Annelated dihydropyridines and the use thereof for preparing...

Details Annelated dihydropyridines and the use thereof for preparing... Annelated dihydropyridines and the use thereof for preparing...

2000-10-05

2002-10-15

Jones, Dwayne C. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S307000, C514S232500, C514S232800, C514S235200

Reexamination Certificate

active

06465483

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to new annelated dihydropyridinoacetic acid derivatives, processes for preparing them and pharmaceutical compositions containing these compounds.
2. Description of the Related Art including information disclosed under 37 CFR 1.97 and 1.98.
Dihydroisoquinolines are known from EP-A 37 934. The compounds specified therein are cardiotonically active and have the effects of increasing contractility and influencing blood pressure. They have been proposed for improving blood circulation through the tissues.and for improving the oxygen supply to the tissues. These possible uses are based on the vascular activity of the compounds. EP-A 251 194 and EP-A 288 048 describe how carbocyclically and heterocyclically annelated dihydropyridines have a cardioprotective or cerebroprotective activity and constitute an entirely new type of Ca-antagonistic compounds. WO 92/11010 describes the use of such compounds for cerebroprotective agents, for treating chronic inflammatory processes and for inhibiting blood clotting and blood platelet aggregation.
BRIEF SUMMARY OF THE INVENTION
The present invention relates to new carbocyclically and heterocyclically annelated dihydropyridines and the pharmaceutical use of these compounds. The new compounds have valuable therapeutically useful properties. They may be used as cardioprotective agents, as cerebroprotective agents (particularly for treating patients who have suffered a stroke or are in danger of suffering a stroke) and as agents for treating chronically inflammatory processes (e.g. bronchial asthma and arthritis). These compounds may also be used as agents with an antiproliferative effect and as agents for treating ulcerative colitis and Crohn's disease.
DETAILED DESCRIPTION OF THE INVENTION
The invention.relates to compounds of general formula I
wherein
A denotes a benzo, indolo or thieno group;
wherein, if A is benzo, m is 2 or 3 (preferably 2, whilst the two R
2
s are in positions 6 and 7) and the substituents R
2
independently of each other denote hydroxy, (C
1-4
)alkoxy, benzyloxy, halogen (F, Cl, Br, I), (C
1-4
)alkyl, methanesulphonyloxy or methanesulphonamido, or two adjacent substituents R
2
may together represent —O—CH
2
—O— or —O—CH
2
—CH
2
—O—; and if A is indolo or thieno,
m is zero;
R
1
denotes thienyl or the group
 wherein
R
7
, R
8
and R
9
independently of one another may represent methyl, ethyl, propyl, phenyl or benzyl, whilst not more than 2 of the substituents can simultaneously represent phenyl or benzyl;
R
3
and R
4
independently of each other have one of the following meanings:
(a) hydrogen,
(b) branched or unbranched C
3-6
-alkenyl,
(c) branched or unbranched C
3-6
-alkynyl, or
(d) branched or unbranched C
1-12
-alkyl, wherein the alkyl may be substituted by
hydroxy,
(C
1-4
)alkoxy,
di(C
1-4
)alkylamino,
furyl,
pyridyl,
pyrrolidinyl, N-methylpyrrolidinyl,
morpholino,
indolyl,
nitrilo,
thienyl,
adamantyl,
cyclohexyl,
phenoxy,
naphthyloxy or phenyl, [whilst this phenyl or the phenyl contained in the phenoxy group may be mono-, di- or trisubstituted by hydroxy, (C
1-4
)alkoxy, benzyloxy, halogen (F, Cl, Br, I), CF
3
, N
3
, CN, (C
1-4
)alkyl, adamantyl, —SO
2
NH
2
, —NHCOCH
3
, —NHSO
2
CH
3
or CH
3
SO
2
O— or by the bridge —O—CH
2
—O—;] or by two unsubstituted phenyl groups;
or R
3
represents hydrogen and R
4
represents cyclohexyl, phenyl (whilst this phenyl may be mono-, di- or trisubstituted by hydroxy, (C
1-4
)alkoxy, benzyloxy, halogen (F, Cl, Br, I), CF
3
, N
3
, (C
1-4
)alkyl, adamantyl, —SO
2
NH
2
, —NHCOCH
3
, —NHSO
2
CH
3
or CH
3
SO
2
O— or by the bridge —O—CH
2
—O—); pyridyl or N-benzylpiperidyl;
or R
3
and R
4
together with the nitrogen atom to which they are bound represent pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, whilst the piperazinyl ring may optionally be N-substituted by methyl, unsubstituted phenyl, mono- or di(C
1-4
)alkoxyphenyl, cyano-substituted phenyl, pyrimidinyl, phenyl(C
1-4
)alkyl, (C
1-4
)alkylphenyl or
or the salts thereof with physiologically acceptable acids or complex-forming agents.
Compounds of formula I form tautomers of formula II
The tautomers can be separated by known methods, e.g. by column chromatography or selective reduction (NaBH
4
or catalytic reduction).
The compounds of formula II may occur in cis- and/or trans-form:
If the structure of a compound is not expressly stated, the mention of formula I should be taken as including structure II as well.
In the definitions used in the text the radicals and groups may be identical or different, i.e. if one of the above-mentioned substituents occurs several times in a particular molecule, the meaning can be selected freely within the scope of the definitions provided.
The term alkyl means C
1-6
-alkyl and C
1-4
-alkyl radicals which may be substituted or, as alkyl radicals, are part of a functional group such as alkoxy or alkylthio. The alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, isobutyl and tert.-butyl radicals as well as the various isomeric pentyl and hexyl radicals, such as e.g. isopentyl, neopentyl, n-pentyl and n-hexyl radicals.
The above definition thus also applies even when the alkyl radical itself is substituted and/or is itself part of an alkoxyalkyl-, alkoxycarbonyl-, alkoxy-, alkylthio-, alkylsulphonyl-, monoalkylamino-, alkylmethyl-, alkylthiomethyl- or dialkylamino- group or the alkyl radical, as a substituent, is bound to an aromatic heterocyclic or carbocyclic system.
The halogens are fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine and, to a lesser extent, iodine.
C
3-6
-cycloalkyl indicates cyclopropane, cyclobutane, cyclopentane and cyclohexane.
C
5-6
-cycloalkenes denote e.g. cyclopentene, cyclohexene and cyclohexadiene.
C
3-6
-alkynes are the isomeric hexenes, pentenes, butynes and propynes, preferably propargyl.
The C
3-6
-alkenes are the isomeric hexenes, pentenes, butenes and propenes, preferably allyl.
A preferred aspect of the invention consists of compounds of general formula I wherein
A denotes a benzo- or thieno group;
wherein, if A is benzo, m is 2, the R
2
s are in positions 6 and 7 and independently of one another represent hydroxy, (C
1-4
)alkoxy, benzyloxy, halogen (F, Cl, Br, I), (C
1-4
)alkyl, methanesulphonyloxy or methanesulphonamido, or two adjacent substituents R
2
may together represent —O—CH
2
—O— or —O—CH
2
—CH
2
—O—; and if A is thieno, m is zero;
R
1
denotes thienyl or the group
 wherein
R
7
, R
8
and R
9
independently of one another may represent methyl, ethyl, propyl, phenyl or benzyl, whilst not more than 2 of the substituents can simultaneously represent phenyl or benzyl;
R
3
and R
4
independently of each other represent
(a) hydrogen,
(b) branched or unbranched C
3-6
-alkenyl,
(c) branched or unbranched C
3-6
-alkynyl, or
(d) branched or unbranched C
1-12
-alkyl, wherein the alkyl may be substituted by
hydroxy,
(C
1-4
)alkoxy,
di(C
1-4
)alkylamino,
furyl,
pyridyl,
pyrrolidinyl, N-methylpyrrolidinyl,
morpholino,
indolyl,
nitrilo,
thienyl,
adamantyl,
cyclohexyl,
phenoxy,
naphthyloxy or phenyl, whilst this phenyl or the phenyl contained in the phenoxy group may be mono-, di- or trisubstituted by hydroxy, (C
1-4
)alkoxy, benzyloxy, halogen (F, Cl, Br, I), CF
3
, N
3
, (C
1-4
)alkyl, adamantyl, —SO
2
NH
2
or —NHCOCH
3
or by the bridge —O—CH
2
—O—;
or R
3
denotes hydrogen and R
4
denotes cyclohexyl, phenyl, fluorophenyl, pyridyl or N-benzylpiperidyl;
or R
3
and R
4
together with the nitrogen atom to which they are bound represent pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, whilst the piperazinyl ring may optionally be N-substituted by methyl, unsubstituted phenyl, mono- or di(C
1-4
)alkoxyphenyl, pyrimidinyl, phenyl(C
1-4
)alkyl or
Preferably, A represents the annelated ring systems
wherein R
2
is as hereinbefore defined.
Also preferred according to the invention are compounds I wherein A is indolo and the other substituents are as hereinb

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