Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-17
2003-11-11
Desai, Rita (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S018000
Reexamination Certificate
active
06645973
ABSTRACT:
SUMMARY OF THE INVENTION
The invention relates to spiro[2H-1-benzopyran-2,4′-piperidine] derivatives, to pharmaceutical compositions containing the same, as well as to the use of these spiro[2H-1-benzopyran-2,4′-piperidine] derivatives in therapy.
BACKGROUND OF THE INVENTION
The simplest &agr;-amino acid glycine has a number of important roles in the mammalian central nervous system (CNS). Along with &ggr;-aminobutyric acid (GABA), it is a major post-synaptic inhibitory transmitter in the spinal cord and brainstem, acting through ligand gated ion channels. Interaction of glycine with these receptors can be antagonized by the alkaloid strychnine. These receptors are therefore referred to as ‘strychnine sensitive’ glycine receptors. Glycinergic neurotransmission is important in the processing and control of visual, auditory and motor signalling. Glycine is also an obligatory co-agonist along with glutamate at the N-methyl-D-aspartate (NMDA) receptor. Glycine therefore functions in excitatory transmission by modulating the actions of glutamate, the major excitatory neurotransmitter in the CNS. In addition the amino acid plays a role in the metabolism of peptides and proteins, including the exchange of one-carbon units.
Control of the availability of glycine for any of the above processes will potentially influence their function and provide means of treating a number of diseases and conditions. Apart from metabolism, one of the major processes controlling the concentrations of free glycine in the proximity of strychnine-sensitive and strychnine-insensitive glycine receptors is the functioning of selective high affinity glycine transporters. These proteins can actively limit the spread of glycine beyond the immediate environs of receptors, thus maintaining both spatial and temporal fidelity of receptor activation, Rapid sequestering of transmitter into neuronal or glial cells via the transporter will:also conserve glycine for future release.
Glycine transporters have been cloned to reveal two major classes, GlyT-1 and GlyT-2. GlyT-1 is expressed throughout the brain with higher mRNA levels being detected in caudal areas and cellular localisation being predominantly glial. Three isoforms of GlyT-1, 1a, 1b and 1c, arising from differential splicing and exon usage have been identified by Kim et al. (Molecular Pharm. 1994, 45, 608-617). The cloning and expression of a further human isoform GlyT-1d was recently disclosed in European Patent Application EP 951543 (Allelix Neuroscience, Inc.).
GlyT-2 distribution, as indicated by immunochemistry studies, corresponds closely to that of inhibitory ‘strychnine sensitive’ glycine receptors, particularly in the spinal cord.
By regulating the synaptic levels of glycine, the glycine transporters GlyT-1 and GlyT-2 are expected to selectively influence the activity at NMDA receptors and at strychnine-sensitive glycine receptors, respectively.
Compounds which alter the functional activity of glycine transporters may therefore result in changes in tissue glycine levels which can be useful in the treatment of a number of disease states. Such disease states include those associated with decreased or exaggerated function of NMDA receptors, namely psychosis, depression, dementia and other forms of impaired cognition, such as attention deficit disorders. NMDA receptors have further been implicated in conditions arising from neuronal cell death and neurodegeneration such as, for example, stroke (head trauma), Alzheimer's disease, Parkinson's disease and Huntington's disease. Enhanced inhibitory glycinergic transmission resulting from inhibition of GlyT-2 or GlyT-1 activity may be useful in the treatment of muscle hyperactivity associated with spasticity, myoclonus and epilepsy. Compounds elevating spinal glycine may also possess analgesic properties.
Compounds that inhibit glycine transport via the Gly-T1 or Gly-T2 transporters are disclosed in WO 971451.15 (TROPHIX PHARM. INC.), in WO 97/45423 (TROPHIX PHARM. INC.), in WO 99/34790 (ALLELIX NEUROSCIENCE INC.) and in WO 00/07978 (AKZO NOBEL N. V.) as compounds useful in the treatment of the neurological and neuropsychiatric disorders discussed above. There exists a need for additional compounds suitable for the treatment of psychiatric and neurological disorders, especially for compounds having a selective pharmacological profile.
BRIEF SUMMARY OF THE INVENTION
It has now been found that spiro[2H-1-benzopyran-2,4′-piperidine] derivatives having the general formula I
wherein
the dotted line represents an optional bond;
Y represents 1-4 substituents independently selected from hydrogen, halogen, (C
1-6
)alkyl (optionally substituted with one or more halogens), (C
1-6
)alkyloxy (optionally substitued with one or more halogens or with (C
3-6
)cycloalkyl), (C
2-6
)alkenyloxy, (C
2-6
)alkynyloxy, (C
3-6
)cycloalkyloxy, (C
6-12
)aryloxy, (C
7-15
)arylalkyloxy, heteroaryloxy, heteroarylalkyloxy, SR
3
, NR
3
R
4
, OSO
2
R
5
and NR
3
SO
2
R
4
;
2 substituents Y may together form O—(CH
2
)n—O or O—(CF
2
)n—O, where n is 1 or 2; or Y represents a fused (C
5-6
)aryl group;
X represents 1-3 substituents independently selected from hydrogen, halogen, hydroxy, (C
1-4
)alkyloxy, SR
3
, NR
3
SO
2
R
4
and (C
1-4
)alkyl, optionally substituted with halogen;
R
1
is hydrogen, (C
1-4
)alkyl or (C
6-12
)aryl;
R
2
, R
3
and R
4
are independently hydrogen or (C
1-4
)alkyl;
R
5
is (C
1-4
)alkyl (optionally substituted with one or more halogens) or (C
6-12
)aryl (optionally substituted with (C
1-4
)alkyl); or a pharmaceutically acceptable salt thereof, selectively inhibit glycine transport by the human GlyT-1 transporter as compared to the human GlyT-2 transporter, and can be used in the treatment or prevention of schizophrenia, depression, dementia and other forms of impaired cognition, or of neurodegenerative diseases like Alzheimer's, Parkinson's and Huntington's disease, or of muscle hyperactivity associated with spasticity, myoclonus and epilepsy.
DETAILED DESCRIPTION OF THE INVENTION
The term (C
1-6
)alkyl, as used in the definition of formula 1, means a branched or straight chain alkyl group having 1-6 carbon atoms, like hexyl, pentyl, neopentyl (2,2-dimethylpropyl), butyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl and methyl. Likewise, the term (C
1-4
)alkyl refers to an alkyl group having 1-4 carbon atoms.
In the term (C
1-6
)alkyloxy, (C
1-6
)alkyl means a branched or an unbranched alkyl group as previously defined. The (C
1-6
)alkyloxy group may be substituted with 1-3 halogens or with (C
1-6
)cycloalkyl, which means a cyclic alkyl group having 3-6 carbon atoms, like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Examples of such substituted (C
1-6
)alkyloxy groups are trifluoromethyloxy and cyclopropylmethyloxy. The term halogen means F, Cl, Br, or I. When halogen is a substituent at an alkyl group, F is preferred. A preferred halogen substituted alkyl group is trifluoromethyl. The term (C
2-6
)alkenyl, such as used in the term (C
2-4
)alkenyloxy, means a branched or straight chain alkenyl group having 2-6 carbon atoms, such as ethenyl (vinyl), 2-propenyl (allyl), isopropenyl and 2-butenyl.
The term(C
2-6
)alkynyl, such as used in the term (C
2-6
)alkynyloxy, means a branched or straight chain alkynyl group having 2-6 carbon atoms, such as propargyl.
In the term (C
6-12
)aryloxy, as used in the definition of formula I, (C
6-12
)aryl means an aromatic hydrocarbon group having 6-12 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl, indenyl or biphenyl. These aromatic groups may be substituted with halogen, or with (C
1-4
)alkyl or (C
1-4
)alkyloxy, wherein (C
1-4
)alkyl has the previously given meaning and may be substituted with halogen or (C
1-4
)alkyloxy.
The term (C
7-15
)arylalkyl, as used in the definition of Formula I, means an arylalkyl group having 7 to 15 carbon atoms, wherein the alkyl group is a (C
1-4
)alkyl group and the aryl group is a (C
6-12
)aryl as previously defined. Phenyl(C
1-6
)alkyl groups are
Gibson Samuel George
Miller David John
Akzo Nobel
Desai Rita
Milstead Mark W.
LandOfFree
Spiro(2h-1-benzopyran-2,4-piperidine)derivatives as glycine... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Spiro(2h-1-benzopyran-2,4-piperidine)derivatives as glycine..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Spiro(2h-1-benzopyran-2,4-piperidine)derivatives as glycine... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3154313