Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2000-06-23
2001-10-30
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S188000, C514S346000, C514S352000, C514S354000, C514S356000, C514S191000, C514S824000
Reexamination Certificate
active
06310051
ABSTRACT:
The present invention relates to the use of chelating agents and their metal chelates in medicine, in particular in treating or preventing atherosclerosis and related conditions.
It has been estimated that half of all deaths in Western countries result from atherosclerosis, a disease in which cholesterol-rich “foam cells” accumulate and form plaques in arterial walls, obstructing blood flow, which ultimately leads to heart attack or stroke.
It has been found that elevated lipoprotein concentration in plasma accelerates the development of atherosclerosis. Recent research has shown oxidative modification of low density lipoprotein (LDL) to be an early and important event in the development of atherosclerosis (Steinberg et al, N Engl J Med 320: 915, 1989).
The precursors of atherosclerotic foam cells are predominantly circulating monocytes and macrophages and it has been found that the cholesterol content of these foam cells increases upon interaction with oxidatively modified forms of low density lipoproteins (Palinski et al, Proc Natl Acad Sci 86: 1372, 1986; Montgomery et al, Proc Natl Acad Sci 83: 6631, 1986). It is well known that the redox-active transition metals iron and copper enhance LDL oxidation, probably through a process involving superoxide radicals, and thus, these ions are believed to be of importance in the initiation of atherosclerosis. It is envisaged that oxidation of LDL occurs by a mechanism similar to that seen in membranes during ischaemia-reperfusion and anthracycline toxicity with superoxide, where iron and copper serve central, catalytic roles (see Ryan & Aust, Crit Rev Toxicol 22: 119, 1992).
Oxidation of LDL results, among other things, in an impaired nitric oxide-dependent vasorelaxation (Kugiyama et al, Nature 344: 160, 1990). The impaired nitric oxide-dependent vasorelaxation may, in turn, cause hypertension, which by itself is one of the primary risk factors for cardiovascular diseases in humans. The impaired vasorelaxation may be due to inactivation of nitric acid by superoxide.
It will be appreciated that there thus exists a continuing need for compounds which are able to treat or prevent atherosclerosis, for example by inhibiting LDL oxidation.
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 atherosclerosis and related conditions.
In one aspect the invention thus provides the use of a dipyridoxyl or aminopolycarboxylic acid based chelating agent, or a metal chelate or salt thereof, in the manufacture of a therapeutic agent for use in the treatment or prophylaxis of atherosclerosis and related conditions in the human or non-human animal body.
In a further 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 atherosclerosis and related conditions 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;
each R
4
independently represents hydrogen or C
1-3
alkyl; and
each R
9
independently may be absent or represents hydrogen, alkyl, hydroxyalkyl or carboxyalkyl).
In another aspect the invention provides a method of treatment of the human or non-human animal body to combat or prevent atherosclerosis and related conditions, said method comprising administering to said body an effective amount of a chelating agent selected from dipyridoxyl and aminopolycarboxylic acid based chelating agents and metal chelates and salts thereof, preferably a compound of formula I or a metal chelate or salt thereof.
Related conditions to atherosclerosis include conditions such as hypertension which can be treated indirectly by the prevention of atherosclerosis or alternatively, directly since it is envisaged that the inhibiton of the oxidation of LDL may alleviate impaired nitric-oxide dependent vasorelaxation.
Also, it is envisaged that the compounds according to the invention may be useful in cytotoxic antimicrobial treatment, e.g. to combat infections associated with bacteria, protozoa, parasites etc. Protozoal infections which may be treated using the compounds of the invention include malaria, e.g.
Plasmodium falciparium
and
Pneumocystis carinii
, trypanosomiasis (Chagas' disease) and leichmaniasis. Methods of metal detoxification are also envisaged using the compounds of the invention. For example, these may be used to treat iron intoxication such as in thalassemia.
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.
Andersson Rolf Goran Gustav
Grant Derek
Griffith Tudor
Jynge Per
Karlsson Jan Olof Gustav
Bacon & Thomas PLLC
Nycomed Imaging AS
Reamer James H.
LandOfFree
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