Arylalkylpiperazine compounds as antioxidants

Details Arylalkylpiperazine compounds as antioxidants Arylalkylpiperazine compounds as antioxidants

1999-03-18

2001-05-15

Raymond, Richard L. (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S360000, C544S363000, C544S369000, C544S373000, C544S376000, C544S377000, C544S392000, C544S401000, C514S252130, C514S253010, C514S253060, C514S254020, C514S254090, C514S254110, C514S255030

Reexamination Certificate

active

06232314

ABSTRACT:

The present invention relates to arylalkylpiperazine compounds, methods for their manufacture, pharmaceutical formulations of such compounds and their use in therapy, particularly in the treatment of disorders related to neurological damage of the central nervous system.
Damage to the neurones of the central nervous system may result from acute events that lead to ischaemia or other forms of hypoxia, or from neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease or lateral amyotrophic sclerosis. The mechanism of such neuronal injury is complex, however, extensive investigation of such processes has identified the over stimulation of receptors for excitatory amino acids, for example L-glutamate, and oxidative processes as playing a role in the pathway to neurodegeneration resulting from both acute ischaemic or anoxic events and a wide variety of chronic neurological disorders (Coyle et al., 1993; and Lipton et al., 1994). These two mechanisms are not totally independent, part of the cascade of events that follow over stimulation of receptors for excitatory amino acids has been shown to be an effective increase in the generation of reactive free radicals. Recent evidence also indicates that two cytodestructive events may be involved in excitotoxic/free radical-induced cell death—necrosis and apoptosis (Bonfocco et al., 1995). The latter event, also termed programmed cell death, is considered to occur in normal development and in the aging process.
Glutamate is the major excitatory neurotransmitter present in the brain and spinal cord, and glutamate receptors are divided into two main subtypes, ionotropic and metabotropic. A particular ionotropic glutamate receptor identified as being involved in excitatory amino acid induced neuronal damage in the brain and central nervous system is the N-methyl-D-aspartate (NMDA) receptor complex (Meldrum et al., 1989; and Choi, 1992). This receptor-ionophore complex has a number of modulatory sites associated with it, including the glycine site, the NMDA or glutamate site, the channel, the polyamine site, a pH sensitive region, a redox site, and a zinc-binding site. Compounds that block the activity of the NMDA receptor complex by binding to these various sites and by preventing subsequent entry of Ca
2+
have been indicated as neuroprotective agents. For example, ifenprodil and eliprodil have been reported as interacting with the polyamine sensitive binding site of the NMDA receptor (Carter et al., 1989 and 1990; Reynolds et al., 1989; Robinson et al., 1990; Beart et al., 1995) and have been reported as having neuroprotective properties in models of neurodegeneration following ischaemia (Gotti et al., 1988). Similarly, compounds that modulate voltage-sensitive sodium channels may also inhibit release of excitatory amino acids and may be useful in neuronal protection (Lysko et al., 1995 and Urenjak et al., 1996).
The present invention is directed to the provision of new compounds that have both free radical scavenging activity and block excitatory amino acid activity, preferably at the NMDA receptor complex via its polyamine site.
Some compounds of the present invention also display an affinity for voltage-sensitive sodium channels.
Accordingly in a first aspect, the present invention provides arylalkylpiperazine compounds of formula (1)
wherein
B is aryl or optionally substituted aryl;
R
1
is hydroxy;
R
2
and R
3
are the same or different and are independently selected from hydrogen or C
1-3
alkyl;
m is 0, 1 or 2. Preferably m is 0 or 1;
D is a linking chain of atoms which may be optionally substituted and contains from 1-8 atoms in the chain, and wherein preferably the atoms of the chain are carbon, oxygen, nitrogen or sulfur, more preferably the atoms of the chain are carbon atoms present either as a carbonyl, a straight chain or branched alkyl, oxoalkyl, alkenyl or oxoalkenyl group of 1-6 carbons; examples of D include (CH
2
)
n
, C(═O)(CH
2
)
n−1
, C(═O)CH═CH or (CH
2
)
n
CH═CH wherein n is 1-6
E is a phenolic antioxidant group or a corresponding amino derivative thereof, wherein the phenolic hydroxyl is replaced by amino, with antioxidant properties; and salts thereof, solvates thereof, pharmaceutically acceptable derivatives thereof, prodrugs thereof, tautomers thereof and/or isomers thereof.
In this specification “aryl” used either alone or in compound words such as “aryloxy”, “arylthio”, “arylamino” or “diarylamino” denotes single, polynuclear, conjugated and fused residues of aromatic hydrocarbons or aromatic heterocyclic ring systems. Examples of aryl include but are not limited to phenyl, naphthyl, fluorenyl, pyrenyl, pyridyl, pyrrolyl, imidazoloyl, pyrazolyl, pyrimidinyl, thiazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, benzodioxanyl, benzodioxoloyl and the like.
In this specification “optionally substituted” means that a group may be further substituted by one or more groups selected from alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxy, alkyloxy, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, nitro, acyl, amido, alkylamido, dialkylamido, carboxyl, or two optional substituents may together with the carbon atoms to which they are attached form a 5- or 6-membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur. Optional substituents may themselves bear additional optional substituents. Preferred optional substituants include C
1-3
alkyl such as for example methyl, ethyl and trifluoromethyl, fluoro, chloro, bromo, hydroxy, C
1-3
alkyloxy such as for example methoxy, ethoxy and trifluoromethoxy, and amino.
Throughout the specification, the term “alkyl”, used either atone or in compound words such as “alkyloxy” is denoted, unless otherwise defined, to mean both the straight chain C
1-6
alkyl or branched chain C
3-6
alkyl and the branched or unbranched C
3-6
cycloalkyl and includes optionally substituted alkyl. Examples of straight chain C
1-6
alkyl and branched chain C
3-6
alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl and the like. Examples of C
3-6
cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like Haloalkyl groups such as trifluromethyl are examples of optionally substituted alkyl groups.
Throughout the specification, the term “alkenyl”, used either alone or in compound words such as “alkenyloxy” is denoted, unless otherwise defined, to mean both the straight chain C
2-6
alkenyl or branched chain C
3-6
alkenyl and the branched or unbranched C
3-6
cycloalkenyl and includes optionally substituted alkenyl. Examples of straight chain C
2-6
alkenyl and branched chain C
3-6
alkenyl include ethylenyl, propenyl, isopropenyl, butenyl, isobutenyl, dimethylbutenyl, pentenyl, methylpentenyl, hexenyl and the like. Examples of C
3-6
cycloalkyl include cyclobutenyl, cyclopentenyl, cyclohexenyl and the like.
“Oxoalkyl” and “oxoalkenyl” mean an alkyl or alkenyl group which includes a carbonyl group other than as the linking group.
“Acyl” means a group represented by C(═O)alkyl or C(═O)alkenyl. Acyl groups derived from amino acids are included within the meaning of “acyl”.
The following groups wherein each R in each group may be the same or different and is independently selected from hydrogen or alkyl are representative examples of the groups which may be utilised as the antioxidant group, E, of the compounds of formula (1). Preferably at least one R group is alkyl. More preferably at least two R groups are alkyl. Preferably the alkyl groups are C
1-4
alkyl. Preferably the alkyl groups are not substituted. The preferred point of attachment of the antioxidant moiety is indicated by an arrow:
The following groups are respresenative examples of the groups B, the preferred point of attachment of the moiety is indicated by an arrow:
A preferred group of compounds

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