Orally active iron (III) chelators

Details Orally active iron (III) chelators Orally active iron (III) chelators

1999-11-30

2002-09-10

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S296000

Reexamination Certificate

active

06448273

ABSTRACT:

The present invention relates to novel compounds having activity as orally active metal chelators, particularly iron chelators, to pharmaceutical compositions containing these and to their use in treating disorders associated with iron distribution, particular disorders involving excess of iron and presence of iron dependent parasites.
BACKGROUND OF THE INVENTION
Members of the hydroxypyridone class are well known for their ability to chelate iron in physiological environment and these have reported as useful in treating iron related disorders such as thalassaemia. For example, see U.S. Pat. Nos. 4,840,958, 5,480,894 and Hider et al (1996) Acta Haematologica 95:6-12. By virtue of their low molecular weight and high affinity for iron (III) these compounds now provide the possibility of removing iron from iron overloaded patients with the hope of providing oral activity. Related compounds for such use are disclosed in U.S. Pat. No. 4,585,780 wherein the characteristics required for oral activity are discussed further.
Two particular compounds referred to by Hider et al, CP20 and CP94 (see Tables 1 and 2 herein), have proved to be effective in man, but both have disadvantages in that they are rapidly inactivated by phase II metabolism and are able to cross the placenta and blood brain barrier. The extensive biotransformation of these compounds is reflected by their limited ability excess body iron in thalassaemic patients.
The requirements for orally active chelators are set out in Table 4 of Hider et al as (i) good absorption from tile gastrointestinal tract, (ii) efficient liver extraction, (iii) poor entry into peripheral cells such as thymus, muscle, heart and bone marrow and (iv) poor ability to penetrate the blood-brain barrier and maternal/placental barriers. This reference refers to desired partition coefficients (K
part
), herein referred to as distribution coefficient values (D
pH7.4
), for these properties as (i) >0.2, (ii) >1.0, (iii) <0.001 and (iv) <0.001, respectively rendering one compound seemingly unsuited to satisfying all four criteria. Hider et suggest the pro-drag strategy to be one possible route forward but no specific compounds have so far been found to meet all criteria.
Pivalic acid esters of hydroxyalkyl substituted 3-hydroxypyridin-4ones have been studied as pro-drugs and found to lead to efficient excretion of iron, in bile and urine, but as reported by Hider et al these are now thought to potentially interfere with the carnitine cycle and thus may not be suitable for use in regular and/or large doses in man.
It is known that the 2-(1′-hydroxyethyl) metabolite of 1,2-diethyl-3-hydroxypyridin-4-one (CP94) produced in rat is an active iron chelator (see Singh et al (1992) Drug Metabolism and Disposition Vol 20. No 2, page 256-261). EP 0494754 A proposes 1-hydroxyethyl as one of many possible substituents at any of the pyridin-4-one positions 1, 2, 5 or 6 for use as iron chelator in treatment of malaria; none of these compounds are however exemplified as made or tested for activity. EP 0768302 A (Novartis) describes a series of related 3-hydroxypyridin-4-ones in which the 2-position is substituted by a methyl group which carries an optionally substituted phenyl or heteroyl ring and a free or esterified hydroxy group. The phenyl or heteroyl group is taught as an essential element of these compounds.
DESCRIPTION OF THE INVENTION
The present inventors now have provided a group of 3-hydroxypyridin-4-one iron chelators having improved properties as compared to the prior art as assessed against the criteria set out above. The preferred compounds of the invention are all characterised by meeting a further criterion (v) in so far as they have a pM for Iron III, i.e. affinity for iron as Fe III, of at least 20, preferably in excess of 23. Preferred compounds have efficiency of iron mobilisation of in excess of 52% when given orally to rats. The definition of pM used herein is the negative log concentration of ferric ion in solution when the total amount of iron equals 10
−6
M and the concentration of ligand is 10
−5
M and pH is 7.4.
The present compounds offer the prospect of effective pharmaceutical formulations having reduced levels of active agent, with particular properties of selective targeting of the chelating activity to tissues where the iron level requires alteration, particularly the liver. A particular property of preferred compounds of the invention is that they are not significantly metabolised through conjugation and, in some preferred forms, are provided as prodrugs.
Thus in a first aspect of the present invention there is provided a novel 3-hydroxypyridin-4-one compound or derivative thereof of formula I
wherein
R is hydrogen or a group that is removed by metabolism in vivo to provide the free hydroxy compound,
R
1
is an aliphatic hydrocarbon group or an atiphatic hydrocarbon group substituted by a hydroxy group or a carboxylic acid ester, sulpho acid ester or a C
1-6
alkoxy, C
6
-aryloxy or C
7-10
aralkoxy ether thereof, and
R
3
is selected from hydrogen and C
1-6
alkyl;
characterised in that
R
2
is selected from groups
(i) —CONH—R
5
(ii) —CR
6
R
6
OR
7
(iii) —CONHCOR
5
and (iv) —CON(C
n
H
2n+1
)
2
R
4
is selected from hydrogen, C
1-6
alkyl and a group as described for R
2
;
R
5
is selected from hydrogen and optionally hydroxy, alkoxy, aryloxy or aralkoxy substituted C
1-13
alkyl, aryl and C
7-13
aralkyl,
R
6
is independently selected from hydrogen and C
1-13
alkyl,
R
7
is selected from hydrogen, C
1-13
alkyl, aryl and C
7-13
aralkyl
and n is an integer of 1 to 6, whereby C
n
H
2n+1
is C
1-6
alkyl or a pharmaceutically acceptable salt of any such compound
with the proviso that the compound is not one of 1-ethyl-2-(1′-hydroxyethyl)-3-hydroxypyridin-4-one and 1-methyl-2-hydroxymethyl-3-hydroxypyridoin-4-one.
Preferably at least one of R, R
1
or R
7
is such as to form a 3-ester or ether prodrug. Those skilled in the art will recognise the term 3-ester or ether prodrug to mean compounds wherein the 3-hydroxy group has been esterified with a carboxylic or sulpho acid, or formed into an ether with a C
1-6
alkyl or C
1-10
aralkyl group which is removed in vivo to provide the free hydroxy compound. Typically such carboxylic acid esters or ethers are of C
1-7
type, i.e. the 3-substituent is —O—R
8
or —OC(O)—R
8
where R
8
is C
1-6
alkyl or C
1-10
aralkyl.
More preferably R
5
and R
7
are independently selected from C
1-6
alkyl, aryl or aralkyl, e.g. benzyl, which may be substitued with C
1-6
alkoxy. More preferably R
6
is independently selected from hydrogen or C
1-6
alkyl. Most preferably R
7
is methyl or ethyl.
The positions 5 and 6 are preferably unsubstituted, ie. R
3
and R
4
are preferably hydrogen, but may be substituted with conventional pyrdin-4-one substituents as disclosed by the prior art as suitable in iron chelators.
Where R
1
is an aliphatic carbon group substituted by hydroxy and that hydroxy is esterified the ester acyl group is preferably of formula —CO—R
9
where R
9
is C
1-6
alkyl or C
1-10
aryl, more preferably being —CO-Phenyl or —CO-hetero, eg. heterocylic rings with one of two nitrogen members and three to five carbons.
R
1
and R
5
are conveniently independently selected C
1-6
alkyl, preferably methyl or ethyl, but preferably may be a hydroxy, alkoxy or esterified hydroxy terminated C
1-6
alkyl group. Where R
1
is a hydroxy terminated alkyl it is advantageous that the alkyl group is of 3 to 6 carbons long, more preferably being 3 carbons long, e.g. where R
1
is —(CH
2
)
3
—OH, as such compounds are known to be metabolised in vivo to the corresponding —(CH
2
)
2
—CO
2
H derivative with consequent advantages of low D
pH7.4
after metabolism, e.g. in the liver.
Most preferred compounds are of the type where R
2
is of groups (i) or (ii).
More preferably R
2
is a group —CR
6
R
6
OR
7
wherein R
6
is independently selected at each occurrence from hydrogen, C
1-13
alkyl or C
6
aryl and R
7
is C
1-6
alkyl, more preferably methyl or eth

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