Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-11-18
2004-08-31
Davis, Brian (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S317000, C514S428000, C514S653000, C544S173000, C546S240000, C548S570000, C564S355000, C564S361000, C564S366000, C564S503000
Reexamination Certificate
active
06784175
ABSTRACT:
The invention relates to the use of at least one substituted 1-amino-5-phenylpentane-3-ol and/or 1-amino-6-phenylhexane-3-ol compound and/or one of the enantiomers thereof and/or one of the diastereomers thereof and/or one of the corresponding physiologically tolerable salts thereof in the manufacture of a medicament with an N-methyl-D-aspartate (NMDA) antagonistic effect.
Knowledge of the physiological significance of ion channel selective substances has been gained through the development of the patch clamp technique. Of particular significance is the NMDA ion channel, through which a considerable proportion of synapse communications runs. The exchange of calcium ions between a neuronal cell and its environment is controlled by this ion channel. The effect of NMDA antagonists on the flow of calcium ions into the interior of the cell can be demonstrated using the patch clamp technique.
In an inactivated state, the NMDA ion channels are closed by single magnesium ions which are inside the channel but cannot pass therethrough owing to their size. In an activated state, the smaller calcium and sodium ions can pass through the channel. The (+)-MK801 binding site of the NMDA ion channel (ionotropic NMDA receptor) is also inside this membrane protein. Substances with an NMDA anatagonist effect, such as phencyclidine (PCP), ketamine or MK801 occupy this binding site (so-called “channel blockers”) and thus close the NMDA ion channel in question.
NMDA ion channels play an important role in many physiological and pathophysiological processes, such as, for example, epilepsy, schizophrenia, neurodegenerative diseases, especially in Alzheimer's disease, Huntington's disease and Parkinson's disease, cerebral ischaemia and infarction, psychoses caused by raised amino acid level, cerebral oedema, under-supply of the central nervous system, in particular with hypoxia and anoxia, AIDS dementia, encephalomyelitis, Tourette's syndrome, perinatal asphyxia and tinnitus.
The aim of this invention was therefore to make medicaments available which exhibit an NMDA antagonist effect and are therefore suitable for the preventative treatment of cerebrovascular attacks (strokes) and/or the treatment of epilepsy and/or schizophrenia and/or neurodegenerative diseases, in particular Alzheimer's disease, Huntington's disease or Parkinson's disease and/or cerebral ischaemia and/or cerebral infarction and/or psychoses caused by raised amino acid level and/or cerebral oedema and/or under-supply of the central nervous system, in particular hypoxia and/or anoxia and/or AIDS dementia and/or encephalomyelitis and/or Tourette's syndrome and/or perinatal asphyxia and/or tinnitus.
Surprisingly, it was found that substituted 1-amino-5-phenylpentane-3-ol and 1-amino-6-phenylhexane-3-ol compounds of general formula I below and the enantiomers, diastereomers and physiologically tolerable salts thereof exhibit a marked NMDA antagonistic effect and therefore are highly suitable for influencing the above mentioned physiological and pathophysiological processes.
The object of this invention is the use of at least one substituted 1-amino-5-phenylpentane-3-ol and/or 1-amino-6-phenylhexane-3-ol compound of general formula I,
where n=1 or 2,
group A represents an optionally substituted aryl or heteroaryl group,
groups R
1
and R
2
, the same or different, stand for a C
1-6
alkyl group, preferably a C
1-3
alkyl group, or groups R
1
and R
2
together form a (CH
2
)
2-6
chain, which may also be phenyl substituted or may be attached to a phenyl ring to form a bicyclic system in which the cyclic aliphatic moiety and the phenyl ring share two carbon atoms.
groups R
3
and R
4
, the same or different, stand for a C
1-6
alkyl group, preferably a C
1-3
alkyl group, preferable a C
1-3
alkyl group, an optionally substituted aryl group or optionally substituted aryl group which is bound via a C
1-3
alkylene group, or groups R
3
and R
4
together represent (CH
2
)
3-6
or CH
2
CH
2
OCH
2
CH
2
,
groups R
5
, R
6
and R
7
, the same or different, represent H, F, Cl, Br, I, CF
3
, OR
8
, SO
2
CH
3
, SO
2
CF
3
, phenyl, CN, NO
2
or a C
1-6
alkyl group, preferably a C
1-3
alkyl group,
group R
8
stands for H, a C
1-6
alkyl group, preferably a C
1-3
alkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group or for a optionally substituted aryl or heteroaryl group which is bound via a C
1-3
alkylene group,
and/or one of the enantiomers thereof and/or one of the diastereomers thereof and/or a corresponding physiologically tolerable salt for the manufacture of a medicament with an NMDA antagonistic effect.
Physiologically tolerable salts of the compounds of general formula I and/or enantiomers thereof and/or diastereomers thereof may be hydrochloride, hydrobromide, sulphate, sulphonate, phosphate, tartrate, embonate, formate, acetate, propionate, benzoate, oxalate, succinate, citrate, glutamate, fumarate, aspartate, glutarate, stearate, butyrate, malonate, lactate, mesylate or a mixture of at least two of these salts.
Alkyl groups means branched, unbranched and cyclic hydrocarbon groups, which can also be substituted at least simply, preferably with a halogen group and/or a hydroxyl group, particularly preferably with fluorine and/or a hydroxyl group. If these alkyl groups contain more than one substituent, then these substituent may be the same or different. The alkyl groups are preferably methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-diemethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, cyclopropyl, cyclopropylmethyl, 2-methylcyclopropyl, cyclopentyl, cyclohexyl, CHF
2
, CF
3
or CH
2
OH.
An aryl group also means at least a phenyl or naphthyl group substituted simply with an OR
8
, halogen, preferably F and/or Cl, CN, NO
2
, C
1-6
alkyl or phenyl group, whereby the R
8
group has the meaning according to general formula I. The phenyl groups can also be condensed with further rings.
A heteroaryl group also means 5- or 6-member, unsaturated, heterocyclic compounds, optionally containing fused aryl groups, which contain at least one heteroatom, preferably nitrogen, oxygen or sulphur, particularly preferably nitrogen or oxygen and which optionally also can be substituted at least simply with an OR
8
, halogen, preferably F and/or Cl, CN, NO
2
, C
1-6
alkyl or phenyl group, whereby the R
8
group has the meaning according to general formula I. Preferred, optionally substituted, heteroaryl groups are furan, thiophene, pyrrole, pyridine, pyrimidine, quinoline, isoquinoline, phthalazine or quinazoline.
In a preferred embodiment of this invention, at least one compound of general formula I is used, in which groups R
1
and R
2
together form a (CH
2
)
2-6
chain, which can also be phenyl substituted or attached to a phenyl ring to form a bicyclic system in which the cyclic aliphatic moiety and the phenyl ring share two carbon atoms and groups R
3
to R
8
and A have the meaning according to general formula I.
Also preferable is the use of at least one compound of general formula I, in which A means an unsubstituted or substituted phenyl, thiophenyl or furyl group and groups R
1
to R
8
have the meaning according to general formula I.
Also preferable is the use of at least one compound of general formula I, in which groups R
5
to R
7
, the same or different, mean H, a halogen or a CF
3
group and groups R
1
to R
4
, R
8
and A have the meaning according to general formula I.
Also preferable is the use of at least one compound of general formula I, in which the phenyl ring in general formula I is substituted once or twice in an ortho-position and groups R
1
to R
8
and A have the meaning according to general formula I.
Also preferable is the use of at least one compound of general formula I, in which A represents a phenyl ring, which is substituted once or twice in an ortho-position and groups R
1
to R
8
have the meaning according to general formula I.
In a particu
Chizh Boris
Englberger Werner
Sundermann Bernd
Davis Brian
Gruenenthal GmbH
Perman & Green LLP
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