U.S. patent number RE34,313 [Application Number 07/769,492] was granted by the patent office on 1993-07-13 for pharmaceutical compositions.
This patent grant is currently assigned to National Research Development Corporation. Invention is credited to Robert C. Hider, George Kontoghiorghes, Jack Silver, Michael A. Stockham.
United States Patent |
RE34,313 |
Hider , et al. |
July 13, 1993 |
Pharmaceutical compositions
Abstract
Compounds which are a 1-hydroxypyrid-2-one in which one or more
of the hydrogen atoms attached to ring carbon atoms are replaced by
a substituent selected from aliphatic acyl, aliphatic amide,
aliphatic amine, carboxy, cyano, aliphatic ester, halogen, hydroxy
and sulpho groups, alkoxy groups and alkoxy groups substituted by
an alkoxy, aliphatic amide, aliphatic amine, aliphatic ester,
halogen or hydroxy group, aliphatic hydrocarbon groups and
aliphatic hydrocarbon groups substituted by an alkoxy, aliphatic
ester, halogen or hydroxy group, but excluding compounds in which
said replacement of hydrogen atoms in the compound is effected only
by substituents selected from aliphatic hydrocarbon groups, halogen
groups and aliphatic hydrocarbon groups substituted by a halogen
group, or a salt thereof containing a physiolgically acceptable ion
or ions, are of value in the treatment of patients having a toxic
concentration of a metal, particularly iron, in the body whilst the
iron complexes of such compounds are of value in the treatment of
iron deficiency anaemia.
Inventors: |
Hider; Robert C. (Clacton,
GB2), Kontoghiorghes; George (London, GB2),
Silver; Jack (London, GB2), Stockham; Michael A.
(Saffron Walden, GB2) |
Assignee: |
National Research Development
Corporation (London, GB2)
|
Family
ID: |
27262198 |
Appl.
No.: |
07/769,492 |
Filed: |
October 1, 1991 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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253579 |
Oct 5, 1988 |
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Reissue of: |
651772 |
Sep 18, 1984 |
04587240 |
May 6, 1986 |
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Foreign Application Priority Data
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Sep 23, 1983 [GB] |
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8325496 |
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Current U.S.
Class: |
514/188; 424/646;
514/348; 514/823; 546/2; 546/296; 546/6 |
Current CPC
Class: |
A61K
31/44 (20130101); C07F 15/025 (20130101); C07D
213/89 (20130101) |
Current International
Class: |
A61K
31/44 (20060101); C07F 15/00 (20060101); C07D
213/89 (20060101); C07F 15/02 (20060101); C07D
213/00 (20060101); C07D 213/69 (); A61K
031/555 () |
Field of
Search: |
;514/188,348
;424/10,147,295,646 ;546/2,6,296 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0643504 |
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Jun 1962 |
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CA |
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0093498 |
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EP |
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0094149 |
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EP |
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0138420 |
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JP |
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GB |
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GB |
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2117766 |
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GB |
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2118176 |
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Oct 1983 |
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GB |
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Other References
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Primary Examiner: Griffin; Ronald W.
Attorney, Agent or Firm: Nixon & Vanderhye
Parent Case Text
.Iadd.This is a continuation of application Ser. No. 07/253,579,
filed Oct. 5, 1988, now abandoned which is a Reissue application of
U.S. Pat. No. 4,587,240 issued May 6, 1986. .Iaddend.
Claims
We claim:
1. A method for the treatment of a patient having a toxic
concentration of iron in the body which comprises administering to
said patient a compound being a 1-hydroxypyrid-2-one in which one
or more of the hydrogen atoms attached to ring carbon atoms are
replaced by a substituent selected from aliphatic acyl, aliphatic
amide, cyano, aliphatic ester, halogen and hydroxy groups, alkoxy
groups and alkoxy groups substituted by an alkoxy, aliphatic amide,
aliphatic ester, halogen or hydroxy group, aliphatic hydrocarbon
groups and aliphatic hydrocarbon groups substituted by an alkoxy,
aliphatic ester, halogen or hydroxy group, but excluding compounds
in which said replacement of hydrogen atoms is effected only by
substituents selected from aliphatic hydrocarbon groups, halogen
groups and aliphatic hydrocarbon groups substituted by a halogen
group, or a salt thereof containing a physiologically acceptable
cation in an amount effective to reduce said toxic concentration of
the metal.
2. The method according to claim 1, in which at least one of the
ring carbon atom substituents is a hydroxy, alkoxy or substituted
alkoxy group, or a hydroxy- or alkoxy-substituted aliphatic
hydrocarbon group.
3. The method according to claim 2 in which at least one of the
ring carbon atom substituents is a hydroxy group, an alkoxy group
of 1 to 5 carbon atoms, an alkoxy group of 2 to 4 carbon atoms
substituted by a hydroxy group, or an alkoxy group of 2 to 4 carbon
atoms substituted by an alkoxy group of 1 to 4 carbon atoms, the
total number of carbon atoms in the alkoxyalkoxy group being 3 to
6.
4. The method according to claim 3, in which the ring carbon atoms
of the 1-hydroxypyrid-2-one are substituted by a single one of said
substituents and additionally by one or more aliphatic hydrocarbon
groups of 1 to 4 carbon atoms.
5. The method according to claim 3, in which the ring carbon atoms
of the 1-hydroxypyrid-2-one are substituted only by a single one of
said substituents.
6. The method according to claim 5, in which the single one of said
substituents is located at the 4-position of the
1-hydroxypyrid-2-one.
7. The method according to claim 1, in which the
1-hydroxypyrid-2-one is 1-hydroxy-4-methoxypyrid-2-one,
4-ethoxy-1-hydroxypyrid-2-one, 1,4-dihydroxypyrid-2-one,
1-hydroxy-4-(2'-hydroxyethoxy)-pyrid-2-one,
1-hydroxy-4-(3'-hydroxypyropoxy)-pyrid-2-one or
1-hydroxy-4-(2'-methoxyethoxy)-pyrid-2-one.
8. The method according to claim 1, wherein said at least one
substituent is an alkoxy group substituted by an alkoxy, aliphatic
amide, aliphatic ester, halogen or hydroxy group.[., and wherein at
least one additional hydrogen atom may be substituted by a hydroxy
group.]..
9. The method of claim 8, wherein one of the said hydrogen atoms
attached to the ring carbon atoms of the 1-hydroxypyrid-2-one is
replaced by a C.sub.2-4 alkoxy group substituted by a hydroxy group
or by a C.sub.1-4 alkoxy group, with the total number of carbon
atoms in the alkoxyalkoxy group ranging from 3 to 6, and wherein at
least one more of the said hydrogen atoms can be replaced by an
aliphatic .Iadd.hydrocarbon .Iaddend.group of 1 to 4 carbon
atoms.
10. A method for the treatment of a patient to effect an increase
in the level of iron in the patient's bloodstream which comprises
adminstering to said patient a compound being an iron complex of a
1-hydroxypyrid-2-one in which one or more of the hydrogen atoms
attached to ring carbon atoms are replaced by a substituent
selected from aliphatic acyl, aliphatic amide, cyano, aliphatic
ester, halogen and hydroxy groups, alkoxy groups and alkoxy groups
substituted by an alkoxy, aliphatic amide, aliphatic ester, halogen
or hydroxy group, aliphatic hydrocarbon groups and aliphatic
hydrocarbon groups substituted by an alkoxy, aliphatic ester,
halogen or hydroxy group, but excluding compounds in which said
replacement of hydrogen atoms is effected only by substituents
selected from aliphatic hydrocarbon groups, halogen groups and
aliphatic hydrocarbon groups substituted by a halogen group, in an
amount effective to achieve such an increase.
11. The method according to claim 10, in which at least one of the
ring carbon atom substituents is a hydroxy, alkoxy or substituted
alkoxy, group, or a hydroxy- or alkoxy-substituted aliphatic
hydrocarbon group.
12. The method according to claim 11, in which at least one of the
ring carbon atom substituents is a hydroxy group, an alkoxy group
of 1 to 5 carbon atoms, an alkoxy group of 2 to 4 carbon atoms
substituted by a hydroxy group, or an alkoxy group of 2 to 4 carbon
atoms substituted by an alkoxy group of 1 to 4 carbon atoms, the
total number of carbon atoms in the alkoxyalkoxy group being 3 to
6.
13. The method according to claim 12, in which the ring carbon
atoms of the 1 -hydroxypyrid-2-one are substituted by a single one
of said substituents and additionally by one or more aliphatic
hydrocarbon groups of 1 to 4 carbon atoms.
14. The method according to claim 12, in which the ring carbon
atoms of the 1-hydroxypyrid-2-one are substituted only by a single
one of said substituents.
15. The method according to claim 14 in which the single one of
said substituents is located at the 4-position of the
1-hydroxypyrid-2-one.
16. The method according to claim 10, in which the
1-hydroxypyrid-2-one is 1-hydroxy-4-methoxypyrid-2-one,
4-ethoxy-1-hydroxypyrid-2-one, 1,4-dihydroxypyrid-2-one,
1-hydroxy-4-(2'-hydroxyethoxy)-pyrid-2-one,
1-hydroxy-4-(3'-hydroxypropoxy)-pyrid-2-one or
1-hydroxy-4-(2'-methoxyethoxy)-pyrid-2-one.
17. The method according to claim 16, in which the iron complex is
the neutral 3:1 1-hydroxypyrid-2-one:iron(III) complex.
18. The method according to claim 10, in which the iron complex is
the neutral 3:1 1-hydroxypyrid-2-one:iron(III) complex.
19. A pharmaceutical composition comprising a neutral 3:1
1-hydroxypyrid-2-one:iron(III) complex of a 1-hydroxypyrid-2-one in
which one .[.or more.]. of the hydrogen atoms attached to ring
carbon atoms .[.are.]. .Iadd.is .Iaddend.replaced by a substituent
selected from aliphatic acyl, aliphatic amide, cyano, aliphatic
ester, halogen and hydroxy groups, alkoxy groups and alkoxy groups
substituted by an alkoxy, aliphatic amide, aliphatic ester,
.[.halogen.]. or hydroxy group, .[.aliphatic hydrocarbon groups.].
and aliphatic hydrocarbon groups substituted by an alkoxy,
aliphatic ester, .[.halogen.]. or hydroxy group, .[.but excluding
compounds in which said replacement of hydrogen atoms is effected
only by substituents selected from aliphatic hydrocarbon groups,
halogen groups and aliphatic hydrocarbon groups substituted by a
halogen group,.]. together with a physiologically acceptable
diluent or carrier.
20. The pharmaceutical composition according to claim 19, which
comprises a sterile, pyrogen-free diluent.
21. The pharmaceutical composition according to claim 19 which
comprises a solid carrier.
22. The pharmaceutical composition according to claim 21 which is
adapted to release of the iron complex in the intestine rather than
in the stomach.
23. The pharmaceutical composition according to claim 19 in unit
dosage form.
24. The pharmaceutical composition according to claim 19, in which
.[.at least one of.]. the ring carbon atom .[.substituents.].
.Iadd.substituent .Iaddend.is a hydroxy group, an alkoxy group of 1
to 5 carbon atoms, an alkoxy group of 2 to 4 carbon atoms
substituted by a hydroxy group, or an alkoxy group of 2 to 4 carbon
atoms substituted by an alkoxy group of 1 to 4 carbon atoms, the
total number of carbon atoms in the alkoxyalkoxy group being 3 to
6.
25. A compound being a neutral 3:1 1-hydroxypyrid-2-one:iron (III)
complex of a 1-hydroxypyrid-2-one in which one .[.or more.]. of the
hydrogen atoms attached to ring carbon atoms .[.are.]. .Iadd.is
.Iaddend.replaced by a substituent selected from aliphatic acyl,
aliphatic amide, cyano, aliphatic ester, halogen and hydroxy
groups, alkoxy groups and alkoxy groups substituted by an alkoxy,
aliphatic amide, aliphatic ester, .[.halogen.]. or hydroxy group,
.[.aliphatic hydrocarbon groups.]. and aliphatic hydrocarbon groups
substituted by an alkoxy, aliphatic ester, .[.halogen.]. or hydroxy
group .[.but excluding compounds in which said replacement of
hydrogen atoms is effected only by substituents selected from
aliphatic hydrocarbon groups, halogen groups and aliphatic
hydrocarbon groups substituted by a halogen group.]..
26. The compound according to claim 25, in which .[.at least one of
the ring carbon atom substituents.]. .Iadd.the ring carbon atom
substituent .Iaddend.is a hydroxy, alkoxy, substituted alkoxy, or
hydroxy- or alkoxy-substituted aliphatic hydrocarbon group.
27. The compound according to claim 26, in which .[.at least one of
the ring carbon atom substituents.]. .Iadd.the ring carbon atom
substituent .Iaddend.is a hydroxy group, an alkoxy group of 1 to 5
carbon atoms, an alkoxy group of 2 to 4 carbon atoms substituted by
a hydroxy group or an alkoxy group of 2 to 4 carbon atoms
substituted by an alkoxy group of 1 to 4 carbon atoms, the total
number of carbon atoms in the alkoxyalkoxy group being 3 to 6.
.[.
28. The compound according to claim 27, in which the ring carbon
atoms of the 1-hydroxypyrid-2-one are substituted by a single one
of said substituents and additionally by one or more aliphatic
hydrocarbon groups of 1 to 6 carbon atoms..]. .[.29. The compound
according to claim 27, in which the ring carbon atoms of the
1-hydroxypyrid-2-one are substituted
only by a single one of said substituents..]. 30. The compound
according to claim .[.29.]. .Iadd.27.Iaddend., in which the
.[.single one of.]. said .[.substituents.]. .Iadd.substituent
.Iaddend.is located at the 4-position
of the 1-hydroxypyrid-2-one. 31. The compound according to claim
30, in which the 1-hydroxypyrid-2-one is
1-hydroxy-4-methoxypyrid-2-one, 4-ethoxy-1-hydroxy-pyrid-2-one,
1,4-dihydroxypyrid-2-one,
1-hydroxy-4-(2-(2'-hydroxyethoxy)pyrid-2-one,
1-hydroxy-4-(3'-hydroxypropoxy)-pyrid-2-one or
1-hydroxy-4-(2'-methoxyethoxy)-pyrid-2-one. .Iadd.32. A
pharmaceutical composition, comprising a neutral 3:1
1-hydroxypyrid-2-one:iron(III) complex of a 1-hydroxypyrid-2-one in
which one or more of the hydrogen atoms attached to ring carbon
atoms are replaced by a substituent selected from aliphatic acyl,
aliphatic amide, cyano, aliphatic ester, halogen and hydroxy
groups, alkoxy groups and alkoxy groups substituted by an alkoxy,
aliphatic amide, aliphatic ester, halogen or hydroxy group,
aliphatic hydrocarbon groups and aliphatic hydrocarbon groups
substituted by an alkoxy, aliphatic ester, halogen or hydroxy
group, but excluding compounds in which said replacement of
hydrogen atoms is effected only by substituents selected from
aliphatic hydrocarbon groups, halogen groups and aliphatic
hydrocarbon groups substituted by a halogen group, together with a
physiologically acceptable diluent or carrier, wherein said
composition is adapted to release of the iron complex in the
intestine
rather than the stomach. .Iaddend. .Iadd.33. A pharmaceutical
composition comprising a neutral 3:1 1-hydroxypyrid-2-one:iron(III)
complex of a 1-hydroxypyrid-2-one in which one or more of the
hydrogen atoms attached to ring carbon atoms are replaced by a
substituent selected from aliphatic acyl, aliphatic amide, cyano,
aliphatic ester, halogen and hydroxy groups, C.sub.2-5 alkoxy
groups and alkoxy groups substituted by a alkoxy, aliphatic amide,
aliphatic ester, halogen or hydroxy group, aliphatic hydrocarbon
groups and aliphatic hydrocarbon groups substituted by an alkoxy,
aliphatic ester, halogen or hydroxy group, but excluding compounds
in which said replacement of hydrogen atoms is effected only by
substituents selected from aliphatic hydrocarbon groups, halogen
groups and aliphatic hydrocarbon groups substituted by a halogen
group, together with a physiologically acceptable solid carrier.
.Iaddend. .Iadd.34. A pharmaceutical composition comprising a
neutral 3:1 1-hydroxypyrid-2-one in which one or more of the
hydrogen atoms attached to ring carbon atoms are replaced by a
substituent selected from aliphatic acyl, aliphatic amide, cyano,
aliphatic ester, halogen and hydroxy groups, C.sub.2-5 alkoxy
groups and alkoxy groups substituted by an alkoxy, aliphatic amide,
aliphatic ester, halogen or hydroxy group, aliphatic hydrocarbon
groups and aliphatic hydrocarbon groups substituted by an alkoxy,
aliphatic ester, halogen or hydroxy group, but excluding compound
in which said replacement of hydrogen atoms is effected only by
substituents selected from aliphatic hydrocarbon groups, halogen
groups and aliphatic hydrocarbon groups substituted by a halogen
group, together with a physiologically acceptable diluent or
carrier, wherein said composition is adapted to release of the iron
complex in the intestine rather than in the stomach. .Iaddend.
.Iadd.35. A pharmaceutical composition comprising a neutral 3:1
1-hydroxypyrid-2-one:iron(III) complex of a 1-hydroxypyrid-2-one in
which one or more of the hydrogen atoms attached to the ring carbon
atoms are replaced by a substituent selected from aliphatic acyl,
aliphatic amide, cyano, aliphatic ester, halogen and hydroxy
groups, C.sub.2-5 alkoxy groups and alkoxy groups substituted by an
alkoxy, aliphatic amide, aliphatic ester, halogen or hydroxy group,
aliphatic hydrocarbon groups and aliphatic hydrocarbon groups
substituted by an alkoxy, aliphatic ester, halogen or hydroxy
group, at least one of the ring carbon atom substituents being a
hydroxy group, an alkoxy group of 2 to 5 carbon atoms, an alkoxy
group of 2 to 4 carbon atoms substituted by a hydroxy group, or an
alkoxy group of 2 to 4 carbon atoms substituted by an alkoxy group
of 1 to 4 carbon atoms, the total number of carbon atoms in the
alkoxyalkoxy group being 3 to 6, together with a physiologically
acceptable diluent or carrier. .Iaddend. .Iadd.36. A pharmaceutical
composition comprising a neutral 3:1 1-hydroxypyrid-2-one:iron(III)
complex of a 1-hydroxypyrid-2-one in which one or more of the
hydrogen atoms attached to the ring carbon atoms are replaced by a
substituent selected from aliphatic acyl, aliphatic amide, cyano,
aliphatic ester, halogen and hydroxy groups, alkoxy groups and
alkoxy groups substituted by an alkoxy, aliphatic amide, aliphatic
ester, halogen or hydroxy group, C.sub.2-6 aliphatic hydrocarbon
groups and aliphatic hydrocarbon groups substituted by an alkoxy,
aliphatic ester, halogen or hydroxy group, but excluding compounds
in which said replacement of hydrogen atoms is effected only by
substituents selected from aliphatic hydrocarbon groups, halogen
groups and aliphatic hydrocarbon groups substituted by a halogen
group, together with a
physiologically acceptable solid carrier. .Iaddend. .Iadd.37. The
pharmaceutical composition according to claim 36 which is adapted
to release of the iron complex in the intestine rather than in the
stomach.
.Iaddend. .Iadd.38. A pharmaceutical composition comprising a
neutral 3:1 1-hydroxypyrid-2-one:iron(III) complex of a
1-hydroxypyrid-2-one in which one or more of the hydrogen atoms
attached to the ring carbon atoms are replaced by a substituent
selected from aliphatic acyl, aliphatic amide, cyano, aliphatic
ester, halogen and hydroxy groups, alkoxy groups and alkoxy groups
substituted by an alkoxy, aliphatic amide, aliphatic ester, halogen
or hydroxy group, C.sub.2-6 aliphatic hydrocarbon groups and
aliphatic hydrocarbon groups substituted by an alkoxy, aliphatic
ester, halogen or hydroxy group, at least one of the ring carbon
atoms substituents being a hydroxy group, an alkoxy group of 1 to 5
carbon atoms, an alkoxy group of 2 to 4 carbon atoms substituted by
a hydroxy group, or an alkoxy group of 2 to 4 carbon atoms
substituted by an alkoxy group of 1 to 4 carbon atoms, the total
number of carbon atoms in the alkoxyalkoxy group being 3 to 6,
together with a physiologically acceptable diluent or carrier.
.Iaddend. .Iadd.39. A compound being a neutral 3:1
1-hydroxypyrid-2-one:iron(III) complex of a 1-hydroxypyrid-2-one in
which one or more of the hydrogen atoms attached to the ring carbon
atoms are replaced by a substituent selected from aliphatic acyl,
aliphatic amide, cyano, aliphatic ester, halogen and hydroxy
groups, C.sub.2-5 alkoxy groups and alkoxy groups substituted by an
alkoxy, aliphatic amide, aliphatic ester, halogen or hydroxy group,
aliphatic hydrocarbon groups and aliphatic hydrocarbon groups
substituted by an alkoxy, aliphatic ester, halogen or hydroxy
group, at least one of the ring carbon atom substituents being a
hydroxy, alkoxy, substituted alkoxy, or hydroxy- or
alkoxy-substituted aliphatic hydrocarbon group.
.Iaddend. .Iadd.40. The compound according to claim 38, in which at
least one of the ring carbon atom substituents is a hydroxy group,
an alkoxy group of 2 to 5 carbon atoms, an alkoxy group of 2 to 4
carbon atoms substituted by a hydroxy group, or an alkoxy group of
2 to 4 carbon atoms substituted by an alkoxy group of 1 to 4 carbon
atoms, the total number of
carbon atoms in the alkoxyalkoxy group being 3 to 6. .Iaddend.
.Iadd.41. The compound according to claim 40, in which the ring
carbon atoms of the 1-hydroxypyrid-2-one are substituted by a
single one of said substituents and additionally by one or more
aliphatic hydrocarbon groups of 1 to 6 carbon atoms. .Iaddend.
.Iadd.42. The compound according to claim 40, in which the ring
carbon atoms of the 1-hydroxypyrid-2-one are substituted only by a
single one of said substituents. .Iaddend. .Iadd.43. The compound
according to claim 42, in which the single one of said substituents
is located at the 4-position of the 1-hydroxypyrid-2-one.
.Iaddend. .Iadd.44. A compound being a neutral 3:1
1-hydroxypyrid-2-one:iron (III) complex of a 1-hydroxypyrid-2-one
in which one or more of the hydrogen atoms attached to ring carbon
atoms are replaced by a substituent selected from aliphatic acyl,
aliphatic amide, cyano, aliphatic ester, halogen and hydroxy
groups, alkoxy groups and alkoxy groups substituted by an alkoxy,
aliphatic amide, aliphatic ester, halogen or hydroxy group,
C.sub.2-6 aliphatic hydrocarbon groups and aliphatic hydrocarbon
groups substituted by an alkoxy, aliphatic ester, halogen or
hydroxy group, at least one of the ring carbon atom substituents
being a hydroxy, alkoxy, substituted alkoxy, or hydroxy- or
alkoxy-substituted aliphatic hydrocarbon group. .Iaddend. .Iadd.45.
The compound according to claim 44, in which at least one of the
ring carbon atom substituents is a hydroxy group, an alkoxy group
of 1 to 5 carbon atoms, an alkoxy group of 2 to 4 carbon atoms
substituted by a hydroxy group, or an alkoxy group of 2 to 4 carbon
atoms substituted by an alkoxy group of 1 to 4 carbon atoms, the
total number of carbon atoms in the
alkoxyalkoxy group being 3 to 6. .Iaddend. .Iadd.46. The compound
according to claim 45, in which the ring carbon atoms of the
1-hydroxypyrid-2-one are substituted by a single one of said
substituents and additionally by one or more aliphatic hydrocarbon
groups of 2 to 6 carbon atoms. .Iaddend. .Iadd.47. The compound
according to claim 45, in which the ring carbon atoms of the
1-hydroxypyrid-2-one are substituted only by a single one of said
substituents. .Iaddend. .Iadd.48. The compound according to claim
47, in which the single one of said substituents is located at the
4-position of the 1-hydroxypyrid-2-one. .Iaddend. .Iadd.49. The
pharmaceutical composition according to claim 32, which comprises a
sterile, pyrogen-free diluent. .Iaddend. .Iadd.50. The
pharmaceutical composition according to claim 32 which comprises a
solid carrier. .Iaddend. .Iadd.51. The pharmaceutical composition
according to claim 32, in which at least one of the ring carbon
atom substituents is a hydroxy group, an alkoxy group of 1 to 5
carbon atoms, an alkoxy group of 2 to 4 carbon atoms substituted by
a hydroxy group or an alkoxy group of 2 to 4 carbon atoms
substituted by an alkoxy group of 1 to 4 carbon atoms, the total
number of carbon atoms in the alkoxyalkoxy group being 3 to 6.
.Iaddend. .Iadd.52. A compound being a neutral 3:1
1-hydroxypyrid-2-one:iron(III) complex of a 1-hydroxypyrid-2-one of
the formula ##STR8## wherein one of the hydrogen atoms attached to
ring carbon atoms is
replaced by an aliphatic amide substituent. .Iaddend. .Iadd.53. The
compound of claim 52, wherein one of said hydrogen atoms attached
to ring carbon atoms is replaced by an aliphatic amide of the
formula --CONH.sub.2 or a group --CONH.sub.2 wherein one or more of
the hydrogen atoms of this group is replaced by a C.sub.1-3
aliphatic hydrocarbon group. .Iaddend. .Iadd.54. The compound of
claim 52, wherein one of said hydrogen atoms attached to ring
carbon atoms is replaced by an aliphatic amide of the formula
--CONH.sub.2 or --CONHCH.sub.3. .Iaddend. .Iadd.55. The
pharmaceutical composition of claim 32 in which more than one
hydrogen atom attached to ring carbon atoms are replaced by one of
said
substituent. .Iaddend. .Iadd.56. A pharmaceutical composition
comprising a neutral 3:1 1-hydropyrid-2-one:iron (III) complex of a
1-hydroxypyrid-2-one in which one or more of the hydrogen atoms
attached to ring carbon atoms are replaced by a substituent
selected from aliphatic acyl, aliphatic amide, cyano, aliphatic
ester, halogen and hydroxy groups, C.sub.2-5 alkoxy groups and
alkoxy groups substituted by an alkoxy, aliphatic amide, aliphatic
ester, halogen or hydroxy group, aliphatic hydrocarbon groups and
aliphatic hydrocarbon groups substituted by an alkoxy, aliphatic
ester, halogen or hydroxy group, but excluding compounds in which
said replacement of hydrogen atoms is effected only by substituents
selected from aliphatic hydrocarbon groups, halogen groups and
aliphatic hydrocarbon groups substituted by a halogen group,
together with a physiologically acceptable diluent or carrier.
.Iaddend. .Iadd.57. A pharmaceutical composition comprising a
neutral 3:1 1-hydropyrid-2-one:iron (III) complex of a
1-hydroxypyrid-2-one in which one or more of the hydrogen atoms
attached to ring carbon atoms are replaced by a substituent
selected from aliphatic acyl, aliphatic amide, cyano, aliphatic
ester, halogen and hydroxy groups, alkoxy groups and alkoxy groups
substituted by an alkoxy, aliphatic amide, aliphatic ester, halogen
or hydroxy group, C.sub.2-6 aliphatic hydrocarbon groups and
aliphatic hydrocarbon groups substituted by an alkoxy, aliphatic
ester, halogen or hydroxy group, but excluding compounds in which
said replacement of hydrogen atoms is effected only by substituents
selected from aliphatic hydrocarbon groups, halogen groups and
aliphatic hydrocarbon groups substituted by a halogen group,
together with a physiologically acceptable diluent or carrier.
.Iaddend. .Iadd.58. A compound being a neutral 3:1
1-hydroxypyrid-2-one:iron (III) complex of a 1-hydroxypyrid-2-one
in which one or more of the hydrogen atoms attached to ring carbon
atoms are replaced by a substituent selected from aliphatic acyl,
aliphatic amide, cyano, aliphatic ester, halogen and hydroxy
groups, C.sub.2-5 alkoxy groups and alkoxy groups substituted by an
alkoxy, aliphatic amide, aliphatic ester, halogen or hydroxy group,
aliphatic hydrocarbon groups and aliphatic hydrocarbon groups
substituted by an alkoxy, aliphatic ester, halogen or hydroxy
group, at least one of the ring carbon atom substituents being a
hydroxy, alkoxy, substituted alkoxy, or hydroxy- or
alkoxy-substituted aliphatic hydrocarbon group. .Iaddend. .Iadd.59.
A compound being a neutral 3:1 1-hydroxypyrid-2-one:iron (III)
complex of a 1-hydroxypyrid-2-one in which one or more of the
hydrogen atoms attached to ring carbon atoms are replaced by a
substituent selected from aliphatic acyl, aliphatic amide, cyano,
aliphatic ester, halogen and hydroxy groups, alkoxy groups and
alkoxy groups substituted by an alkoxy, aliphatic amide, aliphatic
ester, halogen or hydroxy group, C.sub.2-6 aliphatic hydrocarbon
groups and aliphatic hydrocarbon groups substituted by an alkoxy,
aliphatic ester, halogen or hydroxy group, at least one of the ring
carbon atom substituents being a hydroxy, alkoxy, substituted
alkoxy, or hydroxy- or alkoxy-substituted aliphatic hydrocarbon
group.
.Iaddend. .Iadd.60. A pharmaceutical composition, comprising a
neutral 3:1 1-hydropyrid-2-one:iron (III) complex of a
1-hydroxypyrid-2-one in which one or more of the hydrogen atoms
attached to ring carbon atoms are replaced by a substituent
selected from aliphatic acyl, cyano, aliphatic ester, halogen and
hydroxy groups, alkoxy groups and alkoxy groups substituted by an
alkoxy, aliphatic amide, aliphatic ester, halogen or hydroxy group,
aliphatic hydrocarbon groups and aliphatic hydrocarbon groups
substituted by an alkoxy, aliphatic ester, halogen or hydroxy
group, but excluding compounds in which said replacement of
hydrogen atoms is effected only by substituents selected from
aliphatic hydrocarbon groups, halogen groups and aliphatic
hydrocarbon groups substituted by a halogen group, together with a
physiologically acceptable diluent or carrier, wherein said
composition is adapted to release of the iron complex in the
intestine rather than the stomach. .Iaddend. .Iadd.61. A
pharmaceutical composition comprising a neutral 3:1
1-hydropyrid-2-one:iron (III) complex of a 1-hydroxypyrid-2-one in
which one or more of the hydrogen atoms attached to ring carbon
atoms are replaced by a substituent selected from aliphatic acyl,
cyano, aliphatic ester, halogen and hydroxy groups, C.sub.2-5
alkoxy groups and alkoxy groups substituted by an alkoxy, aliphatic
amide, aliphatic ester, halogen or hydroxy group, aliphatic
hydrocarbon groups and aliphatic hydrocarbon groups substituted by
an alkoxy, aliphatic ester, halogen or hydroxy group, but excluding
compounds in which said replacement of hydrogen atoms is effected
only by substituents selected from aliphatic hydrocarbon groups,
halogen groups and aliphatic hydrocarbon groups substituted by a
halogen group, together with a physiologically acceptable diluent
or carrier. .Iaddend. .Iadd.62. A pharmaceutical composition
comprising a neutral 3:1 1-hydropyrid-2-one:iron (III) complex of a
1-hydroxypyrid-2-one in which one or more of the hydrogen atoms
attached to ring carbon atoms are replaced by a substituent
selected from aliphatic acyl, cyano, aliphatic ester, halogen and
hydroxy groups, alkoxy groups and alkoxy groups substituted by an
alkoxy, aliphatic amide, aliphatic ester, halogen or hydroxy group,
C.sub.2-6 aliphatic hydrocarbon groups and aliphatic hydrocarbon
groups substituted by an alkoxy, aliphatic ester, halogen or
hydroxy group, but excluding compounds in which said replacement of
hydrogen atoms is effected only by substituents selected from
aliphatic hydrocarbon groups, halogen groups and aliphatic
hydrocarbon groups substituted by a halogen group, together with a
physiologically acceptable diluent or carrier. .Iaddend. .Iadd.63.
A compound being a neutral 3:1 1-hydropyrid-2-one:iron (III)
complex of a 1-hydroxypyrid-2-one in which one or more of the
hydrogen atoms attached to ring carbon atoms are replaced by a
substituent selected from aliphatic acyl, cyano, aliphatic ester,
halogen and hydroxy groups, C.sub.2-5 alkoxy groups and alkoxy
groups substituted by an alkoxy, aliphatic amide, aliphatic ester,
halogen or hydroxy group, aliphatic hydrocarbon groups and
aliphatic hydrocarbon groups substituted by an alkoxy, aliphatic
ester, halogen or hydroxy group, but excluding compounds in which
said replacement of hydrogen atoms is effected only by substituents
selected from aliphatic hydrocarbon groups, halogen groups and
aliphatic hydrocarbon groups substituted by a halogen group.
.Iaddend. .Iadd.64. A compound being a neutral 3:1
1-hydropyrid-2-one:iron (III) complex of a 1-hydroxypyrid-2-one in
which one or more of the hydrogen atoms attached to ring carbon
atoms are replaced by a substituent selected from aliphatic acyl,
cyano, aliphatic ester, halogen and hydroxy groups, alkoxy groups
and alkoxy groups substituted by an alkoxy, aliphatic amide,
aliphatic ester, halogen or hydroxy group, C.sub.2-6 aliphatic
hydrocarbon groups and aliphatic hydrocarbon groups substituted by
an alkoxy, aliphatic ester, halogen or hydroxy group, but excluding
compounds in which said replacement of hydrogen atoms is effected
only by substituents selected from aliphatic hydrocarbon groups,
halogen groups and aliphatic hydrocarbon groups substituted by a
halogen group. .Iaddend. .Iadd.65. The method according to claim 8,
wherein at least one additional hydrogen atom is substituted by an
hydroxy group. .Iaddend. .Iadd.66. A pharmaceutical composition
comprising a neutral 3:1 1-hydropyrid-2-one:iron (III) complex of a
1-hydroxypyrid-2-one in which one or more of the hydrogen atoms
attached to ring carbon atoms are replaced by a substituent
selected from aliphatic acyl, aliphatic amide, cyano, aliphatic
ester, halogen and hydroxy groups, alkoxy groups and alkoxy groups
substituted by an alkoxy, aliphatic amide, aliphatic ester, halogen
or hydroxy group, aliphatic hydrocarbon groups and aliphatic
hydrocarbon groups substituted by an alkoxy, aliphatic ester,
halogen or hydroxy group, but excluding compounds in which said
replacement of hydrogen atoms is effected only by substituents
selected from aliphatic hydrocarbon groups, halogen groups and
aliphatic hydrocarbon groups substituted by a halogen group,
wherein at least one substituent is an alkoxy group substituted by
an alkoxy, aliphatic amide, aliphatic ester, halogen or hydroxy
group, together with a physiologically acceptable diluent or
carrier. .Iaddend. .Iadd.67. A pharmaceutical composition according
to claim 66, wherein the 1-hydroxypyrid-2-one contains one of said
substituted alkoxy group substituents and can contain one or more
substituents which are an aliphatic hydrocarbon group. .Iaddend.
.Iadd.68. A pharmaceutical composition according to claim 67,
wherein one or more of the hydrogen atoms attached to the ring
carbon atoms is replaced by a C.sub.2-4 alkoxy group substituted
either by a hydroxy group or by a C.sub.1-4 alkoxy group, with the
total number of carbon atoms in the alkoxyalkoxy group ranging from
3 to 6, and wherein at least one more of the said hydrogen atoms
can be replaced by an aliphatic hydrocarbon group of 1 to 4 carbon
atoms. .Iaddend. .Iadd.69. A compound being a neutral 3:1
1-hydropyrid-2-one:iron (III) complex of a 1-hydroxypyrid-2-one in
which one or more of the hydrogen atoms attached to ring carbon
atoms are replaced by a substituent selected from aliphatic acyl,
aliphatic amide, cyano, aliphatic ester, halogen and hydroxy
groups, alkoxy groups and alkoxy groups substituted by an alkoxy,
aliphatic amide, aliphatic ester, halogen or hydroxy group,
aliphatic hydrocarbon groups and aliphatic hydrocarbon groups
substituted by an alkoxy, aliphatic ester, halogen or hydroxy
group, but excluding compounds in which said replacement of
hydrogen atoms is effected only by substituents selected from
aliphatic hydrocarbon groups, halogen groups and aliphatic
hydrocarbon groups substituted by a halogen group, wherein at least
one substituent is an alkoxy group substituted by an alkoxy,
aliphatic amide, aliphatic ester, halogen or hydroxy group.
.Iaddend. .Iadd.70. A compound according to claim 69, wherein the
1-hydroxypyrid-2-one contains one of said substituted alkoxy group
substituents and can contain one or more substituents which are an
aliphatic hydrocarbon group. .Iaddend.
.Iadd. A compound according to claim 69, wherein one or more of the
hydrogen atoms attached to the ring carbon atoms is replaced by a
C.sub.2-4 alkoxy group substituted either by a hydroxy group or by
a C.sub.1-4 alkoxy group, with the total number of carbon atoms in
the alkoxyalkoxy group ranging from 3 to 6, and wherein at least
one or more of the said hydrogen atoms can be replaced by an
aliphatic hydrocarbon
group of 1 to 4 carbon atoms. .Iaddend. .Iadd.72. The
pharmaceutical composition according to claim 35, in which the
4-position of the
1-hydroxypyrid-2-one is substituted. .Iaddend. .Iadd.73. The
pharmaceutical composition according to claim 38, in which the
4-position of the 1-hydroxypyrid-2-one is substituted. .Iaddend.
.Iadd.74. The pharmaceutical composition according to claim 56, in
which the 4-position of the 1-hydroxypyrid-2-one is substituted.
.Iaddend. .Iadd.75. The pharmaceutical composition according to
claim 57, in which the 4-position of the 1-hydroxypyrid-2-one is
substituted. .Iaddend. .Iadd.76. The pharmaceutical composition
according to claim 61, in which the 4-position of the
1-hydroxypyrid-2-one is substituted. .Iaddend. .Iadd.77. The
pharmaceutical composition according to claim 62, in which the
4-position of the 1-hydroxypyrid-2-one is substituted. .Iaddend.
.Iadd.78. The compound according to claim 39, in which the
4-position of the 1-hydroxypyrid-2-one is substituted. .Iaddend.
.Iadd.79. The compound according to claim 44, in which the
4-position of the 1-hydroxypyrid-2-one is substituted. .Iaddend.
.Iadd.80. The compound according to claim 58, in which the
4-position of the 1-hydroxypyrid-2-one is substituted. .Iaddend.
.Iadd.81. The compound according to claim 59, in which the
4-position of the 1-hydroxypyrid-2-one is substituted. .Iaddend.
.Iadd.82. The compound according to claim 63, in which the
4-position of the 1-hydroxypyrid-2-one
is substituted. .Iaddend. .Iadd.83. The compound according to claim
64, in which the 4-position of the 1-hydroxypyrid-2-one is
substituted. .Iaddend. .Iadd.84. A pharmaceutical composition
comprising a neutral 3:1 1-hydropyrid-2-one:iron (III) complex of a
1-hydroxypyrid-2-one in which one or more of the hydrogen atoms
attached to the ring carbon atoms are replaced by a substituent
selected from aliphatic acyl, aliphatic amide, cyano, aliphatic
ester, halogen and hydroxy groups, alkoxy groups substituted by an
alkoxy, aliphatic amide, aliphatic ester, halogen or hydroxy group,
aliphatic hydrocarbon groups and aliphatic hydrocarbon groups
substituted by an alkoxy, aliphatic ester, halogen or hydroxy
group, but excluding compounds in which said replacement of
hydrogen atoms is effected only by substituents selected from
aliphatic hydrocarbon groups, halogen groups and aliphatic
hydrocarbon groups substituted by a halogen group, together with a
physiologically acceptable diluent or carrier. .Iaddend. .Iadd.85.
A pharmaceutical composition comprising a neutral 3:1
1-hydropyrid-2-one:iron (III) complex of a 1-hydroxypyrid-2-one in
which one or more of the hydrogen atoms attached to ring carbon
atoms are replaced by a substituent selected from aliphatic acyl,
aliphatic amide, cyano, aliphatic ester, halogen and hydroxy
groups, alkoxy groups and alkoxy groups substituted by an alkoxy,
aliphatic amide, aliphatic ester, halogen or hydroxy group and
aliphatic hydrocarbon groups substituted by an alkoxy, aliphatic
ester, halogen or hydroxy group, but excluding compounds in which
said replacement of hydrogen atoms is effected only by substituents
selected from halogen groups and aliphatic hydrocarbon groups
substituted by a halogen group, together with a physiologically
acceptable diluent or carrier. .Iaddend. .Iadd.86. A compound being
a neutral being a a neutral 3:1 1-hydropyrid-2-one:iron (III)
complex of a 1-hydroxypyrid-2-one in which one or more of the
hydrogen atoms attached to ring carbon atoms are replaced by a
substituent selected from aliphatic acyl, aliphatic amide, cyano,
aliphatic ester, halogen and hydroxy groups, alkoxy groups
substituted by an alkoxy, aliphatic amide, aliphatic ester, halogen
or hydroxy group, aliphatic hydrocarbon groups and aliphatic
hydrocarbon groups substituted by an alkoxy, aliphatic ester,
halogen or hydroxy group, but excluding compounds in which said
replacement of hydrogen atoms is effected only by substituents
selected from aliphatic hydrocarbon groups, halogen groups and
aliphatic hydrocarbon groups substituted by a halogen group.
.Iaddend. .Iadd.87. A compound being a neutral 3:1
1-hydropyrid-2-one:iron (III) complex of a 1-hydroxypyrid-2-one in
which one or more of the hydrogen atoms attached to ring carbon
atoms are replaced by a substituent selected from aliphatic acyl,
aliphatic amide, cyano, aliphatic ester, halogen and hydroxy
groups, alkoxy groups and alkoxy groups substituted by an alkoxy,
aliphatic amide, aliphatic ester, halogen or hydroxy group and
aliphatic hydrocarbon groups substituted by an alkoxy, aliphatic
ester, halogen or hydroxy group, but excluding compounds in which
said replacement of hydrogen atoms is effected only by substituents
selected from halogen groups and aliphatic hydrocarbon groups
substituted by a halogen group. .Iaddend. .Iadd.88. A
pharmaceutical composition comprising a neutral 3:1
1-hydropyrid-2-one:iron (III) complex of a 1-hydroxypyrid-2-one in
which one or more of the hydrogen atoms attached to the ring carbon
atoms are replaced by a substituent selected from aliphatic acyl,
aliphatic amide, cyano, aliphatic ester, halogen and hydroxy
groups, alkoxy groups and alkoxy groups substituted by an alkoxy,
aliphatic amide, aliphatic ester, halogen or hydroxy group and
aliphatic hydrocarbon groups substituted by an alkoxy, aliphatic
ester, halogen or hydroxy group, at least one of the ring carbon
atom substituents being an aliphatic amide group, together with a
physiologically acceptable diluent or carrier. .Iaddend. .Iadd.89.
A pharmaceutical composition according to claim 88, in which the
4-position of the 1-hydroxypyrid-2-one is substituted by said
aliphatic amide group. .Iaddend. .Iadd.90. A compound being a
neutral 3:1 1-hydropyrid-2-one:iron (III) complex of a
1-hydroxypyrid-2-one in which one or more of the hydrogen atoms
attached to the ring carbon atoms are replaced by a substituent
selected from aliphatic acyl, aliphatic amide, cyano, aliphatic
ester, halogen and hydroxy groups, alkoxy groups and alkoxy groups
substituted by an alkoxy, aliphatic amide, aliphatic ester, halogen
or hydroxy group, aliphatic hydrocarbon groups and aliphatic
hydrocarbon groups substituted by an alkoxy, aliphatic ester,
halogen or hydroxy group, at least one of the substituents being an
aliphatic amide group. .Iaddend. .Iadd.91. A compound according to
claim 90, in which the 4-position of the 1-hydroxypyrid-2-one is
substituted by said aliphatic amide group. .Iaddend. .Iadd.92. A
pharmaceutical composition comprising a neutral 3:1
1-hydropyrid-2-one:iron (III) complex of a 1-hydroxypyrid-2-one in
which one or more of the hydrogen atoms attached to ring carbon
atoms are replaced by a substituent selected from aliphatic acyl,
aliphatic amide, cyano, aliphatic ester, halogen and hydroxy
groups, alkoxy groups and alkoxy groups substituted by an alkoxy,
aliphatic amide, aliphatic ester, halogen or hydroxy group,
aliphatic hydrocarbon groups and aliphatic hydrocarbon groups
substituted by an alkoxy, aliphatic ester, halogen or hydroxy
group, but excluding compounds in which said replacement of
hydrogen atoms is effected only by substituent selected from
aliphatic hydrocarbon groups, halogen groups and aliphatic
hydrocarbon groups substituted by a halogen group, together with a
physiologically acceptable solid carrier. .Iaddend. .Iadd.93. A
method for the treatment of a patient having a toxic concentration
of iron in the body which comprises administering to said patient a
1-hydroxypyrid-2-one of the formula ##STR9## wherein one of the
hydrogen atoms attached to the ring carbon atoms is replaced by an
aliphatic amide substituent, or a salt thereof containing a
physiologically acceptable cation in an amount effective to reduce
said
toxic concentration of the metal. .Iaddend. .Iadd.94. The method
according to claim 93, wherein one of said hydrogen atoms attached
to ring carbon atoms is replaced by an aliphatic amide of the
formula --CONH.sub.2 or a group --CONH.sub.2 wherein one or more of
the hydrogen atoms of this group is replaced by a C.sub.1-3
aliphatic hydrocarbon group. .Iaddend. .Iadd.95. The method
according to claim 93, wherein one of said hydrogen atoms attached
to ring carbon atoms is replaced by an aliphatic amide of the
formula --CONH.sub.2 or --CONHCH.sub.3. .Iaddend. .Iadd.96. A
method for the treatment of a patient to effect an increase in the
level of iron in the patient's blood-stream which comprises
administering to said patient a compound being a neutral 3:1
1-hydropyrid-2-one:iron (III) complex of a 1-hydroxypyrid-2-one of
the formula ##STR10## wherein one of the hydrogen atoms attached to
the ring carbon atoms is replaced by an aliphatic amide
substituent, or a salt thereof containing a physiologically
acceptable cation in an amount effective to achieve such
an increase. .Iaddend. .Iadd.97. The method according to claim 96,
wherein one of said hydrogen atoms attached to ring carbon atoms is
replaced by an aliphatic amide of the formula --CONH.sub.2 or a
group --CONH.sub.2 wherein one or more of the hydrogen atoms of
this group is replaced by a C.sub.1-3 aliphatic hydrocarbon group.
.Iaddend. .Iadd.98. The method according to claim 96, wherein one
of said hydrogen atoms attached to ring carbon atoms is replaced by
an aliphatic amide of the formula --CONH.sub.2 or --CONHCH.sub.3.
.Iaddend.
Description
This invention relates to compounds for use in medicine,
particularly in the treatment of iron overload.
Certain pathological conditions such as thalassaemia, sickle cell
anaemia, idiopathic haemochromatosis and aplastic anaemia are
treated by regular blood transfusions. It is commmonly found that
such transfusions lead to a widespread iron overload, which
condition can also arise through increased iron absorption by the
body in certain other circumstances. Iron overload is most
undesirable since, following saturation of the ferritin and
transferrin in the body, deposition of iron can occur and many
tissues can be adversely affected, particular toxic effects being
degenerative changes in the myocardium, liver and endocrine organs.
Such iron overload is most often treated by the use of
desferrioxamine. However, this compound is an expensive natural
product obtained by the culture of Streptomyces and, as it is
susceptible to acid hydrolysis, it cannot be given orally to the
patient and has to be given by a parenteral route. Since relatively
large amounts of desferrioxamine may be required daily over an
extended period, these disadvantages are particularly relevant and
an extensive amount of research has been directed towards the
development of alternative drugs. However, work has been
concentrated on three major classes of iron chelating agents or
siderophores, namely hydroxamates, ethylenediamine tetra-acetic
acid (EDTA) analogues and catechols. The hydroxamates generally
suffer from the same defects as desferrioxamine, being expensive
and acid labile, whilst the other two classes are ineffective at
removing iron from intracellular sites. Moreover, some cathechol
derivatives are retained by the liver and spleen and EDTA analogues
possess a high affinity for calcium and so are also likely to have
associated toxicity problems.
We have accordingly studied the iron chelating ability of a wide
range of compounds and have identified a group of compounds as
being of particular use for the treatment of conditions involving
iron overload. These compounds consist of a 1-hydroxypyrid-2-one in
which one or more of the hydrogen atoms attached to ring carbon
atoms are replaced by one of a carefully selected group of
substituents. None of these compounds has previously been used
therapeutically. Thus, although certain of the substituted
compounds described herein have been suggested as potential
anti-microbial agents, subsequent tests reported from the same
source (Nishimura et al, Ann. Rept. Shionogi Res. Lab., 1966, 16,
37) showed the compounds to have negligible activity. In vitro
tests illustrated the lack of anti-bacterial and anti-fungal
activity and, although some compounds showed some anti-protozoal
activity in vitro, when tested in mice against the fungus
Trichomonas vaginalis all of the compounds tested proved to be
inactive. Moreover, although it has been reported that
1-hydroxypyrid-2-one will form metal complexes, including an iron
complex, it has never before been appreciated that certain
substituted derivatives of this compound might be used with great
advantage in a pharmaceutical context for the treatment of
conditions producing toxic concentrations of iron in the body.
Accordingly the present invention comprises a compound being a
1-hydroxypyrid-2-one in which one or more of the hydrogen atoms
attached to ring carbon atoms are replaced by a substituent
selected from aliphatic acyl, aliphatic amide, aliphatic amine,
carboxy, cyano, aliphatic ester, halogen, hydroxy and sulpho
groups, alkoxy groups and alkoxy groups substituted by an alkoxy,
aliphatic amide, aliphatic amine, aliphatic ester, halogen or
hydroxy group, aliphatic hydrocarbon groups and aliphatic
hydrocarbon groups substituted by an alkoxy, aliphatic ester,
halogen or hydroxy group, but excluding compounds in which said
replacement of hydrogen atoms in the compound is effected only by
substituents selected from aliphatic hydrocarbon groups, halogen
groups and aliphatic hydrocarbon groups substituted by a halogen
group, or a salt thereof containing a physiologically acceptable
ion or ions, for use in medicine.
Such compounds may be used in both human and veterinary treatment
but are of particular interest for the treatment of the human body
by therapy, especially in the context of the treatment of iron
overload.
The 1-hydroxypyrid-2-ones are tautomeric compounds, being
alternatively named as 2-hydroxypyridine 1-oxides, the two
tautomeric structures being shown below for the unsubstituted
parent compound. ##STR1##
The ability of both the free compound and its iron complex to
permeate membranes is important in the context of the treatment of
iron overload, and it is also desirable for both to possess some
degree of water solubility. A good indication of the physical
properties of a compound and its iron complex in this respect is
provided by the value of the partition coefficient (K part)
obtained on partition between n-octanol and tris hydrochloride (20
mM, pH 7.4; tris representing 2-amino-2-hydroxymethylpropane
1,3-diol) at 20.degree. C. and expressed as the ratio
(concentration of compound in organic phase)/(concentration of
compound in aqueous phase). Preferred compounds show a value of K
part for the free compound of above 0.02 but less than 3.0,
especially of above 0.2 but less than 1.0, together with a value of
K part for the neutral 3:1 hydroxypyridone:iron-(III) complex of
above 0.02 but less than 6.0, especially of above 0.2 but less than
1.0. The following comments upon preferences among the groups used
for replacement of hydrogen atoms attached to carbon atoms of the
pyridone ring are directed towards the use of compounds having
partition coefficients in the free and complexed state which lie in
these preferred ranges. For examples of measured partition
coefficients of specific compounds reference should be made to
Table 1 of Example 2.
More than one of the ring carbon atoms may be substituted, for
example two of such atoms, either by the same substituent group or
by different substituent groups, for example by halogen or
especially by an aliphatic hydrocarbon group together with another
type of substituent, although compounds in which only one of the
ring carbon atoms is substituted are preferred. Substitution may
occur at any of the 3-, 4-, 5-and 6-positions or at a combination
of two or more of these positions. Particularly when the ring
carbon atoms are substituted by the larger groups, however, there
may be an advantage in avoiding substitution on a carbon alpha to
the ##STR2## system. The system is involved in the complexing with
iron and the close proximity of one of the larger aliphatic
hydrocarbon groups may lead to steric effects which inhibit complex
formation. Substitution at the 5- and particularly the 4-position
is thus of some especial interest.
Where a ring carbon atom is substituted by an aliphatic hydrocarbon
group, this group may be cyclic or acyclic, having a branched chain
or especially a straight chain in the latter case, and may be
unsaturated or especially saturated. Groups of from 1 to 6 carbon
atoms, particularly of 1 to 4 and especially of 1 to 3 carbon
atoms, are of most interest. Alkyl groups are preferred, for
example cyclic groups such as cyclopropyl and especially cyclohexyl
but, more particularly preferred are acyclic groups such as
isopropyl, n-propyl, ethyl and especially methyl. However, although
substitution by an aliphatic hydrocarbon group, for example methyl,
in addition to another substituent as specified above is quite
acceptable, it will not generally contribute with any particular
advantage to the properties of the compound and is thus not of
especial interest.
In the case of substituted aliphatic hydrocarbon groups, the
preferences as to the nature of these groups are broadly as
expressed above with regard to the hydrocarbon group and
hereinafter with regard to the substituent, for example these
groups conveniently being substituted alkyl groups of 1 to 3 carbon
atoms and particularly substituted methyl groups such as
chloromethyl, ethoxymethyl, and especially hydroxymethyl. In
general, however, substituents as defined hereinbefore other than
aliphatic hydrocarbon groups and substituted aliphatic hydrocarbon
groups are of the most interest. Various preferences may be
expressed among such other substituent groups, the following
comments applying equally to these groups when substituted on the
ring directly and, where appropriate, also to the groups when
substituted on an aliphatic hydrocarbon or alkoxy group which is
itself substituted on the ring.
An aliphatic acyl group may contain a sulphonyl or carbonyl group.
The latter type are however preferred and although the acyl group
may be a formyl group, alkylcarbonyl groups are of most interest.
Such acyl groups may, for example, be of 2 to 4 or 5 carbon atoms,
and particularly may contain alkyl groups of the type described
above as being preferred as an aliphatic hydrocarbon group
substituent on the ring, being, for example, --COCH.sub.2 CH.sub.3
or especially --COCH.sub.3. Alkoxy groups may conveniently be of 1
to 4 carbon atoms and contain similar alkyl groups to those which
are preferred in the alkylcarbonyl groups, examples of such
substituents being ethoxy and particularly methoxy. Alkoxy groups
which are substituted, however, may often conveniently contain 2 or
more carbon atoms in view of the relative instability of groups
such as ##STR3## etc., so that a particular substituted alkoxy
group of interest is --OCH.sub.2 CH.sub.2 OCH.sub.3. Moreover, the
presence of a hydrophilic substituent on an alkoxy group will tend
to offset the hydrophobic effect of the aliphatic hydrocarbon group
which that alkoxy group contains, thereby sometimes favouring the
use of slightly larger alkoxy groups when these are substituted.
Substituent alkoxy groups are of particular interest in the context
of the present invention and are discussed in more detail
hereinafter.
Amine substituents may consist of a group --NH.sub.2 or its charged
equivalent, a group --NH.sub.3, which will be associated with a
physiologically acceptable anion, for example a chloride or other
halide ion, a solubilising ion such as that from methane sulphonic
or isethionic acid, or an anion derived from the hydroxy group of
the ring (OH.fwdarw.O.sup.-), or such a --NH.sub.2 or NH.sub.3
group in which one or more of the hydrogen atoms is replaced by an
aliphatic hydrocarbon group, for example such a group as is
described above as a substitutent. Amide substituents may contain a
sulphonyl or a carbonyl group. The latter type are, however, of
most interest and the further discussion will therefore refer to
them although it applies equally to the sulphonyl type. The amide
substituent may be of the unsubstituted form --CONH.sub.2, i.e.
being a carbamoyl group, or may contain a nitrogen atom which is
mono- or di-substituted as just described for the amine
substituents, for example being a group --CONHCH.sub.3, etc.
Alternatively, the ##STR4## grouping of the amide substituent may
be arranged in the opposite sense so that the nitrogen atom of the
amide grouping is attached to the ring, the carbonyl group being
attached to an aliphatic hydrocarbon group, for example an alkyl
group such as is described above as a substituent, or in the case
of a carboxylic acid amide but not in that of a sulphonic acid
amide, to hydrogen. In the case of an amide group arranged in this
opposite sense, the nitrogen atom may carry a hydrogen atom or be
mono-substituted as discussed for amide substituents of the first
mentioned form, that form of amide substituent being the one of
particular interest.
Carboxy and sulpho substituents, the former of which are preferred,
may be present as the group --CO.sub.2 H or --SO.sub.3 H, or as the
anion derived therefrom in combination with a physiologically
acceptable cation, for example as described hereinafter. Ester
substituents may contain a sulphonyloxy or preferably a carbonyloxy
group and this may be arranged in either sense, i.e. with a
carboxylic acid ester the group --CO.O-- may have either the
carbonyl group or the oxy group linked to the carbon atom of the
ring (through an aliphatic hydrocarbon group on which the ester
group is substituted, where appropriate). The other group of oxy
and carbonyl will be linked to an aliphatic hydrocarbon group
forming part of the ester group or, in the case where this is a
carbonyl group may alternatively be linked to hydrogen (this latter
possibility does not apply in the case of sulphonic acid esters).
Once again, preferred aliphatic hydrocarbon groups contained by the
ester group are those described above as substituents. Ester groups
in which the oxy group is linked to the ring are preferred, for
example the groups --O.COCH.sub.3 and --O.COC.sub.2 H.sub.5 rather
than --CO.sub.2 CH.sub.3 and --CO.sub.2 CH.sub.2 CH.sub.3. With
aliphatic hydrocarbon groups or alkoxy groups substituted by an
ester group there is a particularly strong preference for the oxy
group to be attached to this aliphatic hydrocarbon group or alkoxy
group, groups such --CH.sub.2 O.COCH.sub.3 therefore being of
interest. Halogen substituents may conveniently be iodo, fluoro,
bromo or especially chloro.
Among preferred substituents are the hydroxy group, and also alkoxy
groups, for example ethoxy and particularly methoxy, and, more
particularly, substituted alkoxy groups, especially those
substituted by a hydroxy group or another alkoxy group, for example
the substituted ethoxy groups such as --OCH.sub.2 CH.sub.2
OCOCH.sub.3, --OCH.sub.2 CH.sub.2 NHCOCH.sub.3, --OCH.sub.2
CH.sub.2 NH.sub.2 and especially --OCH.sub.2 CH.sub.2 OH and
--OCH.sub.2 CH.sub.2 OCH.sub.3. Hydroxy substituted aliphatic
hydrocarbon groups, for example hydroxymethyl, are also of
generally greater interest than other substituted aliphatic
hydrocarbon groups.
Although simple alkoxy substituents, the alkoxy groups of
hydroxyalkoxy substituents and both components of alkoxyalkoxy
substituents may, as indicated previously, be of a range of sizes,
for example 1 to 6 carbon atoms, certain factors result in a
preference for groups of a particular size. Thus, the
hydrophilic/hydrophobic balance in a compound, which is indicated
by its K.sub.part value, may be adjusted to a value in the
preferred range quoted hereinbefore by the use of additional ring
substituents, so that the hydrophobic effect of a large
unsubstituted alkoxy group can be offset by the presence of a
further hydrophilic substituent, such as a hydroxy group, on
another carbon atom of the ring. However, it is generally
preferable to use a single substituent which itself confers the
appropriate degree of balance. Accordingly, unsubstituted alkoxy
group substituents of 1 to 3 or 4, preferably 1 or 2 carbon atoms,
and hydroxy substituted alkoxy group substituents of 2 to 4,
preferably 2 or 3 carbon atoms (substituted methoxy groups being of
less interest in view of the instability of the ##STR5## linkage
referred to previously), are of particular interest. For similar
reasons there is particular interest in alkoxy substituted alkoxy
group substituents of 2 to 4, preferably 2 or 3 carbon atoms, in
the first alkoxy group substituted onto the ring and of 1 to 4,
preferably 1 to 3 carbon atoms in the second alkoxy group which is
substituted onto the first alkoxy group, with the proviso that the
overall number of carbon atoms is preferably no greater than 6, and
especially no greater than 3 or 4 carbon atoms.
Although the hydroxy, methoxy, hydroxymethoxy and methoxyethoxy
groups already referred to are of particular interest as
substituents, other specific examples of alkoxy and substituted
alkoxy groups, in addition to those specifically mentioned
previously, are 3-hydroxypropoxy, 2-hydroxy-1-methylethoxy and
3-methoxypropoxy.
Hydroxy, alkoxy, substituted alkoxy and other groups may
conveniently be substituted at the 4-position of a
1-hydroxypyrid-2-one, for example at the 4-position of
1-hydroxy-6-methylpyrid-2-one or other C-methyl substituted
1-hydroxypyrid-2-one or, more especially, at the 4-position of
otherwise unsubstituted 1-hydroxypyrid-2-one. Specific examples of
compounds according to the present invention are thus as follows:
##STR6## wherein R is a substituent group as defined hereinbefore,
for example methyl and especially 6-methyl, hydroxy, etc., x is 0,
1, 2 or 3 (the ring not containing any further substituent R when x
is 0), n is 0, 1, 2, 3 or 4, m is 1, 2, 3 or 4 and R' is hydrogen
or --(CH.sub.2)nCH.sub.3, preferences among the groups at the
4-position being as described hereinbefore.
The compounds may, if desired, contain substituent groups,
particularly an aliphatic amine, carboxy or sulpho group, in the
salt form. Alternatively, a salt may be formed with the ##STR7##
system produced by the loss of a proton from the hydroxy group
N-substituted at the 1-position of the ring (or C-substituted at
the 2-position of the ring in the tautomeric form). Such salts
contain a physiologically acceptable cation, for example the cation
of an alkali metal such as sodium, quaternary ammonium ions or
protonated amines such as the cation derived from tris (tris
represents 2-amino-2-hydroxymethyl propane 1,3-diol). Salt
formation may be advantageous in increasing the water solubility of
a compound but, in general, the use of the compounds themselves
rather than their salts, is preferred.
Certain of the substituted 1-hydroxypyrid-2-ones described herein
are known compounds, in particular the compounds having a single
substituent at the 4-position which is an acetamido, amino, butoxy,
carbamyl, carboxy, cyano, ethoxy, ethoxycarbonyl, methoxy or
propoxy group, but all the other components described above are
believed to be novel, including the particularly interesting
compounds which are substituted by an additional hydroxy group, for
example 1,4-dihydroxypyrid-2-one. The present invention thus
includes, per se, the compounds described hereinbefore but
excluding these known compounds.
The substituted 1-hydroxypyrid-2-ones (or 2-hydroxypyridine
N-oxides) for use in the present invention may be synthesised by
various routes applying standard reactions for the introduction of
the substituent groups within the art of pyridine chemistry. In
particular, substituents may be introduced either by replacement of
a hydrogen atom or of an existing substituent at the appropriate
position or positions in a pyridine or pyridine 1-oxide ring
system. Pyridine compounds may conveniently be converted to the
corresponding pyridine 1-oxide by the use of an oxidizing agent
such as peracetic or perbenzoic acid. The oxygen atom at the
2-position of compounds according to the present invention may
conveniently be introduced by the basic hydrolysis of a halogen
group or the acidic hydrolysis of an alkoxy group, for example a
methoxy group, at that position, preferably in a pyridine 1-oxide
rather than a pyridine and conveniently following introduction of
the other substituent groups or groups. Such a procedure will
introduce a hydroxy group at the 2-position as in the
2-hydroxypyridine N-oxide tautomeric form shown hereinbefore.
Such procedures and the preparation of various suitable
intermediates are described in the art, for example by Shaw et al,
J. Amer. Chem. Soc., 1949, 71, 70 and ibid, 1950, 72, 4362, and
particularly by Mizukami et al, Ann. Rept. Shionogi Res. Lab.,
1966, 16, 29. A particularly useful type of intermediate for the
preparation of the compounds described herein is a nitro
substituted 2-chloro-pyridine N-oxide, 4-nitro, 5-nitro and
3,5-dinitro substituted compounds all being reported in the
literature. Thus, 2-chloro-4-nitropyridine-1-oxide, for example,
may be subjected to nucleophilic substitution to replace the nitro
group by an alkoxy group or alkoxy substituted alkoxy group, for
example --OCH.sub.3 or --OCH.sub.2 CH.sub.2 OCH.sub.3, the chloro
group then being converted to a hydroxy group by basic hydrolysis.
Alternatively, a nitro group substituent may be reduced to give an
amino group which may in turn be acylated.
The compounds may be converted to salts formed with the anion
produced by the loss of the hydroxy group proton or with a
substituent such as a carboxy, sulpho or amino group by reaction
with the appropriate base or acid according to standard procedures
(amino substituted compounds of a zwitterion type containing a
cation from the amino group and such a hydroxy group-derived anion
may be prepared by crystallisation from aqueous media at a pH of
about 9).
In general, it is preferred that the compounds are isolated in
substantially pure form, i.e. substantially free from by-products
of manufacture.
It will be appreciated that these are not the only routes available
to these compounds and that various alternatives may be used as
will be apparent to those skilled in the art, as will be the routes
to the various intermediates required.
Moreover, it will be appreciated that certain of the compounds may
be converted in vivo to other compounds which will be involved in
the metal binding activity observed in vivo. This will be true, for
example, of compounds containing ester groups which are likely to
be converted to carboxy groups when the compounds are administered
orally.
The compounds may be formulated for use as pharmaceuticals for
veterinary, for example in an avian or particularly a mammalian
context, or particularly human use by a variety of methods. For
instance, they may be applied as an aqueous, oily or emulsified
composition incorporating a liquid diluent which most usually will
be employed for parenteral administration and therefore will be
sterile and pyrogen free. However, it will be appreciated from the
foregoing discussion in relation to desferrioxamine that oral
administration is to be preferred and the compounds of the present
invention may be given by such a route. Although compositions
incorporating a liquid diluent may be used for oral administration,
it is preferred to use compositions incorporating a solid carrier,
for example a conventional solid carrier material such as starch,
lactose, dextrin or magnesium stearate, the oral composition then
conveniently being of a formed type, for example as tablets,
capsules (including spansules), etc.
The present invention accordingly further comprises a
pharmaceutical composition containing a compound being a a
1-hydroxypyrid-2-one in which one or more of the hydrogen atoms
attached to ring carbon atoms are replaced by a substituent
selected from aliphatic acyl, aliphatic amide, aliphatic amine,
carboxy, cyano, aliphatic ester, halogen, hydroxy and sulpho
groups, alkoxy groups and alkoxy groups substituted by an alkoxy,
aliphatic amide, aliphatic amine, aliphatic ester, halogen or
hydroxy group, aliphatic hydrocarbon groups and aliphatic
hydrocarbon groups substituted by an alkoxy, aliphatic ester,
halogen or hydroxy group, but excluding compounds in which said
replacement of hydrogen atoms in the compound is effected only by
substituents selected from aliphatic hydrocarbon groups, halogen
groups and aliphatic hydrocarbon groups substituted by a halogen
group, or a salt thereof formed between the anion produced by the
loss of the hydroxy group proton and a physiologically acceptable
cation, together with a physiologically acceptable solid
carrier.
Other forms of administration than by injection or through the oral
route may also be considered in both human and veterinary contexts,
for example other forms known in the art such as the use of
suppositories or pessaries, particularly for human
administration.
Compositions may be formulated in unit dosage form, i.e. in the
form of discrete portions each comprising a unit dose, or a
multiple or sub-multiple of a unit dose. Whilst the dosage of
active compound given will depend on various factors, including the
particular compound which is employed in the composition, it may be
stated by way of guidance that satisfactory control of the amount
of iron present in the human body will often be achieved using a
daily dosage of about 0.1 g to 5 g, particularly of about 0.5 g to
2 g, veterinary doses being on a similar g/Kg body weight ratio.
However, it will be appreciated that it may be appropriate under
certain circumstances to give daily dosages either below or above
these levels. Where desired, more than one compound according to
the present invention may be administrated in the pharmaceutical
composition or, indeed, other active compounds may be included in
the composition.
Although suggestions have previously been made concerning use of
certain of the compounds described herein in a pharmaceutical
context as anti-microbials, these suggestions did not lead to a
therapeutic use for the compounds. We have found that the
1-hydroxypyrid-2- ones described herein are particularly suited to
the removal of iron from patients having an iron overload. The
compounds form neutral 3:1 iron complexes at most physiological pH
values, and have the advantage that they do not co-ordinate calcium
or magnesium. Both the compounds and their complexes will partition
into n-octanol indicating that they will permeate biological
membranes, this property being confirmed in practice by tests of
the ability of the .sup.59 Fe labelled iron complexes to permeate
erythrocytes.
The 1-hydroxypyrid-2-ones possess a high affinity for iron(III), as
evidenced by log K.sub.sol values (log K.sub.sol is defined as
being equal to log .beta..sub.Fe(L)n +21--[pK.sub.sp +n log
a.sub.L(H+) +m log a.sub.L (Ca++)] where log .beta..sub.Fe(L)n is
the cumulative affinity constant of the ligand in question for
iron(III), pK.sub.sp is the negative logarithm of the solubility
product for Fe(OH).sub.3 and has a value of 39, n and m are the
number of hydrogen and calcium ions, respectively, which are bound
to the ligand, and a.sub.L(H+) and a.sub.L (Ca++) are the
affinities of the ligand for hydrogen ions and calcium ions,
respectively). In order to solubilise iron(III) hydroxide, log
K.sub.sol must be greater than 0 and in order to remove iron from
transferrin, log K.sub.sol should be in excess of 6.0. The log
K.sub.sol values for 1,4-dihydroxypyrid-2-one and
1-hydroxy-4-methoxypyrid-2-one by way of example, are 9.9 and 11.3,
respectively, thus comparing favourably with those of the bidentate
hydroxamates at about 4.0, of catechols at about 8.0, of
desferrioxamine at 6.0 and of diethylenetriamine pentaacetic acid
(DTPA) at 2.0. Moreover, the ability of the compounds to remove
iron efficiently has been confirmed both by in vitro test and also
by in vivo tests in mice. It is particularly significant that these
latter tests are successful whether the compound is given
intraperitoneally or orally by stomach tube, the compounds
generally either being stable under acidic conditions or being
converted thereby to acid stable active compounds. Oral activity is
not generally present among the other types of compound previously
suggested for use as iron co-ordinating drugs and although certain
EDTA analogues do show such activity, they possess drawbacks for
pharmaceutical use.
In addition to the use described hereinbefore for the treatment of
general iron overload, the hydroxypyridones described herein are
also of interest for use in certain pathological conditions where
there may be an excess of iron deposited at certain sites even
though the patient does not exhibit a general iron overload, this
being the case, for example, in certain arthritic and cancerous
conditions. Indeed in some patients having such conditions, the
patient may exhibit an overall aneamia and the metal-free
1-hydroxypyrid-2-ones may then be used in conjunction with an iron
complex, for example an iron complex of the same or another of
these 1-hydroxypyrid-2-ones, the iron complex acting to correct the
overall anaemia whilst the metal-free compound acts to remove iron
from pathological to physiological sites. Such iron complexes of
the 1-hydroxypyrid-2-ones and their use in this context are
discussed in detail hereinafter.
Uses of the compounds of the present invention for combination with
metals other than iron may extend to the treatment of body fluids
outside the body or even to quite other contexts than the treatment
of patients. One particular area of some interest involves the
treatment of patients on haemodialysis who may show a dangerous
build up of aluminium in the body. For the treatment of such
patients the compounds of the present invention may be
insolubilised through attachment to a support material and then
contacted with the patient's blood to remove aluminium therefrom.
The support material may conveniently be one of various types of
polymer described in the art for use in similar contexts, for
example a carbohydrate material which may be of an agarose, dextran
or other type, or a polystyrene or other material such as is used
in ion-exchange resins.
Various approaches known in the art may be used for effecting
attachment of the compounds to such support materials but one
convenient approach is to use an acidic or basic group on the
support material to provide an amide type linkage through reaction
with the hydroxypyridone. Hydroxypyridones of particular interest
in this context are those containing acidic or basic substituents
on a ring carbon atom, i.e. those containing an aliphatic amine or
a sulpho or especially a carboxy group substituent. (Substituted
hydroxypyridones containing such a substituent which is an
ionisable group are in fact generally of rather lesser interest for
use in the pharmaceutical compositions of the present invention in
view of their less effective membrane permeating properties.)
Just as iron overload can pose problems in some patients, iron
deficiency anaemia can pose problems in others. As well as being of
value as the metal-free compounds for the treatment of conditions
involving iron overload, the substituted 1-hydroxypyrid-2-ones
described hereinbefore are of interest in the iron complex form for
the treatment of iron deficiency anaemia.
An adequate supply of iron to the body is an essential requirement
for tissue growth in both man and animals. Although there is
normally an ample amount of iron in the diet, the level of
absorption of iron from food is generally low so that the supply of
iron to the body can easily become critical under a variety of
conditions. Iron deficiency anaemia is commonly encountered in
pregnancy and may also present a problem in the newly born,
particularly in certain animal species such as the pig. Moreover,
in certain pathological conditions there is a mal distribution of
body iron leading to a state of chronic anaemia. This is seen in
chronic diseases such as rheumatoid arthritis, certain haemolytic
diseases and cancer.
Although a wide range of iron compounds is already marketed for the
treatment of iron deficiency anaemia, the level of iron uptake by
the body from these compounds is often quite low, necessitating the
administration of relatively high dosage levels of the compound.
The administration of high dose, poorly absorbed, iron complexes
may cause siderosis of the gut wall and a variety of side effects
such as nausea, vomiting, constipation and heavy malodorous stools.
We have now found that the iron complexes of the substituted
1-hydroxypyrid-2-ones described hereinbefore, none of which are
believed to have been previously prepared, are of particular value
in the treatment of such conditions.
Accordingly the present invention further comprises an iron complex
of a 1-hydroxypyrid-2-one in which one or more of the hydrogen
atoms attached to ring carbon atoms are replaced by a substituent
selected from aliphatic acyl, aliphatic amide, aliphatic amine,
carboxy, cyano, aliphatic ester, halogen, hydroxy and sulpho
groups, alkoxy groups and alkoxy groups substituted by an alkoxy,
aliphatic amide, aliphatic amine, aliphatic ester, halogen or
hydroxy group, aliphatic hydrocarbon groups and aliphatic
hydrocarbon groups substituted by an alkoxy, aliphatic ester,
halogen or hydroxy group, but excluding compounds in which said
replacement of hydrogen atoms in the compound is effected only by
substituents selected from aliphatic hydrocarbon groups, halogen
groups and aliphatic hydrocarbon groups substituted by a halogen
group.
The comments made hereinbefore in relation to K.sub.part values for
the metal-free compounds and their corresponding iron complexes in
the case of preferred compounds apply equally to the selection of
preferred metal-free compounds and of preferred iron complexes. The
comments made hereinbefore with regard to preferences as to the
nature and position of substituents thus apply equally in relation
to the iron complexes.
The iron complexes present in the pharmaceutical composition
according to the present invention preferably contain iron in the
ferric state. Although the use of complexes containing iron in the
ferrous state may be considered, such complexes tend to be less
stable and are thus of less interest. The iron complexes are
preferably neutral, i.e. there being an internal balance of charges
between the metal cation and the ligand(s) bound covalently thereto
without the necessity for the presence of a non-covalently bound
ion or ions, for example a chloride ion, to achieve balance.
Moreover, the use of hydroxypyridones containing ionisable
substituent groups is of less interest and it is preferred that
this internal balance of charges is achieved by complexing with the
iron cation the appropriate number of anions derived from a
hydroxypyridone by the loss of a hydroxy proton which are necessary
to produce neutrality. Preferred iron complexes of use in the
present invention are thus of the 3:1 form, containing three
hydroxypyridone anions complexed with a ferric cation. It will be
appreciated, however, that the invention does not exclude the use
of complexes of the 1:1 or particularly the 2:1 form, usually in
association with a physiologically acceptable anion or anions to
achieve neutrality, for example the chloride ion. It will be
appreciated, therefore, that the invention particularly includes as
compounds, per se, a neutral iron complex containing 1 molar
proportion of iron(III) and 3 molar proportions of a
hydroxypyridone as defined hereinbefore.
The iron complexes are conveniently prepared by the reaction of the
hydroxypyridone and iron ions, the latter conveniently being
derived from an iron salt, particularly a ferric halide and
especially ferric chloride. The reaction is conveniently effected
in a suitable mutual solvent and water may often be used for this
purpose. If desired, however, an aqueous/organic solvent mixture
may be used or an organic solvent, for example ethanol, methanol,
chloroform and mixtures of these solvents together and/or with
water where appropriate. In particular, methanol or especially
ethanol may be used as the solvent where it is desired to effect
the separation of at least a major part of a by-product such as
sodium chloride by precipitation whilst the iron complex is
retained in solution. Alternative procedures may, however, be used
and will be apparent to those skilled in the art.
It will be appreciated that the nature of the iron complex obtained
by the reaction of a hydroxypyridone and iron ions will depend both
on the proportion of these two reactants and upon the pH of the
reaction medium. Thus, for the preparation of the 3:1 ferric
complex, for example, the hydroxypyridone and the ferric salt are
conveniently mixed in solution in a 3:1 molar proportion and the pH
adjusted to a value in the range of 6 to 9, for example 7 or 8. If
a similar excess of hydroxypyridone:iron is employed, but no
adjustment is made of the acidic pH which results on the admixture
of the hydroxypyridone and an iron salt such as ferric chloride,
then a mixture of the 2:1 and 1:1 complex will instead be obtained.
Adjustment of the pH may conveniently be effected by the addition
either of sodium carbonate or of a hydroxide base such as sodium or
ammonium hydroxide, the use of a hydroxide base being or particular
interest when preparing the iron complexes in batches of 20 g or
more. When using a hydroxide base, the reaction may conveniently be
carried out in a medium containing water as the solvent, for
example in water or an ethanol:water mixture, and the pH adjusted
by the addition of a 2 molar aqueous solution of the base. It will
be appreciated that the presence of water in the reaction mixture
will lead to the retention of a by-product in the iron complex on
evaporation of the solvent (a chloride where the iron salt is
ferric chloride). However, this can be removed, if desired, by
procedures such as crystallisation from a suitable solvent system
or sublimation in the particular case of ammonium chloride.
Reaction to form the iron complex is generally rapid and will
usually have proceeded substantially to completion after 5 minutes
at about 20.degree. C., although a longer reaction time may be used
if necessary. Following separation of any precipitated by-product,
such as sodium chloride in the case of certain solvent systems, the
reaction mixture may conveniently be evaporated on a rotary
evaporator or freeze dried to yield the solid iron complex. This
may, if desired, be crystallised from a suitable solvent, for
example water, an alcohol such as ethanol, or a solvent mixture,
including mixtures containing an ether. The present invention thus
further includes a process for the preparation of an iron complex
of a 1-hydroxypyrid-2-one as defined hereinbefore which comprises
reacting said hydroxypyridone with iron ions and isolating the
resultant complex.
Whilst for some uses it may be appropriate to prepare the iron
complex in substantially pure form, i.e. substantially free from
by-products of manufacture, in other cases, for example with a
solid oral formulation as described hereinafter, the presence of
by-products such as sodium chloride may be quite acceptable. In
general however, the neutral 3:1 [hydroxypyridone:iron(III)]
complex is of particular interest in a form free from by-products
which are complexes containing different proportions of
hydroxypyridone and iron, in particular the 2:1 and 1:1 complexes.
Accordingly the present invention includes an iron complex, for
example the 3:1 hydroxypyridone:iron(III) complex, of a
1-hydroxypyrid-2-one as defined hereinbefore, when in a form
substantially free from iron complexes of the hydroxypyridone
containing other proportions of iron. As indicated hereinafter, it
may be advantageous under some circumstances for the iron complex
to be used in admixture with the free hydroxypyridone and, if
desired, such a mixture may be obtained directly by reacting a
molar proportion of the hydroxypyridone and iron ions of greater
than 3:1.
The iron complexes may be formulated as pharmaceuticals for
veterinary, for example in an avian or particularly a mammalian
context, or human use by a variety of methods and the invention
includes a pharmaceutical composition comprising an iron complex as
hereinbefore defined together with a physiologically acceptable
diluent or carrier. The comments made hereinbefore with regard to
the formulation of the metal-free compounds apply equally to the
iron complexes, although in this instance compositions for
parenteral administration are of greater interest particularly in
the context of animal treatment. The problems of iron deficiency
anaemia in newly born pigs arise primarily during the first three
weeks or so of their life when a very rapid weight gain takes
place. The iron complexes of the present invention may be used to
treat piglets directly by a parenteral route, such as intramuscular
or oral, for example as a liquid preparation "injected into the
mouth". However, an alternative approach is to enhance the iron
content of the milk on which the piglets are feeding by treating
the mother pig using oral or parenteral administration, for example
an injectable slow release preparation (such an approach may also
be an interest in a human context). When it is applicable to feed
piglets on foodstuffs other than the milk of the mother pig, it may
also be possible to effect the pharmaceutical administration of the
iron complex in this other foodstuff.
As with the metal-free compounds, the dosage of the hydroxypyridone
iron complex which is given will depend on various factors,
including the particular compound which is employed in the
composition. It may be stated by way of guidance, however, that
maintenance of the amount of iron present in the human body at a
satisfactory level will often be achieved using a daily dosage, in
terms of the iron content of the compound, which lies in a range
from about 0.1to 100 mg and often in a range from 0.5 to 10 mg, for
example 1 or 2 mg, veterinary doses being on a similar g/Kg body
weight ratio. However, it will be appreciated that it may be
appropriate under certain circumstances to give daily dosages
either below or above these levels. In general, the aim should be
to provide the amount of iron required by the patient without
administering any undue excess and the properties of the
pharmaceutical compositions according to the present invention are
particularly suited to the achievement of this aim.
Where desired, an iron complex of more than one hydroxypyridone as
described above may be present in the pharmaceutical composition or
indeed other active compounds may be included in the composition,
for example compounds having the ability to facilitate the
treatment of anaemia, such as folic acid. Another additional
component which may be included in the composition, if desired, is
a source of zinc. Iron compounds used in the treatment of iron
deficiency anaemia can inhibit the mechanism of zinc uptake in the
body and this can cause serious side effects in the foetus when
treating anaemia in a pregnant female. It is believed, however,
that the iron complexes of the present ivnention have a further
advantage in that they either do not have this effect or exhibit
the effect at a lower level than the compounds at present used in
the treatment of anaemia. Accordingly, it may often be the case
that the level of zinc providing compound added to the composition
may not require to be high or, with preferred formulations of the
iron complexes, may be dispensed with altogether.
It has never before been appreciated that the iron complexes such
as those described herein might be used, and with great advantage,
in a pharmaceutical context. Accordingly the present invention
includes an iron complex of a 1-hydroxypyrid-2-one as defined
hereinbefore for use in medicine, particularly in the treatment of
iron deficiency anaemia (in the broad sense of this term).
We have found that the iron complexes described herein are of value
in the treatment of iron deficiency anaemia both in humans and also
in a veterinary context, particularly for the treatment of various
mammalian species and especially pigs. The complexes will partition
into n-octanol indicating that they are able to permeate biological
membranes, this property being confirmed in practice by tests of
the ability of the .sup.59 Fe labelled iron complexes to permeate
erythrocytes. The ability of the compounds in this respect will
depend on the nature of the substituent(s) present therein and the
reflection of this ability in the K.sub.part values of various
compounds has been referred to hereinbefore.
The ability of the iron complexes of the present invention to
promote iron uptake with a high level of efficiency, as compared
with a range of other iron complexes currently marketed for the
treatment of iron deficiency anaemia, has been confirmed by
measurements in the rat small intestine. Once present in the
bloodstream, the complexes will donate iron to transferrin, a
position of equilibrium being set up between the complexes and
transferrin. It is because of the existence of this equilibrium
that the corresponding free hydroxypyridones may equally be used in
the treatment of iron overload, although certain of these compounds
may be of particular value for use in the free state for iron
removal and other may be of particular value for use as complexes
for iron supply.
Certain aspects of their formulation may enhance the activity of
the complexes in particular contexts. Thus, although the neutral
3:1 ferric complexes are of particular value as being stable over a
wide pH range from about 4 or 5 up to 10, they will dissociate at
the pH values of less than 4 prevailing in the stomach to form a
mixture of the 2:1 and 1:1 complex together with the free
hydroxypyridone. If these complexes and the free hydroxypyridone
are cleared simultaneously from the stomach, when they reach the
small intestine a large proportion of the 3:1 complex should reform
under the alkaline conditions present therein. However, in the
event that this dissociation under acid conditions leads to a
significant reduction in the uptake of iron by the body, due for
instance to absorption of the free hydroxypyridone through the
stomach wall, the uptake may be improved by using one or more of
the following procedures in the formulation of the iron
complex.
Firstly, one of several variations may be employed which avoid or
reduce exposure of the iron complex to the acidic conditions of the
stomach. Such approaches may involve various types of controlled
release system, ranging from one, which may for example be based on
a polymer, which simply provides a delayed release of the complex
with time, through a system which is resistant to dissociation
under acidic conditions, for example by the use of buffering, to a
system which and is biased towards release under conditions such as
prevail in the small intestine, for example a pH sensitive system
which is stabilised towards a pH of 1 to 3 such as prevails in the
stomach but not one of 7 to 9 such as prevails in the small
intestine. Since the pH of the stomach is higher after a meal, it
may be advantageous, whatever method of formulation is used, to
administer the iron complexes at such a time.
A particularly convenient approach to a controlled release
composition involves encapsulating the iron complex by a material
which is resistant to dissociation in the stomach intestine (or
possibly, if the dissociation is slow, in the large intestine).
Such encapsulation may be achieved with liposomes, phospholipids
generally being resistant to dissociation under acidic conditions.
The liposomally entrapped 3:1 iron(III) complexes can therefore
survive the acid environment of the stomach without dissociating to
the 2:1 and 1:1 complexes, and the free hydroxypyridone. On entry
into the small intestine, the pancreatic enzymes rapidly destroy
the phospholipid-dependent structure of the liposomes thereby
releasing the 3:1 complex. Liposome disruption is further
facilitated by the presence of bile salts. However, it is usually
more convenient to effect the encapsulation, including
microencapsulation, by the use of a solid composition of a pH
sensitive nature.
The preparation of solid compositions adapted to resist
dissociation under acidic conditions but adapted towards
dissociation under non-acidic conditions is well known in the art
and most often involves the use of enteric coating, whereby
tablets, capsules, etc, or the inidividual particles or granules
contained therein, are coated with a suitable material. Such
procedures are described, for example, in the article entitled
"Production of enteric coated capsules" by Jones in Manufacturing
Chemist and Aerosol News, May 1970, and in such standard reference
books as "Pharmaceutical Dosage Forms, Volume III by Liebermann and
Lackmann (published by Marcel Decker). One particular method of
encapsulation involves the use of gelatine capsules coated with a
cellulose acetate phthalate/diethylphthalate layer. This coating
protects the gelatin capsule from the action of water under the
acid conditions of the stomach where the coating is protonated and
therefore stable. The coating is however destablised under the
neutral/alkaline conditions of the intestine where it is not
protonated, thereby allowing water to act on the gelatin. Once
released in the intestine the rate of permeation of the intestine
wall by the water soluble 3:1 iron-(III) complex is relatively
constant irrespective of the position within the intestine, i.e.
whether in the jejunum, ileum or large intestine. Other examples of
methods of formulation which may be used include the use of
polymeric hydrogel formulations which do not actually encapsulate
the iron complex but which are resistant to dissociation under
acidic conditions.
A second approach to countering the effect of the acidic conditions
prevailing in the stomach is to formulate the iron complex in the
pharmaceutical composition together with the metal-free
hydroxypyridone from which it is derived. The dissociation of the
neutral 3:1 ferric complex, for example, involves various
equilibria between this complex, the 2:1 and 1:1 complexes, and the
metal-free compound, so that the presence of the latter will
inhibit this dissociation. Any proportion of the free compound can
be advantageous in this context but little further advantage
accrues from increasing the proportion beyond a certain level. A
preferred range for the molar proportion of the free compound
present in compositions according to the present invention is thus
from 0 to 100 moles free hydroxypyridone:1 mole of iron complex,
particularly the neutral 3:1 iron-(III) complex. Conveniently, a
proportion of up to no more than 20, 30 or 50 moles:1 mole is used
with a lower level of 0.5, 1 or 2 moles:1 mole. Although to obtain
a marked effect upon dissociation of the iron complex a proportion
of at least 5 or 10 moles:1 mole is usually employed it should be
emphasised that even a molar ratio such as 1:1 will achieve a
noticeable degree of acid stabilisation of the iron complex. Thus,
although a range of, for example, from 10 moles:1 to 20 moles:1
mole of metal-free hydroxypyridone:iron complex will often be
suitable to produce a marked effect, a range of, for example, 3 or
even 1 mole:1 mole to 10 moles:1 mole will still produce a
worthwhile effect without requiring administration of the larger
amounts of the hydroxypyridone. The use of such a mixture is an
important feature of the present invention since it can enable one
to obtain almost quantitative uptake of iron from the complex. It
should be appreciated, however, that the equilibrium between the
complexes of various types and the metal-free compound will be
effected by any take up of the latter in the body and the degree of
such uptake from the stomach, for example, will depend on the
particular metal-free compound.
A further advantage than prevention of dissociation of the iron
complex under acidic conditions may accrue from the use of a free
hydroxypyridone in admixture with its iron complex. Thus, as
referred to hereinbefore, in certain pathological conditions there
may be an excess of iron deposited at certain sites even though the
patient exhibits an overall anaemia. In patients having such
conditions the use of such a mixture has the advantage that the
iron complex will remedy the overall anaemia whilst the free
hydroxypyridone will act to remove iron from pathological to
physiological sites. Moreover, there may be an advantage in
formulating the iron complex of one hydroxypyridone as described
herein with another one of such hydroxypyridones in free form or
with a mixture of the corresponding free hydroxypyridone, present
primarily to prevent dissociation of the iron complex, and of
another such hydroxypyridone in free form, present primarily to
effect iron transfer. Thus, it is preferable for the
hydroxypyridone present in an iron donor to be rapidly metabolized
so as to effect its removal from the system once it has given up
its iron at an appropriate site in the system, whilst it is
preferable for a hydroxypyridone being used as an iron remover not
to be rapidly metabolized so that it remains in the system, taking
up iron, for an extended period. For this reason the use of
different hydroxypyridones in the free form and as the iron complex
has certain advantages. Moreover, different hydroxypyridones may,
for other reasons, function more efficiently either in the free
form as an iron remover or in complex form as an iron donor. If
desired, the free hydroxypyridone may alternatively be used in the
form of a salt formed with the anion produced by the loss of a
hydroxy proton and containing a physiologically acceptable cation,
for example as described hereinbefore.
It will be appreciated that, as an alternative to combination with
a different free hydroxypyridone of the same type, the iron complex
may be used in combination with another iron chelating agent, for
example an alternative form of hydroxypyridone such as is described
in UK patent application Nos. 8308056, (published under the number
GB 211876A (U.S. application Ser. No. 478,493, filed Mar. 24,
1983), and 8407181 (published under the number GB 2146807A (U.S.
application Ser. No. 592,271, filed Mar. 22, 1984, now U.S. Pat.
No. 4,585,780 issued Apr. 29, 1986).
When a free 1-hydroxypyrid-2-one is present in admixture with an
iron complex of the same or a different 1-hydroxypyrid-2-one for
the purpose of acting as an iron remover, then the amount of the
metal-free compound may be different than when the free
hydroxypyridone necessarily corresponds to that present in the iron
complex and is present primarily to prevent dissociation. Thus the
daily dosage of the iron complex may be as above and the daily
dosage of the free hydroxypyridone may be that described in
relation to the use of such compounds in iron overload conditions.
Thus, it will be seen that the proportion of iron complex and free
hydroxypyridone used in such a context may extend across a wide
range but preferred amounts of the free compound tend to be higher
than in the other instance involving the prevention of dissociation
of the complex.
It will be appreciated that the present invention also includes a
method for the treatment of a patient which comprises administering
to said patient an amount of an iron complex of a
1-hydroxypyrid-2-one as described hereinbefore in order to effect
an increase in the levels of iron in the patient's blood
stream.
In addition to the pharmaceutical uses of the iron complexes
discussed above they are also of potential interest as a source of
iron in various other contexts including in cell and bacterial
growth, in plant growth, as a colouring agent and in the control of
iron transport across membranes.
This invention is illustrated by the following Examples.
EXAMPLES
EXAMPLE 1
The preparation of 1,4-dihydroxypyrid-2-one
(1) 2-Chloro-4-nitropyridine-1-oxide
2-Chloro-pyridine-1-oxide (10 g) is in an ice bath and treated with
concentrated H.sub.2 SO.sub.4 (15 ml), followed by the dropwise
addition of a mixture of concentrated H.sub.2 SO.sub.4 (15 ml) and
fuming HNO.sub.3 (27 ml, s.g. 1.5) over a 70 minute period. The
acidic solution is heated in a steam bath for 2.5 hours, then
allowed to reach room temperature and poured onto ice water (600
ml), stirring being continued until all the ice has melted . The
resultant solid is filtered off and dissolved in hot chloroform,
the solution being dried and the solvent evaporated in vacuo to
give a yellow solid. The aqueous filtrate obtained after the
removal of the original solid is neutralised with saturated aqueous
Na.sub.2 CO.sub.3 and extracted continuously with chloroform, the
extract being dried and evaporated in vacuo to yield a yellow
solid. The two yellow solids are combined and recrystallised from
ethanol to give 2-chloro-4-nitro-pyridine-1-oxide as yellow
crystals (7.46 g, 56%).
(2) 2,4-Dimethoxypyridine-1-oxide
Sodium methoxide is prepared by dissolving sodium metal (0.66 g) in
methanol (33 ml). This solution is mixed with 2-chloro-4-nitro-
pyridine-1-oxide (2.3 g) in methanol (20 ml) and the mixture is
refluxed for 6 hours, then filtered and the solvent evaporated in
vacuo. The resultant solid is extracted with chloroform, the
chloroform solution then being reduced in volume and left to
crystallise, yielding 2,4-dimethoxypyridine-1-oxide in 54%
yield.
(3) 1,4-Dihydroxypyrid-2-one
2,4-Dimethoxypyrid-1-oxide is refluxed together with 20% w/v HCl
for 13 hours. On cooling the solution 2,4-dihydroxypyridine-1-oxide
is obtained as an orange-white solid (0.42 g, 30%), .delta.(d.sub.6
DMSO+trace of D.sub.2 O), 6.08 (s, 1H), 6.12 (q, 1H), 7.88 (d,
1H).
EXAMPLE 2
The preparation of 1-hydroxy-4-methoxypyrid-2-one
(1) 2-Chloro-4-methoxypyridine-1-oxide
Sodium (0.46 g) is dissolved in absolute methanol (50 ml) and the
resultant solution of sodium methoxide is added to a solution of
2-chloro-4-nitropyridine-1-oxide (3.5 g, prepared as described in
Example 1) in methanol (10 ml). The reaction mixture is allowed to
stand at room temperature for 50 hours and is then subjected to
rotary evaporation to give 2-chloro-4-methoxypyridine-1-oxide.
(2) 1-Hydroxy-4-methoxypyrid-2-one
2-Chloro-4-methoxypyridine-1-oxide (3.3 g) is dissolved in 10% w/v
aqueous NaOH (33 ml) and the mixture is heated on a steam bath for
3.5 hours when it is cooled and acidified with concentrated HCl to
a pH of 2.5 to yield white crystals. Recrystallisation of these
from water gives 1-hydroxy-4-methoxypyrid-2-one (0.75 g, 20%), m.p.
174.degree.-175.degree. C., .delta.(D.sub.2 O) 5.9 (s, 1H), 6.00
(q, 1H), 7.5 (d, 1H).
EXAMPLE 3
Preparation of 1-hydroxy-4-(2'-methoxyethoxy)-pyrid-2-one
(1) 2-Chloro-4-(2'-methoxyethoxy)-pyridine-1-oxide
Sodium metal (0.23 g) is dissolved in redistilled methoxyethanol
(30 ml). The resulting solution is added to
2-chloro-4-nitro-pyridine-1-oxide (1.75 g, prepared as described in
Example 1) and stirred for 28 hours at 20.degree. C. The
methoxy-ethanol is removed by distillation under reduced pressure
leaving an oily brown solid which is washed with diethyl either (25
ml) and then dissolved in water (25 ml). The aqueous solution is
extracted into chloroform (3.times.25 ml) and the extracts are then
evaporated in vacuo to give
2-chloro-4-(2'-methoxyethoxy)-pyridine-1-oxide as a yellow
solid.
(2) 1-Hydroxy-4-(2'-methoxyethoxy)-pyrid-2-one
2-Chloro-4-(2'-methoxyethoxy)-pyridine-1-oxide is treated with 10%
w/v aqueous NaOH and the mixture is heated on a steam bath for 3
hours. The resulting solution is acidified to pH 2 with
concentrated HCl, the reduced in volume by evaporating in vacuo and
left to crystallise. The resultant white solid is recrystallised
from ethanol to give 1-hydroxy-4-(2'-methoxyethoxy)-pyrid-2-one
(0.58 g, 29%), m.p. 134.degree. C., .delta.(CDCl.sub.3) 3.42 (s,
3H), 3.7 (t, 1H), 4.08 (t, 1H), 6.05 (d, 1H), 6.05 (q, 1H), 7.62
(t, 1H).
EXAMPLE 4
Partition data on 1-hydroxypyrid-2-ones and their iron
complexes
The partition coefficient K part, being the ratio (concentration of
compound in n-octanol)/(concentration of compound in aqueous phase)
on partition between n-octanol and aqueous tris hydrochloride (20
mM, pH 7.4), is measured at 20.degree. C. the compounds of Examples
1 to 3 and 1-hydroxypyrid-2-one by way of comparison, and for their
iron complexes (at 10.sup.-4 M) by spectrophotometry. Acid washed
glassware is used throughout and, following mixing of 5 ml of the
10.sup.-4 M aqueous solution with 5 ml n-octanol for 1 minute, the
aqueous n-octanol mixture is centrifuged at 1,000 g for 30 seconds.
The two resulting phases are separated for a concentration
determination by spectrophotometry on each. For the free
hydroxypyridones, the range 220-340 nm is used for concentration
determinations whilst for the iron complexes, the range 340-640 mm
is used.
Values typical of those obtained are shown in Table 1.
TABLE 1 ______________________________________ Partition
coefficients Partition coefficient K.sub.part Iron complex
[Fe.sup.III - Compound Free Compound (compound).sub.3 ]
______________________________________ 1-hydroxypyrid-2-one 0.3
0.95 1,4-dihydroxypyrid-2-one 0.04 0.04
1-hydroxy-4-methoxypyrid-2-one 0.15 4.85
1-hydroxy-4-(2'-methoxyethoxy)- 0.14 0.6 pryid-2-one
______________________________________
EXAMPLE 5
In vitro tests of iron binding capacity
The 1-hydroxypyrid-2-ones used in this Example were prepared as
described in Examples 1, 2 and 3, and 1-hydroxypyrid-2-one was also
used for comparative purposes.
(1) Mobilisation of iron from ferritin
Horse spleen ferritin (Sigma) was without further purification and
its iron content was estimated spectrophotometrically at 420 nm.
The ferritin solution in phosphate buffered saline (Dulbecco-OXOID,
10.sup.-6 M, pH 7.4) was enclosed in a Visking dialysis tube and
dialysed against a 3.times.10.sup.-3 M buffered solution of one of
various pyridones as indicated in Table 2. The absorption spectrum
of the resulting iron(III) complex in the dialysis solution was
recorded after 6 and 24 hours. For comparative purposes, the
procedure was repeated using a blank control.
The results are shown in Table 2 where the percentage of
ferritin-bound iron removed by the compound under test is shown.
For comparative purposes, results reported in the literature for
similar tests with 1.times.10.sup.-3 M desferrioxamine (Crichton et
al, J. Inorganic Bio-chem., 1980, 13, 305) and with
6.times.10.sup.-3 M LICAMS (Tufano et al, Biochem. Biophys. Acta,
1981, 668, 420) are also given in the Table. It will be seen that
the pyridone compounds are able to remove iron effectively from
ferritin in contrast with desferrioxamine and LICAMS (although the
latter will remove iron in the presence of ascorbic acid such a
mixture is very difficult to manage clinically). These results
shown in Table 2 may be confirmed by separating apoferritin (in
admixture with ferritin) and the particular hydroxypyridone
iron(III) complex from the reaction product in each case by
chromatography on Sephadex G10.
TABLE 2 ______________________________________ Removal of iron from
ferritin Percentage of iron removed Compound 6 hours 24 hours
______________________________________ Control 0 0
1-hydroxypyrid-2-one 34.sup.(1) -- 1,4-dihydroxypyrid-2-one 22 54
1-hydroxy-2-methoxypyrid-2-one 13 46
1-hydroxy-4-(2'-methoxyethoxy)- 2 8 pyrid-2-one Desferrioxamine(1
mM) 1.5 -- LICAMS(6 mM + 12 mM 7 -- ascorbic acid)
______________________________________ .sup.(1) 1hydroxypyrid-2-one
iron complex precipitated from incubation medium.
(2) Mobilisation of iron from transferrin
Human transferrin (Sigma) was loaded with iron(III) by the method
of Bates and Schlaback, J. Biol. Chem. (1973) 248, 3228. .sup.59
Iron(III) transferrin (10.sup.-5 M) was incubated with a
4.times.10.sup.-3 M solution in tris HCl (0.1 M, pH 7.4) of one of
various pyridones as indicated in Table 3 for periods of 6 hours
and 24 hours. The solution was then dialysed against phosphate
buffered saline for 24 hours. The .sup.59 Fe remaining in the
dialysis tube was then received. For comparative purposes, this
procedure was repeated with desferrioxamine and EDTA.
The results are shown in Table 3 in terms of the percentage of
transferrin bound iron removed by the compound under test.
illustrate the efficiency of the compounds at iron removal. The
results shown in Table 3 may be confirmed by separating
apotransferrin (in admixture with transferrin) and the particular
hydroxypyridone iron complex from the reaction product in each case
by chromatography on Sephadex G10.
TABLE 3 ______________________________________ Removal of iron from
transferrin Percentage of iron removed Compound 6 hours 24 hours
______________________________________ 1-hydroxypyrid-2-one 60 73
1,4-dihydroxypyrid-2-one 80 91 1-hydroxy-4-methoxypyrid-2-one 70 71
1-hydroxy-4-(2'-methoxyethoxy)- 72 75 pyrid-2-one Desferrioxamine
17 22 EDTA 27 67 ______________________________________
EXAMPLE 6
In vivo tests of iron binding capacity
The 1-hydroxypyrid-2-one used in this Example was prepared as
described in Example 1.
Mice were injected intraperitoneally with iron dextran (2 mg) at
weekly intervals over a four week period. Two weeks after the final
injection, the mice were injected via the tail vein with .sup.59 Fe
Lactoferrin (human lactoferrin, 1 mg per injection 2 .mu.Ci). The
mice were then caged individually. After a ten day period,
1,4-hydroxypyrid-2-one was administered to groups of 8 mice at 10
mg per mouse either intraperitoneally or intragastrically (in each
case 3 of the mice received only one dose whilst 5 received 2 doses
at a 24 hour interval). The excretion of iron was recorded at
either 12 or 24 hourly intervals over a three day period before and
a two day period after administration of the compound. For
comparative purposes, the procedure was repeated with a blank
control and with desferrioxamine, also at 10 mg per mouse (the
intraperitoneally treated mice receiving one dose of
desferrioxamine and the intragastrically treated mice two doses at
a 24 hour interval).
The results are shown in Table 4, being given on the basis of the
control representing 100% excretion, and illustrate the particular
advantage of the pyridones as compared with desferrioxamine for
oral administration. It should be mentioned that the large standard
deviation (SD) values are somewhat misleading as uniformly positive
results can yield high SDs which might be taken to suggest that the
results are not significantly different from zero. However, this is
not the case here, the large SD values being a consequence of the
large range among the positive responses.
TABLE 4 ______________________________________ Excretion of iron in
vivo Intraperitoneal Intragastric Administration Administration
Number Excretion Number Excretion of of .sup.59 Fe .+-. SD of of
.sup.59 Fe .+-. SD Compound Mice percent Mice percent
______________________________________ Control 12 100 .+-. 10 -- --
1,4-dihydro- 11 195 .+-. 57 6 166 .+-. 40 xypyrid-2-one
______________________________________
EXAMPLE 7
Preparation of iron complexes
The iron complex of 1-hydroxy-4-methoxypyrid-2-one is prepared by
either procedure (a) or procedure (b). (a) An aqueous solution of
ferric chloride is reacted for 5 minutes at room temperature with
an aqueous solution containing 3 molar equivalents.sup.(1) of
1-hydroxy-4-methoxypyrid-2-one. The resultant solution is adjusted
to pH 7.0 using 2 molar aqueous sodium hydroxide and is then freeze
dried. The resulting powder is extracted with chloroform, filtered
and the filtrate subjected to rotary evaporation to give an
essentially quantitative yield of the neutral complex containing
the 1-hydroxy-4-methoxypyrid-2-one anion and the ferric cation in
3:1 proportion. Recrystallisation of the 3:1 complex from ethanol
gives orange crystals, m.p. 103.degree.-106.degree. C.
(b) An ethanolic solution of ferric chloride is reacted for 5
minutes at room temperature with a chloroform solution containing 3
molar equivalents of 1-hydroxy-4-methoxypyrid-2-one. The resultant
solution is neutralised by the addition of solid sodium carbonate,
the precipitated sodium chloride removed by filtration and the
filtrate evaporated to give an essentially quantitative yield of
the 3:1 complex, m.p. 103.degree.-106.degree. C.
The 3:1 iron(III) complexes of 1,4-dihydroxypyrid-2-one and
1-hydroxy-4-(2'-methoxyethoxy)-pyrid-2-one may be prepared in an
exactly similar manner.
When an excess (5 to 50 molar equivalents) of any pyridone is used,
both procedure (a) and procedure (b) lead to an essentially
quantitative yield of the excess pyridone in free form in admixture
with the 3:1 complex.
EXAMPLE 8
The ability of iron complexes to donate iron to apotransferrin
Apotransferrin (10.sup.-4 M) and the iron complex of
1-hydroxy-4-methoxypyrid-4-one (10.sup.-4 M; prepared as described
in Example 7) were incubated together in tris hydrochloride (50 mM,
buffered to pH 7.4) at 37.degree. C. for 10 minutes when a 1 ml
aliquot was removed from the medium and added to a PD10 colum. 0.5
ml fractions were collected directly into scintillation vials for
counting. The .sup.59 Fe associated with both the apotransferrin
and the ligand was estimated and it was found that over 90% of the
iron was removed from the iron complex.
EXAMPLE 9
In vitro tests on permeation of rat jejunal sac by iron
complexes
The iron uptake into the serosal space of the inverted rat jejunal
sac was compared for various iron compounds. Rats (male Sprague
Dawley, 60 g) were killed and the jejunum removed, everted and cut
into three segments (4 cm length). The segments were tied at both
ends and filled with Krebs Ringer buffer (0.2 ml) and incubated in
Krebs Ringer buffer containing .sup.59 Fe complexes at 37.degree.
C. for periods up to 1 hour. The contents of the sac were counted
for .sup.59 Fe and measured spectrophotometrically.
The results obtained for the three iron complexes described in
Example 7 and for seven other iron compounds which are each
contained in preparations marketed for the treatment of iron
deficiency anaemia are shown in Table 5, the iron uptake for each
compound being shown relative to that for ferric chloride as 1. It
will be seen that the complexes of Example 7 each provide a level
of iron uptake which is significantly higher than the levels
observed for any of the 7 compounds in current use for the
treatment or iron deficiency anaemia.
TABLE 5 ______________________________________ Relative Relative
Iron Iron Compound Uptake Compound Uptake
______________________________________ FeCl.sub.3 1 FeCl.sub.3 1
Fe.sup.III complex of: Fe.sup.II sulphate 2.4
1,4-dihydroxypyrid-2-one 9.4 Fe.sup.II fumarate 4.0
1-hydroxy-4-methoxy- 12.3 Fe.sup.II gluconate 1.6 pyrid-2-one
1-hydroxy-4-(2'-methoxy- 11.4 Fe.sup.II succinate 2.0
ethoxy)-pyrid-2-one Fe.sup.III EDTA 3.6 Fe.sup.III ascorbate 0.4
Fe.sup.III citrate 2.0 ______________________________________
* * * * *