Ethanesulfonyl-piperidine derivatives

Details Ethanesulfonyl-piperidine derivatives Ethanesulfonyl-piperidine derivatives

2000-06-02

2001-10-30

Rotman, Alan L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S219000, C546S236000

Reexamination Certificate

active

06310213

ABSTRACT:

BACKGROUND OF THE INVENTION
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 subunit families show a distinct distribution in different brain areas. Heteromeric combinations of NR-1 members with different NR-2 subunits 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.
Compounds of formula I and their salts are generically, but not specifically, known compounds, described in WO 95/25721. They are described to possess activities on the glutamate receptor or AMPA receptor for the treatment of diseases which are related to these receptors. Furthermore similar compounds are described in EP 824 098, in which the piperidine ring is substituted by a hydroxy group in 4-position. These compounds are described as possessing activity with regard to 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 are neuroprotective in an animal stroke model, namely, a permanent occlusion of the middle cerebral artery. However, in vitro and in vivo cardiotoxicity studies show that these compounds have the propensity to prolong cardiac action potential duration in vitro and consequently the ‘QT’-interval in vivo and thus, have the potential 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 nERG potassium type 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 recombinant human ERG potassium channels heterologously.
The compounds of the present invention are NMDA (N-methyl-D-aspartate)-receptor-subtype selective blockers. NMDA receptors 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. However when overactive, NMDA receptors contribute to neurodegeneration. Therefore compounds which block NMDA receptor activation without undesirable side effects are therapeutically important.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the general formula
wherein
R
1
signifies hydrogen or hydroxy;
R
2
signifies hydrogen or methyl; and
X signifies —O— or —CH
2
—
and to their pharmaceutically acceptable acid addition salts.
It has now surprisingly been found that the compounds of formula I are NMDA NR2B subtype selective antagonists whilst they share the highly specific subtype selective blocking properties compounds of the prior art, for example of 1-[2-(4-hydroxy-phenoxy)-ethyl]-4-(4-methyl-benzyl)-piperidin-4-ol (9), and are neuroprotectants. They are less active as blockers of the hERG potassium channels and, thus, are much less likely to have pro-arrhythmic activity in man. In view of their activity as NMDA receptor blockers, compounds of this invention are useful in treating neurodegeneration caused by NMDA receptor overactivity while avoiding pro-arrhythmic activity.
Objects of the present invention are novel compounds of formula I, the 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 them.
DETAILED DESCRIPTION OF THE INVENTION
This invention is directed to compounds of formula I above. The compounds of the invention are preferably by which is meant the substitutents at positions 3 and 4 are cis in relation to each other (e.g. both R
1
and X are S isomers, or both R
1
and X are R isomers).
In one embodiment of the compounds of this invention, X is —O—. An example of such a compound is 4-[2-(4-p-tolyloxy-piperidin-1-yl)-ethanesulfonyl]-phenol.
In another embodiment of the compounds of this invention, X is —CH
2
—. An example of such a compound is 4[-2-(4-benzyl-piperidine-1-yl)-ethanesulfonyl]-phenol.
In compounds where X is —CH
2
—, it is preferred that R
1
is hydroxy. In one embodiment, R
2
is hydrogen, especially where R
1
is hydroxy. Examples of such compounds are (+)(3R,4R)-4-benzyl-1-[2-(4-hydroxy-benzenesulfonyl)-ethyl]-piperidin-3-ol, (−)(3S,4S)-4-benzyl-1-[2-(4-hydroxy-benzenesulfonyl)-ethyl]-piperidin-3-ol, and (3RS,4RS)-4-benzyl-1-[2-(4-hydroxy-benzenesulfonyl)-ethyl]-piperidin-3-ol.
In other compounds where X is —CH
2
—, it is preferred that R
1
is hydroxy. In one embodiment, R
2
is methyl, especially where R
1
is hydroxy. Examples of such compounds are,
(+)(cis)-1-[2-(4-hydroxy-benzenesulfonyl)-ethyl]-4-(4-methyl-benzyl)-piperindin-3-ol,
(−)(cis)-1-[2-(4-hydroxy-benzenesulfonyl)-ethyl]-4-(4-methyl-benzyl)-piperidin-3-ol, and (3RS,4RS)-1-[2-(4-hydroxy-benzenesulfonyl)-ethyl]-4-(4-methyl-benzyl)-piperidin-3-ol.
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.
The data in the following table demonstrates the high selectivity of compounds of the present invention.
4[-2-(4-benzyl-piperidine-1-yl)-ethanesulfonyl]-phenol (1),
4-[2-(4-p-tolyloxy-piperidin-1-yl)-ethanesulfonyl]-phenol (2),
(−)(3S,4S)-4-benzyl-1-[2-(4-hydroxy-benzenesulfonyl)-ethyl]-piperidin-3-ol (3),
(+)(3R,4R)-4-benzyl-1-[2-(4-hydroxy-benzenesulfonyl)-ethyl]-piperidin-3-ol (4),
(3RS,4RS)-4-benzyl-1-[2-(4-hydroxy-benzenesulfonyl)-ethyl]-piperidin-3-ol (5),
(−)(cis)-1-[2-(4-hydroxy-benzenesulfonyl)-ethyl]-4-(4-methyl-benzyl)-piperidin-3-ol (6),
(+)(cis)-1-[2-(4-hydroxy-benzenesulfonyl)-ethyl]-4-(4-methyl-benzyl)-piperidin-3-ol (7)
(3RS,4RS)-1[-2-(4-hydroxy-benzenesulfonyl)-ethyl]-4-(4-methyl-benzyl)-piperidin-3-ol (8)
Selectivity Profile of NMDA NR2B Subtype Selective Antagonists
Inhibition of 3H [R-
(R*, S*)]-

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