Neuroprotective substituted piperidine compounds with...

Details Neuroprotective substituted piperidine compounds with... Neuroprotective substituted piperidine compounds with...

2001-03-19

2002-08-13

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S217000, C546S219000

Reexamination Certificate

active

06432985

ABSTRACT:

FIELD OF INVENTION
The present invention is generally related to substituted piperidine compounds and more particularly to compounds with activity as NMDA receptor subtype selective blockers that have low activity as blockers of hERG potassium channels.
The present invention relates to the compound of formula
to its R,R- and S,S-enantiomers and to their pharmaceutically acceptable acid addition salts.
The compounds of the present invention are NMDA (N-methyl-D-aspartate)-receptor-subtype selective blockers, which have a key function in modulating neuronal activity and plasticity which makes them key players in mediating processes underlying development of CNS including learning and memory formation and function.
Under pathological conditions of acute and chronic forms of neurodegeneration overactivation of NMDA receptors is a key event for triggering neuronal cell death. NMDA receptors are composed of members from two subunit families, namely NR-1 (8 different splice variants) and NR-2 (A to D) originating from different genes. Members from the two sub-unit families show a distinct distribution in different brain areas. Heteromeric combinations of NR-1 members with different NR-2 sub-units result in NMDA receptors, displaying different pharmacological properties. Possible therapeutic indications for NMDA receptor subtype specific blockers include acute forms of neurodegeneration caused, e.g., by stroke or brain trauma; chronic forms of neurodegeneration such as Alzheimer's disease, Parkinson's disease, Huntington's disease or ALS (amyotrophic lateral sclerosis); neurodegeneration associated with bacterial or viral infections, diseases such as schizophrenia, anxiety and depression and acute/chronic pain.
Objects of the present invention are novel compounds of formula I, its R,R- and S,S-enantiomers, racemic mixtures of these enantiomers and pharmaceutically acceptable salts of these novel compounds; their use in the treatment or prophylaxis of diseases caused by overactivation of respective NMDA receptor subtypes, which include acute forms of neurodegeneration caused, e.g., by stroke or brain trauma; chronic forms of neurodegeneration such as Alzheimer's disease, Parkinson's disease, Huntington's disease or ALS (amyotrophic lateral sclerosis); neurodegeneration associated with bacterial or viral infections, and diseases such as schizophrenia, anxiety, depression and acute/chronic pain; the use of these compounds for manufacture of corresponding medicaments; processes for the manufacture of these novel compounds; and medicaments containing the compounds of the invention.
The term “pharmaceutically acceptable acid addition salts” embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, lactic acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
4-Hydroxy-piperidin derivatives are described, for example in EP 824 098, in which the piperidine ring is substituted by one hydroxy group in 4-position. These compounds are described to possess activities on the NMDA receptor and are useful in the treatment of acute forms of neurodegeneration caused, for example, by stroke and brain trauma, and chronic forms of neurodegeneration such as Alzheimer's disease, Parkinson's disease, ALS (amyotrophic lateral sclerosis), neurodegeneration associated with bacterial or viral infections and acute/chronic pain.
It is known from EP 824 098 that these compounds are good NMDA receptor subtype specific blockers with a high affinity for NR2B subunit containing receptors and low affinity for NR2A subunit containing receptors.
Activity versus &agr;
1
-adrenergic receptors is also low and the compounds are active in vivo against audiogenic seizures in mice in the low mg/kg range. Importantly, these compounds were neuroprotective in an animal stroke model, namely, a permanent occlusion of the middle cerebral artery. However, in vitro and in vivo cardiotoxicity studies showed that these compounds had the propensity to prolong cardiac action potential duration in vitro and consequently the ‘QT’-interval in vivo and thus, had a potential liability to produce cardiac arrhythmias. The ability of such compounds to prolong the cardiac action potential was identified as being due to an action at the hERG type potassium channel, which is important for action potential repolarisation in humans and other species, and most compounds known to prolong the QT-interval in man are active at blocking this channel. Thus, the compounds of the prior art block heterologously recombinant human ERG potassium channels.
It has now surprisingly been found that the following preferred compounds of formula I (3R,4R) and (3S,4S)-4-benzyl-1-[2-(4-hydroxy-phenoxy)-ethyl]-piperidine-3,4-diol, (3R,4R)-4-benzyl-1-[2-(4-hydroxy-phenoxy)-ethyl]-piperidine-3,4-diol and (3S,4S)-4-benzyl-1-[2-(4-hydroxy-phenoxy)-ethyl]-piperidine-3,4-diolare NMDA NR2B subtype selective antagonists. These preferred compounds of the invention share the highly specific subtype selective blocking properties of compounds of the prior art, for example of 1-[2-(4-hydroxy-phenoxy)-ethyl]-4-(4-methyl-benzyl)-piperidin-4-ol (EP 824 098), and are neuroprotectants in vivo, unlike the compounds of EP 824098, the preferred compounds of the invention are significantly less active as blockers of the hERG potassium channels and, thus, are much less likely to have pro-arrhythmic activity in man.
In the following table the high selectivity of compounds of the present invention is demonstrated.
Selectivity profile of NMDA NR2B subtype selective antagonists
Inhibition of
Inhibition of
Inhibition of
[3H]-Ro 25-
[3H]-Prazosin
hERG K+ current
6981 binding
binding
IC
50
(&mgr;M) (effect
Compound
IC
50
(&mgr;M)
a
IC
50
(&mgr;M)
b
(%) at 10 &mgr;M
c
)
EP 824098
0.010
3.5
0.69
&mgr;M
1-[2-(4-hydroxy-
phenoxy)-ethyl]-4-
(4-methyl-benzyl)-
piperidin-4-ol
I (racemate)
0.045
27
>10
&mgr;M (45%),
I-1 (R,R)
0.038
25
>10
&mgr;M (44%)
I-2 (S,S)
0.039
30
>10
&mgr;M (40%)
a
Inhibition of [3H]-Ro 25-6981 binding indicates affinity for NMDA NR2B subunit containing receptors.
b
Inhibition of [3H]-Prazosin binding indicates affinity for &agr;
1
-adrenergic receptors.
c
Indicates potency for blockade of recombinant human ERG potassium channels expressed in a mammalian cell line (chinese hamster ovary cells, CHO).
The novel compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example by a process described below, which process comprises
reacting a compound of formula
with a compound of formula
and deprotecting the hydroxy group to give compounds of formulae
and, preferably, converting the compounds obtained into a pharmaceutically acceptable acid addition salts.
In accordance with the described process variant, 4-benzyl-3,4-dihydroxy-piperidine, (3R,4R)-4-benzyl-3,4-dihydroxy-piperidine or (3S,4S)-4-benzyl-3,4-dihydroxy-piperidine is treated with 1-benzyloxy-4-(2-chloro-ethoxy)-benzene in the presence of K
2
CO
3
. The reaction is carried out at about 80-100° C. The O-protecting group is then cleaved off in conventional manner, for example by hydrogenating in the presence of Pd/C.
The acid addition salts of the compounds of formula I are especially well suited for a pharmaceutical use.
The following schemes 1 and 2 describe the preparation of the compound of formula I and its desired enantiomeric forms. The starting materials of formulae III and 1-benzyloxy-4-(2-chloro-ethoxy)-benzene are known compounds or can be prepared by methods known in the art.
In schemes 1 and 2 the following abbreviations have been used:
Z—Cl
benzylchloroformate
MCPBA
meta-chloroperbenzoic acid
DMAP
dimethylaminopyridine
Pd/C
palladium on carbon catalyst
DMF
dimethylformamide
Bn
benzyl
wherein “hal” may be chloro or bromo.
The detailed description

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