Substituted phenylcyclohexane carboxylic acid amides that...

Details Substituted phenylcyclohexane carboxylic acid amides that... Substituted phenylcyclohexane carboxylic acid amides that...

2001-11-29

2004-04-06

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C544S370000

Reexamination Certificate

active

06716849

ABSTRACT:

The present invention relates to substituted phenylcyclohexanecarboxamides having adenosine-uptake-inhibiting action, to processes for their preparation and to their use in medicaments, in particular for treating ischaemic brain disorders.
Adenosine is an endogenic effector with cell-protective activity, in particular under cell-damaging conditions with limited oxygen and substrate supply, such as, for example, in ischaemia, stroke and brain trauma. The neuroprotective action of adenosine is essentially effected via suppression of presynaptic glutamate release and limitation of postsynaptic depolarization. This prevents toxic calcium influx into postsynaptic nerve cells via NMDA receptors. Under ischaemic or hypoxic conditions, the extracellular concentration of adenosine in the CNS is dramatically increased.
There are various indications of a neuroprotective, anticonvulsive, analgesic and sleep-inducing potential of adenosine-uptake inhibitors, since they enhance the intrinsic effects of adenosine by inhibiting its cellular reuptake. Accordingly, adenosine-uptake inhibitors can be administered orally or intravenously for the prevention and treatment of cerebral ischaemia, stroke, reperfusion damage, brain trauma, oedema, spasms, epilepsy, respiratory arrest, cardiac arrest, Reye's syndrome, cerebral thrombosis, emboli, tumours, haemorrhages, encephalomyelitis, hydroencephalitis, spinal injuries, post-operative brain damage, injuries to the retina or the optical nerve after glaucoma, ischaemia, hypoxia, oedema or trauma and in the treatment of schizophrenia, sleep disturbances and pain (
Cerebrovasc. Brain Metab. Rev
. 1992, 4, 364-369
; Drug Dev. Res
. 1993, 28, 410-415
; Science
1997, 276, 1265-1268
; ‘Adenosine in the Nervous System
’, Ed.: Trevor Stone, Academic Press Ltd. 1991, 217-227
; Ann. Rep. Med. Chem
. 1998, 33. 111-120).
Adenosine-uptake inhibitors can also be employed for potentiating the effect of nucleobase, nucleoside or nucleotide antimetabolites in the chemotherapeutical treatment of cancer and antiviral (for example HIV) chemotherapy (
Curr. Med. Chem
. 1997, 4, 35-66).
EP-A0 611 767 and EP-A-0 725 064 disclose phenylcyclohexylcarboxamides which can be used for treating atherosclerosis and/or restenosis.
The present invention relates to compounds of the general formula (I)
in wherein
A, D, E and G are identical or different and represent CH groups or nitrogen atoms,
L
1
and L
2
are identical or different and independently of one another each represents one or more radicals selected from the group consisting of hydrogen, halogen, hydroxyl, carboxyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy or (C
1
-C
6
)-alkoxy-carbonyl,
R
1
represents the CH
2
—OH group, or
represents a radical of the formula CO—NR
4
R
5
in which
R
4
and R
5
are identical or different and each represents hydrogen or (C
1
-C
6
)-alkyl,
R
2
represents (C
3
-C
8
)-cycloalkyl,
represents (C
1
-C
8
)-alkyl which is optionally interrupted by an oxygen or sulphur atom or by a radial NR
6
.
represents a 4 to 8-membered saturated heterocycle which is attached to the imidazole ring via a nitrogen atom and which optionally contains a further oxygen or sulphur atom, or
represents a 4- to 8-membered saturated heterocycle which contains a radical of the formula NR
7
and optionally additionally one nitrogen, oxygen or sulphur atom,
where (C
3
-C
8
)cycloalkyl, (C
1
-C
8
)-alkyl which is optionally interrupted by one oxygen or sulphur atom, the 4- to 8-membered saturated heterocycle which is attached to the imidazole ring via a nitrogen atom and which optionally contains one further oxygen or sulphur atom and optionally (C
1
-C
8
)-alkyl which is interrupted by a radical NR
6
and optionally the 4 to 8-membered saturated heterocycle which contains a radical of the formula NR
7
and optionally additionally one nitrogen, oxygen or sulphur atom are substituted by one to three hydroxyl groups and/or by a radical of the formula —NR
8
R
9
in which
R
6
and R
7
are identical or different and each represents hydrogen, (C
1
-C
6
)-alkyl, hydroxy-(C
1
-C
6
)-alkyl or (C
3
-C
7
)-cycloalkyl.
R
8
and R
9
are identical or different and each represents hydrogen, (C
1
-C
6
)-alkyl or (C
3
-C
7
)-cycloalkyl,
or
R
8
and R
9
together with the nitrogen atom form a 4- to 8-membered saturated heterocycle which may optionally additionally contain one oxygen or sulphur atom or a radical of the formula NR
10
in which
R
10
represents hydrogen, (C
1
-C
6
)alkyl or (C
3
-C
7
)-cycloalkyl and
R
3
represents a phenyl, naphthyl, pyrimidinyl, pyridyl, furyl or thienyl ring, where the rings are optionally mono- or polysubstituted by radicals selected from the group consisting of halogen, hydroxyl, carboxyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy or (C
1
-C
6
)-alkoxycarbonyl,
and their 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.
The compounds of the general formula (I) according to the invention can occur in different 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 and to the diastereomers and their respective mixtures. The racemic forms, like the diastereomers, can be separated in a known manner into the stereoisomerically uniform components.
Furthermore, certain compounds can be present in tautomeric forms. This is known to the person skilled in the art, and such compounds are likewise included in the scope of the invention.
(C
1
-C
8
)-Alkyl, C
1
-C
6
)-alkyl etc., represent a straight-chain or branched alkyl radical having 1 to 8 or 1 to 6 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl. Preference is given to a straight-chain or branched alkyl radical having 1 to 4 carbon atoms (C
1
-C
4
). Particular preference is given to a straight-chain or branched alkyl radical having 1 to 3 carbon atoms (C
1
-C
3
).
(C
1
-C
8
)-Alkyl, (C
1
-C
6
)-alkyl etc., which is interrupted by one oxygen or sulphur atom and which is substituted by one to three hydroxyl groups and/or by a radical of the formula —NR
8
R
9
represents, for example, 1,3-dihydroxy-prop-2-oxy-methyl, 2-hydroxy-ethoxy-methyl, 2-hydroxy-prop-1-oxy-methyl, 3-hydroxy-prop-1-oxy-methyl, morpholin-4-yl-methyl, piperidin-1-yl-methyl, 2-amino-ethyl, 2-dimethylamino-ethyl or diethylamino-methyl.
(C
1
-C
8
)-Alkyl, (C
1
-C
6
)-alkyl etc., which is interrupted by a radical N
6
and which is optionally substituted by one to three hydroxyl groups and/or by a radical of the formula —NR
8
R
9
represents, for example, N-(2-hydroxy-ethyl)-aminomethyl, N-(2-hydroxy-ethyl)-N-methyl-aminomethyl or N,N-bis-(2-hydroxy-ethyl)-aminomethyl.
Hydroxy-(C
1
-C
6
)-alkyl or hydroxy-(C
1
-C
4
)-alkyl represents a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms. The examples which may be mentioned are: hydroxymethyl, 2-hydroxy-ethyl, 2-hydroxy-prop-1-yl, 3-hydroxy-prop-1-yl, 3-hydroxy-prop-2-yl, 2-hydroxy-but-1-yl, 5-hydroxy-pent-1-yl and 6-hydroxy-hex-1-yl. Preference is given to 2-hydroxy-ethyl.
(C
1
-C
6
)-Alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy. Preference is given to a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms (C
1
-C
4
). Particular preference is given t

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