Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-12-17
2001-07-10
Davis, Zinna Northington (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S261000
Reexamination Certificate
active
06258828
ABSTRACT:
The present invention relates to the use of chelating agents and their metal chelates in medicine, in particular in treating conditions resulting from the presence of free radicals in the body, e.g. in the treatment of ischaemia-related diseases.
Short-lived but highly reactive free radicals have long been believed to be involved in various sorts of tissue damage, especially during reperfusion of ischaemic tissue and in radiation-induced injury. A key factor in the production of many free radicals is believed to be the availability of ferric ions which stimulate the formation of free radicals, such as hydroxyl, peroxyl and hydroperoxyl radicals, and singlet oxygen which cause membrane damage via lipid peroxidation.
Ischaemia-related diseases, in particular coronary artery diseases, account for the majority of deaths in Western countries. The reintroduction of oxygenated blood into ischaemic tissues can, in many cases, result in various forms of cardiac dysfunction, including arrhythmias, myocardial “stunning”, arterial spasm and endothelial damage (Kirschner et al. J. Amer. College of Surgeons 179: 103-117 (1994)). Furthermore, inactivation of NO, believed to have cardioprotective effects, can occur (see e.g. Vegh et al. Br. J. Pharmacol. 107: 910-911 (1992) and Lefer et al. Circulation 88: 2337-2350 (1993)).
Recent studies suggest that reperfusion injuries are largely a result of the production of oxygen-derived free radicals during reoxygenation of the perfused tissues. This is particularly so not only during the introduction of blood and oxygen during the early reperfusion period, but also in the subsequent protracted period of inflammatory response in the previously ischemic tissues.
It will be appreciated that there thus exists a continuing need for compounds which are able to treat or prevent conditions arising from the presence of free radicals in the body, in particular compounds which are able to prevent reperfusion injuries.
The medical use of chelating agents and their metal chelates is well established, for example in diagnostic techniques such as X-ray, magnetic resonance imaging (MRI), ultrasound imaging or scintigraphy. A wide variety of chelating agents and metal chelates are known or have been described.
Aminopoly (carboxylic acid or carboxylic acid derivative) chelating agents and their metal chelates are well known and are described for example in EP-A-299795, EP-A-71564, DE-A-3401052, EP-A-203962 and EP-A-436579.
Dipyridoxyl based chelating agents and their chelates with trivalent metals have been described by Taliaferro (Inorg. Chem. 23: 1183-1192 (1984)). The compound N,N′-dipyridoxyl ethylenediamine-N,N′-diacetic acid (PLED) has been evaluated as a chelating agent for the preparation of gallium or indium containing radiopharmaceuticals (see Green et al. Int J. Nucl. Med. Biol, 12(5): 381-386 (1985)).
A number of PLED derivatives and analogues have also been described for use in MRI contrast media, in particular the chelating agent N,N′-bis-(pyridoxal-5-phosphate)-ethylenediamine-N,N′-diacetic acid (DPDP) and its manganese (II) chelate, Mn DPDP (see EP-A-290047 and EP-A-292761).
We have now found that certain chelating agents, in particular dipyridoxyl and aminopolycarboxylic acid based chelating agents, and their metal chelates are particularly effective in treating or preventing tissue damage caused by free radicals and which are capable of relieving symptoms associated with reperfusion of ischaemic tissue.
In one aspect the invention provides the use of a compound of formula I
or a metal chelate or salt thereof in the manufacture of a therapeutic agent for use in the treatment or prophylaxis of conditions resulting from the presence of free radicals in the human or non-human animal body (wherein in formula I
each R
1
independently represents hydrogen or —CH
2
COR
5
;
R
5
represents hydroxy, optionally hydroxylated alkoxy, amino or alkylamido;
each R
2
independently represents a group XYR
6
;
X represents a bond, or a C
1-3
alkylene or oxoalkylene group optionally substituted by a group R
7
;
Y represents a bond, an oxygen atom or a group NR
6
;
R
6
is a hydrogen atom, a group COOR
8
, an alkyl, alkenyl, cycloalkyl, aryl or aralkyl group optionally substituted by one or more groups selected from COOR
8
, CONR
8
2
, NR
8
2
, OR
8
, ═NR
8
, ═O, OP(O) (OR
8
)R
7
and OSO
3
M;
R
7
is hydroxy, an optionally hydroxylated, optionally alkoxylated alkyl or aminoalkyl group;
R
8
is a hydrogen atom or an optionally hydroxylated, optionally alkoxylated alkyl group;
M is a hydrogen atom or one equivalent of a physiologically tolerable cation, e.g. an alkali or alkaline earth cation, an ammonium ion or an organic amine cation, such as a meglumine ion;
R
3
represents a C
1-8
alkylene group, preferably a C
1-6
, e.g. a C
2-4
alkylene group, a 1,2-cycloalkylene group, or a 1,2-arylene group; and
each R
4
independently represents hydrogen or C
1-3
alkyl).
In another aspect the invention provides a method of treatment of the human or non-human animal body to combat or prevent conditions associated with the presence of free radicals in the body, said method comprising administering to said body a compound of formula I or a metal chelate or salt thereof.
Other chelators suitable for use in the method of the invention include the macrocyclic and more preferably linear or branched aminopolycarboxylic acid chelants of EP-A-299795, EP-A-71564, DE-A-3401052, EP-A-203962, EP-A-436579 and the phosphorus oxyacid analogs. Preferred chelating agents include amides of DTPA and EDTA in which the nitrogens of the amide groups may be substituted by one or more C
1-18
alkyl groups, e.g. DTPA.BMA and EDTA.BMA.
As used herein the terms “alkyl” and “alkylene” include both straight-chained and branched, saturated and unsaturated hydrocarbons. The term “1,2-cycloalkylene” includes both cis and trans cycloalkylene groups and alkyl substituted cycloalkylene groups having from 5-8 carbon atoms. The term “1,2-arylene” includes phenyl and napthyl groups and alkyl substituted derivatives thereof having from 6 to 10 carbon atoms.
Unless otherwise specified, any alkyl, alkylene or alkenyl moiety may conveniently contain from 1 to 20, preferably 1-8, more preferably 1-6 and especially preferably 1-4 carbon atoms.
Cycloalkyl, aryl and aralkyl moieties may conveniently contain 3-18, preferably 5-12 and especially preferably 5-8 ring atoms. Aryl moieties comprising phenyl or naphthyl groups are preferred. As aralkyl groups, phenyl C
1-3
alkyl, especially benzyl, are preferred.
Where groups may optionally be substituted by hydroxy groups, this may be monosubstitution or polysubstitution and, in the case of polysubstitution, alkoxy and/or hydroxy substituents may be carried by alkoxy substituents.
In formula I, R
5
is preferably hydroxy, C
1-8
alkoxy, ethylene glycol, glycerol, amino or C
1-8
alkylamido. Preferably each group R
1
represents —CH
2
COR
5
in which R
5
is hydroxy.
In the compounds of formula I, X is preferably a bond or a group selected from CH
2
, (CH
2
)
2
, CO, CH
2
CO, CH
2
CH
2
CO or CH
2
COCH
2
. Preferably, Y represents a bond.
The compounds of formula I may have the same or different R
2
groups on the two pyridyl rings and these may be attached at the same or different ring positions. However, it is especially preferred that substitution be at the 5- and 6-positions, most especially the 6-position, i.e. para to the hydroxy group. Compounds in which the R
2
groups are identical and identically located, e.g. 6,6′, are especially preferred.
Preferred as groups R
6
are mono- or poly(hydroxy or alkoxylated) alkyl groups or a group of the formula OP(O) (OR
8
)R
7
.
R
7
is preferably hydroxy or an unsubstituted alkyl or aminoalkyl group.
Particularly preferred identities for group R
2
include CHR
7
OCO(CH
2
)
x
Ph and CHR
7
OCO(CH
2
CO)
x
Ph (wherein x is 1 to 3), CHR
7
OCOBu
t
, CH
2
N(H)R
6′
, CH
2
N(R
6′
)
2
, N(H)R
6′
, N(R
6′
)
2
, CH
2
OH, CH
2
OR
6′
, COOR
6′
, CON(H)R
6′
, CON(R
Jynge Per
Karlsson Jan O. G.
Towart Robertson
Bacon & Thomas
Davis Zinna Northington
Nycomed Imaging AS
Robinson Binta
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