Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-30
2002-09-24
Richter, Johann (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S457000, C514S460000, C514S577000, C514S681000, C514S688000, C514S690000, C549S398000, C549S399000, C549S403000, C568S335000, C568S336000, C568S337000
Reexamination Certificate
active
06455578
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to aromatic derivatives of formula (I) hereinafter reported and to iron complexes thereof, for the preparation of pharmaceutical compositions useful as normalising agents of the iron level.
STATE OF THE ART
Iron overload in the body, due to major defects in iron metabolism, such as genetic hemochromatosis and thalassemia, or due to minor causes, such as for example transfusions for hemolytic anemia, can bring the physiological defense reaction to saturation, thus having a toxic effect.
Such an effect is due to the expansion of the “Free Iron Pool”, which induces the production of oxygen active species responsible for the inactivation of cellular enzymes, for modifications in the membrane lipids, for DNA alterations, etc. (E. Cadenas,
Ann. Rev. Biochem.,
1989, 58: 79-110).
Therefore the consequences of the “Free Iron Pool” expansion can range from genotoxicity of the metal which causes the develop of tumours, to various organ pathologies, such as cirrhosis, diabetes, cardiopathy, hypogonadism and arthropathy.
Even in absence of an increase of the total iron in the body, an expansion of “Free Iron Pool” may happen, in association with many pathologic conditions, as for example neurodegenerative pathologies (M. Gassen et al.,
Pharmacol. Toxicol.,
1997, 80(4): 159-166), atherosclerosis (A. J. Matthews et al.,
J. Surg. Res.,
1997, 73(1): 35-40), ischaemic cardiopathy (T. P. Tuomainen et al.,
Circulation,
1998, 97(15): 1461-1466), chronic diseases of intestine (R. A. Floyd et al.,
Dig. Dis. Sci.,
October 1996, 41(10): 2078-86), and may cause the beginning or the development of the pathobiological event.
A strict correlation between alterations in the iron methabolism and HIV infections (J. R. Boelaert et al.,
Infect. Agents Dis.,
January 1996, 5(1): 36-46), as well as a connection between cardiotoxicity induced by iron and methabolism of antineoplastic agents in persons subjected to antitumoural therapy (G. Minotti et al.,
J. Clin. Invest., April
1995, 95(4): 1595-605), has been recently observed.
Moreover, it has been proved that the presence of “Free Iron” has a predominant role in the reactions bearing to the formation of free radicals and to the propagation of the damages due to free radicals, to which are associated for example inflammatory pathologies, such as arthritis and pyelonephritis (R. Gupta et al.,
Comp. Immunol. Microbiol. Infect. Dis.,
1997, 20(4): 299-307), and senescence (M. C. Corti et al.,
Am. J. Cardiol.,
1997, 79(2): 120-127).
At present, it is known the use of iron chelating agents in the treatment of systemic iron overload, associated to pathologies such as thalassemia or hemochromatosis.
The compounds used in such treatments show several drawbacks. For example, desferrioxamine, one of the substances more frequently used in this type of treatments, besides iron it binds many other important metals, such as aluminum, it is a very expensive product, it cannot be administered by oral route, and it has a half-life so short that continuous administration by subdermal infusion is necessary (R. J. Rothman et al.,
Mol. Pharmacol.,
1992, 42: 703-710).
Other medicaments are known containing complexing agents of iron, such as deferiprone and derivatives thereof, showing a great bioavailability, but also a high toxicity caused just by their bioavailability, which bring for example to the onset of agranulocythemia, epathic fibrosis, etc. (N. F. Olivieri et al.,
N. Engl. J. Med.,
1998, 339(7): 417-423).
Moreover, the medicaments, used up to now, have a dramatic effect on the cellular methabolism of iron, on which they produce a deep unbalance: as a matter of fact, they recall a great quantity of metal from the deposits of the organism and therefore they can be administered neither in the precox phases nor for sake of prophilaxys during hemochromatosis or thalassemia, nor in conditions in which the expansion of “Free Iron Pool” should be contrasted avoiding a variation in the quantity of the functional iron or of the iron stored in deposits.
It is therefore deeply felt the need of new compounds suitable for preparing pharmaceutical compositions, able to act as chelating agents of the total iron as well as of the “Free Iron Pool”, by removing it from cells and eliminating the resulting complex in urine.
It is felt as much the need of new pharmaceutical compositions for the treatment of pathologies to which a lack of iron in the body is associated.
SUMMARY OF THE INVENTION
Now the Applicant has surprisingly found that aromatic derivatives of formula (I):
wherein:
R
1
is
wherein R
3
and R
4
are selected from between H and OH, provided that R
3
and R
4
are not simultaneously H, and
R
2
is H; or
R
1
and R
2
, taken together, are
wherein R
5
is selected from between CH
3
and (CH
2
)
5
OH,
are able to bind stably the iron, in particular Fe(III).
Said compounds of formula (I) are suitable for the preparation of pharmaceutical compositions for oral administration, and show a high absorption and a high ability to permeate the biological membranes, in the form of free ligands as well as in the form of iron complexes.
Said pharmaceutical compositions are therefore useful for the treatment of all the pathological conditions related to an iron overload, in the case of an increase of the total iron as well as in the case of a relative increase in the iron level due to the expansion of the “Free Iron Pool”.
The iron complexes of the formula (I) compounds are also useful for the preparation of pharmaceutical compositions to be used in the treatment of pathologies related to a deficiency of iron, in the acute phase as well as for the chronic pathology.
It is therefore one object of the present invention the compounds of formula (I) for the preparation of pharmaceutical compositions for the use, in particular, as iron chelating agents, and the complexes thereof useful as iron release agents for hypoferremia.
Further object of the present invention are the compounds of formula (I) wherein
R
1
is
wherein R
3
is OH and R
4
is H, OH, and R
2
is H; or R
1
and R
2
, taken together, are
wherein R
5
is (CH
2
)
5
OH.
Features and advantages of compounds of formula (I) as iron chelating agents and of the iron complexes thereof according to the present invention will be illustrated in detail in the following description.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compounds having the formula (I) above reported for the preparation of pharmaceutical compounds, in particular of pharmaceutical compounds for the use as iron chelating agents. The iron complexes of the present formula (I) compounds have therapeutic application too, as agents for the iron release.
The present formula (I) compounds, which can be easily prepared according to processes known in the art, show a high affinity for iron, in particular for Fe(III), giving stable complexes of such metal presenting different metal/ligand ratios. Concerning the preparation of said complexes, they are tipically prepared by reacting a compound of formula (I) with Fe(III) ions deriving from a ferric salt selected from the group consisting of inorganic salts of Fe(III), preferably perchlorate, chloride and sulphate, and more preferably perchlorate.
Said reaction is carried out in a solvent selected from the group consisting of acetone, chloroform, dichloromethane and aqueous solutions containing from 5 to 10% of dimethylsulphoxide, preferably in acetone.
Chelation experiments of iron have been carried out with the present formula (I) compounds wherein R
1
and R
2
, taken together, are
wherein R
5
is selected from between CH
3
and (CH
2
)
5
OH, and it has been found that they form a Fe(III) complex having a molar ratio ligand:metal equal to 2:1.
The preparation of said complex is preferably carried out at room temperature by reacting a compound of formula (I) with ferric perchlorate in acetone.
The stability constant of the Fe (III) complex with the compound of formula (I) wherein R
1
and R
2
, taken together,
Abelman ,Frayne & Schwab
Laboratoire Medidom S.A.
Richter Johann
Witherspoon Sikarl A.
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