U.S. patent number RE46,555 [Application Number 14/464,568] was granted by the patent office on 2017-09-19 for deuterated catecholamine derivatives and medicaments comprising said compounds.
This patent grant is currently assigned to Teva Pharmaceuticals International GmbH. The grantee listed for this patent is Teva Pharmaceuticals International GmbH. Invention is credited to Rudolf-Giesbert Alken, Frank Schneider.
United States Patent |
RE46,555 |
Alken , et al. |
September 19, 2017 |
Deuterated catecholamine derivatives and medicaments comprising
said compounds
Abstract
The present invention concerns deuterated catecholamine
derivatives as well as pharmaceuticals containing these compounds.
In addition, the invention concerns the use of deuterated
catecholamine derivatives as well as physiologically acceptable
salts thereof, and also pharmaceutical compositions, which contain
these compounds, also in combination with enzyme inhibitors, for
the treatment of dopamine deficiency diseases or diseases which are
based on disrupted tyrosine transport or disrupted tyrosine
decarboxylase, as well as other disorders.
Inventors: |
Alken; Rudolf-Giesbert
(Neuenhagen, DE), Schneider; Frank (Berlin,
DE) |
Applicant: |
Name |
City |
State |
Country |
Type |
Teva Pharmaceuticals International GmbH |
Jona |
N/A |
CH |
|
|
Assignee: |
Teva Pharmaceuticals International
GmbH (Jona, CH)
|
Family
ID: |
1000002579387 |
Appl.
No.: |
14/464,568 |
Filed: |
August 20, 2014 |
PCT
Filed: |
February 16, 2007 |
PCT No.: |
PCT/EP2007/001555 |
371(c)(1),(2),(4) Date: |
August 18, 2008 |
PCT
Pub. No.: |
WO2007/093450 |
PCT
Pub. Date: |
August 23, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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Reissue of: |
12224120 |
Feb 16, 2007 |
8247603 |
Aug 21, 2012 |
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Foreign Application Priority Data
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Feb 17, 2006 [DE] |
|
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10 2006 008 316 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P
25/16 (20180101); A61P 25/00 (20180101); C07C
229/36 (20130101); C07B 59/001 (20130101); C07C
229/36 (20130101); A61P 43/00 (20180101); A61P
25/14 (20180101); C07B 59/001 (20130101); A61P
25/18 (20180101); C07B 2200/07 (20130101); C07B
2200/07 (20130101) |
Current International
Class: |
C07B
59/00 (20060101); A61K 31/198 (20060101); C07C
229/08 (20060101); A61P 25/00 (20060101); C07C
229/36 (20060101) |
Field of
Search: |
;562/446
;560/37,38,39,40 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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|
2049115 |
|
Apr 1972 |
|
DE |
|
2049807 |
|
Apr 1972 |
|
DE |
|
102 61 807 |
|
Jul 2004 |
|
DE |
|
0357565 |
|
Mar 1990 |
|
EP |
|
2004056306 |
|
Jul 2004 |
|
WO |
|
2004056724 |
|
Jul 2004 |
|
WO |
|
Other References
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1683-1692, Nov. 1981. cited by applicant .
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Isotope Tracer Method", Proceedings of Japanese Society for
Biomedical Mass Spectrometry, 13, (9) 1988, 229-232. cited by
applicant .
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of Specifically Deuterated 3,4-Dihydroxyphenylamines and
(+/-)-3,4-Dihydroxyphenylalanines" F. Binns, J. A. G. King, A.
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and the synthesis of (.+-.)-3,4-dihydroxy[.beta.-2H2]
phenylalanine" D.J. Bennett, G.W. Kirby, and V.A. Moss, J. Chem
Soc. C: Organic , 1970, 2049-2051. cited by applicant .
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Kishimoto, Akira; Nakao, Takehisa Current Therapeutic Research,
vol. 20(3), Sep. 1976, 308-318. cited by applicant .
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vivo assay based on the liberation of deuterium or tritium into the
body water from ring-labeled L-phenylalanine" Sheldon Milstien and
Seymour Kaufman J. Biol. Chem. 1975 250: 4782-4785. cited by
applicant .
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acids" Shui-Tein Chen, Chen-Chen Tu, and Kung-Tsung Wang
Biotechnology Letters vol. 14 No. 4 (Apr. 1992) pp. 269-274. cited
by applicant .
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normal and pyridoxine-deficient rats" T. L Sourkes, Miriam H.
Wiseman-Distler, J. F. Moran, G. F. Murphy, and Simonne Saint Cyr
Biochem J. Dec. 1964; 93(3): 469-474. cited by applicant .
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L-erythro-[2,3-.sup.2H.sub.2] amino acids using optically active
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examiner .
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Neuro-Psychopharmacol. & Biol. Psychiat., 9:675-80 (1985).
cited by applicant.
|
Primary Examiner: Jones; Dwayne C.
Attorney, Agent or Firm: Baker & Hostetler LLP
Claims
The invention claimed is:
.[.1. Deuterated catecholamine derivatives of the general formula I
##STR00002## R.sup.1 is H or D, or a group that is easily
hydrolytically or enzymatically cleavable under physiological
conditions, R.sup.2 indicates D, R.sup.3 is H, D, C.sub.1 to
C.sub.6 alkyl or C.sub.1 to C.sub.6-cycloalkyl, deuterated to
C.sub.1 to C.sub.6 wherein alkyl or C.sub.1 to C.sub.6-cycloalkyl,
or a group that is easily hydrolytically or enzymatically cleavable
under physiological conditions, R.sup.4 indicates H or D, or a
group that is easily hydrolytically or enzymatically cleavable
under physiological conditions, R.sup.5 is H or D, and one of
R.sup.6 is H and the other R.sup.6 is D, as well as their
physiologically acceptable salts and their stereoisomers,
enantiomeres or diastereomers in optically pure form..].
.[.2. Deuterated catecholamine derivatives according to claim 1,
wherein R.sup.1 is H or D, R.sup.3 is H, D, 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 deuterated C.sub.5 to C.sub.6-cycloalkyl,
R.sup.4 indicates H or D, and R.sup.5 is D..].
.[.3. Deuterated catecholamine derivatives according to claim 1,
wherein R.sub.1 is H or D, R.sup.3 is D, 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 deuterated C.sub.5 to C.sub.6-cycloalkyl, R.sup.4
indicates H or D, and R.sup.5 is D..].
.[.4. Deuterated catecholamine derivatives according to claim 1,
wherein R.sub.1 is H or D, R.sup.3 is H, D, 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 deuterated C.sub.5 to C.sub.6-cycloalkyl,
R.sup.4 indicates H or D, and R.sup.5 is D..].
.[.5. Deuterated catecholamine derivatives according to the general
formula I, wherein R.sub.1 is H or D, R.sup.3 is C.sub.1 to
C.sub.6-alkyl or C.sub.5 to C.sub.6-cycloalkyl, R.sup.4 indicates H
or D, and R.sup.5 is D..].
.[.6. Deuterated catecholamine derivatives according to claim 1,
wherein R.sub.1 is H or D, R.sup.3 is methyl, R.sup.4 indicates H
or D, and R.sup.5 is D..].
.[.7. Deuterated catecholamine derivatives according to claim 1,
wherein R.sup.1 is H or D, R.sup.3 is ethyl, R.sup.4 indicates H or
D, and R.sup.5 is D..].
.[.8. Deuterated catecholamine derivatives according to claim 1,
wherein R.sup.1 is H or D, R.sup.3 is perdeuteroethyl, R.sup.4
indicates H or D, and R.sup.5 is D..].
.[.9. Deuterated catecholamine derivatives according to claim 1,
wherein R.sup.1 is H or D, R.sup.3 is perdeuteroethyl, R.sup.4
indicates H or D, and R.sup.5 is D..].
.[.10. Deuterated catecholamine derivatives according to claim 1,
wherein R.sup.1 is H or D, R.sup.3 is perdeuteroethyl, R.sup.4
indicates D, and R.sup.5 is H or D..].
.[.11. Deuterated catecholamine derivatives according to claim 1,
namely R/R-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic
acid, R/R-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic
acid methyl ester,
R/R-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid
ethyl ester,
R/S-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid,
R/S-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid
methyl ester,
R/S-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid
ethyl ester,
S/R-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid,
S/R-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid
methyl ester,
S/R-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid
ethyl ester,
S/S-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid,
S/S-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid
methyl ester,
S/S-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid
ethyl ester, 2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5-
dihydroxyphenyl) propionic acid,
2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5- dihydroxyphenyl)
propionic acid methyl ester,
2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5- dihydroxyphenyl)
propionic acid ethyl ester,
R/R-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5- dihydroxyphenyl)
propionic acid, R/R-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5-
dihydroxyphenyl) propionic acid methyl ester,
R/R-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5- dihydroxyphenyl)
propionic acid ethyl ester,
R/S-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5- dihydroxyphenyl)
propionic acid,
R/S-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid methyl ester,
R/S-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5- dihydroxyphenyl)
propionic acid ethyl ester,
S/R-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5- dihydroxyphenyl)
propionic acid, S/R-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5-
dihydroxyphenyl) propionic acid methyl ester,
S/R-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5- dihydroxyphenyl)
propionic acid ethyl ester,
S/S-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5- dihydroxyphenyl)
propionic acid, S/S-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5-
dihydroxyphenyl) propionic acid methyl ester, and
S/S-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5- dihydroxyphenyl)
propionic acid ethyl ester..].
12. A pharmaceutical composition.[., which contains.].
.Iadd.comprising a .Iaddend.deuterated .[.catecholamines according
to claim 1 as well as.]. .Iadd.catecholamine that is
R/R-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid,
R/S-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid,
S/R-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid, or
S/S-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid, or
a .Iaddend.physiologically acceptable .[.salts.]. .Iadd.salt
.Iaddend.thereof, for .[.the treatment of.]. .Iadd.treating
.Iaddend.Parkinson's disease, .[.of.]. .Iadd.treating
.Iaddend.restless leg syndrome, .[.of.]. .Iadd.treating
.Iaddend.dystonia, .[.for.]. inhibiting prolactin secretion,
.[.for.]. stimulating the release of growth hormone, .[.for the
treatment of.]. .Iadd.treating .Iaddend.neurological symptoms of
chronic manganese .[.intoxications.]. .Iadd.intoxication.Iaddend.,
.[.of.]. .Iadd.treating .Iaddend.amyotrophic lateral sclerosis
.[.and of.]..Iadd., or treating .Iaddend.multiple system
atrophy.[., in addition to.]. .Iadd.and further comprising a
.Iaddend.pharmaceutically acceptable .[.adjuvants and additives.].
.Iadd.adjuvant or additive.Iaddend..
13. .[.A.]. .Iadd.The .Iaddend.pharmaceutical composition.[., which
contains deuterated catecholamines according to.]. .Iadd.of
.Iaddend.claim .[.1 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.]. .Iadd.12, further comprising .Iaddend.one or more enzyme
inhibitors.[., in addition to pharmaceutically acceptable adjuvants
and additives.]..
14. The pharmaceutical composition .[.according to.]. .Iadd.of
.Iaddend.claim 13, .[.further characterized in that.].
.Iadd.wherein .Iaddend.the enzyme inhibitor .[.or the enzyme
inhibitors involve.]. .Iadd.is a .Iaddend.decarboxylase
.[.inhibitors.]. .Iadd.inhibitor, .Iaddend.and/or .Iadd.a
.Iaddend.catechol-.[.0.]..Iadd.O.Iaddend.-methyltransferase
.[.inhibitors.]. .Iadd.inhibitor, .Iaddend.and/or .Iadd.a
.Iaddend.monoamine oxidase .[.inhibitors.]. .Iadd.inhibitor,
.Iaddend.and/or .Iadd.a .Iaddend..beta.-hydroxylase
.[.inhibitors.]. .Iadd.inhibitor.Iaddend..
15. The pharmaceutical composition .[.according to.]. claim
.[.13.]. .Iadd.14.Iaddend., .[.further characterized in that.].
.Iadd.wherein .Iaddend.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.Iadd.-.Iaddend.dihydroxy-.alpha.-methylhydroc-
innamic acid (carbidopa),
L.Iadd.-.Iaddend.serine.Iadd.-.Iaddend.2-(2,3,4-trihydroxybenzyl)
hydrazide, glycine 2-(2,3,4-trihydroxybenzyl) hydrazide and
L-tyrosine 2.Iadd.-.Iaddend.(2,3,4-trihydroxybenzyl) hydrazide
.[.as well as.]. .Iadd.or a .Iaddend.physiologically acceptable
.[.salts.]. .Iadd.salt .Iaddend.thereof.
16. The pharmaceutical composition .[.according to.]. .Iadd.of
.Iaddend.claim 14, .[.further characterized in that.].
.Iadd.wherein .Iaddend.the .[.catechol-0-methyltransferase.].
.Iadd.catechol-O-methyltransferase .Iaddend.inhibitor is
.[.selected from.]. entacapone .[.and.]. .Iadd.or
.Iaddend.cabergoline .[.as well as.]. .Iadd.or a
.Iaddend.physiologically acceptable .[.salts.]. .Iadd.salt
.Iaddend.thereof.
17. The pharmaceutical composition .[.according to.]. .Iadd.of
.Iaddend.claim 14, .[.further characterized in that.].
.Iadd.wherein .Iaddend.the monoamine oxidase inhibitor is
.[.selected from the group consisting of.]. selegiline, moclobemide
.[.and.]..Iadd., or .Iaddend.tranylcypromine .[.as well as.].
.Iadd.or a .Iaddend.physiologically acceptable .[.salts.].
.Iadd.salt .Iaddend.thereof.
18. The pharmaceutical composition .[.according to.]. .Iadd.of
.Iaddend.claim 14, .[.further characterized in that.].
.Iadd.wherein .Iaddend.the .beta.-hydroxylase inhibitor is
.[.selected from.]. calcium 5-butyl picolinate .[.and.]. .Iadd.or
.Iaddend.calcium 5-pentyl picolinate .[.as well as.]. .Iadd.or a
.Iaddend.physiologically acceptable .[.salts.]. .Iadd.salt
.Iaddend.thereof.
.Iadd.19. The pharmaceutical composition of claim 12, for treating
Parkinson's disease..Iaddend.
.Iadd.20. The pharmaceutical composition of claim 12, for treating
restless leg syndrome..Iaddend.
.Iadd.21. The pharmaceutical composition of claim 12, for treating
dystonia..Iaddend.
.Iadd.22. The pharmaceutical composition of claim 12, for treating
chronic manganese intoxication..Iaddend.
.Iadd.23. The pharmaceutical composition of claim 12, for treating
amyotrophic lateral sclerosis..Iaddend.
.Iadd.24. The pharmaceutical composition of claim 12, for treating
multiple system atrophy..Iaddend.
.Iadd.25. The pharmaceutical composition of any one of claims 19 to
24, wherein the deuterated catecholamine is
S/S-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic
acid..Iaddend.
Description
The invention concerns deuterated catecholamine derivatives as well
as pharmaceuticals containing these compounds.
Know 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 to dopamine in the
brain.
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.
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).
Examples of COMT inhibitors are entacapone (Comtan.RTM.) and
cabergoline and frequently used MAO inhibitors are selegiline
hydrochloride, moclobemide and tranylcypromine.
Calcium 5-butyl picolinate and calcium 5-pentyl picolinate are
described as inhibitors for dopamine-.beta.-hydroxylase (DE
2,049,115).
WO-A 2004/056724 discloses deuterated catecholamine having two
deuterium atoms in the .beta.-position. These compounds exhibit
improved pharmacokinetic and/or pharmacodynamic properties with
respect to undeuterated compounds and as compared to L-DOPA.
An object of the present invention is to prepare deuterated
catecholamine derivatives, which have improved pharmacokinetic
and/or pharmacodynamic properties when compared to compounds
already known, as well as to prepare catecholamine derivatives,
which can be utilized for the prophylaxis of psychoses including
schizophrenia, and which can be used for producing pharmaceuticals
for the prophylaxis of psychoses.
It has been surprisingly found that the deuterated catecholamine
derivatives according to the invention have substantially better
pharmacokinetic and/or pharmacodynamic properties than the
undeuterated compounds and the .beta.,.beta.-di-deuterated
compounds known in the art and that they can also be utilized for
the prophylaxis of psychoses and can be used for producing
pharmaceuticals for the prophylaxis of psychoses.
According to the invention, the object is thus solved by the
preparation of compounds of general formula I:
##STR00001## wherein R.sup.1 is H or D, or a group that is easily
hydrolytically or enzymatically cleavable under physiological
conditions, R.sup.2 indicates H or D, R.sup.3 is H, D, 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, R.sup.4 indicates H or D, or a group that
is easily hydrolytically or enzymatically cleavable under
physiological conditions, R.sup.5 is H or D, and R.sup.6 is H or D,
as well as their physiologically acceptable salts and their
stereoisomers, enantiomeres or diastereomers in optically pure
form.
Preferred are compounds according to general formula I wherein both
residues R6 are not simultaneously Deuterium (D).
Groups that are easily hydrolytically or enzymatically cleavable
under physiological conditions are known to one skilled in the art.
The groups are common protective groups which are used in synthesis
or that are such protective groups which lead to so-called
prodrugs.
These groups may be selected from the group comprising 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.6cycloalkyl, deuterated
or partly deuterated C.sub.1 to C.sub.6alkyl, that may be branched
or unbranched, or deuterated or partly deuterated C.sub.5 to
C.sub.6-cycloalkyl.
According to the invention deuterated catecholamine derivatives
according to formula 1 are preferred, wherein R.sup.1 is H or D,
R.sup.2 indicates H or D, R.sup.3 is H, D, 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 deuterated C.sub.5 to C.sub.6-cycloalkyl, R.sup.4
indicates H or D, R.sup.5 is D, and R.sup.6 is H or D, under the
proviso that both residues R.sup.6 are not simultaneously D.
Preferred are deuterated catecholamine derivatives according to
formula 1, wherein R.sup.1 is H or D, R.sup.2 indicates D, R.sup.3
is D, 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 deuterated C.sub.5 to
C.sub.6-cycloalkyl, R.sup.4 indicates H or D R.sup.5 is D, and
R.sup.6 is H or D, under the proviso that both residues R.sup.6 are
not simultaneously D.
Preferred are also deuterated catecholamine derivatives according
to formula 1, wherein R.sup.1 is H or D, R.sup.2 indicates D,
R.sup.3 is H, D, 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
deuterated C.sub.5 to C.sub.6-cycloalkyl, R.sup.4 indicates H or D,
R.sup.5 is D and R.sup.6 is H or D, under the proviso that both
residues R.sup.6 are not simultaneously D.
Preferred are deuterated catecholamine derivatives according to the
general formula I, wherein R.sup.1 is H or D, R.sup.2 indicates D,
R.sup.3 is C.sub.1 to C.sub.6-alkyl or C.sub.5 to
C.sub.6-cycloalkyl, R.sup.4 indicates H or D, R.sup.5 is D, and
R.sup.6 is H or D, under the proviso that both residues R.sup.6 are
not simultaneously D.
Preferred are deuterated catecholamine derivatives according to
formula 1, wherein R.sup.1 is H or D, R.sup.2 indicates D, R.sup.3
is methyl, R.sup.4 indicates H or D, R.sup.5 is D, and R.sup.6 is H
or D, under the proviso that both residues R.sup.6 are not
simultaneously D.
Preferred are deuterated catecholamine derivatives according to
formula 1, wherein R.sup.1 is H or D, R.sup.2 indicates D, R.sup.3
is ethyl, R.sup.4 indicates H or D R.sup.5 is D, and R.sup.6 is H
or D, under the proviso that both residues R.sup.6 are not
simultaneously D.
Preferred are deuterated catecholamine derivatives according to
formula 1, wherein R.sup.1 is H or D, R.sup.2 indicates D, R.sup.3
is perdeuteroethyl, R.sup.4 indicates H or D R.sup.5 is D and,
R.sup.6 is H or D, under the proviso that both residues R.sup.6 are
not simultaneously D.
Preferred are deuterated catecholamine derivatives according to
formula 1, wherein R.sup.1 is H or D, R.sup.2 indicates H or D,
R.sup.3 is perdeuteroethyl, R.sup.4 indicates H or D, R.sup.5 is D,
and R.sup.6 is H or D, under the proviso that both residues R.sup.6
are not simultaneously D.
Preferred are deuterated catecholamine derivatives according to
formula 1, wherein R.sup.1 is H or D, R.sup.2 indicates H or D,
R.sup.3 is perdeuteroethyl, R.sup.4 indicates D R.sup.5 is H or D,
and R.sup.6 is H or D, under the proviso that both residues R.sup.6
are not simultaneously D.
Preferred are deuterated catecholamine derivatives according to
formula 1, namely 2-amino-2-deutero-3-(3,4-dihydroxyphenyl)
propionic acid, 2-amino-2-deutero-3-(3,4-dihydroxyphenyl) propionic
acid methyl ester, 2-amino-2-deutero-3-(3,4-dihydroxyphenyl)
propionic acid ethyl ester,
D-2-amino-2-deutero-3-(3,4-dihydroxyphenyl) propionic acid,
D-2-amino-2-deutero-3-(3,4-dihydroxyphenyl) propionic acid methyl
ester, D-2-amino-2-deutero-3-(3,4-dihydroxyphenyl) propionic acid
ethyl ester, L-2-amino-2-deutero-3-(3,4-dihydroxyphenyl) propionic
acid, L-2-amino-2-deutero-3-(3,4-dihydroxyphenyl) propionic acid
methyl ester, L-2-amino-2-deutero-3-(3,4-dihydroxyphenyl) propionic
acid ethyl ester, D,L-2-amino-2-deutero-3-(3,4-dihydroxyphenyl)
propionic acid, D,L-2-amino-2-deutero-3-(3,4-dihydroxyphenyl)
propionic acid methyl ester,
D,L-2-amino-2-deutero-3-(3,4-dihydroxyphenyl) propionic acid ethyl
ester, R/R-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl) propionic
acid, R/R-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl) propionic
acid methyl ester,
R/R-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl) propionic acid
ethyl ester, R/S-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)
propionic acid, R/S-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)
propionic acid methyl ester,
R/S-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl) propionic acid
ethyl ester, S/R-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)
propionic acid, S/R-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)
propionic acid methyl ester,
S/R-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl) propionic acid
ethyl ester, S/S-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)
propionic acid, S/S-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)
propionic acid methyl ester,
S/S-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl) propionic acid
ethyl ester,
2-amino-2-deutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid,
2-amino-2-deutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid methyl ester,
2-amino-2-deutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid ethyl ester,
D-2-amino-2-deutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid,
D-2-amino-2-deutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid methyl ester,
D-2-amino-2-deutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid ethyl ester,
L-2-amino-2-deutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid,
L-2-amino-2-deutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid methyl ester,
L-2-amino-2-deutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid ethyl ester,
D,L-2-amino-2-deutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid,
D,L-2-amino-2-deutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid methyl ester,
D,L-2-amino-2-deutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid ethyl ester,
2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid,
2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid methyl ester,
2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid ethyl ester,
R/R-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid,
R/R-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid methyl ester,
R/R-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid ethyl ester,
R/S-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid,
R/S-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid methyl ester,
R/S-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid ethyl ester,
S/R-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid,
S/R-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid methyl ester,
S/R-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid ethyl ester,
S/S-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid,
S/S-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid methyl ester, and
S/S-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid ethyl ester.
Another embodiment of the 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 trans-port or disrupted tyrosine decarboxylase,
such as Parkinson's disease, restless leg syndrome, dystonia, for
the inhibition of prolactin secretion, for the stimulation of the
release of growth hormone, for the treatment of neurological
symptoms of chronic manganese intoxications, of amyotrophic lateral
sclerosis and of multiple system atrophy.
Preferred is the use of deuterated catecholamine derivatives 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 the inhibition of 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.
It is advantageous if 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.
It is particularly advantageous if the decarboxylase inhibitor is
selected from the group consisting of the following: 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.
In particular, it is also advantageous if the
catechol-O-methyltransferase inhibitor is selected from entacapone
and cabergoline as well as physiologically acceptable salts
thereof.
It is also preferred if the monoamine oxidase inhibitor is selected
from the group consisting of selegiline, moclobemide and
tranylcypromine, as well as physiologically acceptable salts
thereof.
In addition, it is particularly preferred if the hydroxylase
inhibitor is selected from calcium 5-butyl picolinate and calcium
5-pentyl picolinate as well as physiologically acceptable salts
thereof.
Another subject of the invention is the use of the deuterated
catecholamines according to the invention as well as
physiologically acceptable salts thereof for the production of
pharmaceuticals 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 the inhibition of 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.
Another subject of the present invention is a pharmaceutical
composition which contains the deuterated catecholamines according
to the invention as well as their physiologically acceptable salts
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 the inhibition of 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.
Particularly advantageous is a pharmaceutical composition which
contains the 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 the inhibition of prolactin secretion, for stimulating of 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.
A pharmaceutical composition is particularly preferred in which 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.
Additionally preferred is a pharmaceutical composition in which 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.
Particularly advantageous is a pharmaceutical composition in which
the catechol-O-methyltransferase inhibitor is selected from
entacapone and cabergoline as well as their physiologically
acceptable salts.
Additionally advantageous is a pharmaceutical composition in which
the monoamine oxidase inhibitor is selected from the group
consisting of selegiline, moclobemide and tranylcypromine as well
as physiologically acceptable salts thereof.
In addition, a pharmaceutical composition is preferred in which the
.beta.-hydroxylase inhibitor is selected from calcium 5-butyl
picolinate and calcium 5-pentyl picolinate as well as
physiologically acceptable salts thereof.
Another subject of the invention is the use of the deuterated
catecholamine derivatives according to the invention as well as
physiologically acceptable salts thereof for use in the prophylaxis
of psychoses, particularly in predisposed patients, for the
prophylaxis of a relapse and also particularly for the treatment of
acute psychoses, for example, with negative symptomatology.
Particularly preferred is the use of the deuterated catecholamine
derivatives according to the invention as well as physiologically
acceptable salts thereof, in combination with one or more enzyme
inhibitors, for use in the prophylaxis of psychoses and for use in
acute psychoses, preferably psychoses with negative
symptomatology.
Particularly preferred is the use of the deuterated catecholamine
derivatives according to the invention as well as physiologically
acceptable salts thereof, if the enzyme inhibitor or the enzyme
inhibitors are decarboxylase inhibitors and/or
catechol-O-methyltransferase inhibitors and/or monoamine oxidase
inhibitors and/or .beta.-hydroxylase inhibitors.
Particularly preferred is the use of the deuterated catecholamine
derivatives according to the invention as well as physiologically
acceptable salts thereof, if 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.
The use of the deuterated catecholamine derivatives according to
the invention as well as physiologically acceptable salts thereof
is advantageous, if the catechol-O-methyl-transferase inhibitor is
selected from entacapone and cabergoline as well as physiologically
acceptable salts thereof.
In addition, the use of the deuterated catecholamine derivatives
according to the invention as well as physiologically acceptable
salts thereof is advantageous, if the monoamine oxidase inhibitor
is selected from the group consisting of selegiline, moclobemide
and tranylcypromine as well as physiologically acceptable salts
thereof.
The use of the deuterated catecholamine derivatives according to
the invention as well as physiologically acceptable salts thereof
is particularly advantageous, if the .beta.-hydroxylase inhibitor
is selected from calcium 5-butyl picolinate and calcium 5-pentyl
picolinate as well as physiologically acceptable salts thereof.
Another subject of the invention 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 use in the prophylaxis of psychoses.
Still another subject of the invention is a pharmaceutical
composition which contains the deuterated catecholamines according
to the invention as well as physiologically acceptable salts
thereof for use in the prophylaxis of psychoses and for the
treatment of acute psychoses, in addition to pharmaceutically
acceptable adjuvants and additives.
Particularly advantageous is a pharmaceutical composition which
contains the deuterated catecholamines according to the invention
as well as physiologically acceptable salts thereof for the
prophylaxis of psychoses and for the therapy of acute psychoses as
well as one or more enzyme inhibitors, in addition to
pharmaceutically acceptable adjuvants and additives.
Particularly preferred is a pharmaceutical composition in which the
enzyme inhibitor or the enzyme inhibitors are decarboxylase
inhibitors and/or catechol-O-methyltransferase inhibitors and/or
monoamine oxidase inhibitors and/or .beta.-hydroxylase
inhibitors.
Additionally advantageous is a pharmaceutical composition in which
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.
Particularly advantageous is a pharmaceutical composition in which
the catechol-O-methyltransferase inhibitor is selected from
entacapone and cabergoline as well as physiologically acceptable
salts thereof.
Particularly advantageous is a pharmaceutical composition in which
the monoamine oxidase inhibitor is selected from the group
consisting of selegiline, moclobemide and tranylcypromine as well
as physiologically acceptable salts thereof.
Particularly preferred is a pharmaceutical composition in which the
.beta.-hydroxylase inhibitor is selected from calcium 5-butyl
picolinate and calcium 5-pentyl picolinate as well as
physiologically acceptable salts thereof.
The production of the compounds according to the invention is known
to one skilled in the art. Analogous production methods are used as
described, for example, in DE-A 102 61 807.
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).
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
there from in an aqueous acid solution.
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 alkalis 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 new compound, 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 again releasing the base
from the salt.
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.
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 usually used
pharmaceutical-technical adjuvants corresponding to the desired
type of application. The preferred preparations consist of a form
of 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.
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.
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.
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.
The production of the pharmaceutical preparations according to the
invention is known in and of itself, 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.
As known from WO-A 2004/056724,
L-2-Amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) propionic acid
is a selectively deuterated L-DOPA derivative with better
pharmacokinetic and pharmacodynamic properties when compared to
L-DOPA. Administration of
L-2-Amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) propionic acid
to male Wistar rats increased dopamine in the striatum
significantly more compared to non-deuterated L-DOPA.
It has been surprisingly found that
L-2-Amino-2,3-dideutero-3-(3,4-dihydroxyphenyl) propionic acid
increased dopamine in the striatum significantly more than
L-2-Amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) propionic acid,
although the compound has less deuterium at the beta position of
the side chain of its molecule (Example 15 and Table 1).
Furthermore, whereas
L-2-Amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) propionic acid
reduces the striatal output of norepinephrine compared to L-DOPA,
L-2-Amino-2,3-dideutero-3-(3,4-dihydroxyphenyl) propionic acid does
not block the formation of norepinephrine.
Therefore, L-2-Amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)
propionic acid has two advantages, it provides more dopamine and
enough norepinephrine which has been shown to play an important
role in compensating for the loss in dopaminergic function (Archer
and Fredriksson, 2006, Neural Transm., 113(9): 1119-29; Cathala et
al. 2002, Neuroscience, 115(4): 1059-65; Tong et al. 2006, Arch
Neurol, 63(12): 1724-8).
The highly soluble L-DOPA methyl ester has been shown to function
as a prodrug of L-DOPA. In animal experiments, L-DOPA methyl ester
given orally or intraperitoneally was equivalent on a molar basis
to L-DOPA. However, therapeutic equivalence was not maintained with
continuous intravenous infusion in Patients with Parkinson's
disease exhibiting severe on-off phenomena. The optimal infusion
rate for L-DOPA methyl ester was 2.7 times that required for L-DOPA
(Stocchi et al. 1992, Movement Disorders, 7: 249-256).
Surprisingly, L-2-Amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)
propionic acid methyl ester is therapeutically equivalent to
L-2-Amino-2,3-dideutero-3-(3,4-dihydroxyphenyl) propionic acid
during continuous intravenous infusion.
The following examples are given to explain the present invention
in more detail but shall not be understood to limit the scope of
the invention.
EXAMPLE 1
D,L-2-Amino-2-deutero-3-(3,4-dihydroxyphenyl) propionic acid
2.5 g Levodopa are dissolved in 60 mL CH.sub.3CO.sub.2D under argon
and then reacted with 0.25 mL benzaldehyde under reflux. Following
elimination of acetic acid and benzaldehyde by distillation in
vacuum, 2 mL of methanol are added. The product is precipitated
slowly with 10 mL ethyl acetate/toluene (1:1). After drying under
vacuum, 2.2 g D,L-2-Amino-2-deutero-3-(3,4-dihydroxyphenyl)
propionic acid are isolated.
Yield: 87.6%
EXAMPLE 2
D,L-2-Amino-2-deutero-3-(3,4-dihydroxyphenyl) methyl propionate
2.0 g of D,L-2-Amino-2-deutero-3-(3,4-dihydroxyphenyl) propionic
acid are dissolved in 30 mL methanol and cooled to -10.degree. C.
and reacted dropwise with 1 ml of thionyl chloride. The reaction
batch is then heated to 40.degree. C. for 15-hours. The volatile
substances in the reaction batch are eliminated in vacuum and 10 ml
of water and 15 ml of a solution of 0.8 g of sodium hydrogen
carbonate, 1 g of sodium sulfate and 1 mg of ascorbic acid are
added. The pH of the solution is adjusted to a value of 7 by
addition of a dilute sodium hydroxide solution. The product is
transferred to the organic phase by extraction with oxygen-free
ethyl acetate, which contains 0.01%
2,6-ditert-butyl-4-methoxyphenol. The organic phase is dried and
then the solvent is distilled off 50 ml of oxygen-free diethyl
ether are added to the residue and after this material is left to
stand overnight, the
D,L-2-amino-2-deutero-3-(3,4-dihydroxyphenyl)methyl propionate
precipitates. After recrystallization from an oxygen-free
methanol/diethyl ether mixture, which is combined with
2,6-di-tert-butyl-4-methoxyphenol, 1.8 g of product is
isolated.
Yield: 84.9%
EXAMPLE 3
L-2-Amino-2-deutero-3-(3,4-dihydroxyphenyl) propionic acid
1.15 g of D,L-2-Amino-2-deutero-3-(3,4-dihydroxyphenyl)methyl
propionate are dissolved in 30 mL of a 0.2-molar sodium bicarbonate
solution (pH 8.2). 200 .mu.L of alcalase are added and the pH of
the solution is kept at this value by means of
carbonate-bicarbonate buffer. The course of the reaction is
monitored by HPLC and the reaction is terminated by the addition of
hydrochloric acid when the concentration of the propionate ester
has been reduced to one-half. The deuterated amino acid contained
in the solution is separated from the deuterated methyl ester
chromatographically by use of the solvent system of
acetonitrile/0.1% aqueous trifluoroacetic acid (15:85) and 0.51 g
of L-2-amino-2-deutero-3-(3,4-dihydroxyphenyl) propionic acid is
isolated.
Yield: 95% (based on the proportion of L-enantiomer)
Melting point: 287-290.degree. C.
C.sub.9H.sub.10NO.sub.4D:
calc. C, 54.54%; H, 5.09%; N, 7.07%; O, 32.29%; D, 1.02%.
found C, 54.45%; H+D, 6.08; N, 7.02.
.sup.1H-NMR (400 MHz, d6-DMSO): 6.58 (d, 1H); 6.54 (s, 1H); 6.47
(d, 1H); 3.07 (d, 1H); 2.90 (d, 1H)
EXAMPLE 4
L-2-Amino-2-deutero-3-(3,4-dihydroxyphenyl)methyl propionate
2.0 g of L-2-Amino-2-deutero-3-(3,4-dihydroxyphenyl) propionic acid
are dissolved in 30 mL methanol are cooled to -10.degree. C. and
reacted dropwise with 1 ml of thionyl chloride. The reaction batch
is then heated to 40.degree. C. for 15 hours. The volatile
substances in the reaction batch are eliminated in vacuum and 10 ml
of water and 15 ml of a solution of 0.8 g of sodium hydrogen
carbonate, 1 g of sodium sulfate and 1 mg of ascorbic acid are
added. The pH of the solution is adjusted to a value of 7 by
addition of a dilute sodium hydroxide solution. The product is
transferred to the organic phase by extraction with oxygen-free
ethyl acetate, which contains 0.01%
2,6-ditert-butyl-4-methoxyphenol. The organic phase is dried and
then the solvent is distilled off 50 ml of oxygen-free diethyl
ether are added to the residue and after the material is left to
stand overnight, the
L-2-amino-2-deutero-3-(3,4-dihydroxyphenyl)methyl propionate
precipitates. After recrystallization from an oxygen-free
methanol/diethyl ether mixture, which is combined with
2,6-di-tert-butyl-4-methoxyphenol, 1.9 g of product is
isolated.
Yield: 89.6%
C.sub.10H.sub.12NO.sub.4D:
calc. C, 56.60%; H, 5.70%; N, 6.60%: O, 30.16%; D, 0.95%.
found C, 56.65%; H+D, 6.63%; N, 6.54%.
.sup.1H-NMR (400 MHz, d6-DMSO): 6.58 (d, 1H); 6.54 (s, 1H); 6.47
(d, 1H); 3.81 (s, 3H); 3.07 (d, 1H); 2.90 (d, 1H)
EXAMPLE 5
L-2-Amino-2-deutero-3-(3,4-dihydroxyphenyl)ethyl propionate
2.0 g of L-2-Amino-2-deutero-3-(3,4-dihydroxyphenyl) propionic acid
are dissolved in 30 mL ethanol are cooled to -10.degree. C. and
reacted dropwise with 1 ml of thionyl chloride. The reaction batch
is then heated to 40.degree. C. for 15 hours. The volatile
substances in the reaction batch are eliminated in vacuum and 10 ml
of water and 15 ml of a solution of 0.8 g of sodium hydrogen
carbonate, 1 g of sodium sulfate and 1 mg of ascorbic acid are
added. The pH of the solution is adjusted to a value of 7 by
addition of a dilute sodium hydroxide solution. The product is
transferred to the organic phase by extraction with oxygen-free
ethyl acetate, which contains 0.01%
2,6-ditert-butyl-4-methoxyphenol. The organic phase is dried and
then the solvent is distilled off 50 ml of oxygen-free diethyl
ether are added to the residue, and after the material is left to
stand overnight, the
L-2-amino-2-deutero-3-(3,4-dihydroxyphenyl)ethyl propionate
precipitates. After recrystallization from an oxygen-free
ethanol/diethyl ether mixture, which is combined with
2,6-ditert-butyl-4-methoxyphenol, 2 g of product is isolated.
Yield: 88.5%
C.sub.11H.sub.14NO.sub.4D:
calc. C, 58.40%; H, 6.24%; N, 6.19%; O, 28.29%; D, 0.89%.
found C, 58.32%; H+D, 7.03%; N, 6.12%.
.sup.1H-NMR (400 MHz, d6-DMSO): 6.58 (d, 1H); 6.54 (s, 1H); 6.47
(d, 1H); 4.15 (q, 2H); 3.07 (d, 1H); 2.90 (d, 1H); 1.21 (t, 3H)
EXAMPLE 6
L-2-Amino-2,3(S)-dideutero-3-(3,4-dihydroxyphenyl) propionic
acid
2.5 g of N-acetyl-3-methoxy-4-acetoxy cinnamic acid are dissolved
in 30 mL methanol containing 0.027 g sodium hydroxide and placed
into an autoclave. The oxygen is replaced by nitrogen before the
reactor is filled with deuterium gas. At the same time 0.5 g of
Monsanto catalyst are prepared in 2.5 mL toluene by treating with
deuterium gas. After addition of the catalyst to the autoclave, the
"hydrogenation" is started at 60.degree. C. and 4-5 bar. After 4
hours, the excess of deuterium gas is removed and the solvent is
distilled of. The sodium salt of the deuterated product is isolated
and recrystallized.
Yield: 2.4 g (94%)
0.9 g of the sodium salt are dissolved in 2.5 mL of hydrobromic
acid (23%) and heated to reflux at about 105-110.degree. C.
Afterwards, the reaction mixture is cooled to 25-30.degree. C. and
the pH is adjusted to 3 by addition of concentrated sodium
hydroxide solution to start the precipitation of
L-2-Amino-2,3(S)-dideutero-3-(3,4-dihydroxyphenyl) propionic acid.
The precipitate is washed with cold water and recrystallized in hot
water under protective gas. After recrystallization, 0.51 g of the
product are isolated.
Yield: 85.1%
Melting point: 286-299.degree. C.
C.sub.9H.sub.9NO.sub.4D.sub.2:
calc. C, 54.27%; H, 4.55%; N, 7.03%; O, 32.13%; D, 2.02%.
found C, 54.15%; H+D, 6.50%; N, 7.08%.
.sup.1H-NMR (400 MHz, d6-DMSO): 6.59 (d, 1H); 6.54 (s, 1H); 6.48
(d, 1H); 2.74 (m, 1H)
EXAMPLE 7
L-2-Amino-2,3(S)-dideutero-3-(3,4-dihydroxyphenyl)methyl
propionate
The compound is produced according to the description for the
mono-deuterated compound (cf. example 4).
Yield: 91%
C.sub.10H.sub.11D.sub.2NO.sub.4:
calc. C, 56.33%; H, 5.20%; N, 6.57%; O, 30.01%; D, 1.89%.
found C, 56.22%; H+D, 7.01; N, 6.45.
.sup.1H-NMR. (400 MHz, d6.-DMSO): 6.59 (d, 1H); 6.54 (S, 1H); 6.48
(d, 1H); 2.72 (m, 1H); 3.81 (s, 3H).
EXAMPLE 8
L-2-Amino-2,3(S)-dideutero-3-(3,4-dihydroxyphenyl)ethyl
propionate
The compound is produced according to the description for the
mono-deuterated compound (cf. example 5).
Yield: 93%,
C.sub.11H.sub.13D.sub.2NO.sub.4:
calc. C, 58.14%; H, 5.77%; N, 6.16%; O, 28.16%; D, 1.77%.
found C, 58.10%; H+D, 7.48%; N, 6.10%.
.sup.1H-NMR (400 MHz, d6-DMSO): 6.59 (d, 1H); 6.54 (s, 1H); 6.48
(d, 1H); 2.72 (m, 1H); 4.17 (q, 2H); 1.22 (t, 3H).
EXAMPLE 9
L-2-Amino-2-deutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid
0.2 g of L-2-Amino-2-deutero-3-(3,4 dihydroxyphenyl) propionic acid
are placed into an autoclave and 10 mL of D.sub.2O are added. The
autoclave is evacuated and heated to 190.degree. C. for 24 hours.
The solvent is eliminated and acetic acid ethyl ester is added. The
solvent is distilled of and the residue washed with cold acetone.
Thereafter, 0.17 g of the product are isolated.
Yield: 84%
C.sub.9H.sub.7NO.sub.4D.sub.4:
calc. C, 53.72%; H, 3.51%: N, 6.96%; O, 31.81%; D, 4.00%.
found C, 53.65%; H+D, 7.45%; N, 6.90%.
.sup.1H-NMR (400 MHz, d6-DMSO): 3.06 (d, 1H); 2.88 (d, 1H)
EXAMPLE 10
L-2-Amino-2-deutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)methyl
propionate
The compound is produced according to the description for the
mono-deuterated compound (cf. example 4).
Yield: 89%.
C.sub.10H.sub.9NO.sub.4D.sub.4:
calc. C, 55.80%; H, 4.21%; N, 6.51%; O, 29.73%; D, 3.74%.
found C, 55.71%; H+D, 7.89%; N, 6.53%.
.sup.1H-NMR (400 MHz, d6-DMSO): 3.81 (s, 3H); 3.08 (d, 1H); 2.88
(d, 1H)
EXAMPLE 11
L-2-Amino-2-deutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)ethyl
propionate
The compound is produced according to the description for the
mono-deuterated compound (cf. example 5).
Yield: 92%.
C.sub.11H.sub.11NO.sub.4D.sub.4:
calc. C, 57.63%; H, 4.84%; N, 6.11%; O, 27.91%; D, 3.51%.
found C, 57.57%; H+D, 8.31%; N, 6.15%.
.sup.1H-NMR (400 MHz, d6-DMSO): 4.17 (q, 2H); 3.06 (d, 1H); 2.88
(d, 1H); 1.21 (t, 3H)
EXAMPLE 12
L-2-Amino-2,3-dideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)
propionic acid
0.2 g of L-2-Amino-2-deutero-3-(3,4-dihydroxyphenyl) propionic acid
are placed into an autoclave and 10 mL of D.sub.2O are added. The
autoclave is evacuated and heated to 190.degree. C. for 24 hours.
The solvent is eliminated and acetic acid ethyl ester is added. The
solvent is distilled of and the residue washed with cold acetone.
Thereafter, 0.16 g of the product are isolated.
Yield: 79.2%
C.sub.9H.sub.6NO.sub.4D.sub.5:
calc. C, 53.46%; H, 2.99%; N, 6.93%; O, 31.65%; D, 4.98%.
found C, 53.49%; H+D, 7.92%; N, 6.88%.
.sup.1H-NMR (400 MHz, d6-DMSO): 2.76 (m, 1H)
EXAMPLE 13
L-2-Amino-2,3-dideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)methyl
propionate
The compound is produced according to the description for the
mono-deuterated compound (cf. example 4).
Yield: 90%
C.sub.11H.sub.8D.sub.5NO.sub.4:
calc. C, 55.54%; H, 3.73%; N, 6.48%; O, 29.59%; D, 4.66%.
found C, 55.50%; H+D, 8.31; N, 6.45%.
.sup.1H-NMR (400 MHz, d6-DMSO): 3.80 (s, 3H); 2.74 (m, 1H)
EXAMPLE 14
L-2-Amino-2,3-dideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)ethyl
propionate
The compound is produced according to the description for the
mono-deuterated compound (cf. example 5).
Yield: 93%
C.sub.11H.sub.10D.sub.5NO.sub.4:
calc. C, 57.38%; H, 4.38%; N, 6.08%; O, 27.79%; D, 4.37%.
found C, 57.34%; H+D, 8.71%; N, 6.04%.
.sup.1H-NMR (400 MHz, d6-DMSO): 4.15 (q, 2H); 2.75 (m, 1H); 1.21
(t, 3H)
EXAMPLE 15
Striatal Dopamine Output Measured by Microdialysis
The striatal output of dopamine was measured in Male Wistar rats
following intraperitoneal administration of 50 mg/kg
L-2-Amino-3-(3,4-dihydroxyphenyl) propionic acid (L-DOPA),
L-2-Amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) propionic acid
(WO-A 2004/056724, Example 6) and
L-2-Amino-2,3-dideutero-3-(3,4-dihydroxyphenyl) propionic acid
(Example 6), respectively. Male wistar rats (BK Universal,
Sollentuna, Sweden) weighing about 300 g at the time of experiment
were anaesthetized with a cocktail containing fentanyl citrate
(0.39 mg/kg) and fluanisone (12.5 mg/kg, Hypnorm.RTM.,
Janssen-Cilag) and midazolam (6.25 mg/kg, Dormicum.RTM., Roche)
diluted in distilled water (1:1:2; 5 ml/kg i.p.) and mounted in a
stereotaxic frame. Dialysis probes were implanted in the
dorsolateral striatum (AP: +0.6: ML+3.0: DV -6.2 relative to bregma
and the dural surface according to the atlas of Paxinos and Watson
(1998)). Dialysis occurs through a semipermeable membrane (Filtral
AN69, Hospal Industrie, France) with an active surface length of
3.5 mm. Dialysis experiments were conducted approximately 48 h
after surgery in freely moving rats. The rats received 30 min
before administration of test items 10 mg/kg Carbidopa, (i.p.). The
dialysis probe was perfused with a physiological perfusion solution
(Apoteksbolaget, Sweden) at a rate of 2.5 ml/min set by a
microinfusion pump (Harvard Apparatus, Holliston, Mass.). Dialysate
was collected over 15 min intervals and automatically injected into
a high performance liquid chromatography (HPLC) system. On-line
quantification of dopamine in the dialysate was accomplished by
electrochemical detection (ESA, Chelmsford, Mass.). The location of
microdialysis probes was verified in slices of formalin-fixed
tissue stained with neutral red. The baseline corrected
concentrations (fmol/min) were plotted over the time.
Comparison of AUC.sub.0-t (area under the curve) values revealed
that the increase of dopamine in the striatum following
administration of 50 mg/kg
L-2-Amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) propionic acid
was about twice as high compared to
L-2-Amino-3-(3,4-dihydroxyphenyl) propionic acid (L-DOPA) as
displayed in Table 1. The increase of striatal dopamine following
administration of 50
mg/kgL-2-Amino-2,3-dideutero-3-(3,4-dihydroxyphenyl) propionic acid
(Example 6) was even threefold higher than that measured after
administration of L-DOPA.
TABLE-US-00001 TABLE 1 Baseline corrected dopamine output in the
striatum AUC.sub.0-t Compound [fmol/min * min]
L-2-Amino-3-(3,4-dihydroxyphenyl) propionic acid 228
L-2-Amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) 533 propionic
acid L-2-Amino-2,3-dideutero-3-(3,4-dihydroxyphenyl) 685 propionic
acid (Ex. 6)
* * * * *