Title: N-substituted 3-hydroxy-4-pyridinones and pharmaceuticals containing thereof
Abstract: N-substituted 3-hydroxy-4-pyridinones and metal chelates, methods of preparing N-substituted 3-hydroxy-4-pyridinones and metal chelates, and pharmaceutical compositions containing new N-substituted 3-hydroxy-4-pyridinones and/or their metal chelates. Use of N-substituted 3-hydroxy-4-pyridinones and their metal chelates as pharmaceutical agents for the treatment of diseases, such as parasitic and viral infections, conditions associated with inflammation and infection, and conditions mediated by cell-proliferation or collagen formation.
Patent Number: 6,932,960 Issued on 08/23/2005 to Liu
| Inventors:
|
Liu; Shuang (Chelmsford, MA)
|
| Assignee:
|
Bristol-Myers Squibb Pharma Company (Princeton, NJ)
|
| Appl. No.:
|
803724 |
| Filed:
|
March 18, 2004 |
| Current U.S. Class: |
424/1.65; 534/10; 546/193; 546/296; 544/131 |
| Intern'l Class: |
A61K 051/00; C07F 005//00 |
| Field of Search: |
424/165
534/10
546/193,296
544/131
|
References Cited [Referenced By]
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|
Primary Examiner: Aulakh; Charanjit S.
Attorney, Agent or Firm: Woodcock Washburn LLP
Parent Case Text
This application is a divisional application of U.S. application Ser. No. 10/358,835
filed Feb. 5, 2003 now U.S. Pat. No. 6,825,204 now allowed, which claims the benefit
of priority of U.S. Provisional Application No. 60/354,339 filed Feb. 5, 2002,
both of which are hereby incorporated by reference.
Claims
1. A radiopharmaceutical of the formula:
or pharmaceutically acceptable salt thereof, wherein:
M is a radionuclide selected from:
64Cu,
67Cu,
67Ga,
68Ga,
99mTc,
111In,
90Y,
149Pr,
153Sm,
159Gd,
166Ho,
169Yb,
177Lu,
86Re, and
188Re;
C
h is an N-substituted 3-hydroxy-4-pyridinone compound of the formula
(I):
##STR10##
or a pharmaceutically acceptable salt thereof, wherein:
X is selected from the group: CH
2, C(O), C(S), P(O)R
3R
4,
SO
2, C(═NH)NH, C(O)NH, and C(S)NH;
R
1 and R
2 are independently selected from: H, C
1--C
10
alkyl substituted with 0-5 R
5, C
2-C
10 alkenyl
substituted with 0-5 R
5, aryl substituted with 0-3 R
5, and
heteroaryl substituted with 0-3 R
5;
R
3 and R
4 are independently selected from: C
1-C
10
alkyl substituted with 0-5 R
5, C
2-C
10 alkenyl
substituted with 0-5 R
5, aryl substituted with 0-3 R
5, and
heteroaryl substituted with 0-3 R
5, or R
3 and R
4 may
be taken together to form a C
5-C
7 cyclic alkyl group optionally
interrupted with O or NR
6;
R
5 is selected from: OH, C(═O)R
6, C(═O)OR
6,
C(═O)NR
6R
7, PO(OR
6)(OR
7), and
S(O)
2OR
6;
R
6 and R
7 are independently selected from: H, C
1-C
10
alkyl, and aryl; and
n is 2 or 3.
2. The radiopharmaceutical according to claim 1 wherein:
M is a radionuclide selected from:
67Ga,
68Ga,
99mTc,
and
111In; and
n is 3.
3. The radiopharmaceutical according to claim 1 wherein:
M is
111In; and
n is 3.
4. The radiopharmaceutical according to claim 1 wherein:
M is
111In;
n is 3.
X is CH
2;
R
1 is H;
R
2 is methyl; and
R
3 and R
4 are taken together form a 6-membered cyclic piperidine
ring.
5. The radiopharmaceutical according to claim 1 wherein:
M is
111In;
n is 3;
X is CH
2;
R
1 is H;
R
2 is methyl; and
R
3 and R
4 are taken together form a 6-membered cyclic morpholine
ring.
6. A method of preparing a radiopharmaceutical of claim 1, comprising the step of:
reacting a salt of said radionuclide with an excess of said N-substituted 3-hydroxy-4-pyridinone
compound of the formula (I).
Description
FIELD OF THE INVENTION
This invention relates to novel N-substituted 3-hydroxy-4-pyridinones and metal
chelates, methods of preparing N-substituted 3-hydroxy-4-pyridinones and metal
chelates, and pharmaceutical compositions containing new N-substituted 3-hydroxy-4-pyridinones
and/or their metal chelates. This invention also relates to the use of N-substituted
3-hydroxy-4-pyridinones and their metal chelates as pharmaceutical agents for the
treatment of diseases, such as parasitic and viral infections, conditions associated
with inflammation and infection, and conditions mediated by cell-proliferation
or collagen formation. This invention particularly relates to the N-substituted
3-hydroxy-4-pyridinones as chelators for chelation therapy of iron overload. This
invention also relates to the use metal chelates of N-substituted 3-hydroxy-4-pyridinones
as NMR contrast agents or radiopharmaceuticals.
BACKGROUND OF THE INVENTION
There are a number of inherited diseases, which are associated with the gradual
accumulation of iron. These include β-thalassaemia major and thalassaemia
intermedia. Due to its facile redox chemistry, excess iron in human body often
results in irreversible damage to endocrine organs and lethal cardiac toxicity.
In humans such excess iron can not be excreted via normal routes, namely, the urine
and the bile, and consequently chelation therapy is essential (
J. Med. Chem.
1998, 41: 3347-3359
; Inorg. Chem. Acta 1999, 291: 238-246).
The objectives of iron-chelation therapy for iron overload are two fold: first,
to produce negative iron balance by removing excess body iron; and second, to detoxify
the excess iron while, and until, the first objective is achieved (
Drug Safety
1997, 17: 407-421). In order to be considered harmless, iron must be fully
coordinated. If any of its six coordination sites remain uncoordinated, iron will
participate in Fenton reactions, resulting in lipid peroxidation with organelle
and cell damage from hydroxyl radicals (
Baillieres Clin. Haematol. 1989,
2: 195-256). Therefore, the iron chelator has to be able to form the iron complex
with extremely high stability. Specificity of iron binding over other metals (e.g.,
zinc and copper) is also necessary to avoid chelation of these metals, which are
needed for normal physiological activities.
Ideally, an iron chelator should have a low degree of penetration into the
central nerve system and should produce a high degree of extraction of iron from
hepatic cells, where iron is present in high levels (
Drug Safety 1997, 17:
407-421
; Acta Haematol. 1996, 95: 6-12). A second constraint of chelator
design is that iron must not be redistributed from liver to other parts (e.g.,
heart and joint) of the body where it may be harmful. This requires that the iron
complex be extremely stable. For a chelator to be efficiently absorbed from the
gut, the molecular weight of the chelator has to be about 400 Dalton.
There has been considerable interest in the design of orally active iron chelators
over the last two decades and many high-affinity iron chelators have been prepared
(
J. Med. Chem. 1990, 33: 1749-1755
; J. Med. Chem. 1993, 36: 2448-2458
;
J. Med. Chem. 1993, 36: 2448-2458
; J. Med. Chem. 1994, 37: 461-466
;
J. Med. Chem. 1994, 37: 93-98
; J. Med. Chem. 1998, 41: 3347-3359
;
Eur. J. Med. Chem. 1999, 34: 475-485
; J. Med. Chem. 2000, 43: 1467-1475
,
J. Pharm. Pharmacol. 2000, 52: 263-272
; Bioorg. Med. Chem. 2001, 9:
563-573
; Bioorg. Med. Chem. 2001, 9: 3041-3047
; Tetrahedron 2001,
57:3479-3486). As a result, 1,2-dimethyl-3-hydroxypyridin-4-one (DMHP, CP20, Deferiprone)
has been selected as the clinical candidate for the treatment of iron overload.
One of the problems with such an N-alkyl-3-hydroxypyridin-4-one is the ability
of the free ligand and the resulting iron complex to rapidly penetrate cell membranes
and other biological barriers (
Drug Met. Disp. 1992, 20: 256-261). A second
problem is that N-alkyl-3-hydroxypyridin-4-ones are rapidly metabolized by glyceronidation
of the 3-hydroxy group, which will lead to disappearance of iron-chelating properties
of the molecule. Despite recent developments, there is a continuing need for new
iron chelators, which have high binding affinity for iron and are able to accumulate
in liver, the major storage organ in iron-overload conditions.
For many years radical scavenging antioxidants have been successfully used to
protect synthetic material and food products from degradating process of oxidation
(
Cosmet. Sci. Technol. Ser. 1997, 16: 159-179). Radical scavengers have
been proposed as neuroprotective agents for the treatment of disorders known to
involve oxidative stress, such as stroke, tramatic brain injury, spinal cord injury,
cerebral tumor, subharrchnoid haemorrage/cerebral vasospam, cerebral ischaemia,
stroke, Alzheimers' disease, Huntington's disease, Parkinson's disease, Friedrich
ataxia, motor neuron disease or multiple sclerosis. However, the effectiveness
of radical scavengers in reducing oxidative stress within living biological environment
is often undermined by the continual production of free radicals mediated by iron.
Since Fe is involved in the production of toxic free radicals, several radical
scavenger-conjugated 3-hydroxy-4-pyridinones have been prepared and studied as
potent inhibitors of lipid peroxidation and cell toxicity (
J. Med. Chem. 2000,
43: 2779-2782). Some display a superior neuroprotective activity compared to dual
administration of the radical scavenger, di-tert-butylphenol, and the iron chelator,
Deferiprone, demonstrating the synergistic effect between the radical scavenger
and the iron chelator.
Vanadium compounds, in vitro, stimulate glucose uptake and inhibit lipid
break down, in a manner remarkably reminiscent of insulin's effect. Vanadium chelates
with organic chelators present ways to fine tune the effect of vanadium, thereby
minimizing any adverse effects without sacrificing important therapeutic benefits.
Many compounds have been proposed as "insulin mimetics". These include vanadium
complexes of pyronates (
J. Med. Chem. 1992, 35: 1489-1491
; J. Am. Chem.
Soc. 1995, 117: 12759-12770
; Can. J. Physiol. Pharmacol. 1995, 73: 55-64
;
Can. J. Physiol. Pharmacol. 1996, 74: 1001-1009
; J. Inorg. Biochem. 1997,
68: 109-116;), pyridinates (
Transition Metal Chem. 2001, 26: 219-223), picolinates
(
Inorg. Chem. 1999, 38: 2288-2297), and cycteine ester (
Inorg. Chim.
Acta 1980, 46: 2288-L119-L125), and have been recently reviewed (
J. Chem.
Soc., Dalton Trans. 2000, 2885-2892
; Coord. Chem. Rev. 2001, 219-221: 1033-1053).
For vanadium to be useful as an orally available insulin mimetic agent, it must
be able to cross biological membranes, both for the initial absorption process
and intracellular uptake. Therefore, the metal chelate must have low molecular
weight, neutral charge, and a fair degree of resistance to hydrolysis. The lipophilicity
of the metal chelates must be balanced with its hydrophilicity, and possess adequate
thermodynamic stability. As bidentate chelators for the design of vanadium chelates
useful as insulin enhancing agents, 3-hydroxy-4-pyrones and 3-hydroxy-4-pyridinones
are exemplary. Both 3-hydroxy-4-pyrones and 3-hydroxy-4-pyridinones form stable
and neutrally charged vanadium chelates, which have an optimal combination of water
solubility, reasonable hydrolytic stability, and significant lipophilicity (
J.
Chem. Soc., Dalton Trans. 2000, 2885-2892
; Coord. Chem. Rev. 2001, 219-221: 1033-1053).
N-Alkyl-3-hydroxy-4-pyridinones form very stable
six-coordinated gadolinium chelates (
Inorg. Chim. Acta 1992, 191: 57-63),
potentially useful as MRI contrast agents. They also form very stable Zn(II) and
Tin(II) complexes, which are useful in dental care formulations (
Polyhedron
2000, 19, 129-135
; Inorg. Chem. 2001, 40, 4384-4388). In addition,
67Ga,
111In and
99mTc complexes of N-alkyl-3-hydroxy-4-pyridinones
have been studied as potential radiopharmaceuticals either for imaging or for the
radiolabeling of white blood cells (
Nucl. Med. Biol. 1992, 19: 327-335
;
Nucl. Med. Biol. 1993, 20, 857-863
; Inorg. Chem. 1994, 33, 5607-5679
;
J. Med. Chem. 1996, 39: 3659-3670
; Eur. J. Nucl. Med. 1999, 26: 1400-1406).
Other potential applications for substituted 3-hydroxy-4-pyridinones also include
their use for the treatment of overload of other metals (e.g., copper, zinc, aluminum
and plutonium) present in the body in deleterious amounts, inflammatory disease
(
J. Biol. Chem. 1996, 271: 7965-7972
; Bioorg. Med. Chem. Lett. 2001,
11: 2573-2575), atherosclerotic disease (
Neuroreport 1999, 10: 717-725),
neoplastic disease, and thrombosis.
UK Patent No. 2 136 807 discloses the use of 3-hydroxy-4-pyridinones for the
treatment
of iron overload arising from various causes, particularly that arising from pathological
conditions such as thalassaemia, sickle cell anaemia, asplatic anaemia, and idiopathic
haemochromatosis, often through the treatment of the first three conditions by
regular blood transfusions. In addition, 3-hydroxy-4-pyridinones are of interest
for the treatment of pathological conditions where there may be an excess of iron
deposited at certain sites even though patients do not exhibit a general iron overload.
EP Patent No. EP0335745 A1 discloses a process for preparation of substituted
3-hydroxy-4-pyridinones. EP Patent No. EP0768302A2 and UK Patent No. GB2 269 589A
also disclose synthesis of N-substituted 3-hydroxy-4-pyridinones and pharmaceutical
compositions containing thereof. The substituent at the N atom is an aliphatic
hydrocarbon group.
U.S. Pat. No. 5,256,676 discloses synthesis of N-substituted 3-hydroxy-4-pyridinones
and a method for the treatment of a patient having a condition caused by an iron-dependent
parasite which comprises administering to that patient a therapeutically effective
amount of N-substituted 3-hydroxy-4-pyridinones.
Proposals have been made in EP Patent No. EP 0316279A2 to modify the 3-hydroxy
group of the 3-hydroxy-4-pyridinones to provide a pro-drug form, i.e., in the form
of a drug which does not itself possess the desired biological activity but which
is converted in vivo to a drug which does. UK Patent No. 2 269 589 specifically
discloses the use of substituted 3-hydroxy-4-pyridinones as chelating agents for
the treatment of iron overload.
International Publication No. WO 98/54138 discloses preparation of
3-hydroxy-4-pyridinones as orally active iron chelators and their pharmaceutical
formulations. The substituent at the N atom contains an aliphatic hydrocarbon group
substituted by a hydroxy group or a carboxylic acid ester, sulfonic acid ester
or a C1-6-alkoxy or C7-10-aralkoxy ether. International Publication No. WO 98/01458
also discloses preparation of N-substituted 3-hydroxy-4-pyridinones as iron(III)
chelators. The N-substituents are selected from polyhydroxycarbons, such as saccharides.
UK Patent No. GB2345058A, International Publication No. WO 99/23075 and European
patent applications EP1006108A1 and EP1006112A1 disclose preparation of N-substituted
hydroxypyridinone derivatives as reactive oxygen species scavengers. The N-substituted
hydroxypyridinone derivatives contain both ortho-hydroxypyridinone and oxygenated
aryl (including heteroaryl) functionalities, which possess the dual ability to
chelate iron and scavenge reactive oxygen species. The N-substituted 3-hydroxy-4-pyridinone
derivatives are particularly useful for the treatment of a condition associated
with oxidative stress, such as oxidative damage of the central nervous system or
an acute or chronic neurological disorder such as tramatic brain injury, spinal
cord injury, cerebral tumor, subharrchnoid haemorrage/cerebral vasospam, cerebral
ischaemia, stroke (ischaemic or haemorragic), Alzheimers' disease, Huntington's
disease, Parkinson's disease, Friedrich ataxia, motor neuron disease or multiple sclerosis.
U.S. Pat. No. 6,046,219 and International Publication Nos. WO 96/22021, WO96/41639,
and WO 99/30562 disclose the use of hydroxypyridinone derivatives useful for the
treatment of fibroproliferative disorders by inhibiting protein hydroxylation.
Inhibitors of protein hydroxylases (including aspartyl/asparaginyl hydroxylase,
prolyl 4-hydroxylase, and deoxyhypusine hydroxylase) block the biochemical events
that are required for the formation of excessive fibrocellular scar tissue, and
therefore have anti-fibroproliferative properties of clinic importance.
U.S. Pat. No. 5,877,210 discloses a conjugate comprising an inhibitor of phosphotyrosine
phosphatase covalently conjugated to a specific binding partner for a cell surface
receptor found on B cells, wherein the inhibitor of phosphotyrosine phosphatase
is a compound comprising a metal chelate of an organic chelator selected from the
group consist of (a) keto-enol tautomers with the keto and enol groups on adjacent
carbon atoms that form 5-membered chelate ring or (b) beta-diketones in which the
two keto groups are separated by one carbon atom, that form a 6-membered chelate
ring. The metal chelates disclosed include V(IV), Cu(II) and Ga(III) complexes
of hydroxypyridinones, hydroxymates and acetylacetone. The inhibitory activity
of 3-hydroxy-4-pyridinones on mammalian tyrosine hydroxylase has also been reported
recently (
Biochem. Pharmacol. 2001, 61: 285-290).
International Publication No. WO 01/12168 discloses a pharmaceutical
composition comprising an iron chelator and another virus-inhibiting compound for
the treatment of viral infection, in particular of the human immunodeficiency (HIV).
The iron chelator is selected from the group of hydroxamates or hydroxypyridinones
while the viral-inhibiting compound is selected from protease inhibitors or reverse
transcriptase inhibitors.
U.S. Pat. No. 6,294,152 discloses Fe(III) complexes of 3-hydroxy-4-pyridinones
useful as MRI contrast agents. In all the cases, the N-substituent is a simple
or substituted alkyl or aryl group.
International Publication No. WO 91/12822 discloses preparation of
Fe(III) and Mn(II) complexes of 3-hydroxy-4-pyridinones useful as MRI contrast
agents. The substituents on the pyridinone ring are simple alkyl groups substituted
with phosphonate or sulfonate groups.
U.S. Pat. Nos. 5,527,790 and 5,866,563 disclose vanadium compositions for the
treatment of elevated blood sugar. Vanadium chelates disclosed include those containing
hydroxamates, o-heterocycle-substituted phenolates, 3-hydroxy-4-pyrones, and N-substituted
3-hydroxy-4-pyridinates. In all the cases, the N-substituent is a simple or substituted
alkyl or aryl group.
U.S. Pat. No. 6,232,340 discloses organovanadium complexes and pharmaceutical
compositions containing hydroxyoxovanadium(V), μ-oxo dimeric vanadium(V),
and cis-dioxovanadium(V) complexes for the treatment of diseases or disease states,
including use as antiproliferative and/or antimetastatic agents.
International Publication No. WO 93/10822 discloses cationic
99mTc(IV)
complexes with N-substituted 3-hydroxy-4-pyridinones as diagnostic scintigraphic
imaging agents. The N-atom is directly attached to a carbon atom from a simple
or substituted alkyl or aryl group.
International Publication No. WO 00/16736 discloses an oral care composition
containing antiplaque agents. The antiplaque agents are metal complexes of Cu(II),
Zn(II), Sn(II), Fe(II), or Fe(III) with a specific class of cyclic α-hydroxylketones,
including 3-hydroxy-4-pyrones.
However, there remains a need for therapeutic agents with enhanced efficacy,
solution stability, and optimal combination of lipophilicity and hydrophilicity.
This invention is directed towards meeting this need.
SUMMARY OF THE INVENTION
One aspect of this invention is to provide novel N-substituted 3-hydroxy-4-pyridinones
and pharmaceutical compositions containing these new N-substituted 3-hydroxy-4-pyridinones
useful for the treatment of overload of iron and other metals (for example copper,
zinc, aluminum and plutonium) present in the body in deleterious amounts.
Another aspect of this invention is to provide a method for the preparation
of new N-substituted 3-hydroxy-4-pyridinones.
Another aspect of invention is related to the use of pharmaceutical compositions
containing new N-substituted 3-hydroxy-4-pyridinones for the treatment of diseases,
such as parasitic and viral infections, conditions associated with inflammation
and infection, and conditions mediated by collagen formation.
Another aspect of invention is related to metal chelates of N-substituted
3-hydroxy-4-pyridinones, methods of preparing metal chelates of new N-substituted 3-hydroxy-4-pyridinones.
Another aspect of invention is to provide pharmaceutical agents or compositions
containing metal chelates of new N-substituted 3-hydroxy-4-pyridinones for the
treatment of diseases, such as viral infections, conditions associated with inflammation
and infection, and conditions mediated by cell-proliferation or collagen formation.
Another aspect of invention is related to the use of metal chelates of new
N-substituted 3-hydroxy-4-pyridinones as NMR contrast agents.
Another aspect of this invention is related to the use metal chelates of
new N-substituted 3-hydroxy-4-pyridinones as diagnostic or therapeutic radiopharmaceuticals.
DETAILED DESCRIPTION OF THE INVENTION
For the last two decades, a large number of N-substituted 3-hydroxy-4-pyridinones
have been synthesized and studied as iron chelators for the treatment of iron overload
(
J. Med. Chem. 1998, 41: 3347-3359
; Inorg. Chem. Acta 1999, 291:
238-246
; Drug Safety 1997, 17: 407-421
; J. Med. Chem. 1990, 33: 1749-1755
;
J. Med. Chem. 1993, 36: 2448-2458
; J. Med. Chem. 1993, 36: 2448-2458
;
J. Med. Chem. 1994, 37: 461-466
; J. Med. Chem. 1994, 37: 93-98
; J.
Med. Chem. 1998, 41: 3347-3359
; Eur. J. Med. Chem. 1999, 34: 475-485
;
J. Med. Chem. 2000, 43: 1467-1475
, J. Pharm. Pharmacol. 2000, 52: 263-272
;
Bioorg. Med. Chem. 2001, 9: 563-573
; Bioorg. Med. Chem. 2001, 9: 3041-3047
;
Tetrahedron 2001, 57:3479-3486). The N-substituted 3-hydroxy-4-pyridinones
of this invention are unique in such a way that the N-atom of the pyridinone ring
is directly connected to the N-atom of a dialkylamino or acylamido-N or sulfonylamido-N
group rather than a simple or substituted alkyl group. As a result, the dialkylamino,
acylamido-N and sulfonylamido-N group imparts increased hydrophilicity. Since the
molecular weight of these new chelators is generally <400 Dalton, they are expected
to be efficiently absorbed from the gut. The lipophilicity arising from aromatic
substituents of the dialkylamino or acylamido-N or sulfonylamido-N group should
result in accumulation of the new chelator in hepatic cells, where iron is present
in high levels. Like other 3-hydroxy-4-pyridinones previously disclosed, the new
chelators form iron complexes with high stability. Therefore, the new N-substituted
3-hydroxy-4-pyridinones of the invention have the potential to be used as pharmaceutical
agents for the treatment of overload of iron and other metals (e.g., copper, zinc,
aluminum and plutonium) present in the body in deleterious amounts.
The N-substituted 3-hydroxy-4-pyridinones of this invention also have the potential
to be used in combination with other pharmaceutical agents for the treatment of
diseases. For example, it is known that iron chelation can influence HIV replication
by inhibiting DNA synthesis via inactivation of iron-dependent ribonucleotide reductase.
It has been demonstrated that the combination use of a virus-inhibiting agent (such
as a protease inhibitor or a reverse transcriptase inhibitor) with an iron chelator
results in synergistic effect for the treatment of viral infection, in particular
of the HIV, (International Publication No. WO 01/12168).
Alternatively, the N-substituted 3-hydroxy-4-pyridinones of this invention
can be conjugated to a protease inhibitor or a reverse transcriptase inhibitor
via a direct covalent bond or through a metabolically cleaveable linker. In this
way, the bioconjugate is bifunctional: inactivation of iron-dependent ribonucleotide
reductase and inhibition of protease or reverse transcriptase, resulting in synergistic
effect for the treatment of viral infection.
The transition metal ion-dependent formation of hydroxyl radical from hydrogen
peroxide in the presence of a reducing agent such as superoxide or ascorbate at
low concentration is an important mechanism of "oxidative stress" leading to irreversible
cell and tissue damage (
Bioorg. Med. Chem. Lett. 2001, 11: 2573-2575). Metal-ion
mediated oxidative stress has been attributed a role in inflammation, atherosclerosis
and Alzheimer's disease. It has been reported that iron chelators function as antioxidants
to decrease plaque and aggregate formation in neurodegenerative diseases and atherosclerosis
(
J. Surg. Res. 1997, 73: 35-42
; Neuroreport 1999, 10: 77-85). Iron
chelators with the radical scavenging capability are of great potential for the
treatment of disorders known to involve oxidative stress, such as stroke, traumatic
brain injury, spinal cord injury, cerebral tumor, subharrchnoid haemorrage/cerebral
vasospam, cerebral ischaemia, stroke, Alzheimers' disease, Huntington's disease,
Parkinson's disease, or multiple sclerosis.
The N-arylsulfonylamido- and N-arylcarboxylamido-substituted 3-hydroxy-4-pyridinones
of this invention are bifunctional with the 3-hydroxy-4-pyridinone moiety for iron
chelation to inhibit Fe-mediated free radical formation and the aryl group (such
as benzene, pyridine and thiophene) for radical scavenging by reacting with hydroxyl
radicals. Aromatic compounds such as phenylalanine and phenols react rapidly with
hydroxyl radicals (
Bioorg. Med. Chem. Lett. 2001, 11: 2573-2575). A synergistic
neuroprotective activity has been reported for radical scavenger-conjugated 3-hydroxy-4-pyridinones
(
J. Med. Chem. 2000, 43: 2779-2782).
Zinc- and iron-containing metalloproteins have been studied as possible targets
for antiviral and anticancer therapy (
Anticancer Res. 2001, 21, 931-958
;
Exp. Biol. Med. 2001, 226, 665-673). Viral and cellular zinc finger proteins
and iron containing proteins are involved in cell proliferation, neovascularization,
apoptosis, and viral infection. Matrix metalloproteinases are zinc metalloenzymes
involved in remodeling of extracellular matrix, and play an important role in cancer
as well as in numerous other disease (
Drug Discovery Today 2001, 6: 478-482
;
Pathol. Oncol. Res. 2001, 7: 14-23
; Molecular Medicine Today 2000, 6:
149-156). It has been proposed that disruption of metalloproteins by iron and zinc
chelators is a key factor in controlling viral and proliferative diseases (
Anticancer
Res. 2001, 21, 931-958).
Various hydroxamates have been synthesized and studied as metalloproteinase
inhibitors (MMPIs) for the treatment of cancer and other diseases (
Chem. Rev.
1999, 99: 2735-2776
; Oncology 2001, 15 (7, suppl.): 39-46
; J. National
Can. Res. 2001, 93: 178-193
; Current Med. Chem. 2001, 8: 425-474
;
Expert Opin. Ther. Patents 2002, 12: 29-43). A recent U.S. patent (U.S. Pat.
No. 6,232,340) discloses vanadium(V) complexes of 3-hydroxy-4-pyrones and N-alkyl
3-hydroxy-4-pyridinones as anti-proliferative and antimetastatic agents. It is
not clear if the anti-proliferative and antimetastatic activity is due to the vanadium(V)
complexes or from the dissociated chelator (3-hydroxy-4-pyrones or 3-hydroxy-4-pyridinones).
However, it is known that Deferiprone (1,2-dimethyl-3-hydroxy-4-pyridinone) binds
Zn(II) with high affinity with Log K
ZnL/[Zn][L]=7.19 (
Inorg. Chem.
Acta 1992, 191, 57-63), and form very stable bis-ligand Zn(II) complexes (
Polyhedron
2000, 19, 129-135
; Inorg. Chem. 2001, 40, 4384-4388). The Log K
ZnL/[Zn][L]
is about 100-fold higher than that of N-hydroxyacetamide (Log K
ZnL/[Zn][L]<5),
the second smallest hydroxamate. Due to the similarity of 3-hydroxy-4-pyrones and
3-hydroxy-4-pyridinones to hydroxamates, one can envisage that the anti-proliferative
and antimetastatic activity of the reported vanadium(V) complexes is actually due
to MMP inhibition by the dissociated 3-hydroxy-4-pyrones and 3-hydroxy-4-pyridinones.
In this connection, the N-substituted 3-hydroxy-4-pyridinones of this invention
have the potential as MMP inhibitors useful for the treatment of cancer and many
other diseases.
Bidentate N-substituted 3-hydroxy-4-pyridinones of this invention have
low molecular weight (<400 Dalton), and are expected to form neutral vanadium chelate
with a fair degree of resistance to hydrolysis. The lipophilicity of the vanadium
chelates can be tuned by varying substituents on both the pyridinone ring and arylsulfonylamido
or arylcarboxylamido group. Like vandium complexes previously described (
J.
Chem. Soc., Dalton Trans. 2000, 2885-2892
; Coord. Chem. Rev. 2001, 219-221:
1033-1053), the vanadium complexes of new N-substituted 3-hydroxy-4-pyridinones
of this invention have the potential to be used as insulin enhancing agents.
Nuclear magnetic resonance (NMR) is based on the absorption of radio-frequency
energy by the magnetic moment of atomic nuclei in samples placed in a strong magnetic
field. Magnetic resonance imaging (MRI) of the human body relies mainly on the
detection of most abundant type of nuclei, the hydrogen in water (and to some extent,
fat). For discrimination of healthy and diseased tissues, adequate contrast is
essential. Such contrast depends not only on differences in water concentration,
but also on the NMR relaxation times T
1 and T
2, which in
turn are related to local mobility and interactions. MRI has become a widely accepted
imaging modality for a variety of diseases. The availability of MRI devices has
led to the use of MRI for the diagnosis of disease states and other internal abnormalities.
Compared to other imaging modalities, MRI provides superior spatial resolution
in tissues, and is safe due to the absence of exposure to X-rays or gamma radiation.
The continued use and rapid development of MRI has stimulated interest in the
development of MRI contrast agents. MRI contrast agents increase both 1/T
1
and 1/T
2 to varying degrees depending on their nature as well as the
applied magnetic field, and are used to improve diagnosis of disease by changing
tissue signal intensity. Most MRI contrast agents commercially available or under
clinical investigations are metal chelates containing paramagnetic metal ions,
such as Fe
3+, Gd
3+, and Mn
2+. Agents such as gadolinium
chelates are best visualized using T
1-weighted images since the percentage
change in 1/T
1 in tissue is much greater than that in 1/T
2 (Caravan,
P. et al.
Chem. Rev. 1999, 99, 2293-2352). Iron-oxide particles generally
lead to a much larger increase in 1/T
2 than in 1/T
1 and are
best seen with in T
2-weighted scans. The metal chelates have proved
to be exceptionally well-tolerated class of contrast media. In particular, gadolinium
MRI contrast agents do not show any nephrotoxicity in contrast to iodinated contrast
media for CT (Runge, V. M.
J. Magn. Reson. Imaging 2000, 12, 205-213).
There are three basic interactions between the metal ion and water molecules
(U.S. Pat. No. 6,294,152). In an inner-sphere interaction, water molecules bind
to and exchange with the metal ion, for a very effective contact. In an outer-sphere
interaction, all the coordination sites of the metal ion are occupied by chelator(s)
so that the water molecules are affected only through translational diffusion past
the paramagnetic metal center. In the second-sphere interaction, the metal ion
is wrapped with a set of donor atoms of a chelator or chelators, which form strong
hydrogen binding with surrounding water molecules.
Mn
2+ ion, which may conveniently be used in the form of
its salt or chelates, has been proposed as an MRI contrast agent due to the five
unpaired electrons in its d-orbitals. Manganese chelates, such as Mn(DPDP) (Teslascan™,
Nycomed Amersham PL), Mn(DTPA), Mn(EDTA), Mn(TPPS
4) and their derivatives,
have been used as MRI contrast agents for detection of liver diseases, cancer,
and cardiovascular diseases. Paramagnetic metal chelates are safe as MRI contrast
agents due to limited presence of free metal ion in the blood stream. Unfortunately,
metal chelates also demonstrate reduced solution relativity relative to free metal
ions due to replacement of coordinated water molecules by a chelator. Unlike the
free metal ion, these manganese chelates are not known to bind endogenous macromolecules
such as albumin. As a consequence, the dosage for metal chelates is much higher
than that for the free Mn
2+ ion.
Manganese(II) chloride has been proposed as an MRI contrast agent using
intravenous injection. Indeed, even at very low i.v. dosages (5-10 μM/kg)
manganese has been found to be particularly effective as a contrast agent for imaging
liver. However, manganese salts, when administered intravenously as a contrast
agent, may be teratogenic at clinical doses, and are known to interfere with the
normal functioning of the heart by replacing calcium in the calcium pump of the heart.
In order to reduce the direct effect on the heart, oral administration of maganese(II)
chloride as a liver imaging agent has been proposed (U.S. Pat. Nos. 5,525,326 and
5,716,598). This ensures the passage of the contrast agent through the liver before
entering heart. Although orally administered maganese(II) chloride is not teratogenic,
the absorption of maganese(II) chloride through the gut is poor. As a result, the
dosage required for clinical efficacy is of the order of 200 μM/kg. Such
a high dosage will result in adverse cardiac effects.
International Publication Nos. WO 96/05867 and WO 97/02842, and U.S.
Pat. Nos. 5,525,326 and 5,716,598 disclose an contrast media comprising a physiologically
tolerable manganese compound, an uptake promoter and a physiologically tolerable
carrier or exipient, having a manganese concentration of at least 0.3 mM or being
in a dosage unit form containing at least 0.3 mM manganese. The uptake promoter
is capable of enhancing manganese transport across the membranes of the gastrointestinal
(GI) tract. Compounds which have been found to be suitable for use as uptake promoters
include reducing compounds containing an α-hydroxy ketone (-C(OH)-CO-) group,
acids containing α- and/or β-hydroxy or amino groups, as well as vitamin
D. The preferred α-hydroxy ketones include ascorbic acid, kojic acid, gluconic
acid and salicylic acid. The uptake promoters most likely act as weak chelators
for Mn
2+ to form a spectrum of Mn
2+ containing species, which
have better GI uptake when administered orally. The disclosed contrast media are
particularly suitable for imaging of the liver.
Mn
2+ has an ionic radius similar to that of Ca
2+,
and is handled similarly in many biological systems (
Circ. Res. 1980, 47:
721-727). For example, Mn
2+ is known to enter cardiac myocytes through
voltage-gated calcium channels (
Brain Res. 1990, 510: 289-295; (
Cell
Calcium 1993, 14: 33-44). Therefore, it has been proposed to use Mn
2+-containing
contrast media to image heart (
Magnetic Resonance in Medicine 2001, 46:
884-890; International Publication No. WO 96/05867, U.S. Pat. Nos. 5,525,326 and
5,716,598). However, the use of a high dosage of Mn
2+ often results
in cardiac toxicity due to replacement of calcium by manganese. To avoid the problem,
Mn
2+-containing contrast media comprising a mixture of Mn
2+/Ca
2+
salts have been proposed (U.S. Pat. No. 5,980,863). The disclosed counter anions
include acetate, gluconate, gluceptate, or lactate. Ascorbic acid has been used
as antioxidant to stabilize Mn
2+ in biological systems.
Fe
3+ also has five unpaired electrons in its d-orbitals.
Fe
3+ metal ions, which interact with water molecules by inner-sphere
mechanism, are very effective for the enhancement of relaxation rate; but high
dosage of the free metal ion often causes toxicity due to iron overload. The use
of iron chelates reduces the toxicity; but the outer-sphere interaction is less
effective in providing relaxation rate enhancement. International Publication No.
WO 91/12822 discloses preparation of Fe 3+ and Mn
2+ complexes of 3-hydroxy-4-pyridinones
useful as MRI contrast agents. U.S. Pat. No. 6,294,152 discloses Fe
3+
complexes of 3-hydroxy-4-pyridinones useful as MRI contrast agents. In all the
cases, substituents on the pyridinone ring contain various hydrogen-binding functionalities,
which are required for effective second-sphere interactions with surrounding water
molecules, thereby enhancement of relaxation rate.
Synthesis of lanthanide complexes of 3-hydroxy-4-pyrones, including maltol
and kojic acid, was previously reported (
J. Inorg. Nucl. Chem. 1975, 37:
1801-1802). The lanthanide, particularly Gd
3+, chelates of N-substituted
3-hydroxy-4-pyridinones of this invention are useful as MRI contrast agents via
inner-sphere mechanism. Due to their large size, the coordination numbers of lanthanide
metal ions are typically 8 and 9. In solution, six coordination sites of Gd
3+
are occupied by three bidentate N-substituted 3-hydroxy-4-pyridinones while the
remaining sites are available for water molecules to provide relaxation enhancement.
Fe
3+ and Mn
2+ chelates of N-substituted 3-hydroxy-4-pyridinones
are useful as MRI contrast agents via outer-sphere or second-sphere mechanism since
they contain a dialkylamino or acylamido or sulfonylamido group, the nitrogen-
or oxygen-heteroatoms of which can be used to form strong hydrogen bonds with surrounding
water molecules. On the other hand, Fe
3+ and Mn
2+ chelates
can be partially dissociated in biological systems to form Fe
3+ and
Mn
2+ containing species, which may interact with water molecules via
an inner-sphere mechanism.
The Ga-67, Tc-99m and In-111 chelates of N-substituted 3-hydroxy-4-pyridinones
of this invention are useful as diagnostic radiopharmaceuticals for scintigraphic
imaging. Tc-99m complexes of N-alkyl-3-hydroxypyridin-4-ones have been studied
as potential radiopharmaceuticals for imaging kidney (
Nucl. Med. Biol. 1993,
20, 857-863
; Inorg. Chem. 1994, 33, 5607-5679) while Ga-67 complexes for
imaging heart (
Nucl. Med. Biol. 1992, 19: 327-335). In-111 complexes of
N-alkyl-3-hydroxypyridin-4-ones have been used for white blood cell labeling (
J.
Med. Chem. 1996, 39: 3659-3670
; Eur. J. Nucl. Med. 1999, 26: 1400-1406).
According to one embodiment (1) of the invention, an N-substituted 3-hydroxy-4-pyridinone
compound is provided, having the following formula:
##STR1##
and a pharmaceutically acceptable salt thereof, wherein:
- X is selected from the group: CH2, C(O), C(S), P(O)R3R4,
SO2, C(═NH)NH, C(O)NH, and C(S)NH;
- R1 and R2 are independently selected from: H,
C1
