U.S. patent number 3,930,017 [Application Number 05/038,647] was granted by the patent office on 1975-12-30 for lowering blood cholesterol and lipid levels.
Invention is credited to Ruediger Beckmann, Horst Kummer.
United States Patent |
3,930,017 |
Kummer , et al. |
December 30, 1975 |
Lowering blood cholesterol and lipid levels
Abstract
The lowering of the blood cholesterol and lipid levels by
administration of a pharmaceutical composition including
dl-alpha-methylthroxine ethyl ester. The basal metabolic rate is
not increased.
Inventors: |
Kummer; Horst (519 Stolberg,
Rhineland, DT), Beckmann; Ruediger (51 Aachen,
DT) |
Family
ID: |
31950596 |
Appl.
No.: |
05/038,647 |
Filed: |
May 22, 1970 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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584089 |
Oct 4, 1966 |
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Foreign Application Priority Data
Current U.S.
Class: |
514/539;
560/40 |
Current CPC
Class: |
C07D
233/78 (20130101) |
Current International
Class: |
C07D
233/78 (20060101); C07D 233/00 (20060101); A61K
031/24 () |
Field of
Search: |
;424/309,319
;260/471A |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Meyers; Albert T.
Assistant Examiner: Fagelson; Anna P.
Attorney, Agent or Firm: Weiser, Stapler & Spivak
Parent Case Text
This application is a division of our application Ser. No. 584,089,
filed Oct. 4, 1966 now abandoned.
Claims
We claim:
1. The method of lowering blood cholesterol and lipid levels
without increasing the basal metabolic rate and exhibiting no
thyrotoxic activity in human patients which comprises administering
orally a pharmaceutical composition which comprises 1 to 25 mg.
dosage of dl-alpha-methylthyroxine ethyl ester and a
pharmaceutically acceptable carrier to said patients.
2. The method of claim 1 wherein the thyroxine is the hydrochloride
salt thereof.
3. The method of claim 2 wherein the oral administration is in
daily dosage of 10 to 25 mg.
4. The method of claim 3 wherein the daily dosage is about 10
mg.
5. The method of claim 4 wherein the daily dosage administration of
the composition to the patients is repeated until there is a
decrease in the cholesterol level in the patient.
6. The method of claim 5 wherein the cholesterol level is decreased
within fourteen days.
7. The method of claim 6 which comprises decreasing the cholesterol
level in the patient over the treatment period.
Description
The present invention relates to new and valuable .alpha.-alkyl
thyronine compounds and more particularly to new and valuable
esters of such compounds, to compositions containing same, and to a
process of making and using such esters.
As confirmed by clinical and pathological observations sclerosis of
blood vessels is rarely observed in patients with hyperfunctioning
thyroid glands. Therefore, many attempts have been made to
favorably influence arteriosclerosis and in particular coronary
sclerosis by the administration of thyroid hormones. In animal
experiments such favorable effect can be demonstrated by a lowering
of the lipid and especially the cholesterol serum level. An adverse
reaction encountered upon the administration of thyroid hormones
which reduces the usefulness of these hormones and/or makes their
administration at least in coronary sclerosis contra-indicated, is
the increase in the basal metabolic rate. The basal metabolic rate
of male rats, for example, determined by the increase in oxygen
consumption, is raised significantly on subcutaneous application of
0.01 mg./kg. of L-thyroxine.
From Irish Pat. No. 365/65 it is known that, on introducing alkyl
radicals in the .alpha.-position of certain thyronine derivatives,
compounds are obtained which are capable of lowering the
cholesterol and lipid level without raising the basal metabolic
rate. If, for example, rats which have been fed on a
cholesterol-rich diet are given subcutaneously 1000.gamma./kg. of
dl-.alpha.-methyl thyroxine sodium daily for a period of 14 days,
the serum cholesterol level of the thus treated rats is lowered
from 380 mg.% to 265 mg.%. When measuring the basal metabolic rate
of rats, subcutaneous administration of 4 mg./kg. of
dl-.alpha.-methyl thyroxine does not cause an increase in oxygen
consumption. In comparison to L-thyroxine dl-.alpha.-methyl
thyroxine only slightly increases oxygen consumption and only after
increasing the dose 2000 times.
The antigoitrogenic activity, i.e. remission of the thyroid gland
enlargement in rats caused by the administration of thiouracil, may
be considered an additional criterion for the undesired
thyreomimetic activity of a tested compound. In this test, 20 mg.
of dl-.alpha.-methyl thyroxine correspond in their activity to
0.020 mg. of L-thyroxine. A reduction in the weight increase as it
is observed after administration of thyroid hormones on account of
the thyreotoxic activity of these compounds, has not been observed
after administration of dl-.alpha.-methyl thyroxine. Thus the final
body weight of rats to which 4.0 mg./kg. of .alpha.-methyl
thyroxine has been administered daily for a period of 14 days is
the same as that of dietary controls.
However, the dl-.alpha.-methyl thyroxine or, respectively, its
salts as it has become known from the said Irish patent have the
disadvantage of being inactive on oral administration.
It is now an object of the present invention to provide new and
valuable .alpha.-alkyl thyronine compounds which are highly
effective agents capable of lowering the cholesterol and lipid
level in the blood without raising the blood metabolic rate and
which can be administered not only parenterally but also
orally.
Another object of the present invention is to provide a simple and
effective process of producing such .alpha.-alkyl thyronine
compounds.
A further object of the present invention is to provide valuable
compositions containing such .alpha.-alkyl thyronine compounds as
active, cholesterol and lipid level-decreasing agents.
Still another object of the present invention is to provide a
process of lowering the cholesterol and lipid blood level in
persons suffering from a high cholesterol and lipid blood
level.
Other objects of the present invention and advantageous features
thereof will become apparent as the description proceeds.
In principle the new and valuable .alpha.-alkyl thyronine compounds
according to the present invention are now esters of .alpha.-alkyl
thyronine compounds of the following Formula I ##SPC1##
wherein
R.sub.1 indicates a linear or branched alkyl radical containing 1
to 6 carbon atoms;
R.sub.2 indicates the amino group or an acylated amino group;
R.sub.3, R.sub.4, and R.sub.5 represent the same or different
substituents, namely hydrogen or iodine atoms; and
R.sub.6 represents an unsubstituted or substituted linear or
branched alkyl radical containing 1 to 6 carbon atoms or an
unsubstituted or substituted cycloalkyl or aralkyl radical, as well
as the addition salts of these compounds with inorganic or organic
bases or acids.
A preferred substituent of the substituent R.sub.6 is the amino
group
wherein R.sub.7 and R.sub.8 are the same or are different
substituents and represent hydrogen, lower alkyl, or, together with
the nitrogen atom to which they are attached, a heterocyclic ring,
which may be interrupted by other hetero atoms. Such heterocyclic
rings are, for instance, the pyrrolidine, piperidine, morpholine-,
or 4-alkyl piperazine ring.
As is evident from Formula I, the compounds of said formula contain
one asymmetric carbon atom which bears four different substituents.
Due to this configuration the compounds may form two optically
active modifications. Resolving of the dl-compound into the two
optically active forms is effected by methods known per se.
Moreover, optically active forms of the compounds of Formula I can
be obtained by using optically active starting materials for their
preparation.
The new compounds of Formula I are obtained by reacting an acid, a
salt, or a reactive derivative of the acid, for instance, a
halogenide or an anhydride of an acid of Formula II ##SPC2##
wherein
R.sub.1 to R.sub.5 represent the same substituents as indicated
above, with a compound of Formula III
wherein
R.sub.6 represents the same substituent as indicated above and
Y represents a hydroxyl group, an esterified hydroxyl group,
halogen or a hydroxyl group, in which the hydrogen atom is replaced
by a metal atom.
Stoichiometric amounts of compounds of Formulas II and III may be
used but also an excess of one of said reactants. Preferably
esterifying catalysts of an acidic nature are added in the event
that the compound of Formula II is not used in the form of its salt
with a base or that the other reactant is not a compound of Formula
III, in which Y represents a hydroxyl group wherein the hydrogen
atom is replaced by a metal atom. In those instances whereby, one
preparing a compound of Formula I, an acid is liberated, basic
agents are preferably added to accelerate the reaction or to bind
the acid. If, on reacting a compound of Formula II with a compound
of Formula III, water is set free, such water may be removed by
means of azeotropic distillation.
The compounds of Formula I can also be obtained by saponifying
under esterifying conditions the nitrile group of a compound of
Formula IV ##SPC3##
wherein
R.sub.1 to R.sub.5 represent the same substituents as indicated
above in the presence of acidic catalysts and of a compound of
Formula V
wherein
R.sub.6 represents the same substituents as indicated above.
Stoichiometric amounts of said compounds of Formulas IV and V may
be used as well as an excess of the compound of Formula V. The
intermediate imino ether salts obtained thereby may be isolated and
transformed into compounds of Formula I in a separate reaction
step.
Compounds of Formula I can also be obtained by subjecting a
compound of Formula VI ##SPC4##
wherein
R.sub.1 and R.sub.3 to R.sub.5 represent the same substituents as
indicated above and
R.sub.9 represents alkyl or aryl, to alcoholysis at room
temperature or at elevated temperature with a compound of Formula
V, if required, with the addition of acids or bases as catalysts
thereby yielding a compound of Formula VII ##SPC5##
wherein
R.sub.1 and R.sub.3 to R.sub.6 represent the same substituents as
indicated above and
R.sub.10 represents an acylated amino group, and then converting
the substituent R.sub.10 into an amino group, if desired.
Furthermore, compounds of Formula I can be obtained by transforming
the carboxamide group of a compound of Formula VIII ##SPC6##
wherein
R.sub.1 and R.sub.3 to R.sub.6 represent the same substituents as
indicated above, by means of a Hofmann rearrangement reaction into
an amino group.
The compounds of Formula I can also be obtained by reacting a
compound of Formula IX ##SPC7##
wherein
R.sub.1 to R.sub.4 and R.sub.6 represent the substituents as
indicated above, at approximately neutral pH-values, preferably at
a slightly basic pH-value with an acid of Formula X ##SPC8##
wherein
R.sub.5 represents the same substituent as indicated above.
This condensation reaction can be performed by dissolving a
compound of Formula IX in a buffer solution, for example, in a
solution of borax and disodium hydrogen phosphate, or in a solution
of citric acid and disodium hydrogen phosphate or in other buffer
solutions or mixtures, at a slightly basic pH-value, preferably at
a pH of 7.6 to 7.8. These buffer solutions may have admixed thereto
a water-soluble organic solvent such as a lower alkanol, dioxane,
dimethyl formamide, dimethyl acetamide, ethylene glycol mono-ethyl
ether, or mixtures of these organic solvents. The resulting
solution of the compound of Formula IX is then reacted with a
corresponding solution of an acid of Formula X. The solution of the
acid of Formula X may be added at once or in portions.
Stoichiometric amounts of the compounds of Formula IX and X may be
used as well as an excess of one of said reactants. The
condensation may also be carried out in the presence of a second
organic solvent which is immiscible with water and forms a
water-insoluble phase. Such solvents are, for instance, higher
alcohols, chlorinated hydrocarbons, and aliphatic or aromatic
hydrocarbons. Catalytically active compounds, such as organic
peroxides or manganous salts may be added and the condensation may
be effected at temperatures below 100.degree.C. under anaerobic or
aerobic conditions, for instance, by introducing oxygen into the
reaction mixture.
The compounds of Formula I can also be obtained by condensing a
reactive ester, preferably the p-tosyl ester, of a compound of
Formula XI ##SPC9##
wherein
R.sub.1, R.sub.6 and R.sub.10 represent the same substituents as
indicated above and
R.sub.11 represents a nitro group or the substituent R.sub.4, with
a compound of Formula XII ##SPC10##
wherein
R.sub.5 represents the same substituent as indicated above and the
protecting group R.sub.12 represents aralkyl which may be
substituted, in the presence of a solvent and/or an inorganic or
organic base, preferably pyridine, and, if required, at elevated
temperature. Thereby, a compound of Formula XIII is obtained:
##SPC11##
wherein
R.sub.1, R.sub.5, R.sub.6, and R.sub.10 to R.sub.12 represent the
same substituents as indicated above.
The nitro group or groups in the resulting compound of Formula XIII
are converted into diazonium groups by reduction and diazotizing.
Thereafter, the diazonium group or groups are transformed into the
substituents R.sub.3 and R.sub.4 by methods known per se, such as
the Sandmeyer reaction, or by desamination. Then the protecting
group R.sub.12 is split off by hydrogenolysis. If desired, the
substituent R.sub.10 may be converted into the amino group.
Furthermore, compounds of Formula I can be obtained by introducing
iodine into a compound of Formula XIV ##SPC12##
wherein
R.sub.1 to R.sub.4 and R.sub.6 represent the same substituent as
indicated above.
Iodination to introduce one or two iodine atoms into the molecule
is preferably effected in alkaline solution by means of iodine and
or other iodizing agents, such as iodine/potassium iodide, N-iodo
acetamide, N-iodo succinimide, iodine chloride, p-toluene sulfonic
acid iodo-amido potassium, and the like.
The compounds of Formula XIV are obtained, for instance, by
reacting the corresponding acid, its salts, or a reactive
derivative thereof with a compound of Formula III following in
principle the method described for the preparation of the compounds
of Formula II.
The compounds of Formula XIV can also be obtained by condensing a
reactive ester, preferably the p-tosylester, of a compound of
Formula XI with a compound of Formula XV. ##SPC13##
wherein
R.sub.12 represents the same substituent as indicated above, in the
presence of a solvent and/or an inorganic or organic base,
preferably pyridine, if required, at elevated temperature to yield
a compound of formula XVI ##SPC14##
wherein
R.sub.1, R.sub.6, and R.sub.10 to R.sub.12 request the same
substituent as indicated above.
The nitro groups in the compounds of Formula XVI are then converted
into the substituents R.sub.3 and R.sub.4, as mentioned above. The
substituent R.sub.12 is split off by hydrogenolysis, preferably in
the presence of a noble metal catalyst and the substituent R.sub.10
is converted, if desired, into an amino group.
The compounds of Formula XIV can also be obtained be reacting a
compound of Formula IX with a compound of Formula XVII
##SPC15##
wherein
R.sub.12 represents the same substituent as indicated above and
An.sup.- represents an anion, in the presence of a basic substance,
preferably in the presence of a metal alcoholate, suitably by using
an alcohol as solvent and by removing from the resulting compound
of Formula XVIII ##SPC16##
wherein
R.sub.1 to R.sub.4, R.sub.6, and R.sub.12 represent the same
substituents as indicated above, the substituent R.sub.12 by
hydrogenolysis.
When compounds of Formula I in which R.sub.2 indicates an acylated
amino group are to be prepared, it is also possible to acylate the
amino group in compounds of Formula I wherein R.sub.2 represents an
amino group, as obtained according to one of the procedures
described above, by reacting with a reactive derivative of a
carboxylic acid, such as an anhydride, an acid halide, or an ester,
by methods known per se.
If desired, compounds of Formula I can be converted to the
corresponding salts by adding bases or acids. Using optically
active bases or acids, the corresponding optically active salts can
be resolved into optically active isomers -- as mentioned before --
by methods known per se.
The following examples serve to illustrate the present invention
without, however, limiting the same thereto. The melting and
boiling points given are uncorrected. In performing the examples,
maximum yields were not intended to be obtained.
EXAMPLE 1
7.91 g. of .alpha.-methyl thyroxine are suspended in 150 ac. of
ethanol. While heating, the solution is saturated with dry hydrogen
chloride. Thereafter, the solvent is distilled off at reduced
pressure. The residue is dissolved in a mixture of ethanol and
water (1:1). Adding a 5% solution of sodium hydrogen carbonate in
water, the ethyl ester of .alpha.-methyl thyroxine precipitates;
melting point: 156.degree.-157.degree.C. after recrystallization
from ethanol. The yield is 6.05 g., i.e. 74% of the theoretical
yield.
EXAMPLE 2
On following the procedure as described in example 1 and using
methanol as the esterifying reactant, the methyl ester of
.alpha.-methyl thyroxine is obtained; melting point:
123.degree.-125.degree.C. after recrystallization from methanol.
The yield is 85% of the theoretical yield.
EXAMPLE 3
2 g. of .alpha.-methyl thyroxine are added in portions to a mixture
of 20 cc. of benzyl alcohol and 5 g. of polyphosphoric acid, warmed
to 95.degree.C. While stirring, the clear solution is heated to
95.degree.C. for 4 hours. After cooling, the solution is poured
into 200 cc. of ice water and extracted with ether. The ether
solution is washed with a solution of 1% ammonia in water, dried
over sodium sulfate and the solvent is distilled off under reduced
pressure. The residue is dissolved in ethanol. On addition of
water, the benzyl ester of .alpha.-methyl thyroxine precipitates;
melting point: 178.degree.-180.degree.C. after recrystallization
from n-butanol.
EXAMPLE 4
5.7 g. of the 3,5-di-iodo-.alpha.-methyl thyronine ethyl ester are
dissolved in a mixture of 60 cc. of butylamine and 120 cc. of
ethanol. A solution of 5.1 g. of iodine in 120 cc. of ethanol is
added drop by drop while stirring. Stirring is continued for one
more hour. The solution is then cooled with ice and neutralized by
adding concentrated hydrochloric acid thereto. On addition of a
solution of sodium acetate, .alpha.-methyl thyroxine ethylester
precipitates; melting point: 156.degree.-157.degree.C. The yield is
83% of the theoretical yield. The compound is identical with that
of example 1. The starting material 3,5-di-iodo-.alpha.-methyl
thyronine ethyl ester used in the preceding example is obtained as
follows:
11.8 g. of 3,5-di-iodo-.alpha.-methyl thyronine are suspended in
240 cc. of absolute ethanol. While cooling, the solution is
saturated with dry hydrogen chloride. While introduction of
hydrogen chloride is continued, the solution is refluxed for
several hours. The resulting clear solution is distilled to dryness
under reduced pressure. The residue is dissolved in a mixture of
ethanol/water (1:1) and neutralized by adding an aqueous 5% sodium
hydrogen carbonate solution. The 3,5-di-iodo-.alpha.-methyl
thyronine ethyl ester precipitates; melting point:
152.degree.-154.degree.C. The yield is 73% of the theoretical
yield.
EXAMPLE 5
On following the procedure described in example 1, the
3,5,3'-tri-iodo-.alpha.-methyl thyronine ethyl ester is obtained by
using 3,5,3'-tri-iodo-.alpha.-methyl thyronine as starting
material; melting point: 177.5.degree.-180.degree.C. after
recrystallization from ethanol. The yield is 78.5% of the
theoretical yield.
The starting material 3,5,3'-tri-iodo-.alpha.-methyl thyronine is
obtained as follows:
5.4 g. of 3,5-di-iodo-.alpha.-methyl thyronine are dissolved in a
mixture of 26 cc. of 1 N sodium hydroxide solution and 108 cc. of
water. A solution of 3.15 g. of p-toluene sulfonic acid-iodo-amide
potassium in 53 cc. of water is added drop by drop thereto at room
temperature. After stirring for some time, 95% acetic acid is added
in an amount sufficient to adjust the pH-value to a pH of 6.0. The
resulting precipitate is filtered off by suction and dissolved in a
mixture of 25 cc. of 2 N sodium hydroxide solution and 62 cc. of
ethanol. The solution is purified by means of activated charcoal.
Thereafter, while heating to boiling, 2 N hydrochloric acid is
added in an amount sufficient to adjust the pH value to a pH of
6.0. The precipitate is filtered off by suction, washed with
ethanol/ water (1:2) and dried under reduced pressure at
100.degree.C. The resulting 3,5,3'-tri-iodo-.alpha.-methyl
thyronine has a melting point of 260.degree.-264.degree.C. The
yield is 66% of the theoretical yield.
EXAMPLE 6
On following the procedure described in example 1 and using
.alpha.-ethyl thyroxine as starting material, the ethyl ester of
.alpha.-ethyl thyroxine is obtained; melting point:
138.degree.-140.degree.C. The yield is 72% of the theoretical
yield.
The starting material .alpha.-ethyl-thyroxine is obtained as
follows:
35.6 g. of 1-p-methoxy phenyl butanone-(2), 19.5 g. of potassium
cyanide, and 62.5 g. of ammonium carbonate are suspended in 330 cc.
of 50% ethanol and are heated to 65.degree.-70.degree.C. for 7
hours while stirring. On cooling and, if necessary, after
introducing carbon dioxide, 5-ethyl-5-(4-methoxy benzyl) hydantoin
crystallizes in white crystals of a melting point of
191.degree.-193.degree.C. after recrystallization from
ethanol/water. The yield is 90% of the theoretical yield.
24.8 g. of said compound are heated under reflux in 110 cc. of 57%
aqueous hydriodic acid for 2 hours. On cooling,
5-ethyl-5-(4-hydroxy benzyl) hydantoin of the melting point of
290.degree.-291.degree.C. is obtained. The yield is 68% of the
theoretical yield.
23.4 g. of said compound are added in portions to 80 cc. of nitric
acid (d = 1.42) at 35.degree.-37.degree.C. while stirring
vigorously. Stirring is continued for 2 hours and the solution is
diluted with 200 cc. of ice water.
5-Ethyl-5-(3,5-dinitro-4'-hydroxy benzyl) hydantoin precipitates in
crystalline form; melting point: 236.degree.-238.degree.C. after
recrystallization from ethanol. The yield is 70% of the theoretical
yield.
64.8 g. of said compound and 42.0 g. of p-toluene sulfochloride are
dissolved in 150 cc. of pyridine and heated under reflux for 10
minutes. The solution is cooled to room temperature. A solution of
62 g. of hydroquinone monomethyl ether in 62 cc. of pyridine is
added thereto. The mixture is heated under reflux for one hour and
six times its volume of ice water is admixed.
5-Ethyl-5-[3,5-dinitro-4-(4'-methoxy phenoxy) benzyl] hydantoin is
obtained; melting point: 195.degree.-197.degree.C. after
recrystallization from diluted acetic acid. The yield is 93% of the
theoretical yield.
43 g. of said compound are dissolved in a mixture of 300 cc. of
methanol and 100 cc. of tetrahydrofuran and are hydrogenated with
hydrogen with the addition of Raney-Nickel catalyst at atmospheric
pressure and room temperature. Thereafter, the catalyst is filtered
off and the solvent is distilled off at reduced pressure. The
residue is recrystallized from ethyl acetate/petroleum ether and
5-ethyl-5-[3,5-diamino-4-(4'-methoxy phenoxy) benzyl] hydantoin is
obtained; melting point: 207.degree.-208.degree.C. The yield is
77.5% of the theoretical yield.
37.0 g. of said compound, dissolved in 80 cc. of glacial acetic
acid, are added drop by drop to 40 cc. of concentrated sulfuric
acid at 10.degree.C. The resulting solution is added drop by drop
to a cooled solution of 17.5 g. of sodium nitrite in a mixture of
175 cc. of concentrated sulfuric acid and 200 cc. of glacial acetic
acid while stirring. Stirring is continued at a temperature of
0.degree.C. for one more hour. The solution is then added rapidly
to a mixture of 87 g. of potassium iodide, 68.0 g. of iodine, and
10.0 g. of urea in 1300 cc. of water to which 450 cc. of chloroform
are admixed, while stirring vigorously. Stirring is continued for
two more hours. The chloroform layer is separated and the aqueous
layer is extracted several times with chloroform. The chloroform
extracts are combined, washed with a solution of sodium bisulfite
in water and then with water, and dried over sodium sulfate. After
filtration, the solvent is distilled off under reduced pressure and
5-ethyl-5-[3,5-di-iodo-4-(4'-methoxy phenoxy) benzyl] hydantoin is
obtained; melting point: 241.degree.-243.degree.C. The yield is 73%
of the theoretical yield.
59.2 g. of said compound are heated under reflux in a mixture of
180 cc. of 57% hydriodic acid and 180 cc. of glacial acetic acid
for one hour. On cooling, 5-ethyl-5-[3,5-di-iodo-4-(4'-hydroxy
phenoxy) benzyl] hydantoin precipitates; melting point:
313.degree.-316.degree.C. after recrystallization from ethanol. The
yield is 93.7 % of the theoretical yield.
115,6 g. of said compound are dissolved in 2,200 cc. of 2N sodium
hydroxide solution and heated in an autoclave at 140.degree.C. for
100 hours. 16 % Hydrochloric acid is added to the hot solution in
an amount sufficient to adjust the pH-value to a pH of 7.0. The
precipitate is filtered off by suction from the hot solution, and
is purified by dissolving it in a mixture of alcohol and
hydrochloric acid, treating the solution with charcoal, and
precipitating the amino acid by means of a saturated solution of
sodium acetate. .alpha.-Ethyl-3,5-di-iodo thyronine of the melting
point: 285.degree.-288.degree. C. is obtained in a yield of 46.6%
of the theoretical yield.
22.1 g. of .alpha.-ethyl-3,5-di-iodo thyronine are dissolved in 130
cc. of a 33 % solution of ehylamine in water and 86.5 cc. of a 1.85
N solution of potassium iodide and iodine are added drop by drop to
the above described solution while stirring. Stirring is continued
for one more hour and 16% hydrochloric acid is added in an amount
sufficient to adjust the ph value to a pH of 5.0. The precipitate
is filtered off, washed with water, and dissolved in 250 cc. of
ethanol with the addition of 100 cc. of 2 N sodium hydroxide
solution. The solution is purified by means of charcoal and is
acidified with 2 N hydrochloric acid to a pH of 6.0. .alpha.-Ethyl
thyroxine, melting at 236.degree.-238.degree.C. is obtained in a
yield of 60% of the theoretical yield.
EXAMPLE 7
On following the procedure described in example 1 and using
.alpha.-n-propyl thyroxine as starting material, the ethyl ester of
.alpha.-n-propyl thyroxine of the melting point:
174.degree.-176.degree.C. is obtained. The yield is 57% of the
theoretical yield.
The starting material .alpha.-n-propyl thyroxine is obtained on
following the procedure described in example 6, but using the
following intermediates:
5-n-Propyl-5-(4-methoxy benzyl) hydantoin, melting point:
244.degree.-245.degree.C. after recrystallization from ethanol.
Yield: 63% of the theoretical yield.
5-n-Propyl-5-(4-hydroxy benzyl) hydantoin, melting point:
286.degree.-288.degree.C. after recrystallization from ethanol.
Yield: 90 % of the theoretical yield.
5-n-Propyl-5-(3,5-dinitro-4-hydroxy benzyl) hydantoin, melting
point: 212.degree.-213.degree.C. after recrystallization from
glacial acetic acid. Yield: 74% of the theoretical yield.
5-n-Propyl-5-[3,5-dinitro-4-(4'-methoxy phenoxy) benzyl] hydantoin,
melting point: 196.degree.-198.degree.C. after recrystallization
from diluted acetic acid. Yield: 55% of the theoretical yield.
5-n-Propyl-5-[3,5-diamino-4-(4'-methoxy phenoxy) benzyl] hydantoin.
Yield: 96% of the theoretical yield.
5-n-Propyl-5-[3,5-di-iodo-4-(4'-methoxy phenoxy) benzyl] hydantoin,
melting point: 247.degree.-248.degree.C. after recrystallization
from methanol/2-ethoxy ethanol.
5-n-Propyl-5-[3,5-di-iodo-4-(4'-hydroxy phenoxy) benzyl] hydantoin,
melting point: 298-299.degree.C. after recrystallization from
ethanol. Yield: 80% of the theoretical yield.
.alpha.-n-Propyl-3,5-di-iodo thyronine, melting point:
278.degree.-280.degree.C. Yield: 58% of the theoretical yield.
.alpha.-n-Propyl thyroxine, melting point:
231.degree.-232.degree.C. Yield: 46.5% of the theoretical
yield.
EXAMPLE 8
On following the procedure described in example 1 and using
(+)-.alpha.-methyl thyroxine as starting material, the ethyl ester
of (+)-.alpha.-methyl thyroxine, melting point:
156.degree.-158.degree.C. is obtained. The yield is 84% of the
theoretical yield. [.alpha.] .sub.D.sup.29 = +11.0.degree.
(concentration = 2% in acetic acid
The (-)-.alpha.-methyl thyroxine ethyl ester is obtained in the
same manner by using (-)-.alpha.-methyl thyroxine as starting
material.
The optically active amino acids used as starting materials are
obtained as follows:
53.9 g. of .alpha.-methyl-3,5-di-iodo thyronine are dissolved in
270 cc. of concentrated formic acid with the addition of 27 cc. of
acetic acid anhydride. After standing for some time the
N-formyl-.alpha.-methyl-3,5-di-iodo thyronine is obtained in white
crystals. The precipitate is filtered off by suction, washed with
water until free of formic acid, and dried. The yield is 45.5 g.
Yield: 80% of the theoretical yield. Melting point:
221.degree.-223.degree.C.
56.7 g. of said compound are suspended in 560 cc. of absolute
isopropanol and refluxed. A solution of 47.3 g. of (-)brucine, in
240 cc. of absolute isopropanol, also heated to reflux, is added.
The solution is refluxed for some time. The (-) brucine salt of
(+)-N-formyl-.alpha.-methyl-3,5-di-iodo thyronine precipitates in
white crystals and is filtered off by suction from the hot
solution. The (-) brucine salt of
(-)-N-formyl-.alpha.-methyl-3,5-di-iodo thyronine precipitates from
the filtrate. It is dissolved in 200 cc. of N ammonia and extracted
several times with chloroform. The aqueous layer is neutralized by
the addition of hydrochloric acid while cooling. Thereby,
(-)-N-formyl-.alpha.-methyl-3,5-di-iodo thyronine precipitates.
Melting point: 234.degree.-236.degree.C. after recrystallization
from aqueous isopropanol. The yield is 74% of the theoretical
yield. [.alpha.] .sub.D.sup.23 -24.degree. (concentration = 5% in
95% ethanol).
The (-)-brucine salt of (+)-N-formyl-.alpha.-methyl-3,5-di-iodo
thyronine is recrystallized from dimethyl formamide/acetic acid
ethyl ester. It has a melting point of 258.degree.-262.degree.C.
The salt is converted into the free acid by following the procedure
described for the (-) isomer. Melting point:
234.degree.-236.degree.C. after recrystallization from isopropanol.
The yield is 90% of the theoretical yield. [.alpha.] .sub.D.sup.22
=+24.2.degree. (concentration = 5% in 95% ethanol).
14.3 g. of (-)-N-formyl-.alpha.-methyl-3,5-di-iodo thyronine are
dissolved in 150 cc. of 16% hydrobromic acid and refluxed for 3
hours. On cooling, the hydrobromide precipitates and is filtered
off. It is dissolved in 70 % ethanol and
(-)-.alpha.-methyl-3,5-di-iodo thyronine is obtained by
precipitation with sodium acetate solution as described for the
racemate. Melting point: 285.degree.-288.degree.C. The yield is 89%
of the theoretical yield. [.alpha.] .sub.D.sup.22 = -14.6.degree.
(concentration = 5% in N hydrochloric acid/ ethanol 1:2).
On following the procedure described above, the
(+)-.alpha.-methyl-3,5-di-iodo thyronine is obtained from
(+)-N-formyl-.alpha.-methyl-3,5-di-iodo thyronine is an analogous
manner. Melting point: 286.degree.-288.degree.C. The yield is 86%
of the theoretical yield. [.alpha.] .sub.D.sup.25 = + 14.5.degree.
(concentration = 5% in N-hydrochloric acid-ethanol 1:2).
On following the procedure described in example 6 for the racemate,
(+)-.alpha.-methyl-thyroxine is obtained from said
(+)-.alpha.-methyl-3,5-di-iodo thyronine. Melting point:
273.degree.-274.degree.C. The yield is 84% of the theoretical
yield. [.alpha.] .sub.D.sup.29 = +10.degree. (concentration = 5% in
N hydrochloric acid/ 95% ethanol 1:2).
EXAMPLE 9
On following the procedure described in example 5, the optically
active ethyl esters of .alpha.-methyl-3,5,3'-tri-iodo thyronine are
obtained using the corresponding optically active starting
materials.
(+)-.alpha.-Methyl-3,5,3'-tri-iodo thyronine ethyl ester; yield:
67% of the theoretical yield. [.alpha.] .sub.D.sup.24 =
+12.0.degree. (concentration = 2% in acetic acid).
(-)-.alpha.-Methyl-3,5,3'-tri-iodo thyronine ethyl ester; yield:
52% of the theoretical yield. [.alpha.] .sub.D.sup.29 =
-11.1.degree. (concentration = 2% in acetic acid).
The optically active starting materials, obtained according to
example 5, are as follows:
(-)-.alpha.-Methyl-3,5,3'-tri-iodo thyronine; melting point:
281.degree.-283.degree.C. [.alpha.] .sub.D.sup.23 = -12.8.degree.
(concentration = 5% in N hydrochloric acid/ethanol 1:2).
(+)-.alpha.-Methyl-3,5,3'-tri-iodo thyronine; melting point:
277.5.degree.-278.degree.C. [.alpha.] .sub.D.sup.22 = +13.0.degree.
(concentration = 5% in N hydrochloric acid/ethanol 1:2).
In place of the methyl, ethyl, and benzyl esters of the racemic or
optically active .alpha.-methyl, .alpha.-ethyl, or .alpha.-n-propyl
thyroxine or 3,5,3'-tri-iodo thyronine, there may be obtained other
lower alkyl esters of said compounds such as the n-propyl,
isopropyl, n-butyl, isobutyl, tertiary butyl, n-amyl, isoamyl,
n-hexyl esters, or cycloalkyl esters such as the cyclopentyl,
cyclohexyl, methyl cyclohexyl esters, or other aralkyl esters such
as the phenyl ethyl, o-methyl benzyl, p-methyl benzyl esters of
.alpha.-alkyl thyroxine or .alpha.-alkyl-3,5,3'-tri-iodo thyronine
by using corresponding starting materials and reactants as
described in the preceding examples.
These alkyl, cycloalkyl, or aralkyl esters of .alpha.-alkyl
thyroxine or 3,5,3'-tri-iodo thyronine may be substituted in their
alkyl, cycloalkyl, or aralkyl ester moiety of the molecule, for
instance, by the hydroxyl group, the esterified hydroxyl group, and
especially by an amino group. Such compounds are, for instance, the
monoglycol ester, the .beta.-acetoxy ethyl ester, the 4-hydroxy
cyclohexyl ester, the 4-acetoxy benzyl ester of .alpha.-ethyl
thyroxine or .alpha.-methyl-3,5,3'-tri-iodo thyronine, and others.
Especially valuable compounds are the compounds in which the ester
moiety is substituted by an amino group. Such compounds are, for
instance, the .beta.-amino ethyl ester, the .beta.-dimethylamino
ethyl ester, the .delta.-di-n-butylamino-n-butyl ester, the
4-dimethylamino benzyl ester, the .beta.-piperidino ethyl ester,
the .gamma.-pyrrolidino-n-propyl ester, the morpholino methyl
ester, the .beta.-piperazino ethyl ester, the .beta.-(4-methyl
piperazino) ethyl ester of .alpha.-methyl. thyroxine or
.alpha.-ethyl-3,5,3'-tri-iodo thyronine, and others.
Likewise, such alkyl, cycloalkyl, or aralkyl esters can be prepared
from other .alpha.-alkyl substituted thyroxine or 3,5,3'-tri-iodo
thyronine compounds such as .alpha.-isopropyl, .alpha.-butyl,
.alpha.-isobutyl, .alpha.-tertiary butyl, .alpha.-n-amyl,
.alpha.-isoamyl, .alpha.-n-hexyl substituted thyroxine or
3,5,3'-tri-iodo thyronine compounds.
In place of the N-formyl-.alpha.-alkyl substituted thyronine
compounds, there may be used other N-acyl-.alpha.-alkyl substituted
thyronine compounds such as the N-acetyl, N-benzoyl compounds and
others.
As stated above, the new esters of .alpha.-alkyl thyroxine or
.alpha.-alkyl-3,5,3'-tri-iodo thyronine compounds from addition
salts with inorganic and organic acids. When using these compounds
therapeutically, such salts are formed with pharmaceutically
acceptable inorganic acids such as hydrochloric acid, hydrobromic
acid, phosphoric acid, sulfuric acid, and others, or organic acids
such as acetic acid, propionic acid, malonic acid, maleic acid,
succinic acid, tartaric acid, citric acid, malic acid, sorbic acid,
benzoic acid, salicylic acid, nicotinic acid, isonicotinic acid,
and others.
As stated above, the new esters have proved, in contrast to other
thyroid hormone preparations, to be especially useful in the
treatment of arteriosclerosis and particularly of coronary
sclerosis because they have a pronounced effect upon the
cholesterol and lipid blood level which is lowered considerably.
Their great advantage over thyroid hormones is that they do not
increase the basal metabolic rate and do not exhibit thyreotoxic
activity.
As stated above, the new esters according to the present invention
have the great advantage over known drugs of the thyronine type
that they can be administered not only parenterally but also orally
without losing their effectiveness and without causing undesired
side-effects such as stenocardia. The new esters are orally
administered in a dosage between about 1 mg./daily and about 25
mg./daily, depending upon the ester used. dl-.alpha.-Methyl
thyroxine ethyl ester, for instance, given orally in an amount of
10 mg./daily reduced the serum cholesterol level of a patient from
288 mg.% to 200 mg.% within 14 days.
The following examples serve to illustrate the preparation of
compositions containing the new esters according to the present
invention as they are used in therapy.
EXAMPLE 10
10.0 g. of d,l-.alpha.-methyl thyroxine ethyl ester, 59.25 g. of
spray-dried lactose, 40.0 g. of microcrystalline cellulose, 10 g.
of dried corn starch, and 0.75 g. of magnesium stearate are
intimately mixed with each other and are compressed, without
preceding granulation, to tablets of a diameter of 7 mm. and a
weight of about 120 mg. Each tablet contains 10 mg. of the
dl-.alpha.-methyl thyroxine ethyl ester.
EXAMPLE 11
The mixture of ingredients described in example 10 is compressed to
biconvex dragee cores which are then sugar coated in rotating
coating and polishing pans to the desired dragee size. Each dragee
contains 10 mg. of d,l-.alpha.-methyl thyroxine ethyl ester.
EXAMPLE 12
10.0 g. of d,l-.alpha.-methyl-3,5,3'-tri-iodo thyronine ethyl ester
are intimately mixed with 117.0 g. of dibasic calcium phosphate
CaHPO.sub.4.2H.sub.2 O, 6.6 g. of liquid paraffin (paraffinum
perliquidum), and 0.5 g. of magnesium stearate. The resulting
mixture is sieved and the powder is filled into gelatin capsules.
Each capsule contains about 130 mg. of the powder with 10 mg. of
said d,l-.alpha.-methyl-3,5,3'-triiodo thyronine ethyl ester.
Of course, many changes and variations in the starting and
intermediate compounds, in the reaction conditions, temperature,
and duration, in the solvents, condensing agents, catalysts, and
other reactants used, in the methods of working up the reaction
mixture and of isolating and purifying the reaction products, in
the preparation of pharmaceutical compositions containing such
compounds, and the like may be made by those skilled in the art in
accordance with the principles set forth herein and in the claims
annexed hereto.
* * * * *