U.S. patent number RE39,132 [Application Number 09/981,586] was granted by the patent office on 2006-06-13 for thiazoline acid derivatives.
This patent grant is currently assigned to University of Florida, Research Foundation, Inc.. Invention is credited to Raymond J. Bergeron, Jr..
United States Patent |
RE39,132 |
Bergeron, Jr. |
June 13, 2006 |
**Please see images for:
( Certificate of Correction ) ** |
Thiazoline acid derivatives
Abstract
Phenyl- and pyridyl-substituted thiazoline acid derivatives
useful in diagnosing and treating pathological conditions
associated with an excess of trivalent metals in humans and
animals.
Inventors: |
Bergeron, Jr.; Raymond J.
(Gainesville, FL) |
Assignee: |
University of Florida, Research
Foundation, Inc. (Gainesville, FL)
|
Family
ID: |
22507049 |
Appl.
No.: |
09/981,586 |
Filed: |
October 17, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
Reissue of: |
09144103 |
Aug 31, 1998 |
06083966 |
Jul 4, 2000 |
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Current U.S.
Class: |
514/365;
548/201 |
Current CPC
Class: |
A61P
25/00 (20180101); A61P 39/04 (20180101); A61P
19/08 (20180101); A61P 1/16 (20180101); A61P
3/12 (20180101); C07D 277/12 (20130101); A61K
31/426 (20130101); A61P 3/00 (20180101); A61P
25/28 (20180101) |
Current International
Class: |
A61K
31/425 (20060101); C07D 277/56 (20060101) |
Field of
Search: |
;514/365 ;548/201 |
References Cited
[Referenced By]
U.S. Patent Documents
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2 247 243 |
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May 1975 |
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FR |
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1292 170 |
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Oct 1972 |
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GB |
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1320534 |
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Jun 1973 |
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GB |
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1382887 |
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May 1975 |
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GB |
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WO94/11367 |
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May 1994 |
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WO |
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Oct 1997 |
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WO |
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WO 99/53039 |
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Oct 1999 |
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WO |
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WO 00/16763 |
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Mar 2000 |
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WO |
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WO 01/27119 |
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Apr 2001 |
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WO |
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|
Primary Examiner: Stockton; Laura L.
Attorney, Agent or Firm: Hamilton, Brook, Smith &
Reynolds, P.C.
Government Interests
Research leading to the completion of the invention was supported
in put by Grant Nos. 3203522-12, RO1HL42817 and RO1DK49108 awarded
by the National Institutes of Health (NIH). The United States
Government has certain rights in and to the claimed invention.
Parent Case Text
RELATED APPLICATIONS
This application contains subject matter related in that disclosed
and claimed in copending U.S. patent application Ser. No.
08/624,289 filed Mar. 29, 1996.
Claims
I claim:
1. A compound of the formula: ##STR00004## wherein: Z is CH or N; R
is HI or acyl; R.sub.1, R.sub.2, R.sub.3 and R.sub.5 may be the
same or different and represent H, alkyl or hydrocarbyl arylalkyl
having up to 14 carbon atoms; R.sub.4 is H or alkyl having 1-4
carbon atoms with the proviso that: R.sub.4 is alkyl having 1-4
carbon atoms when Z is CH, R.sub.5 is H and R.sub.4O is attached to
the carbon atom labelled 4; .Iadd.and that R.sub.5 is H, when Z is
CH, R, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are each H and
R.sub.4O is attached to the carbon atom labeled 3; .Iaddend.a salt
thereof with a pharmaceutically acceptable acid or a
pharmaceutically acceptable complex thereof.
2. A compound of claim 1 wherein Z is N and
R=R.sub.1=R.sub.2=R.sub.3=R.sub.4=R.sub.5=H.
3. A compound of claim 1 wherein Z is CH,
R=R.sub.1=R.sub.2=R.sub.3=R.sub.5=H, and R.sub.4 is alkyl having
1-4 carbon atoms.
4. A compound of claim 3 wherein R.sub.4 is methyl.[., ethyl,
n-propyl, isopropyl, n-butyl, isobutyl or t-butyl.]. .
5. A compound of claim 1 wherein Z is N,
R=R.sub.1=R.sub.2=R.sub.3=R.sub.5=H, and R.sub.4 is alkyl having
1-4 carbon atoms.
6. A compound of claim 5 wherein R.sub.4 is methyl.[., ethyl,
n-propyl, isopropyl, n-butyl, isobutyl or t-butyl.]. .
7. A compound of claim 1 having the formula: ##STR00005## wherein:
Z, R, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 have the
meanings ascribed thereto in claim 1; a salt thereof with a
pharmaceutically acceptable acid or a pharmaceutically acceptable
complex thereof.
8. A compound of claim 7 wherein Z is N and
R=R.sub.1=R.sub.2=R.sub.3=R.sub.4=R.sub.5=H.
9. A compound of claim 7 wherein Z is CH,
R=R.sub.1=R.sub.2=R.sub.3=R.sub.5=H, and R.sub.4 is alkyl having
1-4 carbon atoms.
10. A compound of claim 9 wherein R.sub.4 is methyl.[., ethyl,
n-propyl, isopropyl, n-butyl, isobutyl or t-butyl.]. .
11. A compound of claim 7 wherein Z is N,
R=R.sub.1=R.sub.2=R.sub.3=R.sub.5=H, and R.sub.4 is alkyl having
1-4 carbon atoms.
12. A compound of claim 11 wherein R.sub.4 is methyl.[., ethyl,
n-propyl, isopropyl, or t-butyl.]. .
13. A compound of claim .[.7.]. .Iadd.1 .Iaddend.wherein Z is CH,
R=R.sub.4=R.sub.1=R.sub.2=R.sub.5=H, and R.sub.3 is alkyl having
1-4 carbon atoms.
14. A compound of claim .[.7.]. .Iadd.1 .Iaddend.wherein Z is CH,
R=R.sub.4=R.sub.1=R.sub.2=R.sub.5=H, and R.sub.3 is alkyl having
1-4 carbon atoms.
15. A compound of claim .[.7.]. .Iadd.1 .Iaddend.wherein Z is CH,
R.sub.4=R.sub.3=R.sub.2=R.sub.5=H, and R.sub.1 is alkyl having 1-4
carbon atoms.
16. A compound of claim 7 wherein Z is N,
R=R.sub.4=R.sub.1=R.sub.2=R.sub.5=H, and R.sub.3 is alkyl having
1-4 carbon atoms.
17. A compound of claim 7 wherein Z is N,
R=R.sub.4=R.sub.1=R.sub.3=R.sub.5=H, and R.sub.2 is alkyl having
1-4 carbon atoms.
18. A compound of claim 7 wherein Z is N,
R=R.sub.4=R.sub.3=R.sub.2=R.sub.5=H, and R.sub.1 is alkyl having
1-4 carbon atoms.
19. An optically pure compound of claim 1 or 7.
.[.20. An (S)-enantiomer compound of claim 7 having the formula:
##STR00006## a salt thereof with a pharmaceutically acceptable acid
or a pharmaceutically acceptable complex thereof..].
21. An (S)-enantiomer compound .[.of claim 7.]. having the formula:
##STR00007## .Iadd.a salt thereof with a pharmaceutically
acceptable acid or a pharmaceutically acceptable complex
thereof.Iaddend..
22. An (S)-enantiomer compound .[.of claim 7.]. having the formula:
##STR00008## .Iadd.a salt thereof with a pharmaceutically
acceptable acid or a pharmaceutically acceptable complex
thereof.Iaddend..
.[.23. An (R)-enantiomer compound of claim 7 having the formula:
##STR00009## .].
24. An (R)-enantiomer compound .[.of claim 7.]. having the formula:
##STR00010## .Iadd.a salt thereof with a pharmaceutically
acceptable acid or a pharmaceutically acceptable complex
thereof.Iaddend..
25. An (R)-enantiomer compound .[.of claim 7.]. having the formula:
##STR00011## .Iadd.a salt thereof with a pharmaceutically
acceptable acid or a pharmaceutically acceptable complex
thereof..Iaddend.
26. A pharmaceutical composition in unit dosage form for treating a
pathological condition in a human or non-human animal that is
associated with an excess of a trivalent metal, ion or compound
thereof comprising a therapeutically effective amount of a compound
according to claim 1 or 7 and a pharmaceutically acceptable carrier
therefor.
27. A method of preventing or treating a pathological condition in
a human or non-human animal that is associated with an excess of a
trivalent metal, ion or compound thereof comprising administering
to said animal a therapeutically effective amount of a compound
according to claim 1 or 7.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel thiazoline acids and
derivatives thereof useful as chelators of trivalent metals in
therapeutic applications.
2. Discussion of the Prior Art
While many organisms are auxotrophic for Fe (III), because of the
insolubility of the hydroxide (K.sub.sf=1.times.10.sup.-38) [Acc.
Chem. Res., Vol, 12, Raymond et al, "Coordination Chemistry and
Microbial Iron Transport," pages 183-190 (1979)] formed under
physiological conditions nature has developed rather sophisticated
iron storage and transport systems. Microorganisms utilize low
molecular weight ligands siderophores, while eukaryotes tend to
utilize proteins to transport iron, e.g., transferrin, and store
iron, e.g., ferritin [Trends in Biochem. Sci., Vol. 11, Bergeron,
"Iron: A Controlling Nutrient in Proliferative Processes," pages
133-136 (1986)].
Iron metabolism in primates is characterized by a highly efficient
recycling process with no specific mechanism for eliminating this
transition metal [Clin. Physiol. Biochem., Vol. 4, Finch et al,
"Iron Metabolism," pages 5-10 (1986); Ann. Rev. Nutri., Vol. 1,
Hallberg, "Bioavailability of Dietary Iron in Man," pages 123-147
(1981); N. Engl. J. Med., Vol. 306, Finch et al, "Perspectives in
Iron Metabolism," pages 1520-1528 (1982); and Medicine (Baltimore),
Vol. 49, Fioch et al, "Ferrokinetics in Man," pages 17-53 (1970)].
Because it cannot be effectively cleared, the introduction of
"excess iron" into this closed metabolic loop leads to chronic
overload and ultimately to peroxidative tissue damage [The
Molecular Basis of Blood Diseases, Seligman et al, "Molecular
Mechanisms of Iron Metabolism," page 219 (1987); Biochem. J., VOL
229, O'Connell et al, "The Role of Iron in Ferritin- and
Haemosiderin-Mediated Lipid Peroxidation in Liposomes" pages
135-139 (1985); and J. Biol. Chem., Vol. 260, Thomas et al,
"Ferritin and Superoxide-Dependent Lipid Peroxidation," pages
3275-3280 (1985)]. There are a number of scenarios which can
account for "iron overload," e.g., high-iron diet, acute iron
ingestion or malabsorption of the metal. In each of these
situations, the patient can be treated by phlebotomy [Med. Clin. N.
Am., Vol. 50, Weintraub et al, "The Treatment of Hemochromatosis by
Phlebotomy," pages 1579-1590 (1966)]. However, there are
iron-overload syndromes secondary to chronic transfusion therapy,
e.g., aplastic anemia and thalassemia, in which phlebotomy is not
an option [Iron in Biochemistry and Medicine, Vol. II, Hoffbrand,
"Transfusion Siderosis and Chelation Therapy," page 499 (London,
1980)]. The patient cannot be bled, as the origin of the excess
iron is the transfused red blood cells; thus, the only alternative
is chelation therapy. However, to be therapeutically effective, a
chelator must be able to remove a minimum of between 0.25 and 0.40
mg of Fe/kg per day [Semin. Hematol., Vol. 27, Brittenham,
"Pyridoxal Isonicotinoyl Hydrazone: An Effective Iron-Chelator
After Oral Administration," pages 112-116 (1990)].
Although considerable effort has been invested in the development
of new therapeutics lot managing thalassemia, the subcutaneous (sc)
infusion of desferrioxamine B, a hexacoordinate hydroxamate iron
chelator produced by Streptomyces pilosus [Helv. Chim. Acta, Vol.
43, Bickel et al, "Metabolic Properties of Actinomycetes.
Ferrioxamine B;" pages 2129-2139 (1960)], is still the protocol of
choice. Although the drug's efficacy and long-term tolerability are
well-documented, it suffers from a number of shortcomings
associated with low, efficiency and marginal oral activity.
Although a substantial number of synthetic iron chelators have been
studied in recent years as potential orally active therapeutics,
e.g., pyridoxyl isonicotinoyl hydrazone (PIH) [FEBS Lett., Vol. 97,
Ponka et al, "Mobilization of Iron from Reticulocytes:
Identification of Pyridoxal Isonicotinoyl Hydrazone as a New Iron
Chelating Agent," pages 317-321 (1979)], hydroxypyridones [J. Med.
Chem., Vol. 36, Uhlir et al, "Specific Sequestering Agents for the
Actinides. 21. Synthesis and Initial Biological Testing of
Octadentate Mixed Catecholate-hydroxypyridinonate Ligands," pages
504-509 (1993); and Lancet, Vol. 1, Kontoghiorghes et al,
"1,2-Dimethyl-3-hydroxypyrid-4-one, an Orally Active Chelator for
the Treatment of Iron Overload," pages 1294-1295 (1987)] and
bis(o-hydroxyhenzyl)-ethylenediaminediacetic acid (HBED) analogues
[Ann. N.Y. Acad. Sci., Vol. 612, Grady et al, "HBED: A Potential
Oral Iron Chelator," pages 361--368 (1990)], none bas yet proven to
be completely satisfactory. Interestingly, the siderophores have
remained relatively untouched in this search. Their evaluation as
iron-clearing agents has not at all paralleled the rate of their
isolation and structural elucidation. In fact, until recently,
beyond DFO, only two of some 100 siderophores identified have been
studied in animal models: enterobactin [Gen. Pharmac., Vol. 9,
Guterman et al, "Feasibility, of Enterochelin as an Iron-Chelating
Drug: Studies with Human Serum and a Mouse Model System," pages
123-127 (1978)] and rhodotorulic acid [J. Pharmacol. Exp. Ther.,
Vol. 209, Grady et al, "Rhodotorulic Acid-Investigation of its
Potential as an Iron-Chelating Drug," pages 342-348 (1979)]. While
the former was only marginally effective at clearing iron, the
latter compound was reasonably active. Unfortunately, both of these
cyclic siderophores exhibited unacceptable toxicity, and neither
possessed any oral activity. They was abandoned as there were any
number of synthetic chelators with equally unsatisfactory
properties from which to choose.
U.S. patent application Ser. No. 08/624,289 filed Mar. 29, 1996,
the entire contents and disclosure of which are incorporated herein
by reference, discloses certain
2-pyridyl-.DELTA..sup.2-thiazoline-4-carboxylic acids and
derivatives thereof useful for the treatment of human and non-human
animals in need of therapy entailing the prevention of deposition
of trivalent metals and compounds thereof in their tissues, as well
as the elimination of such metals and compounds from biological
systems overloaded therewith.
It is an object of the present invention to provide additional
novel thiazoline acids and derivatives thereof which, because of
different volumes of distribution in patients and different
lipophilicities than the derivatives of the prior art, provide the
ability to control the pharmacokinetic properties and toxicities of
the drugs.
Another abject of the present invention is to provide novel
pharmaceutical compositions for and methods of treatment of human
and non-human animals in need of therapy entailing the prevention
of deposition of trivalent metals and compounds thereof in tissues
thereof, as well as the elimination of such metals and compounds
from systems over-loaded therewith.
SUMMARY OF THE INVENTION
The above and other object are realized by the present invention,
one embodiment of which comprises compounds of the formula:
##STR00001## wherein: Z is CH or N; R is H or acyl; R.sub.1,
R.sub.2, R.sub.3 and R.sub.5 may be the same or different and
represent H, alkyl or hydrocarbyl arylalkyl having up to 14 carbon
atoms; and R.sub.4 is H or alkyl having 1-4 carbon atoms; a salt
thereof with a pharmaceutically acceptable acid or a
pharmaceutically acceptable complex thereof.
Another embodiment of the invention relates to pharmaceutical
compositions in unit dosage form comprising a therapeutically
effective amount of the above compound and a pharmaceutically
acceptable carrier therefor.
An additional embodiment of the invention concerns methods of
preventing or healing a pathological condition in a human or
non-human animal that is associated with an excess of a trivalent
metal, ion or compound thereof comprising administering to the
animal a therapeutically effective amount of the compound defined
above.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 depicts a reaction scheme for preparing to compounds of the
invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is predicated on the discovery that compounds
of the above formula are valuable bioactive chelators or
sequestrants for trivalent metals such as Fe, Al and Cr. They can
be administered to human and non-human mammals to prevent the
deposition of, e.g., iron, in the tissues thereof. They are also
useful for the elimination of, e.g., iron, from such mammals
afflicted with, e.g., haemochromatosis, haemosiderosis and also
cirrhosis. They also find application in dialysis, encephalopathy,
osteomalacia and Alzheimer's disease.
The compounds described above are characterized by the asymmetric
carbon atom marked with an asterisk (*). The bonds surrounding
these carbon atoms are arranged tetrahedrally and the substituents
thus bonded to the asymmetric carbon atoms are in feed positions.
The formula represents optical antipodes exhibiting either the (S)
or (R) conformation as shown in (i) and (ii) below:
##STR00002##
In The above formula, R is preferably H, but may also be a suitable
acyl group which is cleavable under physiological conditions to the
free hydroxyl compounds and a biologically acceptable acid. Such
aryl groups are known in the art, e.g., the aryl radical of a
carbonic acid semiester, in particular carbonic acid
semi-C.sub.1-C.sub.4-alkyl ester or carbonic acid semi-oxaalkyl
ester in which oxaalkyl has 4-13 chain members such as an acyl
radical --C(.dbd.O)--(O--CH.sub.2--CH.sub.2).sub.n--O-Alk in which
n is an integer from 0 to 4 and Alk represents C.sub.1-C.sub.4
alkyl, in particular methyl or ethyl. Such acyl groups are, for
example, methoxycarbonyl, ethoxycarbonyl or
2-(methoxyethoxy)-ethoxycarbonyl. Further acyl radicals are, for
example, C.sub.1-C.sub.3-alkanoyl such as acetyl or propionyl, or
mono substituted or di-substituted carbamoyl such as
di-C.sub.1-C.sub.4-alkyl carbamoyl, for example, dimethylcarbamoyl
or diethylcarbamoyl, or
C.sub.1-C.sub.4-alkoxycarbonyl-C.sub.1-C.sub.4-alkylcarbareoyl, for
example, methoxycarbonylmethylcarbamoyl,
ethoxycarbonylmethylcarbamoyl or
2-ethoxycarbonylethylcarbamoyl.
R.sub.1, R.sub.2, R.sub.3 and R.sub.5 may be the same or different
and may be H, straight or branched chain alkyl having up to 14
carbon atoms, e.g., methyl, ethyl, propyl and butyl or arylalkyl
wherein the aryl portion is hydrocarbyl and the alkyl portion is
straight or branched chain, the arylalkyl group having up to 14
carbon atoms.
R.sub.4 is H or straight or branched chain alkyl having 1 to 4
carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, t-butyl.
Preferred among compounds of the above formula are those of the
formula: ##STR00003## wherein: Z, R, R.sub.1, R.sub.2, R.sub.3,
R.sub.4 and R.sub.5 have the meanings ascribed above, as well as
sale thereof with pharmaceutically acceptable acids and
pharmaceutically acceptable complexes thereof.
Particularly preferred are those compounds of the above formula
wherein: Z is CH and R=R.sub.1=R.sub.2=R.sub.3=R.sub.4=R.sub.5=H; Z
is N and R=R.sub.1=R.sub.2=R.sub.3=R.sub.4=R.sub.5=H; and most
preferably, the optically port isomers thereof.
It will be understood that salts of the compounds of the above
formula with pharmaceutically acceptable acids also comprise pan of
the present invention. Suitable such acids include hydrochloric,
sulfuric or phosphoric acids, as well as methanesulfonic, arginine,
lysine, and the like.
The invention also includes pharmaceutically acceptable sales of
the carboxylic acids of the above formula. Thus, ammonium salts and
metal salts such as the alkali metal and alkaline earth metals
sails, e.g., sodium, potassium, magnesium or calcium salts, as well
as divalent metal salts such as zinc, and salts with suitable
organic amines, there coming into consideration such salt formation
especially aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or
araliphatic primary, secondary or tertiary mono-, di- or
poly-amines, and also heterocyclic bases. Such amines are, for
example, lower alkylamines, for example, triethylamine,
hydroxy-lower alkylamines, for example, 2-hydroxyethylamine,
bis-(2-hydroxyethyl)-amine or tris-(2-hydroxyethyl)-amine, basic
aliphatic esters of carboxylic acids, for example, 4-aminobenzoic
acid 2-diethylaminoethyl ester, lower alkyleneamines, for example,
1-ethylpiperidine, cycloalkylamines, for example,
dicyclohexylamine, or benzylamines, for example,
N,N'-dibenzylethylenediamine, also bases of the pyridine type, for
example, pyridine, collidine or quinoline. Further salts include
internal salts (zwitterionic forms of compounds of the invention),
wherein a basic group, for example, the basic nitrogen atom present
in the pyridine ring, is protonated by a hydrogen ion originating
from an acid group in the molecule.
Owing to their high solubility and good tolerability, metal ion
complexes of compounds of the above formulae, especially with
suitable paramagnetic and/or radioactive metals, can be used as
contrast agents in diagnostic medicine, for example, X-ray,
radionuclide, ultrasound and/or magnetic resonance diagnostics.
Compounds of the above formulae may be synthesized according to the
reaction scheme set forth in FIG. 1 wherein D-cys is D-cysteine or
a reactive functional derivative thereof.
Free hydroxy groups present in the compounds of the above formulae
are optionally protected by conventional protecting groups. Such
protecting groups protect the hydroxy groups from undesired
condensation reactions, substitution reactions and the like. The
protecting groups can be introduced and removed easily, i.e.,
without undesirable secondary reactions taking place, for example,
by solvolysis or reduction, in a manner known per se. Protecting
groups and the methods by which they are introduced and split off
are described, for example, in "Protective Groups in Organic
Chemistry," Plenum Press, London, New York (1973) and also in
"Melhoden der organischen Chemic;" Houben-Weyl, 4th edition, Vol.
15/1, Georg Thieme Verlag, Stuttgart (1974).
Suitable hydroxy-protecting groups are for example, acyl radicals
such as lower alkanoyl optionally substituted, for example, by
halogen such as 2,2-dichloacetyl, or acyl radicals of carbonic acid
semiesters especially tert.-butoxycarbonyl, optionally substituted
benzyloxycarbonyl, for example, 4-nitrobenzyloxycarbonyl, or
diphenylmetboxycarbonyl, alkenyloxycarbonyl, for example,
allyloxycarbonyl or 2-halo-lower alkoxycarbonyl such as
2,2,2-triehloroethoaycarbonyl, also trityl or formyl, or organic
silyl radicals, also etherifying groups that can readily be split
off such as tert-lower alkyl, for example, tert-butyl, or 2-oxa- or
2-thia-cycloalkyl having 5 or 6 ring atoms, for example,
tetrahydrofuryl or 2-tetrahydropyranyl or corresponding this
analogues, and also optionally substituted 1-phenyl-lower alkyl
such as optionally substituted benzyl or diphenylmethyl, there
coming into consideration as substituents of the phenyl radicals,
for example, halogen such as chlorine, lower alkoxy such as
methoxy, and/or nitro.
A reactive functional derivative of a carboxy group (Y) is, for
example, an acid anhydride, an activated ester or an activated
amide, cyano, a group of the formula --C(OR.sub.n).sub.3 or
--C(.dbd.NH)--R.sub..delta. in which R.sub.n is lower alkyl.
Corresponding derivatives are well known in the art.
Of the anhydrides, the mixed anhydrides are especially suitable.
Mixed anhydrides arc, for example, those with inorganic acids such
as hydrohalic acids, i.e., the corresponding acid halides, for
example, chlorides or bromides, also with hydrazoic acid, i.e., the
corresponding acid azides. Further mixed anhydrides are, for
example, these with organic carboxylic acids such as with lower
alkanecarboxylic acids optionally substituted, for example, by
halogen such as fluorine or chlorine, for example, pivalic acid or
trichloroacetic acid, or with semiesters, especially lower alkyl
semiesters of carbonic acid such as the ethyl or isobutyl semiester
of carbonic acid, or with organic, especially aliphatic or
aromatic, sulfonic acids, for example, p-toluenesulfonic acid. Of
the activated esters, there may be mentioned, for example, esters
with vinylogous alcohols (i.e., enols such as vinylogous lower
alkenols), or iminomethyl ester halides such as dimethyliminomethyl
ester chloride (prepared from the carboxylic acid and, for example,
dimethyl-(1-chlorethylidine)-iminium chloride of the formula
(CH.sub.3).sub.2N.sup.{circle around
(+)}.dbd.C(Cl)CH.sub.3Cl.sup.{circle around (-)}, which can be
obtained, for example, from N,N-dimethylacetamide and phosgene), or
aryl esters such as preferably suitable substituted phenyl esters,
for example, phenyl ester substituted by halogen such as chlorine,
and/or by nitro, for example, 4-nitrophenyl ester,
2,3-dinitrophenyl ester or 2,3,4,5,6-pentachlorophenyl ester,
N-hetero-aromatic esters such as N-benztriazole esters, for
example, 1-benztriazole ester, or N-diacylimino esters such as
N-succinylamino or N-phthalylimino ester. Suitable activated amides
are, for example, imidazolides, also 1,2,4-triazolides,
tetrazolides or 1,2,4-oxadiazolinonides.
A preferred form of this process according to the invention is the
reaction of a compound of the nitrile with a cysteine derivative.
The reaction is carried out in an inert solvent such as an aqueous
solvent at ambient temperature or, preferably, at slightly elevated
temperature, for example, at about 50.degree. to 80.degree. C., and
preferably under an inert gas atmosphere.
In resulting compounds in which one or more functional (hydroxy)
groups arc protected, the latter can be freed, optionally in stages
or simultaneously, in a manner known per se, by means of
solvolysis, especially hydrolysis or acidolysis, or in some cases
also by means of careful reduction. Silyl protecting groups are
advantageously split off with fluorides, for example,
tetraethylammonium fluoride.
Salts of compounds of the invention can be manufactured in a manner
known per se. Thus, salts of compounds having acidic groups can be
formed, for example, by treating with metal compounds such as
alkali metal salts of suitable organic carboxylic acids, for
example, the sodium salt of .alpha.-ethylcaproic acid, or with
inorganic alkali metal or alkaline earth metal salts, for example,
sodium bicarbonate, or with ammonia or a suitable organic amine,
preferably stoichiometric quantities or only a small excess of the
salt-forming agent being used. Acid addition sails of compounds of
the invention are obtained in a customary manner, for example, by
treating with an acid or a suitable anion-exchange reagent.
Internal salts of compounds of the invention (zwilterionic forms)
can be formed, for example, by neutralizing the compounds or salts
such as acid addition salts, to the isoelectric point, for example,
with weak bases, or by treating with liquid ion exchangers.
Salts can be converted in a customary manner into the free
compounds: metal and ammonium salts can he converted into the free
compounds, for example, by treating with suitable acids, and acid
addition salts, for example, by treating with a suitable basic
agent.
The starting materials are available commercially and/or known or
can be manufactured by known processes.
The racemate can be split in a manner known per se, for example,
after conversion of the optical antipodes into diastereoisomers,
for example, by reaction with optically active acids or bases.
The pharmacologically acceptable compounds of the present intention
can be used, for example, for the manufacture of pharmaceutical
compositions which contain an effective amount of the active
substance together or in admixture with inorganic or organic, solid
or liquid, pharmaceutically acceptable carriers.
The pharmaceutical compositions according to the invention are
those which are suitable for enteral, such as oral, administration
and for parenteral, such as subcutaneous, administration to
warm-blooded animals, especially humans, and which contain the
pharmacologically active substance on its own or together with a
pharmaceutically acceptable carrier. The dosage of the active
substance depends on the species of warm-blooded animal and on the
age and individual condition, the illness to be treated and also on
the mode of administration.
The novel pharmaceutical preparations contain from approximately
10% to approximately 95%, and preferably from approximately 20% to
approximately 90%, of the active substance. Pharmaceutical
compositions according to the invention can, for example, be in
unit dose form, such as dragees, tablets, capsules, suppositories
or ampoules, and contain from approximately 0.05 g to approximately
10.0 g, and preferably from approximately 0.3 g to approximately
1.0 g, of the active ingredient.
The pharmaceutical compositions of the present invention ate
manufactured in a manner known per se, for example, by means of
conventional mixing, granulating, confectioning, dissolving or
lyophilizing processes Pharmaceutical compositions for oral use can
be obtained by combining the active substance with one or more
solid carriers, if desired, granulating a resulting mixture and
processing the mixture or granulate, if desired or necessary after
the addition of suitable adjuncts, to form tablets or dragee cores.
In so doing, they can also be incorporated into plastics carriers
which release the active substances or allow them to diffuse in
controlled amounts.
Suitable carriers are especially liners such as guars, for example,
lactose, saccharose, mannitol or sorbitol, cellulose preparations
and/or calcium phosphates, for example, tricalcium phosphate or
calcium hydrogen phosphate, also binders such as starches, for
example, corn, wheat, rice or potato starch, gelatine, tragacanth,
methylcellulose, hydroxypropylmethylcellulose, sodium
carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if
desired, disintegrators such as the above-mentioned starches, also
carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar,
alginic acid or a salt thereof such as sodium alginate. Adjuncts
are especially flow-regulating and lubricating agents, for example,
silica, talc, stearic acid or salts thereof such as magnesium or
calcium stearate, and/or polyethylene glycol. Dragee cores arc
provided with suitable coatings that are, if desired, resistant to
gastric juice, there being used, inter alia, concentrated sugar
solutions which optionally contain gum arabic, tale,
polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide,
lacquer solutions in suitable organic solvent, or solvent mixtures
or, for the manufacture of coatings that are resistant to gastric
juice, solutions of suitable cellulose preparations such as
acetylcellulose phthalate or hydroxypropylmethylcellulose
phthalate. Coloring substances or pigments can he added to the
tablets or dragee coatings, for example, for the purpose of
identification or for indicating different costs of active
substance.
Other orally administrable pharmaceutical compositions are
dry-filled capsules made of gelatin and also soft, sealed capsules
made of gelatin and a plasticizer such as glycerol or sorbitol. The
dry-filled capsules may contain the active ingredient in the form
of a granulate, for example, in admixture with fillers such as corn
starch, binders and/or glidants such as talc or magnesium stearate
and optionally stabilizers. In soft capsules, the active ingredient
is preferably dissolved or suspended in suitable liquids or
wax-like substances such as fatty oils, paraffin oil or
polyethylene glycols, it being possible also for stabilizers to be
added.
Other forms of oral administration am, for example, syrups prepared
in a customary manner that contain the active ingredient in, for
example, suspended form and in a concentration of approximately
from 5% to 20%, and preferably approximately 10%, or in a similar
concentration that provides a suitable single dose when
administered, for example, in measures of 5 or 10 ml. Also suitable
are, for example, powdered or liquid concentrates for preparing
shakes, for example, in milk. Such concentrates can also be packed
in single-dose quantities.
Particularly suitable dosage forms for parenteral administration
are sterile aqueous solutions of an active ingredient in
water-soluble form, for example, a water-soluble salt, or sterile
aqueous injection suspensions which contain substances increasing
the viscosity, for example, sodium, carboxymethyl cellulose,
sorbitol and/or dextran, and optionally stabilizers. In addition,
the active ingredient, with or without adjuvants, can also be in
lyophilized farm and brought into solution prior to parenteral
administration by the addition of suitable solvents.
The invention also relates to compositions for diagnostic purposes
that contain a suitable metal complex of a compound of the formula
wherein Z, R, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are as
previously defined.
The invention also relates to a method of treatment of pathological
conditions in a mammal, especially human, which as has been
described hereinabove, are associated with an excess of a trivalent
metal cation such as aluminum or, especially, iron (III), in the
body, which method comprises administering, preferably orally, a
prophylactically or therapeutically effective amount of a compound
of the formula or of a pharmaceutically acceptable salt thereof.
There are used for this purpose especially the above-mentioned
pharmaceutical composition, a daily dose of from approximately 50
mg to approximately 10,000 mg, and preferably from approximately
300 mg to approximately 1,000 mg, of a compound of the present
invention being administered to a warm-blooded animal of
approximately 70 kg body weight. The dosage can be administered
orally in several, for example, three, individual doses. For
systemic, e.g., subcutaneous, administration, the more
water-soluble salt forms of the compounds of the formula, e.g., the
sodium salt, are preferred, for example, orally, or alternatively,
subcutaneously.
The following examples serve to illustrate the invention, but
should not he construed as a limitation thereof. Temperatures are
given in degrees Centigrade.
Preparation of Drugs
Drug solutions were prepared in 60% water, 40% Cremophor RH-40.
EXAMPLE 1
2,4-Dihydroxybenzonitrile was prepared according to the method of
Marcus in Ber. disch. chem. Ges. 1981, 24, 3651, as follows:
A mixture of 2,4-dihydroxybenzaldehyde (5.0 g, 36.2 mmol), sodium
acetate (5.94 g, 72.4 mmol), nitroethane (5.44 g, 72.4 mmol) and
glacial acetic acid (10 ml) was refluxed for 6 hours. After
cooling, the mixture was poured onto ice (100 g) and extracted with
ethyl acetate (4.times.50 ml). The combined organic layers were
washed with saturated NaHCO.sub.3 until the pH of the aqueous layer
remained at 8, dried (Na.sub.2SO.sub.4) and the solvent removed in
vacuo. Flash chromatography (SiO.sub.2cyclohexane:ethyl
acetate=1:1) afforded 2,4-dihydroxybenzonitrile (2.87 g, 59%) as a
pale yellow solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 6.33
(d, 1H, J=8.6 Hz), 6.43 (s, 1H), 7.37 (d, 1H, J=8.6 Hz), 10.35 (s,
1H), 10.78 (s, 1H), IR (KBc) 2200 cm.sup.-1.
EXAMPLE 2
4,5-Dihydro-2-(2,4-dihydroxyphenyl)-thiazole-4-(S)-carboxylic acid
was prepared as follows:
D-cysteine hydrochloride monohydrate (6.8 g, 38.7 mmol) was added
to a solution of 2,4-dihydroxybenzonitrile (3.5 g, 25.9 mmol)
prepared in Example 1, in a mixture of degassed methanol (105 ml)
and 0,2 To phosphate buffer, pH 5.95 (70 ml). NaHCO.sub.3 (3.25 g,
38.7 mmol) was carefully added and the mixture was slimed at
70.degree. C. under Ar for 54 hours. Volatile components were
removed under reduced pressure and the solution was acidified with
1 N NCL to pH 2. The resulting brown precipitate was vacuum
filtered and the solid was washed with water (40 ml) and ethanol
(20 ml). The crude product was dissolved in saturated NaHCO.sub.3
(700 ml) and the aqueous solution washed with ethyl acetate
(2.times.200 ml). The aqueous layer was filtered through a fine
frit and acidified with 1 N HCI to pH 2. The precipitated product
was vacuum filtered. The aqueous layer was extracted with ethyl
acetate (4.times.400 ml), the combined organic extracts were dried
(Na.sub.2SO.sub.4) and the solvent was removed in vacuo. The
remaining solid was combined with the precipitated product and
dried under high vacuum at 40.degree. C. for 12 hours to give
45-dihydro-2-(2,4-dihydroxyphenyl)-thiazole-4(S)-carboxylic acid
(4.08 g. 66%), mp 266-268.degree. C. (dec) [Ind. J. Chem., Vol.
15B, Kishore et al, pages 255-257 (1977) for (L)-isomer.
261-262.degree. C.]. .sup.1NMR (300 MHz, DMSO-d.sub.6) .delta. 3.61
(m, 2H), 5.38 (dd, 1H, 7.2/9.4 Hz), 6.31 (d, 1H, J=2.3 Hz), 6.38
(dd, 1H, J=2.3/8.6 Hz), 7.25 (d, 1H, J=8.6 Hz), 10.25 (br s, 1H),
12.60 (br s, 1H), 13.15 (br s, 1H). Anal. calc. for
C.sub.10H.sub.9NO.sub.4S: C 50.20, H 3.79, N 5.85. Found: C 50.13,
H 3.82, N 5.85.
Compounds of the invention in the scheme of FIG. 1 wherein Z is N
may be prepared as described above in Examples 1 and 2 substituting
the corresponding pyridyl aldehyde for
2,4-dihydroxybenzaldehyde.
The biological activity and properties of the compounds of the
invention were evaluated as follows employing
4,5-dihydro-2-(2,4-dihydroxyphenyl)-thiazole-4-(S)-carboxylic acid
(1).
EXAMPLE 3
In Rats
Initial besting of 1 was performed in the non-iron-overloaded, bile
duct-cannulated rat [J. Med. Chem., Vol. 34, Bergeron et al,
"Synthesis and Biological Evaluation of Hydroxamate-Based Iron
Chelators," pages 3182-3187 (1991)]. The drug was prepared as a
solution in 40% Cremophor-H.sub.2O and administered at a dose of
150 .mu.mol/kg p.o. The rats were fasted for 24 hours before
dosing. The efficiency of iron excretion induced by 1 was
2.4.+-.0.92%.
EXAMPLE 4
In Monkeys
Given the results in the rat model, the ability of 1 to promote
iron excretion in the non-overloaded primate model [Blood, Vol. 79,
Bergeron et al, "A Comparison of the Iron-Clearing Properties of
1,2-Dimethyl-3-Hydroxypyrid-4-One, 1,2-Diethyl-3-Hydroxypyrid-4-one
and Deferoxamine;" pages 1882-1890 (1992)] was evaluated. The drug
was prepared as a solution in 40% Cremophor-H.sub.2O and
administered at a dose of 150 .mu.mol/kg p.o. The monkeys were
fasted for 24 hours before dosing. Immediately prior to drug
administration, the monkeys were sedated with ketamine (7-10 mg/kg.
i.m.) and given scopolamine (0.04-0.07 mg/kg/i.m. to prevent
ketamine-related salivation and vomiting. At the dose of 150
.mu.mol/kg, the efficiency of 1 was 4.2.+-.1.4% (n=4).
* * * * *