U.S. patent application number 10/630650 was filed with the patent office on 2004-06-17 for stabilized thyroxine compounds.
This patent application is currently assigned to New River Pharmaceuticals Inc.. Invention is credited to Le Clercq, Anne-Frederique, Piccariello, Thomas.
Application Number | 20040116391 10/630650 |
Document ID | / |
Family ID | 23749557 |
Filed Date | 2004-06-17 |
United States Patent
Application |
20040116391 |
Kind Code |
A1 |
Piccariello, Thomas ; et
al. |
June 17, 2004 |
Stabilized thyroxine compounds
Abstract
Throxinyldimethylphosphinate was invented as a prodrug to
stabilize thyroxine, a drug widely used to treat hypothyroidism and
depression. The presence of the dimethylphosphinate group at the
phenolic hydroxyl of thyroxine is key to preventing thyroxine from
decomposing through the proposed pathway. The prodrug will be
hydrolyzed in the stomach or the gut into thyroxine and the
biologically inert dimethylphosphinic acid. Related products may be
stabilized with the same or similar protecting groups.
Inventors: |
Piccariello, Thomas;
(Blacksburg, VA) ; Le Clercq, Anne-Frederique;
(Paris, FR) |
Correspondence
Address: |
HUNTON & WILLIAMS LLP
INTELLECTUAL PROPERTY DEPARTMENT
1900 K STREET, N.W.
SUITE 1200
WASHINGTON
DC
20006-1109
US
|
Assignee: |
New River Pharmaceuticals
Inc.
|
Family ID: |
23749557 |
Appl. No.: |
10/630650 |
Filed: |
July 31, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10630650 |
Jul 31, 2003 |
|
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09440635 |
Nov 16, 1999 |
|
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6627660 |
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Current U.S.
Class: |
514/114 ;
514/540; 514/63 |
Current CPC
Class: |
A61P 5/14 20180101; A61K
31/198 20130101 |
Class at
Publication: |
514/114 ;
514/063; 514/540 |
International
Class: |
A61K 031/695; A61K
031/66; A61K 031/24 |
Claims
1. A composition comprising a triiodothyronine protected at a
phenolic hydroxyl with a protecting group said protecting group
selected from the group consisting of dialkylphosphinate,
diarylphosphinate, alkylarylphosphinate, dialkylphosphate,
diarylphosphate, aklylarylphosphate, acetyl, trialkylsilyl, and
benzyloxy carbonyl.
2. The composition claim 1, wherein the dialkylphosphinate is
selected from a C.sub.1 to C.sub.18 substituted alkyl.
3. The composition claim 1, wherein the dialkylphosphinate is
selected from a C.sub.1 to C.sub.18 unsubstituted alkyl.
4. The composition of claim 1, wherein the dialkylphosphinate is
dimethylphosphinate
5. The composition of claim 1, wherein the dialkylphosphinate is
diethylphosphinate.
6. The composition of claim 1, wherein the diarylphosphinate is a
substituted phenyl.
7. The composition of claim 1, wherein the diarylphosphinate is an
unsubstituted phenyl.
8. The composition claim 1, wherein the dialkylphosphate is
selected from a C.sub.1 to C.sub.18 substituted or unsubstituted
alkyl.
9. The composition of claim 1, wherein the dialkylphosphate is
dimethylphosphate
10. The composition of claim 1, wherein the dialkylphosphate is
diethylphosphate.
11. The composition of claim 1, wherein the diarylphosphate is a
substituted phenyl.
12. The composition of claim 1, wherein the diarylphosphate is an
unsubstituted phenyl.
13. The composition of claim 1, further comprising a
pharmaceutically acceptable excipient.
14. A method of treating a thyroid related condition comprising
treating a patient in need thereof with the composition of claim
13.
15. The method of claim 14 wherein said condition is hypothyroidism
or depression.
16. A method of stabilizing and increasing the shelf life of a
thyroid hormone comprising the composition of claim 1.
17. A composition comprising a reverse triiodothyronine protected
at a phenolic hydroxyl with a protecting group, said protecting
group selected from the group consisting of dialkylphosphinate,
diarylphosphinate, alkylarylphosphinate, dialkylphosphate,
diarylphosphate, acetyl, and benzyloxy carbonyl.
18. The composition of claim 17, further comprising a
pharmaceutically acceptable excipient.
19. A method of treating a thyroid related condition comprising
treating a patient in need thereof with the composition of claim
18.
20. The method of claim 19 wherein said condition is hypothyroidism
or depression.
21. A method of stabilizing and increasing the shelf life of a
thyroid hormone comprising the composition of claim 17.
22. A composition comprising a 3,5 diiodothyronine protected at a
phenolic hydroxyl with a protecting group, said protecting group
selected from dialkylphosphinate, diarylphosphinate,
alkylarylphosphinate, dialkylphosphate, diarylphosphate, acetyl,
and benzyloxy carbonyl
23. The composition of claim 22 wherein the 3,5 diiodothyronine is
selected from 3,5 diiodothyronine, 3',5' diiodothyronine, and 3,3'
diiodothyronine.
24. The composition of claim 23, further comprising a
pharmaceutically acceptable excipient.
25. A method of treating a thyroid related condition comprising
treating a patient in need thereof with the composition of claim
24.
26. The method of claim 25 wherein said condition is hypothyroidism
or depression.
27. A method of stabilizing and increasing the shelf life of a
thyroid hormone comprising the composition of claim 22.
28. A composition comprising a 3-monoiodothyronine protected at a
phenolic hydroxyl with a protecting group selected
dialkylphosphinate, diarylphosphinate, alkylarylphosphinate,
dialkylphosphate, diarylphosphate, acetyl, and benzyloxy
carbonyl.
29. The composition of claim 28, further comprising a
pharmaceutically acceptable excipient.
30. A method of treating a thyroid related condition comprising
treating a patient in need thereof with the composition of claim
29.
31. The method of claim 30 wherein said condition is hypothyroidism
or depression.
32. A method of stabilizing and increasing the shelf life of a
thyroid hormone comprising the composition of claim 28.
33. A composition comprising a thyroxine protected at the phenolic
hydroxyl with a protecting group selected from diarylphosphinate,
alkylarylphosphinate, diarylphosphate, acetyl, and benzyloxy
carbonyl.
34. The composition of claim 33, further comprising a
pharmaceutically acceptable excipient.
35. A method of treating a thyroid related condition comprising
treating a patient in need thereof with the composition of claim
34.
36. The method of claim 35 wherein said condition is hypothyroidism
or depression.
37. A method of stabilizing and increasing the shelf life of a
thyroid hormone comprising the composition of claim 33.
38. The pharmaceutical composition of claim 13, 18, 24, 29, or 34
wherein said composition is in the form of an ingestible
tablet.
39. The pharmaceutical composition of claim 13, 18, 24, 29, or 34
wherein said composition is in the form of an intravenous
preparation.
40. The pharmaceutical composition of claim 13, 18, 24, 29, or 34
wherein said composition is in the form of an oral dosage.
Description
CROSS RELATED APPLICATION
[0001] This application claims priority to and is a
continuation-in-part of U.S. application Ser. No. 09/440,635 filed
on Nov. 16, 1999 which is hereby incorporated by reference in its
entirety.
FIELD OF THE INVENTION
[0002] This invention relates to the use of a protecting group to
stabilize thyroxine and related compounds, thus extending the shelf
life of the drugs.
BACKGROUND OF THE INVENTION
[0003] Thyroid hormones T4 and T3 play a crucial role in metabolic
homeostasis and affect the function of virtually every organ
system. In healthy individuals, serum concentrations of the thyroid
hormones are controlled by a classic negative-feedback system
involving the thyroid gland, the pituitary gland, the hypothalamus
and peripheral tissues, such as the liver. In response to the
thyroid-stimulating hormone (TSH; also known as thyrotropin)
produced by the pituitary, the thyroid gland normally releases an
estimated 70 to 90 mcg of T4 and 15 to 30 mcg of T3 into the blood
stream per day. Although T3 is secreted by the healthy thyroid, the
major portion of T3 in circulation is thought to result from
deiodination of T4 by peripheral tissues, particularly the liver.
Synthesis and release of TSH by the pituitary is stimulated by
thyroid-releasing hormone (TRH) a tripeptide produced by the
hypothalamus in response to changes in metabolism caused by low
levels of the thyroid hormones.
[0004] Thyroid disorders are common and include hyper- and
hypothyroidism. Hypothyroidism is typically characterized by an
elevated level of TSH, but varies widely in its clinical
presentation. Furthermore, while some patients present with obvious
clinical symptoms, others require the use of biochemical tests to
determine the status of thyroid function. As a result,
hypothyroidism is generally considered to be under diagnosed. In
recent years, a number of hypothyroid syndromes with subtle
presentations have been identified. Subclinical hypothyroidism
refers to a condition marked by normal levels of T4 and T3 with
elevated TSH. "Euthyroid sick syndrome" and "low T3 syndrome" refer
to a condition where low serum levels of T3 are present but normal
TSH and T4 levels are observed. These conditions have been
associated with a number of nonthyroidal illnesses including
congestive heart failure, clinical depression, mood disorders.
Whether thyroid hormone replacement therapy is efficacious in the
treatment of such disorders remains to be established.
[0005] Hypothyroidism is the most common disorder of the thyroid
and is manifested through the thyroid gland's inability to produce
sufficient thyroid hormone, primarily 3,3',5-triiodothyronine (also
known as T3). Symptoms associated with hypothyroidism include cold
intolerance, lethargy, fatigue, chronic constipation and a variety
of hair and skin changes. Although none of these conditions are
life threatening, the disease, left untreated, could result in
myxedema, coma, or death.
[0006] The cause of hypothyroidism in the U.S. is brought about by
either autoimmune destruction of the thyroid tissue (Hashimoto's
disease), .sup.131I therapy, or ablative surgery. It is estimated
that 8 to 10 million people in the United States have low thyroid
gland function, but only about 4 to 5 million hypothyroid cases
have been diagnosed and treated. The prevalence of hypothyroidism
increases with age, particularly within the female population. The
modern history of thyroid medication starts in the 1890's when
desiccated pig thyroid was used to treat hypothyroidism. Thyroxine
(3,3', 5, 5'-tetraiodothyronine), also known as T4, was introduced
over forty years ago as a means to deliver the T3 hormone slowly
without subjecting the patient to a transient hyperthyroid state. A
synthetic drug based on blending T3 with T4 in a biomimetic fashion
was introduced as an improved version. The medical community has
discouraged this regimen, however, due to its potential for
life-threatening T3 spikes.
[0007] More recently, SYNTHROID, a synthetic T4 compound, has
captured more than 70% of the hypothyroidism market. SYNTHROID's
sales are reported to be in excess of $500 million (with additional
sales in the market being taken by generic versions of
thyroxine).
[0008] Although T4 is a safe and effective way to treat
hypothyroidism, a potential problem exists. Sufficient data has
been generated that shows that SYNTHROID has a relatively short
shelf life. The FDA has recommended that manufacturers of thyroid
drugs address this problem.
[0009] U.S. Pat. No. 5,225,204 is directed to improving the
stability of levothyroxine sodium. This patent indicates that the
stability of the levothyroxine is affected by the presence of some
carbohydrate excipients, such as dextrose, starch, sugar, and
lactose. This patent claims that stability is achieved through
mixing the levothyroxine with a cellulose carrier, with or without
the addition of either polyvinyl pyrrolidine (PVP) or a
Poloxamer.
[0010] U.S. Pat. No. 5,955,105 is also directed to providing an
improved, stable, solid dosage form of thyroid hormone
pharmaceutical preparations. This patent claims pharmaceutical
preparations of thyroxine drugs including a water-soluble glucose
polymer and a partially soluble or insoluble cellulose polymer to
provide the stability. The indicated stability is determined as an
absence of potency loss when the preparation is stored at 40
degrees C. and 75% relative humidity for six months. U.S. Pat. No.
5,955,105 is hereby incorporated by reference, particularly for its
teachings on components of and production of pharmaceutical
preparations of thyroxine drugs.
[0011] It has been reported that the major product of T4
decomposition is diiodotyrosine (DIT). Latham, et al., showed that
T4 in the blood decomposes into quinone-containing molecules. Both
of these reports lead to the conclusion, heretofore unreported,
that the pathway for T4 decomposition goes through a hydrolysis
step with the loss or cleavage of an iodide. The energy required to
cleave an sp.sup.2-hybridized iodide-carbon bond, as in the case of
T4, is not available under ambient conditions. As shown in FIG. 1,
tautomerization prior to hydrolysis is required in order for T4 to
decompose into DIT and iodoquinone. In other words, the spontaneous
tautomerization of T4 is the "trigger" for its decomposition.
[0012] The energy required to cleave a phosphorus-oxygen bond is
greater than that for breaking a hydrogen-oxygen bond. The present
invention prevents the tautomerization by replacing the hydrogen on
the phenolic hydroxyl with a phosphinate group. By preventing
tautomerization (as shown in FIG. 3), the hydrolysis step cannot
take place, thereby, reducing the lability of T4 to hydrolysis and
increasing its shelf life.
[0013] The dimethylphosphinate group has been used as a protecting
group for tyrosine in peptide synthesis. Ueki et al., Tetrahedron
Letters 27(35):4181-4184 (1986). The purpose of this group,
however, was only to offer protection during peptide synthesis. It
was not used to stabilize any other compounds, and was used only as
part of a step during synthesis, never as a compound for use as a
pharmaceutical composition. One aspect of the present invention is
that it was not heretofore appreciated that stabilization was
necessary in thyroid hormones. This problem is herein both
recognized and solved by the use of phosphinate (and possibly
other) protecting groups on the phenolic hydrogen. The resulting
protected hormone is not deprotected in vitro. Rather, the hormone
or hormone precursor is ingested while still protected by the
phosphinate group.
[0014] The result of the present invention is a prodrug to a
thyroid hormone, which will be converted to the thyroid hormone in
vivo after being provided to the patient in a treatment regimen.
The prodrug will be hydrolyzed in the stomach or the gut into
thyroxine and the biologically inert dimethylphosphinic acid. This
provides a drug with all the therapeutic advantages of SYNTHROID
with the additional advantage of increased stability, i.e., longer
shelf life. Another advantage is that a thyroxine product with
increased stability will be useful in producing either an
injectable product or oral dosage forms such as tablets, capsules,
solutions and oral suspensions (suitable for children) which are
desirable. Yet another advantage of the present invention is a
method to stabilize and increase the shelf life of thyroxine and
related thyroid hormone compounds.
[0015] T3 is metabolically active via binding nuclear thyroid
hormone receptors and modulating transcription of specific genes.
T4 is far less active in the regulation of transcription and is
generally considered a prohormone. The metabolic effects of T4
result from the conversion of T4 to T3 by deiodinase enzymes in
peripheral tissues, and at the subcellular level once T4 enters a
target cell. As noted previously, the T3 in circulation is largely
the result of T4 to T3 conversion in the liver.
[0016] The use of the active hormone, T3, as replacement therapy in
hypothyroid conditions has met with limited success primarily
because occasionally rapid increases in serum concentrations, or
"spiking" levels, of this hormone in the serum occur, which could
prove dangerous to patients whose cardiac status is compromised.
For this reason, therapy with the prohormone, T4, has become the
treatment of choice in hypothyroidism since, to be active, it first
must be converted to T3, in vivo, a process which eliminates the
potential for spiking T3 serum levels and any serious sequela.
However, recent studies of T4 suggest that a general decline in a
patient's ability to convert T4 to T3 is associated with aging, and
also has been observed where stress or concurrent disease is
present. Additionally, a deficiency in the T4 to T3 conversion
capacity of particular organs or organ systems may exist. Given the
problems associated with the use of either T3 or T4 as thyroid
hormone replacement as herein identified, there is a need for an
efficient, effective, low-cost and readily available mechanism for
the delivery of thyroid hormones and derivatives thereof. Further,
there is a need for compositions and methods to treat hypothyroid
conditions and control the absorption of T3 in vivo.
[0017] The compounds of the present invention may be provided in
several useful forms, including pharmaceutical compositions in the
form of ingestable tablets, capsules, oral solutions and
suspensions, or intravenous solutions.
SUMMARY OF THE INVENTION
[0018] One embodiment of the invention comprises an iodothyronine
compound protected at the phenolic hydroxyl with a protecting
group. In a preferred embodiment the iodothyronine compound is a
triiodothyronine protected at a phenolic hydroxyl with a protecting
group said protecting group selected from the group consisting of
dialkylphosphinate, diarylphosphinate, alkylarylphosphinate,
dialkylphosphate, diarylphosphate, aklylarylphosphate, acetyl,
trialkylsilyl, and benzyloxy carbonyl. In another embodiment the
iodothyronine compound is reverse triiodothyronine. In another
embodiment the iodothyronine compound is thyroxine. In another
embodiment the iodothyronine compound is 3,5 diiodothyronine. In
another embodiment the 3,5 diiodothyronine is selected from 3,5
diiodothyronine, 3',5' diiodothyronine, and 3,3' diiodothyronine.
In another embodiment the iodothyronine compound is
3-monoiodothyronine.
[0019] In one embodiment the dialkylphosphinate or dialkylphosphate
is a C.sub.1 to C.sub.18 substituted alkyl, more preferably a
C.sub.1 to C.sub.8 substituted alkyl, and more preferably a C.sub.1
to C.sub.4 substituted alkyl. In another embodiment the
dialkylphosphinate or dialkylphosphate is a C.sub.1 to C.sub.18
unsubstituted alkyl, more preferably a C.sub.1 to C.sub.8
unsubstituted alkyl, and more preferably C.sub.1 to C.sub.4
unsubstituted alkyl. In a preferred embodiment the
dialkylphosphinate is a diethyl or a dimethylphosphinate. In
another preferred embodiment the dialkylphosphate is a diethyl or a
dimethylphosphinate. In another embodiment the diarylphosphinate or
the diarylphosphate is a substituted phenyl or an unsubstituted
phenyl.
[0020] In another embodiment the protected iodothyronine compounds
of the invention are further combined with pharmaceutically
acceptable excipients. In a preferred embodiment the iodothyronine
compositions are utilized in a method of treating disorders related
to improper thyroid function. More preferably, the condition is
related to depression, hypothyroidism, mood disorders, general loss
of thyroid function due to aging, or autoimmune destruction of the
thyroid tissue. Most preferably, the condition being treated is
hypothyroidism.
[0021] In another embodiment, the protected iodothyronine compounds
described above provide increased stability and stabilization of
the thyroid hormone compared to thyroid hormone which is not
protected at the phenolic hydroxyl, resulting in an increase in
shelf life.
[0022] In a preferred embodiment, the protected iodothyronine
compounds are in an oral dosage form suitable for oral
administration. Preferred oral dosage forms are tablets, capsules,
oral solutions, and oral suspensions. In another embodiment the
protected iodothyronine compounds are in the form of an intravenous
preparation.
[0023] The protected iodothyronine compounds prevent
tautomerization from occurring at the phenolic hydroxyl and
therefore the hydrolysis is prevented or delayed. By preventing the
hydrolysis the shelf life and stability of the iodothyronine
compound is increased.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] FIG. 1 shows the pathway of the degradation of T4. Following
tautomerization of T4, the intermediate is subjected to hydrolysis,
to produce DIT and a quinone.
[0025] FIG. 2 is the dimethylphosphinate of T4,
thyroxinyldimethylphosphin- ate.
[0026] FIG. 3 shows the phosphinate-protected T4 and its inability
to tautomerize.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0027] The present invention is practiced by using phosphinate
protecting groups to protect against the decomposition of thyroxine
and related compounds. These related compounds are preferably other
iodothyronines, such as triiodothyronine (T3), 3,5-diiodothyronine
(3,5-T2), 3,3'-diiodothyronine (3,3'-T2), reverse triiodothyronine
(3,3',5'-triiodothyronine, rT3), and 3-monoiodothyronine (3-T1).
The related compounds are also meant to include amino acids such as
thyronine, diiodotyrosine, and iodotyrosine, and may include any
amino acid that is unstable in the presence of trace amounts of
water.
[0028] To practice this invention, thyroxine or a related compound
is reacted with a dialkyl- or diaryl-phosphinate compound, such as
a dialkyl- or diaryl-phosphinic chloride. Most preferably, the
dialkyl group is dimethyl or diethyl. The alkyl group may also be
any hydrocarbon, preferably C.sub.1 to C.sub.18, comprising either
straight chained, branched chained, or cyclic compounds, optionally
substituted with oxygen-, phosphorus-, sulfur- and
nitrogen-containing groups. The aryl group may be any aromatic
group, preferably phenyl, and may be optionally substituted with
alkyl or additional phenyl groups, and may also be optionally
substituted with oxygen-, phosphorus-, sulfur- and
nitrogen-containing groups. The two alkyl groups may be the same or
different. There may also be one alkyl and one aryl group on the
phosphinate. The dimethyl can be replaced with diphenyl, diethyl or
any other dialkyl and get the same level of protection on T4. In
addition, the phosphinate group can be replaced with a similarly
substituted dialkyl-, diaryl-, or alkylaryl-phosphate group. Other
groups that can be used instead of the phosphinate group include
acetyl, trialkylsilyl, and benzyloxy carbonyl.
[0029] "Hydrocarbyl" shall refer to an organic radical comprised of
carbon chains to which hydrogen and other elements are attached.
The term includes alkyl, alkenyl, alkynyl and aryl groups, groups
which have a mixture of saturated and unsaturated bonds,
carbocyclic rings and includes combinations of such groups. It may
refer to straight-chain, branched-chain cyclic structures or
combinations thereof.
[0030] "Aryl" shall refer to aromatic groups which have at least
one ring having a conjugated pi electron system and includes
carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which
may be optionally substituted.
[0031] "Carbocyclic aryl groups" shall refer to groups wherein the
ring atoms on the aromatic ring are carbon atoms. Carbocyclic aryl
groups include monocyclic carbocyclic aryl groups and optionally
substituted naphthyl groups.
[0032] "Monocyclic carbocyclic aryl" shall refer to optionally
substituted phenyl, being preferably phenyl or phenyl substituted
by one to three substituents, such being advantageously lower
alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen, cyano,
trihalomethyl, lower acylamino, lower amino or lower
alkoxycarbonyl.
[0033] "Optionally substituted naphthyl" shall refer to 1- or
2-naphthyl or 1- or 2-naphthyl preferably substituted by lower
alkyl, lower alkoxy or halogen.
[0034] "Heterocyclic aryl groups" shall refer to groups having from
1 to 3 heteroatoms as ring atoms in the aromatic ring and the
remainder of the ring atoms carbon atoms. Suitable heteroatoms
include oxygen, sulfur, and nitrogen, and include furanyl, thienyl,
pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl,
imidazolyl, and the like, all optionally substituted.
[0035] "Optionally substituted furanyl" shall refer to 2- or
3-furanyl or 2- or 3-furanyl preferably substituted by lower alkyl
or halogen.
[0036] "Optionally substituted pyridyl" shall refer to 2-, 3- or
4-pyridyl or 2-, 3- or 4-pyridyl preferably substituted by lower
alkyl or halogen.
[0037] "Optionally substituted thienyl" shall refer to 2- or
3-thienyl, or 2- or 3-thienyl preferably substituted by lower alkyl
or halogen.
[0038] "Biaryl" shall refer to phenyl substituted by carbocyclic
aryl or heterocyclic aryl as defined herein, ortho, meta or para to
the point of attachment of the phenyl ring, advantageously
para.
[0039] "Aralkyl" shall refer to an alkyl group substituted with an
aryl group. Suitable aralkyl groups include benzyl, picolyl, and
the like, and may be optionally substituted.
[0040] "Lower" referred to herein in connection with organic
radicals or compounds respectively defines such with up to and
including 7, preferably up to and including 4 and advantageously
one or two carbon atoms. Such groups may be straight chain or
branched.
[0041] The terms (a) "alkyl amino", (b) "arylamino", and (c)
"aralkylamino", respectively, shall refer to the groups --NRR'
wherein respectively, (a) R is alkyl and R' is hydrogen or alkyl;
(b) R is aryl and R' is hydrogen or aryl, and (c) R is aralkyl and
R' is hydrogen or aralkyl.
[0042] The term "acyl" shall refer to hydrocarbyl-CO-- or
HCO--.
[0043] The terms "acylamino" refers to RCONCR)-- and (RCO.sub.2 N--
respectively, wherein each R is independently hydrogen or
hydrocarbyl.
[0044] The term "hydrocarbyloxycarbonyloxy" shall refer to the
group ROC(O)O-- wherein R is hydrocarbyl.
[0045] The term "lower carboalkoxymethyl" or "lower
hydrocarbyloxycarbonylmethyl" refers to hydrocarbyl-OC(O)CH.sub.2--
with the hydrocarbyl group containing ten or less carbon atoms.
[0046] The term "carbonyl" refers to --C(O)--.
[0047] The term "carboxamide" or "carboxamido" refers to
--CONR.sub.2 wherein each R is independently hydrogen or
hydrocarbyl.
[0048] The term "lower hydrocarbyl" refers to any hydrocarbyl group
of ten or less carbon atoms.
[0049] The term "alkyl" refers to saturated aliphatic groups
including straight-chain, branched chain and cyclic groups.
[0050] The term "alkenyl" refers to unsaturated hydrocarbyl groups
which contain at least one carbon-carbon double bond and includes
straight-chain, branched-chain and cyclic groups.
[0051] The term "alkynyl" refers to unsaturated hydrocarbyl groups
which contain at least one carbon-carbon triple bond and includes
straight-chain, branched-chain and cyclic groups.
[0052] The term "methylene" refers to --CH.sub.2--.
[0053] The term "alkylene" refers to a divalent straight chain or
branched chain saturated aliphatic radical.
[0054] The term "oxy" refers to --O-- (oxygen). The term "thio"
refers to --S-- (sulfur). "Disulfide" refers to --S--S--.
[0055] Although N-protection may not be necessary, the best yield
of throxinyldialkylphosphinate is achieved by first protecting the
nitrogen of T4 or related compound. Any method of protecting the
nitrogen of an amino acid group known in the art may be employed in
protecting the nitrogen of thyroxine and related compounds. Most
preferably, the reagent of choice is
trimethylsilylethoxycarbonyloxysuccinimide. The N-protected T4 is
then treated with dimethylphosphinic chloride or diphenylphosphinic
chloride, as before, and the product of this reaction is
N-deprotected by treatment with trifluoroacetic acid. Deprotection
can also take place using other mild acids, as well.
[0056] The invention thus provides a method to stabilize and
increase the shelf life of thyroxine and related thyroid hormone
products. The compositions of the present invention will be used in
methods of treating hypothyroidism, depression and other related
dysfunctional thyroid hormone conditions. These products will be
used at levels similar to those used in treating hypothyroid
patients with SYNTHROID. Determining the precise levels to be used
in a particular patient may be accomplished using methods well
known to those of skill in the art, including monitoring the levels
of thyroid hormones in the blood using known techniques and
adjusting the dosage accordingly to get blood levels within
acceptable limits. The compositions will be particularly useful in
providing injectable and oral suspension formulations, as well as
tablets, for thyroid hormones.
[0057] The present compounds can be administered by a variety of
routes and in a variety of dosage forms including those for oral,
rectal, parenteral (such as subcutaneous, intramuscular and
intravenous), epidural, intrathecal, intra-articular, topical and
buccal administration. The dose range for adult human beings will
depend on a number of factors including the age, weight and
condition of the patient and the administration route.
[0058] For oral administration, fine powders or granules containing
diluting, dispersing and/or surface-active agents may be presented
in a draught, in water or a syrup, in capsules or sachets in the
dry state, in a non-aqueous suspension wherein suspending agents
may be included, or in a suspension in water or a syrup. Where
desirable or necessary, flavouring, preserving, suspending,
thickening or emulsifying agents can be included.
[0059] Other compounds which may be included by admixture are, for
example, medically inert ingredients, e.g. solid and liquid
diluent, such as lactose, dextrose, saccharose, cellulose, starch
or calcium phosphate for tablets or capsules, olive oil or ethyl
oleate for soft capsules and water or vegetable oil for suspensions
or emulsions; lubricating agents such as silica, talc, stearic
acid, magnesium or calcium stearate and/or polyethylene glycols;
gelling agents such as colloidal clays; thickening agents such as
gum tragacanth or sodium alginate, binding agents such as starches,
arabic gums, gelatin, methylcellulose, carboxymethylcellulose or
polyvinylpyrrolidone; disintegrating agents such as starch, alginic
acid, alginates or sodium starch glycolate; effervescing mixtures;
dyestuff; sweeteners; wetting agents such as lecithin, polysorbates
or laurylsulphates; and other therapeutically acceptable accessory
ingredients, such as humectants, preservatives, buffers and
antioxidants, which are known additives for such formulations.
[0060] Liquid dispersions for oral administration may be syrups,
emulsions or suspensions. The syrups may contain as carrier, for
example, saccharose or saccharose with glycerol and/or mannitol
and/or sorbitol. In particular a syrup for diabetic patients can
contain as carriers only products, for example sorbitol, which do
not metabolize to glucose or which metabolize only a very small
amount to glucose. The suspensions and the emulsions may contain a
carrier, for example a natural gum, agar, sodium alginate, pectin,
methylcellulose, carboxymethylcellulose or polyvinyl alcohol.
[0061] Suspensions or solutions for intramuscular injection may
contain, together with the active compound, a pharmaceutically
acceptable carrier such as sterile water, olive oil, ethyl oleate,
glycols such as propylene glycol and, if desired, a suitable amount
of lidocaine hydrochloride. Solutions for intravenous injection or
infusion may contain a carrier, for example, sterile water that is
generally Water for Injection. Preferably, however, they may take
the form of a sterile, aqueous, isotonic saline solution.
Alternatively, the present compounds may be encapsulated within
liposomes. The present compounds may also utilize other known
active agent delivery systems.
[0062] The present compounds may also be administered in pure form
unassociated with other additives, in which case a capsule, sachet
or tablet is the preferred dosage form.
[0063] Tablets and other forms of presentation provided in discrete
units conveniently contain a daily dose, or an appropriate fraction
thereof, of one of the present compounds. For example, units may
contain from 5 mg to 500 mg, but more usually from 10 mg to 250 mg,
of one of the present compounds.
[0064] It will be appreciated that the pharmacological activity of
the compositions of the invention can be demonstrated using
standard pharmacological models that are known in the art.
Furthermore, it will be appreciated that the inventive compositions
can be incorporated or encapsulated in a suitable polymer matrix or
membrane for site-specific delivery, or can be functionalized with
specific targeting agents capable of effecting site specific
delivery. These techniques, as well as other drug delivery
techniques are well known in the art.
[0065] The invention will now be illustrated by, but is not
intended to be limited to, the following examples.
EXAMPLES
Example 1
Preparation of 2-trimethylsilylethyl Carbonochloridate
(Teoc-Cl)
[0066] To a solution of 2-trimethylsilylethanol (5.0 g, 42.3 mmol)
in dichloromethane (35 mL) at 0.degree. C. was added triethylamine
(4.7 g, 46.5 mmol). To this stirred solution was added dropwise a
solution of triphosgene (4.40 g, 14.8 mmol) in dichloromethane (15
mL); a white precipitant was formed immediately. The mixture was
stirred at low temperature for 15 minutes, the ice bath removed,
and the mixture was stirred for an additional 1 hour at room
temperature. After 1 hour, the white precipitant was filtered and
washed with dichloromethane (.about.60 mL). The combined filtrate
and washings were concentrated. The resultant oily
carbonochloridate was used without further purification.
Example 2
Preparation of
1-[2(Trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-2,5-dione
(Teoc-0Su)
[0067] 2-Trimethylsilylethyl carbonochloridate (4.8 g, 26.9 mmol)
was taken up in dry acetronitrile (50 mL). The solution was cooled
to 0.degree. and solid N-hydroxysuccinimide (4.0 g, 34.8 mmol) was
added with vigorous stirring followed by a solution of dry
triethylamine (3.2 g, 31.6 mmol) in dry acetonitrile (5 mL). The
mixture was stirred at low temperature for 15 minutes, then at room
temperature overnight. The mixture was poured into water (200 ml)
and extracted with ether (4.times.50 mL). The organic extracts were
combined, washed with water (2.times.60 mL), 1 normal hydrochloric
acid (60 mL), again water (60 mL), brine (60 mL), dried with
magnesium sulfate and evaporated to dryness. The residue was taken
up in boiling hexane (200 mL) and the solution allowed to cool.
Crystallization was completed by storage at -15.degree. C. (yield:
1.70 g).
Example 3
Preparation of N-Trimethylsilylethoxycarbonylthyroxine
(Teoc-T4)
[0068] To a stirred suspension of thyroxine (1.66 g, 2.14 mmol) in
DMSO (15 mL) was added triethylamine (3.21 mmol) followed by solid
Teoc-0Su (610 mg, 2.35 mmol). The mixture was stirred at room
temperature overnight then diluted with water (22 mL), acidified
with saturated potassium hydrogen sulfate solution and extracted
with ether (3.times.45 mL). The combined organic extracts were
washed with water (4.times.45 mL), dried with magnesium sulfate,
and evaporated to dryness. (Yield: 1.87 g).
Example 4
Preparation of
[N-Trimethylsilylethoxycarbonyl-O-throxinyl]-dimethylphosph-
inate
[0069] N-Trimethylsilylethoxycarbonylthyroxine (307 mg, 0.334 mmol)
was dissolved in 10-mL dry chloroform, and to the stirred solution
was added anhydrous triethylamine (154 .mu.L, 1.10 mmol). After
stirring for 10 minutes at room temperature, dimethylphosphinyl
chloride (112.7 .mu.L, 1.00 mmol) was added and stirring was
continued at room temperature. After 90 minutes, the reaction
appeared to be nearly completed by TLC analysis
(chloroform/i-propanol/acetic acid, 85:10:5), based on relatively
clean conversion of starting material (R.function. 0.34) to product
(R.function. 0.22). The reaction was quenched by the addition of 20
mL 0.5 N HCl. The product was extracted into chloroform (3.times.30
mL). The combined chloroform layers were washed with brine, dried
over magnesium sulfate and evaporated to dryness, affording 280 mg
[N-trimethylsilylethoxycarbonyl-O-throxinyl]dimethylphosphinate
(84% yield).
Example 5
Preparation of O-Thyroxinyldimethylphosphinate
[0070]
[N-Trimethylsilylethoxycarbonyl-O-thyroxinyl]dimethylphosphinate
(42 mg, 0.042 mmol) was dissolved in 1.5 mL of trifluoroacetic
acid. After 5 minutes stirring at room temperature, TLC analysis
(chloroform/i-propanol/acetic acid, 85:10:5) showed the
deprotection to be complete. The solvent was removed by rotary
evaporation. Azeotropic evaporation with hexane afforded the
product as a fine, white powder in nearly quantitaive yield. NMR
analysis showed the product to be the desired
O-thyroxinyldimethylphosphinate.
* * * * *