Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2001-08-16
2002-06-18
Ramsuer, Robert W. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C544S360000, C546S024000, C546S221000
Reexamination Certificate
active
06407235
ABSTRACT:
FIELD OF INVENTION
The present invention is generally related to acid esters of [2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethansulfonyl]phenol, and more particularly to acid esters that enhance the solubility of the parent compound and are hydrolyzed under in vivo conditions thus serving as prodrugs for the parent compound.
BACKGROUND
A prodrug is in most cases a pharmacologically inactive derivative of a parent drug molecule that requires spontaneous or enzymatic transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule. It has been shown that a molecule with optimal structural configuration and physicochemical properties for eliciting the desired therapeutic response at its target site does not necessarily possess the best molecular form and properties for its delivery to its point of ultimate action. Usually, only a minor fraction of doses administered reaches the target area and since most agents interact with non-target sites as well, an inefficient delivery may result in undesirable side effects. This fact of differences in transport and in situ effect characteristics for many drug molecules is the basic reason why bioreversible chemical derivatization of drugs, i.e., prodrug formation is a means by which a substantial improvement in the overall efficacy of drugs can often be achieved.
Prodrugs are designed to overcome pharmaceutically and/or pharmacokinetically based problems associated with the parent drug molecule that would otherwise limit the clinical usefulness of the drug. The advantage of a prodrug lies in its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent drug, or it enhances absorption from the digestive tract, or it may enhance drug stability for long-term storage.
In recent years several types of bioreversible derivatives have been exploited for utilization in designing prodrugs. Using esters as a prodrug type for drugs containing carboxyl or hydroxyl fumction is most popular. Further well-known are prodrug derivatives of peptides, 4-imidazolidinones and the like, described in Drugs of the Future, 1991, 16(5), 443-458 or N-oxides, described for example in U.S. Pat. No. 5,691,336.
Compounds of formula
are known as NMDA (N-methyl-D-aspartate)-receptor-subtype selective blockers. Compounds of formula II have limited water solubility at physiological pH, not allowing bolus injections. A similar compound of formula II is generically described in WO 95/25721, wherein the formula does not contain a hydroxy group on the piperidine ring. These compounds are described to possess activities on the glutamat receptor or AMPA receptor for the treatment of diseases which are related to these receptors.
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 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. Furthermore, it is known from WO 00/75109, that the compound of formula II is a good NMDA receptor subtype specific blocker, neuroprotective in vivo and less active as blockers of the hERG potassium channels and thus is much less likely to have pro-arrhythmic activity in man.
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 diff rent 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.
SUMMARY
The present invention relates to a compound of the formula
wherein
R is
a) —C(O)(CH
2
)
n
C(O)OH,
wherein R
1
is —N(R
2
)(R
3
) and R
2
/R
3
are hydrogen or lower alkyl, or is a five or six member aromatic or non-aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, sulfur or oxygen, unsubstituted or substituted by lower alkyl,
c) —P(O)(OH)
2
, or is
d) —C(O)(CH
2
)
n
NHC(O)(CH
2
)
n
N(R
2
)(R
3
); and
n is 1, 2, 3 or 4;
or a pharmaceutically acceptable acid addition salt thereof.
It has been found that compounds of formula I may be used as prodrugs of compounds of formula
which are NMDA (N-methyl-D-aspartate)-receptor-subtype selective blockers.
It has surprisingly been shown that the compounds of the invention of formula I fulfill all requirements of a good prodrug. Specifically, it has been shown that compounds of the invention have up to 10-fold higher solubility over the parent compound at physiological pH. Additionally the compounds of the invention have an unexpected stability in solution at room temperature up to 48 h but also demonstrate a fast hydrolysis in plasma.
The present invention is a novel compound of formula I, its use as a prodrug 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.
The most preferred indication in accordance with the present invention is the treatment or prevention of stroke.
DETAILED DESCRIPTION
The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.
As used herein, the term “lower alkyl” denotes a straight- or branched-chain alkyl group containing from 1-7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like.
Preferred lower alkyl groups are groups with 1-4 carbon atoms.
The term “five or six member aromatic or non-aromatic heterocyclic ring containing one or more hetero atoms selected from nitrogen, sulfur or oxygen, unsubstituted or substituted by lower alkyl” denotes, for example pyrrol-1-yl, imidazol-1-yl, piperidin-1-yl, piperazin-1-yl or morpholin-4-yl. Preferred are piperazin-1-yl or morpholin-4-yl. It is preferred that the heterocyclic rings contain one or two hetero atoms.
The term “physiological pH” means a pH of around 7, preferably about 7.4.
Exemplary preferred are compounds of formula 1, in which R is —C(O)(CH
2
)
n
C(O)OH and n is 2, for example the following compound:
Succinic acid mono-{(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl}ester.
Further preferred are compounds of formula 1, in which R is
and R
1
is as above. Especially preferred are compounds wherein R
1
is morpholinyl, 4-methyl-piperazinyl or —N(R
2
)(R
3
) with R
2
and R
3
as above.
Examples of such compounds when R
1
is morpholinyl ar
Alanine Alexander
Buettelmann Bernd
Fischer Holger
Heitz Neidhart Marie-Paule
Huwyler Joerg
Dawson Arthur D.
Hoffmann-La Roche Inc.
Johnston George W.
Ramsuer Robert W.
Rocha-Tramaloni Patricia S.
LandOfFree
Prodrug acid esters of... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Prodrug acid esters of..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Prodrug acid esters of... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2932856