U.S. patent application number 15/678797 was filed with the patent office on 2018-05-03 for position-specific asymmetric deuterium enriched catecholamine derivatives and medicaments comprising said compounds.
The applicant listed for this patent is Teva Pharmaceuticals International GmbH. Invention is credited to Rudolf-Giesbert ALKEN, Frank SCHNEIDER.
Application Number | 20180116989 15/678797 |
Document ID | / |
Family ID | 58638062 |
Filed Date | 2018-05-03 |
United States Patent
Application |
20180116989 |
Kind Code |
A1 |
ALKEN; Rudolf-Giesbert ; et
al. |
May 3, 2018 |
Position-Specific Asymmetric Deuterium Enriched Catecholamine
Derivatives And Medicaments Comprising Said Compounds
Abstract
Herein described are deuterated catecholamine derivatives of the
general Formula I ##STR00001## wherein, R.sub.1 is deuterium,
R.sub.2, and R.sub.3 are independently selected from hydrogen and
deuterium and wherein at least one of R.sub.2 and R.sub.3 has a
deuterium enrichment in the range from 0.02 mol % to 100 mol %
deuterium, and wherein the deuterium enrichment of R.sub.2 and
R.sub.3 is different from each other and that the difference
between the deuterium enrichment of R.sub.2 and R.sub.3 is at least
5 percentage points, R.sub.4 is hydrogen, deuterium, C.sub.1 to
C.sub.6-alkyl or C.sub.5 to C.sub.6-cycloalkyl, deuterated C.sub.1
to C.sub.6-alkyl or C.sub.5 to C.sub.6-cycloalkyl, or a group that
is easily hydrolytically or enzymatically cleavable under
physiological conditions, as well as their physiologically
acceptable salts and their stereoisomers, enantiomers or
diastereomers in optically pure form. The compounds can easily be
prepared by mixing deuterated and non-deuterated compounds in a
predefined ratio. The compounds show anti-Parkinson effect at lower
doses and show lower side effects.
Inventors: |
ALKEN; Rudolf-Giesbert;
(Svedala, SE) ; SCHNEIDER; Frank; (Berlin,
DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Teva Pharmaceuticals International GmbH |
Jona |
|
CH |
|
|
Family ID: |
58638062 |
Appl. No.: |
15/678797 |
Filed: |
August 16, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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|
15402343 |
Jan 10, 2017 |
9763904 |
|
|
15678797 |
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14765430 |
Aug 3, 2015 |
9567289 |
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PCT/EP2014/052267 |
Feb 5, 2014 |
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15402343 |
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61760738 |
Feb 5, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/2866 20130101;
A61K 31/165 20130101; A61K 9/2018 20130101; A61K 9/2054 20130101;
A61K 31/165 20130101; A61K 31/277 20130101; A61K 9/2059 20130101;
A61K 9/2027 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 9/2009 20130101; A61K 9/2853 20130101;
A61K 31/198 20130101; A61K 31/198 20130101; A61K 31/277 20130101;
A61K 9/2013 20130101; A61K 9/2813 20130101 |
International
Class: |
A61K 31/198 20060101
A61K031/198; A61K 9/20 20060101 A61K009/20; A61K 31/165 20060101
A61K031/165; A61K 31/277 20060101 A61K031/277; A61K 9/28 20060101
A61K009/28 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 2, 2013 |
EP |
13182708.1 |
Claims
1. A pharmaceutical composition comprising
L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) propionic acid,
or a physiologically acceptable salt thereof, having a deuterium
enrichment above the natural abundance of deuterium; and
L-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl) propionic acid, or
a physiologically acceptable salt thereof, having a deuterium
enrichment above the natural abundance of deuterium.
Description
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/402,343, filed Jan. 10, 2017, which is a
continuation of U.S. patent application Ser. No. 14/765,430, filed
Aug. 3, 2015, which is a U.S. national stage, filed under 35 U.S.C.
.sctn. 371, of International Patent Application No.
PCT/EP2014/052267, filed Feb. 5, 2014, which claims priority to
U.S. Provisional Application No. 61/760,738, filed Feb. 5, 2013 and
European Patent Application No. 13182708.1, filed Sep. 2, 2013.
These priority applications are incorporated by reference
herein.
[0002] The present invention relates to position-specific
asymmetric deuterium enriched catecholamine derivatives, methods
for their production and medicaments comprising said compounds, as
well as their use in the treatment of Parkinson's disease.
[0003] Known representatives of catecholamines, such as L-DOPA
(levodopa) as well as their carboxylic acid esters, are utilized,
among other things, for the treatment of Parkinson's disease and
restless leg syndrome. Such a pharmaceutical which contains
levodopa is, for example, Dopaflex.RTM.. L-DOPA acts on the
dopamine concentration in neurons of the brain. Unlike dopamine
itself, it can pass through the blood-brain barrier and is
converted into dopamine in the brain.
[0004] In addition, levodopa is administered in combination with
active additives in pharmaceuticals. Combinations of levodopa are
used with peripheral decarboxylase inhibitors, with inhibitors of
the enzyme catechol-O-methyltransferase (COMT), with inhibitors of
the enzyme monoamine oxidase (MAO) and with dopamine
.beta.-hydroxylase inhibitors.
[0005] In this connection, the decarboxylase inhibitors used are,
for example: D,L-serine-2-(2,3,4-trihydroxybenzyl) hydrazide
(benserazide),
(-)-L-.alpha.-hydrazino-3,4-dihydroxy-.alpha.-methylhydrocinnamic
acid (carbidopa), L-serine-2-(2,3,4-trihydroxybenzyl)hydrazide,
glycine-2-(2,3,4-trihydroxybenzyl) hydrazide and
L-tyrosine-2-(2,3,4-trihydroxybenzyl)hydrazide. Examples of
combination preparations of levodopa and decarboxylase inhibitors
include, among others: Madopar.RTM. (levodopa and benserazide
hydrochloride) as well as Nacom.RTM. (levodopa and carbidopa).
[0006] Examples of COMT inhibitors are entacapone (Comtan.RTM.) and
cabergoline, and frequently used MAO inhibitors are selegiline
hydrochloride, moclobemide and tranylcypromine.
[0007] Calcium 5-butyl picolinate and calcium 5-pentyl picolinate
are described as inhibitors for dopamine-.beta.-hydroxylase (DE-A 2
049 115).
[0008] Parkinson's disease is a neurodegenerative disease with a
slow progressive course characterized by different symptoms and
signs that may be present or develop during the progression of
disease. Core symptoms are bradykinesia and at least one of the
following: resting tremor, muscular rigidity and postural reflex
impairment. Other symptoms that may occur during the disease
progression are autonomic disturbances, sleep disturbances,
disturbances in the sense of smell or sense, of temperature as well
as depressive symptoms and cognitive dysfunctions.
[0009] The improvement of the impaired dopaminergic
neurotransmission by administration of L-DOPA is the backbone of
the current pharmacotherapy. Patients with advanced Parkinson's
disease require higher doses of dopaminergics but this is limited
by motor complications, like fluctuations and involuntarily
movements (described as levodopa induced dyskinesia, LIDs).
Fluctuations might be due to the shorter striatal persistence
(half-life) of dopamine especially in advanced Parkinson's disease
patients, also referred to as "Parkinson's patients". A clinical
established approach to prolong striatal dopamine persistence is
the co-administration of MAO-B inhibitors which block the main
metabolic breakdown route of dopamine. The induction of LIDs is
associated in many patients with higher CNS dopamine levels
generated by large L-DOPA doses. Currently there are different
pharmacological means under development to treat existing LIDs.
[0010] .alpha.,.beta.-.beta.-D3-L-DOPA exhibited higher
longer-lasting striatal dopamine levels than L-DOPA.
Correspondingly to the increased availability of dopamine in the
striatum, .alpha.,.beta.,.beta.-D3-L-DOPA showed improved motor
activity compared to L-DOPA in several Parkinson models (Malmlof et
al., Exp Neurol, 2008, 538-542; Malmlof et al., Exp Neurol, 2010,
225: 408-415). The equi-effective dose of
.alpha.,.beta.,.beta.-D3-L-DOPA compared to L-DOPA was about 60%.
The observed longer striatal persistence of dopamine allowed the
assumption that fluctuations might be reduced as well.
[0011] S/S-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic
acid (.alpha.,.beta.-D2-L-DOPA) and
L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)propionic acid
(.alpha.,.beta.,.beta.-D3-L-DOPA) were shown to increase and
prolong the output of striatal dopamine significantly more than
L-DOPA (WO-A 2004/056724 and WO-A 2007/093450).
[0012] The highest striatal dopamine concentrations were found
after administration of .alpha.,.beta.-D2-L-DOPA. Those dopamine
levels were even higher than those after the administration of the
triple-deuterated .alpha.,.beta.,.beta.-D3-L-DOPA which included
the same deuterated positions as the double deuterated L-DOPA.
[0013] At the equi-effective dose (same striatal dopamine levels
and same motor effect as L-DOPA), .alpha.,.beta.,.beta.-D3-L-DOPA
caused significant less dyskinesia than L-DOPA (Malmlof et al., Exp
Neurol, 2010, 225: 408-415).
[0014] The problem to be solved according to the invention is to
improve the activity of the known
.alpha.,.beta.,.beta.-D3-L-DOPA.
[0015] As used herein and in the context of the present invention
the meaning of "deuterated" is extended to partially or completely
deuterated compounds. "Completely deuterated" compounds are
compounds in which at least 98 mol % deuterium are present in the
respective position within the chemical compound (The deviation to
100 Mol % is caused by analytical measurement deviation and
experimental errors.) This means that there has been achieved an
enrichment of deuterium in the respective position and that
hydrogen has been replaced. The respective enrichment may be
performed by chemical reaction in that one uses deuterated starting
materials in chemical reactions or that an hydrogen/deuterium
exchange has been performed by mixing respective compounds.
[0016] "Deuterated" is therefore not related to any naturally
occurring deuterium in hydrogen compounds. As it is known,
deuterium is present in hydrogen in natural abundance to an extend
of 0.015 mol %. Any abundance or enrichment that is greater than
0.02 mol % is understood as being "deuterated" in the sense of this
present invention.
[0017] The problem is solved according to the invention by
providing deuterated catecholamine derivatives of the general
Formula I:
##STR00002##
[0018] wherein
[0019] R.sub.1 is deuterium,
[0020] R.sub.2, and R.sub.3 are independently selected from
hydrogen and deuterium and wherein at least one of R.sub.2 and
R.sub.3 has a deuterium enrichment in the range from 0.02 mol % to
100 mol % deuterium, and
[0021] wherein the deuterium enrichment of R.sub.2 and R.sub.3 is
different from each other and that the difference between the
deuterium enrichment of R.sub.2 and R.sub.3 is at least 5
percentage points,
[0022] R.sub.4 is hydrogen, deuterium, C.sub.1 to C.sub.6-alkyl or
C.sub.5 to C.sub.6-cycloalkyl, deuterated C.sub.1 to C.sub.6-alkyl
or C.sub.5 to C.sub.6-cycloalkyl, or a group that is easily
hydrolytically or enzymatically cleavable under physiological
conditions,
[0023] as well as their physiologically acceptable salts and their
stereoisomers, enantiomers or diastereomers in optically pure
form.
[0024] Deuterated catecholamine derivatives, according to the
invention are preferred, wherein the difference between the
deuterium enrichment of R.sub.2 and R.sub.3 is at least 7
percentage points.
[0025] Deuterated catecholamine derivatives, according to the
invention are preferred, wherein the difference between the
deuterium enrichment of R.sub.2 and R.sub.3 is at least 10
percentage points.
[0026] Deuterated catecholamine derivatives, according to the
invention are preferred, wherein the difference between the
deuterium enrichment of R.sub.2 and R.sub.3 is at least 15
percentage points.
[0027] Deuterated catecholamine derivatives, according to the
invention are preferred, wherein the difference between the
deuterium enrichment of R.sub.2 and R.sub.3 is at least 20
percentage points.
[0028] Deuterated catecholamine derivatives, according to the
invention are preferred, wherein R.sub.4 is selected from the group
comprising hydrogen, deuterium, methyl, perdeuteromethyl, ethyl,
perdeuteroethyl, propyl, perdeuteropropyl, butyl, perdeuterobutyl,
C.sub.1 to C.sub.6-alkyl, that may be branched or unbranched, or
C.sub.5 to C.sub.6-cycloalkyl, deuterated or partly deuterated
C.sub.1 to C.sub.6-alkyl, that may be branched or unbranched, or
deuterated or partly deuterated C.sub.5 to C.sub.6-cycloalkyl.
[0029] Deuterated catecholamine derivatives, according to the
invention are preferred, wherein R.sub.4 is selected from the group
comprising hydrogen, deuterium, methyl, perdeuteromethyl, ethyl,
perdeuteroethyl, propyl, perdeuteropropyl, cyclohexyl, and
perdeuterocyclohexyl.
[0030] Deuterated catecholamine derivatives, according to the
invention are preferred, wherein R.sub.4 is hydrogen.
[0031] Deuterated catecholamine derivatives, according to the
invention are preferred, wherein R.sub.4 is methyl.
[0032] Deuterated catecholamine derivatives, according to the
invention are preferred, wherein R.sub.4 is ethyl.
[0033] Especially preferred according to the present invention is
L-2-amino-2,3,3*-trideutero-3-(3,4-dihydroxyphenyl) propionic acid
(.alpha.,.beta.,.beta.*-D3-L-DOPA), wherein 3* indicates that the
deuterium enrichment in one .beta.-position is about 90 mol %. This
compound has according to the definition of the present invention a
difference in the deuterium enrichment in the .beta.-positions of
about 8 to 10 percentage points. The other positions carrying
deuterium are completely deuterated and show a deuterium enrichment
of at least 98 mol %. This compound is named Test Item D in Tables
1 and 2 as outlined in the present description herein.
[0034] The problem is also solved by providing deuterated
catecholamine derivatives, obtainable by admixing a compound of
general Formula II
##STR00003##
[0035] with a compound of general Formula III or general Formula
IV
##STR00004##
[0036] wherein, in general Formula II, III, or IV,
[0037] R.sub.4 is hydrogen, deuterium, C.sub.1 to C.sub.6-alkyl or
C.sub.5 to C.sub.6-cycloalkyl, deuterated C.sub.1 to C.sub.6-alkyl
or C.sub.5 to C.sub.6-cycloalkyl, or a group that is easily
hydrolytically or enzymatically cleavable under physiological
conditions,
[0038] as well as their physiologically acceptable salts and their
stereoisomers, enantiomers or diastereomers in optically pure
form,
[0039] in a ratio to adjust the deuterium enrichment in position
R.sub.2 or R.sub.3 in general Formula I within the predefined range
of 0.02 mol % to 100 mol % deuterium.
[0040] Preferred are, according to the present invention,
deuterated catecholamine derivatives, wherein the compound
according to general Formula II is selected from the list
comprising
[0041] L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) propionic
acid,
[0042] L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) methyl
propionate,
[0043] L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) ethyl
propionate,
[0044] L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) propyl
propionate,
[0045] L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)
cyclohexyl propionate,
[0046] L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)
perdeuteromethyl propionate,
[0047] L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)
perdeuteroethyl propionate,
[0048] L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)
perdeuteropropylethyl propionate,
[0049] L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)
perdeuterocyclohexyl propionate,
[0050] as well as their physiologically acceptable salts and their
stereoisomers, enantiomers or diastereomers in optically pure
form,
[0051] and wherein the compound according to general Formula III or
general Formula IV is selected from the list comprising
[0052] L-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl) propionic
acid,
[0053] L-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl) methyl
propionate,
[0054] L-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl) ethyl
propionate,
[0055] L-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl) propyl
propionate,
[0056] L-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl) cyclohexyl
propionate,
[0057] L-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)
perdeuteromethyl propionate,
[0058] L-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)
perdeuteroethyl propionate,
[0059] L-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)
perdeuteropropylethyl propionate,
[0060] L-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)
perdeuterocyclohexyl propionate,
[0061] as well as their physiologically acceptable salts and their
stereoisomers, enantiomers or diastereomers in optically pure
form.
[0062] Especially preferred are deuterated catecholamine
derivatives, wherein the percentage of the compound according to
general Formula II is in the range of 0.1 mol % to 99.9 mol %,
preferably in the range of 5 mol % to 95 mol %, especially
preferred in the range of 78 mol % to 95 mol %. Most preferred are
herein deuterated catecholamine derivatives, wherein the percentage
of the compound according to general Formula II is in the range of
88 mol % to 92 mol %. Most preferred are herein also deuterated
catecholamine derivatives, wherein the percentage of the compound
according to general Formula II is in the range of 78 mol % to 82
mol %.
[0063] Therefore, according to the invention a mixture is preferred
in which 90 mol % of
L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) propionic acid
are admixed with 10 mol % of
L-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl) propionic acid, or
in which 80 mol % of
L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) propionic acid
are admixed with 20 mol % of
L-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl) propionic acid, or
in which 85 mol % of
L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) propionic acid
are admixed with 15 mol % of
L-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl) propionic acid, or
in which 70 mol % of
L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) propionic acid
are admixed with 30 mol % of
L-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl) propionic acid.
[0064] A further object of the present invention is a method for
the preparation of deuterated catecholamine derivatives according
to the present invention, by mixing
[0065] (i) a compound according to general Formula I:
##STR00005##
[0066] wherein
[0067] R.sub.1, R.sub.2, R.sub.3, and R.sub.4 have the meaning as
given above,
[0068] as well as their physiologically acceptable salts and their
stereoisomers, enantiomers or diastereomers in optically pure
form,
[0069] wherein the deuterium enrichment of R.sub.2 and R.sub.3 is
different from each other and that the difference between the
deuterium enrichment of R.sub.2 and R.sub.3 has a first predefined
value
[0070] with (ii) at least one compound according to general Formula
I:
##STR00006##
[0071] wherein
[0072] R.sub.1, R.sub.2, R.sub.3, and R.sub.4 have the meaning as
above,
[0073] as well as their physiologically acceptable salts and their
stereoisomers, enantiomers or diastereomers in optically pure
form,
[0074] wherein the deuterium enrichment of R.sub.2 and R.sub.3 is
different from each other and that the difference between the
deuterium enrichment of R.sub.2 and R.sub.3 has a second predefined
value,
[0075] (iii) in a ratio that yields a predefined difference between
the deuterium enrichment of R.sub.2 and R.sub.3, which is in the
range from at least 5 to at least 20 percentage points.
[0076] A further object of the present invention is the use of the
deuterated catecholamine derivatives according to the invention as
well as physiologically acceptable salts thereof, for the treatment
of dopamine deficiency diseases or diseases which are based on
disrupted tyrosine transport or disrupted tyrosine decarboxylase,
such as Parkinson's disease, restless leg syndrome, dystonia, for
inhibiting prolactin secretion, for stimulating the release of
growth hormone, for the treatment of neurological symptoms of
chronic manganese intoxications, of amyotrophic lateral sclerosis
and of multiple system atrophy.
[0077] Preferred is the use of the deuterated catecholamine
derivatives according to the invention as well as physiologically
acceptable salts thereof, in combination with an enzyme inhibitor
or several enzyme inhibitors, for the treatment of dopamine
deficiency diseases or diseases which are based on disrupted
tyrosine transport or disrupted tyrosine decarboxylase, such as
Parkinson's disease, restless leg syndrome, dystonia, for
inhibiting prolactin secretion, for stimulating the release of
growth hormone, for the treatment of neurological symptoms of
chronic manganese intoxications, of amyotrophic lateral sclerosis
and of multiple system atrophy.
[0078] Preferred is the use of the deuterated catecholamine
derivatives according to the invention as well as physiologically
acceptable salts thereof, further characterized in that the enzyme
inhibitor or the enzyme inhibitors involve decarboxylase inhibitors
and/or catechol-O-methyltransferase inhibitors and/or monoamine
oxidase inhibitors and/or .beta.-hydroxylase inhibitors.
[0079] Preferred is the use of the deuterated catecholamine
derivatives according to the invention as well as physiologically
acceptable salts thereof, further characterized in that the
decarboxylase inhibitor is selected from the group consisting of
D,L-serine-2-(2,3,4-trihydroxybenzyl) hydrazide (benserazide),
(+L-.alpha.-hydrazino-3,4-dihydroxy-.alpha.-methylhydrocinnamic
acid (carbidopa), L-serine-2-(2,3,4-trihydroxybenzyl) hydrazide,
glycine-2-(2,3,4-trihydroxybenzyl) hydrazide and
L-tyrosine-2-(2,3,4-trihydroxybenzyl) hydrazide as well as
physiologically acceptable salts thereof.
[0080] Preferred is the use of the deuterated catecholamine
derivatives according to the invention as well as physiologically
acceptable salts thereof further characterized in that the
catechol-O-methyltransferase inhibitor is selected from entacapone
and cabergoline as well as physiologically acceptable salts
thereof.
[0081] Preferred is the use of the deuterated catecholamine
derivatives according to the invention as well as physiologically
acceptable salts thereof, further characterized in that the
monoamine oxidase inhibitor is selected from the group consisting
of selegiline, moclobemide and tranylcypromine as well as
physiologically acceptable salts thereof.
[0082] Preferred is the use of the deuterated catecholamine
derivatives according to the invention as well as physiologically
acceptable salts thereof, further characterized in that the
.beta.-hydroxylase inhibitor is selected from calcium 5-butyl
picolinate and calcium 5-pentyl picolinate as well as
physiologically acceptable salts thereof.
[0083] Preferred is the use of the deuterated catecholamine
derivatives according to the invention as well as physiologically
acceptable salts thereof, for the production of pharmaceuticals for
the treatment of Parkinson's disease, restless leg syndrome, of
amyotrophic lateral sclerosis and of multiple system atrophy.
[0084] A further object of the present invention is a
pharmaceutical composition, which contains deuterated
catecholamines according to the invention as well as
physiologically acceptable salts thereof, for the treatment of
Parkinson's disease, of restless leg syndrome, of dystonia, for
inhibiting prolactin secretion, for stimulating the release of
growth hormone, for the treatment of neurological symptoms of
chronic manganese intoxications, of amyotrophic lateral sclerosis
and of multiple system atrophy, in addition to pharmaceutically
acceptable adjuvants and additives.
[0085] Preferred is a pharmaceutical composition, which comprises
deuterated catecholamines according to the invention as well as
physiologically acceptable salts thereof, for the treatment of
Parkinson's disease, restless leg syndrome, dystonia, for
inhibiting prolactin secretion, for stimulating the release of
growth hormone, for the treatment of neurological symptoms of
chronic manganese intoxications, of amyotrophic lateral sclerosis
and of multiple system atrophy, as well as one or more enzyme
inhibitors, in addition to pharmaceutically acceptable adjuvants
and additives.
[0086] Preferred is a pharmaceutical composition, which comprises
deuterated catecholamines according to the invention, further
characterized in that the enzyme inhibitor or the enzyme inhibitors
involve decarboxylase inhibitors and/or
catechol-O-methyltransferase inhibitors and/or monoamine oxidase
inhibitors and/or .beta.-hydroxylase inhibitors.
[0087] Preferred is a pharmaceutical composition, which comprises
deuterated catecholamines according to the invention, further
characterized in that the decarboxylase inhibitor is selected from
the group consisting of D,L-serine-2-(2,3,4-trihydroxybenzyl)
hydrazide (benserazide),
(-)-L-.alpha.-hydrazino-3,4-dihydroxy-.alpha.-methylhydrocinnamic
acid (carbidopa), L-serine-2-(2,3,4-trihydroxybenzyl) hydrazide,
glycine-2-(2,3,4-trihydroxybenzyl) hydrazide and
L-tyrosine-2-(2,3,4-trihydroxybenzyl) hydrazide as well as
physiologically acceptable salts thereof.
[0088] Preferred is a pharmaceutical composition, which comprises
deuterated catecholamines according to the invention, further
characterized in that the catechol-O-methyltransferase inhibitor is
selected from entacapone and cabergoline as well as physiologically
acceptable salts thereof.
[0089] Preferred is a pharmaceutical composition, which comprises
deuterated catecholamines according to the invention, further
characterized in that the monoamine oxidase inhibitor is selected
from the group consisting of selegiline, moclobemide and
tranylcypromine as well as physiologically acceptable salts
thereof.
[0090] Preferred is a pharmaceutical composition, which comprises
deuterated catecholamines according to the invention, further
characterized in that the .beta.-hydroxylase inhibitor is selected
from calcium 5-butyl picolinate and calcium 5-pentyl picolinate as
well as physiologically acceptable salts thereof.
[0091] Still another object of the present invention is a
pharmaceutical composition, which comprises a mixture of 10 mol %
of L-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl) propionic acid
as well as physiologically acceptable salts thereof, and 90 mol %
of L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) propionic
acid as well as physiologically acceptable salts thereof, in a
pharmacologically active amount, optionally in addition with
pharmaceutically acceptable adjuvants and additives.
[0092] Preferred is a pharmaceutical composition, wherein the
composition further comprises, in a pharmacologically active
amount, carbidopa, benserazide or entacapone or a mixture of the
said compounds.
[0093] The pharmaceutical compositions of the present invention are
very powerful in the treatment of Parkinson's disease as the
asymmetric position specific deuterium enrichment can tune the
known effects of position specific deuterated L-DOPA. This provides
a powerful tool to adjust the treatment according to the symptoms
and side effects that change during disease progression.
[0094] According to the stage of Parkinson's disease in the
respective person, one can use a compounds with a deuterium
enrichment adjusted to the need of the patient under treatment.
This offers new opportunities for a medication that is tailor-made
or customized to the patient.
[0095] Another object of the present invention is a method for the
treatment of dopamine deficiency diseases or diseases which are
based on disrupted tyrosine transport or disrupted tyrosine
decarboxylase, such as Parkinson's disease, restless leg syndrome,
dystonia, for inhibiting prolactin secretion, for stimulating the
release of growth hormone, for the treatment of neurological
symptoms of chronic manganese intoxications, of amyotrophic lateral
sclerosis and of multiple system atrophy with a person who has been
identified as a person who is in the need of the treatment of
dopamine deficiency diseases or diseases which are based on
disrupted tyrosine transport or disrupted tyrosine decarboxylase,
such as Parkinson's disease, restless leg syndrome, dystonia, for
inhibiting prolactin secretion, for stimulating the release of
growth hormone, for the treatment of neurological symptoms of
chronic manganese intoxications, of amyotrophic lateral sclerosis
and of multiple system atrophy, the method comprising administering
to the person deuterated catecholamine derivatives according to the
invention as given in general formula as well as physiologically
acceptable salts thereof.
[0096] Preferred is the method, wherein the administering to the
person is in combination with an enzyme inhibitor or several enzyme
inhibitors.
[0097] Preferred is the method, wherein the enzyme inhibitor or the
enzyme inhibitors involve decarboxylase inhibitors and/or
catechol-O-methyltransferase inhibitors and/or monoamine oxidase
inhibitors and/or .beta.-hydroxylase inhibitors.
[0098] Preferred is the method, wherein the decarboxylase inhibitor
is selected from the group consisting of
D,L-serine-2-(2,3,4-trihydroxybenzyl) hydrazide (benserazide),
(+L-.alpha.-hydrazino-3,4-dihydroxy-.alpha.-methylhydrocinnamic
acid (carbidopa), L-serine-2-(2,3,4-trihydroxybenzyl)hydrazide,
glycine-2-(2,3,4-trihydroxybenzyl)hydrazide and
L-tyrosine-2-(2,3,4-trihydroxybenzyl)hydrazide as well as
physiologically acceptable salts thereof.
[0099] Preferred is the method, wherein the
catechol-O-methyltransferase inhibitor is selected from entacapone
and cabergoline as well as physiologically acceptable salts
thereof.
[0100] Preferred is the method, wherein the monoamine oxidase
inhibitor is selected from the group consisting of selegiline,
moclobemide and tranylcypromine as well as physiologically
acceptable salts thereof.
[0101] Preferred is the method, wherein the .beta.-hydroxylase
inhibitor is selected from calcium 5-butyl picolinate and calcium
5-pentyl picolinate as well as physiologically acceptable salts
thereof.
[0102] The preparation of the deuterated catecholamine derivatives
of the present invention can be performed in at least two principal
ways. One way is to mix compounds with a certain deuterium
enrichment with compounds which have only hydrogen or only a highly
enriched (>98% D) deuterium substitution at a certain position.
By mixing at least two compounds any required enrichment level of
deuterium at any position can be obtained. The other way of
preparation is to add specifically enriched starting material to a
certain step during the preparation process of the compounds
according to the invention.
[0103] The preparation of deuterium enriched catecholamine
derivatives is known from WO-A 2004/056724 and WO-A 2007/093450. In
there, the preparation of selectively deuterated DOPA derivatives
is disclosed that have a deuterium enrichment in the respective
position within the molecule of at least 98%.
[0104] One preferred synthetic pathway is shown in Scheme 1.
##STR00007##
[0105] According to the present invention it is preferred to
prepare the compounds according to the invention by adding
non-deuterated educts 3a and/or 4 and/or 5 to the respective
deuterated compounds. The ratio of deuterated and non-deuterated
compounds is adjusted in such a manner to obtain the desired ratio
in the end product. This method of production has the advantage
that no further mixing steps are required. This obtained product is
then by definition no longer a mixture.
[0106] For the production of the physiologically acceptable salts
of the deuterated catecholamine derivatives according to the
invention, the usual physiologically acceptable inorganic and
organic acids such as hydrochloric acid, hydrobromic acid,
phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric
acid, lactic acid, tartaric acid, malic acid, citric acid,
salicylic acid, adipic acid and benzoic acid can be used.
Additional acids that can be used are described, for example, in
Fortschritte der Arzneimittelforschung, Vol. 10, pp. 224-225,
Birkhauser Publishers, Basel and Stuttgart, 1966, and Journal of
Pharmaceutical Sciences, Vol. 66, pp. 1-5 (1977).
[0107] The acid addition salts are usually obtained in a way known
in and of itself by mixing the free base or solutions thereof with
the corresponding acid or solutions thereof in an organic solvent,
for example, a lower alcohol, such as methanol, ethanol, n-propanol
or isopropanol or a lower ketone such as acetone, methyl ethyl
ketone or methyl isobutyl ketone or an ether such as diethyl ether,
tetrahydrofuran or dioxane. For better crystal precipitation,
mixtures of the named solvents can also be used. In addition,
physiologically acceptable aqueous solutions of acid addition salts
of the compounds used according to the invention can be produced
therefrom in an aqueous acid solution.
[0108] The acid addition salts of the compounds according to the
invention can be converted to the free base in a way known in and
of itself, e.g., with alkali or ion exchangers. Additional salts
can be obtained from the free base by reaction with inorganic or
organic acids, particularly those which are suitable for the
formation of salts that can be employed therapeutically. These or
also other salts of the compound according to the invention, such
as, e.g., the picrate, may also serve for purification of the free
base by converting the free base into a salt, separating this salt,
and afterwards releasing the base from the salt.
[0109] The subject of the present invention is also pharmaceuticals
for oral, buccal, sublingual, nasal, rectal, subcutaneous,
intravenous or intramuscular application as well as for inhalation,
which, in addition to the usual vehicle and dilution agents, also
contain a compound of general Formula I or the acid addition salt
thereof as an active ingredient.
[0110] The pharmaceuticals of the invention are produced, in the
known way and with suitable dosage, with the usual solid or liquid
vehicle substances or dilution agents and the commonly used
pharmaceutical-technical adjuvants corresponding to the desired
type of application. The preferred preparations consist of a form
for administration which is suitable for oral application. Such
forms of administration include, for example, tablets, sucking
tablets, film tablets, dragees, capsules, pills, powders,
solutions, aerosols or suspensions or slow-release forms.
[0111] Of course, parenteral preparations such as injection
solutions are also considered. In addition, suppositories, for
example, have also been named as preparations. Corresponding
tablets can be obtained, for example, by mixing the active
substance with known adjuvants, for example, inert dilution agents
such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone,
bursting agents such as corn starch or alginic acid, binders such
as starches or gelantins, lubricants such as magnesium stearate or
talc and/or agents for achieving a slow-release effect such as
carboxypolymethylene, carboxymethylcellulose, cellulose acetate
phthalate or polyvinyl acetate. The tablets may also consist of
several layers.
[0112] Dragees can also be produced correspondingly, for controlled
or delayed release forms of preparation, by coating the cores
produced analogously to the tablets with agents commonly used in
dragee coatings, for example, polyvinylpyrrolidone or shellac, gum
arabic, talc, titanium dioxide or sugar. The dragee envelope may
also consist of several layers, wherein the adjuvants mentioned
above in the case of tablets can be used.
[0113] Solutions or suspensions containing the active substance
used according to the invention may additionally contain agents
that improve taste, such as saccharin, cyclamate or sugar, as well
as, e.g., taste enhancers such as vanilla or orange extract. They
may also contain suspension adjuvants such as sodium
carboxymethylcellulose or preservatives such as p-hydroxybenzoate.
Capsules containing active substances can be produced, for example,
by mixing the active substance with an inert vehicle such as
lactose or sorbitol and encapsulating this mixture in gelatin
capsules. Suitable suppositories can be produced, for example, by
mixing with vehicle agents provided therefore, such as neutral fats
or polyethylene glycol or derivatives thereof.
[0114] The production of the pharmaceutical preparations according
to the invention is known in the art, and is described in handbooks
known to the person skilled in the art, for example, Hager's
Handbuch [Handbook] (5th ed.) 2, 622-1045; List et al.,
Arzneiformenlehre [Instructions for Drug Forms], Stuttgart: Wiss.
Verlagsges. 1985; Sucker et al., Pharmazeutische Technologie
[Pharmaceutical Technology], Stuttgart: Thieme 1991; Ullmann's
Enzyklopadie [Encyclopedia] (5th ed.) A 19, 241-271; Voigt,
Pharmazeutische Technologie [Pharmaceutical Technology], Berlin:
Ullstein Mosby 1995.
[0115] The following examples shall explain the present invention.
The examples shall be understood only as a preferred embodiment of
the invention. It is not intended to limit the present invention to
the scope of the given examples.
EXAMPLE 1
[0116] The effects on motor performance and the development of
dyskinesia following administration of deuterated L-DOPA
derivatives with different deuterium enrichment at specific
position of the side chain have been compared among each other and
to L-DOPA in the 6-hydroxydopamine (6-OHDA) rodent model of
Parkinson's disease. The tested compounds and the specific
deuterium enrichment of these compounds are displayed in Table
1.
TABLE-US-00001 TABLE 1 Test Items Deuterium Enrichment Name .alpha.
.beta..sub.R .beta..sub.S A L-2-amino-3-(3,4-dihydroxyphenyl) NA NA
NA propionic acid (L-DOPA) B S/S-2-amino-2,3-dideutero-3- >98%
<1% >98% (3,4-dihydroxyphenyl) propionic acid
(.alpha.,.beta.-D2-L-DOPA) C L-2-amino-2,3,3-trideutero-3- >98%
>98% >98% (3,4-dihydroxyphenyl) propionic acid
(.alpha.,.beta.,.beta.-D3-L-DOPA) D L-2-amino-2,3,3*-trideutero-3-
>98% 90% >98% (3,4-dihydroxyphenyl) propionic acid
(.alpha.,.beta.,.beta.*-D3-L-DOPA) (3* or .beta.*, respectively,
indicates that the position is not completely deuterated)
(.beta..sub.R and .beta..sub.S relate to the commonly used R/S
nomenclature indicating the relative positions in optically active
compounds)
[0117] Female Sprague-Dawley rats weighing approximately 225 g were
housed on a 12-hour light/dark cycle and kept on standard
laboratory diet and water ad libitum. The rats were lesioned by
unilateral injection of the neurotoxin 6-OHDA. The lesion was
validated by measuring the rotational activity after i.p. injection
of 2.5 mg/kg D-amphetamine.
[0118] The anti-Parkinson effect (effect on motor performance) was
evaluated by measurement of drug induced contralateral rotations. A
dose effect was established to determine the equipotent
(equi-effective) dose.
[0119] Dyskinesia was evaluated after repeated treatment by scoring
the animals for abnormal involuntary movements. The rats were
scored, by an observer blinded to the experimental design for limb,
axial and orolingual involuntary movements.
[0120] The equipotent dose as percent of L-DOPA dose that caused
the same effect on motor performance and dyskinesia observed
following repeated administration of these doses is shown in Table
2.
TABLE-US-00002 TABLE 2 Results Equipotent Dose Motor Effect
Dyskinesia [% of L-DOPA [% of L-DOPA [% of dyskinesia Test Item
dose] effect] caused by L-DOPA] A 100% 100% 100% B 30% 100% 100% C
60% 100% 50% D 35% 100% 50%
[0121] The effect of .alpha.,.beta.-D2-L-DOPA [B] on motor
performance is significantly greater compared to
.alpha.,.beta.,.beta.-D3-L-DOPA [C] and L-DOPA [A] as reflected by
a lower equipotent dose. However dyskinesia after
.alpha.,.beta.-D2-L-DOPA [B] is not reduced in comparison to L-DOPA
at equipotent dose whereas .alpha.,.beta.,.beta.-D3-L-DOPA [C]
caused significantly less dyskinesia than L-DOPA at equipotent
dose.
[0122] Surprisingly, test item D with almost 100% deuterium
enrichment in position .alpha. and .beta.and 90% in position OR
provides both a motor effect equivalent to the di-deuterated
.alpha.,.beta.-D2-L-DOPA [B] and a reduction of dyskinesia as the
triple-deuterated .alpha.,.beta.,.beta.-D3-L-DOPA [C].
[0123] Test compound D is thus the optimal treatment for late stage
Parkinson patients suffering from motor fluctuations and LIDs and
requiring high doses of L-DOPA.
[0124] The example of compound D shows that asymmetric position
specific deuterium enrichment can tune the known effects of
position specific deuterated L-DOPA. This provides a powerful tool
to adjust the treatment according to the symptoms and side effects
that change during disease progression.
[0125] According to the stage of Parkinson's disease in the
respective person, one can use a compounds with a deuterium
enrichment adjusted to the need of the patient under treatment.
This offers new opportunities for a medication that is tailor-made
or customized to the patient.
EXAMPLE 2
[0126] Preparation of Test Compound D from Table 1
[0127] L-2-Amino-2,3,3*-trideutero-3-(3,4-dihydroxyphenyl)
propionic acid (.alpha.,.beta.,.beta.*-D3-L-DOPA)
[0128] Test item D has a deuterium enrichment of 90% in PR
position.
[0129] D is obtained by mixing 10 mol %
L-2-amino-2,3(S)-dideutero-3-(3,4-dihydroxyphenyl) propionic acid
with 90 mol % L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)
propionic acid (deuterium enrichment >98% in all three
positions). Experimental data for
C.sub.9H.sub.8.1.sup.2H.sub.2.9NO.sub.4
TABLE-US-00003 Calculated: H 6.95 C 54.05 N 7.00 O 32.00 Analyt: H
7.00 C 54.02 N 7.00 O 31.98
[0130] The degree of deuteration has also been determined by NMR
spectroscopy. For that purpose NMR spectra with a 500 MHz
spectrometer have been recorded. As a solvent, d.sub.6-DMSO was
used. The following Table 3 shows the respective position within
the compound of test item D and the integral (AUC=area under curve)
of the registered spectra, reflecting the content of hydrogen at
the respective positions.
TABLE-US-00004 TABLE 3 NMR results Position Integral (AUC) Ring
3.02 .alpha. 0.02 .beta. 0.01 .beta.* 0.10
[0131] The preparation of the starting material
L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) propionic acid
is described in WO-A 2004/056724, the preparation of the starting
material L-2-Amino-2,3(S)-dideutero-3-(3,4-dihydroxyphenyl)
propionic acid is described in WO-A 2007/093450.
[0132] After mixing the compounds the mixture may be processed
further in order to obtain a suitable pharmaceutical product for
the medication of Parkinson's disease as given in the following
examples.
EXAMPLE 3
[0133] Tablet with film coating containing
.alpha.,.beta.,.beta.*-D3-L-DOPA
TABLE-US-00005 Composition of the core:
.alpha.,.beta.,.beta.*-D3-L-DOPA (Test Item D) 40.00 mg Povidone
20.00 mg Sorbitol 7.00 mg Silicon dioxide, highly dispersed 2 mg
Pregelatinated starch 40.00 mg Croscarmellose-sodium 13.30 mg
Carmellose-sodium 20.05 mg Microcrystalline cellulose 41.00 mg
Magnesium stearate 2.00 mg Film coating:
Hydroxypropylmethylcellulose 16.00 mg Macrogol 400 .TM. 2.50 mg
Titanium oxide 3.00 mg Talc 3.00 mg
[0134] Preparation:
[0135] .alpha.,.beta.,.beta.*-D3-L-DOPA (Test Item D) and highly
dispersed silicon dioxide are granulated in a compulsory mixer with
a solution of povidone and sorbitol. The granules are dried,
screened, mixed with pregelatinated starch, croscarmellose sodium,
carmellose sodium and microcrystalline cellulose, then combined
with magnesium stearate and compressed into tablets. The tablets
are film coated with hydroxypropylmethylcellulose, Macrogol,
titanium dioxide and talc.
EXAMPLE 4
[0136] Tablet with film coating containing
.alpha.,.beta.,.beta.*-D3-L-DOPA and Carbidopa
TABLE-US-00006 Composition of the core:
.alpha.,.beta.,.beta.*-D3-L-DOPA (Test Item D) 35.00 mg Carbidopa
25.00 mg Povidone 20.00 mg Sorbitol 7.00 mg Silicon dioxide, highly
dispersed 2 mg Pregelatinated starch 40.00 mg Croscarmellose-sodium
13.30 mg Carmellose-sodium 20.05 mg Microcrystalline cellulose
41.00 mg Magnesium stearate 2.00 mg Film coating:
Hydroxypropylmethylcellulose 16.00 mg Macrogol 400 .TM. 2.50 mg
Titanium oxide 3.00 mg Talc 3.00 mg
[0137] Preparation:
[0138] .alpha.,.beta.,.beta.*-D3-L-DOPA (Test Item D), carbidopa
and highly dispersed silicon dioxide are granulated in a compulsory
mixer with a solution of povidone and sorbitol. The granules are
dried, screened, mixed with pregelatinated starch, croscarmellose
sodium, carmellose sodium and microcrystalline cellulose, then
combined with magnesium stearate and compressed into tablets. The
tablets are film coated with hydroxypropylmethylcellulose,
Macrogol, titanium dioxide and talc.
EXAMPLE 5
[0139] Tablet with film coating containing microencapsulated
.alpha.,.beta.,.beta.*-D3-L-DOPA and Carbidopa
TABLE-US-00007 Composition of the core:
.alpha.,.beta.,.beta.*-D3-L-DOPA (Test Item D) 40.00 mg Carbidopa
25.00 mg Tartaric acid 5.00 mg Povidone 20.00 mg Sorbitol 7.00 mg
Eudragit RL .TM. solid 20.00 mg Silicon dioxide, highly dispersed 2
mg Pregelatinated starch 40.00 mg Croscarmellose-sodium 13.30 mg
Carmellose-sodium 20.05 mg Microcrystalline cellulose 41.00 mg
Magnesium stearate 2.00 mg Film coating:
Hydroxypropylmethylcellulose 16.00 mg Macrogol 400 .TM. 2.50 mg
Titanium oxide 3.00 mg Talc 3.00 mg
[0140] Preparation:
[0141] .alpha.,.beta.,.beta.*-D3-L-DOPA (Test Item D), Carbidopa,
sorbitol and Eudragit are microencapsulated and homogenised in a
barrel mixer with tartaric acid, highly dispersed silicon dioxide,
povidone, pregelatinated starch, croscarmellose sodium, carmellose
sodium and microcrystalline cellulose, then combined with magnesium
stearate and compressed into tablets. The tablets are film coated
with hydroxypropylmethylcellulose, Macrogol, titanium dioxide and
talc.
EXAMPLE 6
[0142] Tablet with film coating containing microencapsulated
.alpha.,.beta.,.beta.*-D3-L-DOPA and benserazide
TABLE-US-00008 Composition of the core:
.alpha.,.beta.,.beta.*-D3-L-DOPA (Test Item D) 40.00 mg Benserazide
25.00 mg Tartaric acid 5.00 mg Povidone 20.00 mg Sorbitol 7.00 mg
Eudragit RLTM solid 20.00 mg Silicon dioxide, highly dispersed 2 mg
Pregelatinated starch 40.00 mg Croscarmellose-sodium 13.30 mg
Carmellose-sodium 20.05 mg Microcrystalline cellulose 41.00 mg
Magnesium stearate 2.00 mg Film coating:
Hydroxypropylmethylcellulose 16.00 mg Macrogol 400TM 2.50 mg
Titanium oxide 3.00 mg Talc 3.00 mg
[0143] The preparation of the film coated tablets is as given in
Example 5.
EXAMPLE 7
[0144] Tablet with film coating containing
.alpha.,.beta.,.beta.*-D3-L-DOPA and benserazide
TABLE-US-00009 Composition of the core:
.alpha.,.beta.,.beta.*-D3-L-DOPA (Test Item D) 35.00 mg Benserazide
25.00 mg Povidone 20.00 mg Sorbitol 7.00 mg Silicon dioxide, highly
dispersed 2 mg Pregelatinated starch 40.00 mg Croscarmellose-sodium
13.30 mg Carmellose-sodium 20.05 mg Microcrystalline cellulose
41.00 mg Magnesium stearate 2.00 mg Film coating:
Hydroxypropylmethylcellulose 16.00 mg Macrogol 400 .TM. 2.50 mg
Titanium oxide 3.00 mg Talc 3.00 mg
[0145] Preparation:
[0146] .alpha.,.beta.,.beta.*-D3-L-DOPA (Test Item D), carbidopa,
and highly dispersed silicon dioxide are granulated in a compulsory
mixer with a solution of povidone and sorbitol. The granules are
dried, screened, mixed with pregelatinated starch, croscarmellose
sodium, carmellose sodium and microcrystalline cellulose, then
combined with magnesium stearate and compressed into tablets. The
tablets are film coated with hydroxypropylmethylcellulose,
Macrogol, titanium dioxide and talc.
EXAMPLE 8
[0147] Tablet with film coating containing
.alpha.,.beta.,.beta.*-D3-L-DOPA and carbidopa and entacapone
TABLE-US-00010 Composition of the core:
.alpha.,.beta.,.beta.*-D3-L-DOPA (Test Item D) 40.00 mg Carbidopa
25.00 mg Entacapone 200.00 mg Povidon K30 20.00 mg Crospovidone
Type B 15.00 mg Mannitol 9.00 mg Silicon dioxide, highly dispersed
2 mg Pregelatinated starch 40.00 mg Croscarmellose-sodium 13.30 mg
Carmellose-sodium 20.05 mg Microcrystalline cellulose 41.00 mg
Magnesium stearate 2.00 mg Film coating:
Hydroxypropylmethylcellulose 16.00 mg Macrogol 400 .TM. 2.50 mg
Titanium oxide 3.00 mg Talc 3.00 mg
[0148] The preparation of the film coated tablet is performed as
described in Example 3.
* * * * *