to 7 carbon atoms, or denotes straight-chain or branched alkyl having up to 8 carbon atoms,
R
11
has the abovementioned meaning of R
10
and is identical to or different from this or denotes hydrogen or phenyl,
R
12
denotes hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by hydroxyl or straight-chain or branched alkoxy having up to 6 carbon atoms, or by benzyloxy which for its part can be substituted by halogen or trifluoromethyl or by straight-chain or branched alkyl having up to 4 carbon atoms,
R
13
is hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms or a radical of the formula
R
14
and R
15
are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, or denote phenyl or benzyl, each of which is optionally substituted up to 2 times by identical or different substituents from the group consisting of halogen, trifluoromethyl, cyano and nitro or by straight-chain or branched alkyl having up to 6 carbon atoms,
R
16
has the abovementioned meaning of R
14
and R
15
and is identical to or different from this, or denotes pyridyl or a radical of the formula —CO—NH—L,
wherein
L denotes phenyl which is optionally substituted by halogen or trifluoromethyl,
R
17
likewise has the abovementioned meanings of R
14
and R
15
and is identical to or different from these, or denotes a radical of the formula —NMM′,
wherein
M and M′ are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or benzyl,
R
18
denotes hydrogen or straight-chain or branched alkenyl, alkinyl or alkyl in each case having up to 8 carbon atoms, the latter optionally being substituted by cyano or phenyl which for its part can be substituted by halogen or trifluoromethyl or by straight-chain or branched alkyl having up to 6 carbon atoms,
R
19
denotes straight-chain or branched alkoxy having up to 8 carbon atoms, benzoyl or the group —NMM′,
wherein
M and M′ have the abovementioned meaning,
R
20
denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or benzyl,
E denotes an oxygen or sulphur atom, or a group of the formula —N—R
10
,
Z denotes a sulphur or oxygen atom or the —CH
2
— group
and
R represents a radical of the formula
wherein
X denotes the group —CH
2
—CH
2
—, —CH═CH— or —C≡C—,
R
21
, R
22
and R
23
are identical or different and denote a hydroxyl protective group, hydrogen or a radical of the formula —CO—R
24
or —CO
2
—R
25
,
wherein
R
24
and R
25
are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms or phenyl,
or
R
21
and R
22
together form a radical of the formula
In the context of the present invention, physiologically acceptable salts are preferred. Physiologically acceptable salts of the Quinolylmethoxyphenyl-acetic acid amides can be salts of the substances according to the invention with mineral acids, carboxyl acids or sulphonic acids. Particularly preferred salts are e.g. those 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.
Depending on the side chains listed under R, the compounds according to the invention in each case have 1 or 2 asymmetric carbon atoms, to which the radicals —OR
21
and —OR
22
are bonded. They can therefore exist in various stereochemical forms.
The invention relates both to the individual isomers and to their mixtures. Depending on the relative position of the radicals —OR
21
/—OR
22
, the substances according to the invention can thus be present in the erythro configuration or in the threo configuration. This can be illustrated by way of example:
In turn, two enantiomers both of the substances in the threo and in the erythro configuration in each case exist.
Moreover, the substances according to the invention can be present in the E configuration or the Z configuration on account of the double bond (X═—CH═CH—). Those compounds are preferred which have the E configuration.
The aldehydes in each case are additionally in equilibrium with the corresponding pyrans
Preferred compounds of the general formula (I) are those
in which
D represents a hetero- or carbocyclic radical of the formula
wherein
R
1
, R
2
, R
3
and R
4
are identical or different and denote hydrogen or methyl, or R
4
denotes hydroxyl,
R
5
denotes phenyl which is optionally substituted up to 2 times by identical or different substituents from the group consisting of fluorine, chlorine, bromine and trifluoromethyl or by straight-chain or branched alkyl having up to 6 carbon atoms,
R
6
, R
7
, R
8
and R
9
are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or cyclopropyl, cyclopentyl or cyclohexyl,
or in each case R
6
and R
7
and/or R
8
and R
9
together form a cyclopropyl, cyclopentyl or cyclohexyl ring and/or R
8
and R
9
together form a cyclopentenyl or cyclohexenyl ring,
R
10
denotes cyclopropyl, cyclopentyl or cyclohexyl, or denotes straight-chain or branched alkyl having up to 6 carbon atoms,
R
11
has the abovementioned meaning of R
10
and is identical to or different from this or denotes hydrogen,
R
12
denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxyl or straight-chain or branched alkoxy having up to 4 carbon atoms, or by benzoyl which for its part can be substituted by fluorine, chlorine, bromine, trifluoromethyl or methyl,
R
13
denotes straight-chain or branched alkyl having up to 6 carbon atoms or a radical of the formula
R
14
and R
15
are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, or denote phenyl or benzyl, each of which is optionally substituted by fluorine, chlorine, bromine, trifluoromethyl, cyano or nitro or by straight-chain or branched alkyl having up to 4 carbon atoms,
R
16
has the abovementioned meaning of R
14
and R
15
and is identical to or different from this, or denotes pyridyl or a radical of the formula —CO—NH—L,
wherein
L denotes phenyl which is optionally substituted by fluorine, chlorine, bromine or trifluoromethyl,
R
17
likewise has the abovementioned meanings of R
14
and R
15
and is identical to or different from these, or denotes a radical of the formula —NMM′,
wherein
Angerbauer Rolf
Bischoff Hilmar
Fey Peter
Hubsch Walter
Krause Hans-Peter
Bayer Aktiengesellschaft
Norris & McLaughlin & Marcus
Philipps Maxim
Rao Deepak R.
Shah Mukund J.
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