U.S. patent application number 13/820024 was filed with the patent office on 2013-08-01 for deuterated analogs of pridopidine useful as dopaminergic stabilizers.
This patent application is currently assigned to IVAX INTERNATIONAL GMBH. The applicant listed for this patent is Clas Sonesson. Invention is credited to Clas Sonesson.
Application Number | 20130197031 13/820024 |
Document ID | / |
Family ID | 44653278 |
Filed Date | 2013-08-01 |
United States Patent
Application |
20130197031 |
Kind Code |
A1 |
Sonesson; Clas |
August 1, 2013 |
DEUTERATED ANALOGS OF PRIDOPIDINE USEFUL AS DOPAMINERGIC
STABILIZERS
Abstract
The present invention provides novel deuterated analogs of
Pridopidine, i.e. 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine.
Pridopidine is a drug substance currently in clinical development
for the treatment of Huntington's disease. In other aspects the
invention relates to pharmaceutical compositions comprising a
deuterated analog of Pridopidine of the invention, and to
therapeutic applications of these analogs.
Inventors: |
Sonesson; Clas; (Goteborg,
SE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sonesson; Clas |
Goteborg |
|
SE |
|
|
Assignee: |
IVAX INTERNATIONAL GMBH
Rapperswil
CH
|
Family ID: |
44653278 |
Appl. No.: |
13/820024 |
Filed: |
August 31, 2011 |
PCT Filed: |
August 31, 2011 |
PCT NO: |
PCT/EP11/64954 |
371 Date: |
April 10, 2013 |
Current U.S.
Class: |
514/317 ;
546/236 |
Current CPC
Class: |
C07D 211/24 20130101;
C07D 211/32 20130101; A61K 31/451 20130101; A61P 25/14 20180101;
C07B 59/002 20130101; A61P 25/00 20180101; A61P 25/28 20180101 |
Class at
Publication: |
514/317 ;
546/236 |
International
Class: |
C07D 211/32 20060101
C07D211/32 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 3, 2010 |
DK |
PA 2010 70385 |
Claims
1. A fully or partially deuterated analog of
4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine represented by
Formula 1 ##STR00002## or a pharmaceutically acceptable salt
thereof, wherein at least one of R.sup.1-R.sup.21 represents
deuterium (D); and the remaining of R.sup.1-R.sup.23 represent
hydrogen (H).
2. The deuterated analog or pharmaceutically acceptable salt
thereof according to claim 1, wherein R.sup.1-R.sup.2 represent
deuterium (D); and all of R.sup.1-R.sup.23 represent hydrogen (H);
or at least one of R.sup.1-R.sup.7 represents deuterium (D); and
the remaining of R.sup.1-R.sup.23 represent hydrogen (H); or all of
R.sup.1-R.sup.7 represent deuterium (D); and all of R.sup.8-R.sup.2
represent hydrogen (H); or R.sup.8, R.sup.9, R.sup.10 and R.sup.11
represent deuterium (D); and all of R.sup.1-R.sup.7 and
R.sup.12-R.sup.23 represent hydrogen (H); or R.sup.12 represents
deuterium (D); and all of R.sup.1-R.sup.11 and R.sup.13-R.sup.23
represent hydrogen (H); or R.sup.17-R.sup.20 represent deuterium
(D); and all of R.sup.1-R.sup.16 and R.sup.21-R.sup.23 represent
hydrogen (H).
3-7. (canceled)
8. A pharmaceutical composition which comprises a therapeutically
effective amount of a deuterated analog of
4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine or a
pharmaceutically acceptable salt thereof according to claim 1,
together with at least one pharmaceutically acceptable carrier,
excipient or diluent.
9-10. (canceled)
11. A method for treatment, prevention or alleviation of a dopamine
mediated disorder of a living animal which comprises administering
to such a living animal body a therapeutically effective amount of
a deuterated analog of
4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine or a
pharmaceutically acceptable salt thereof according to claim 1.
12. A pharmaceutical composition which comprises a therapeutically
effective amount of a deuterated analog of
4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine or a
pharmaceutically acceptable salt thereof according to claim 2
together with at least one pharmaceutically acceptable carrier,
excipient or diluent.
13. A method for treatment, prevention or alleviation of a dopamine
mediated disorder of a living animal which comprises administering
to such a living animal body a therapeutically effective amount of
a deuterated analog of
4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine or a
pharmaceutically acceptable salt thereof according to claim 2.
14. The deuterated analog or pharmaceutically acceptable salt
thereof according to claim 2, wherein R.sup.1-R.sup.2 represent
deuterium (D); and all of R.sup.3-R.sup.23 represent hydrogen
(H).
15. The deuterated analog or pharmaceutically acceptable salt
thereof according to claim 2, wherein at least one of
R.sup.1-R.sup.7 represents deuterium (D); and the remaining of
R.sup.1-R.sup.23 represent hydrogen (H).
16. The deuterated analog or pharmaceutically acceptable salt
thereof according to claim 2, wherein all of R.sup.1-R.sup.7
represent deuterium (D); and all of R.sup.8-R.sup.23 represent
hydrogen (H).
17. The deuterated analog or pharmaceutically acceptable salt
thereof according to claim 2, wherein R.sup.8, R.sup.9, R.sup.10
and R.sup.11 represent deuterium (D); and all of R.sup.1-R.sup.7
and R.sup.12-R.sup.23 represent hydrogen (H).
18. The deuterated analog or pharmaceutically acceptable salt
thereof according to claim 2, wherein R.sup.12 represents deuterium
(D); and all of R.sup.1-R.sup.11 and R.sup.13-R.sup.23 represent
hydrogen (H).
19. The deuterated analog or pharmaceutically acceptable salt
thereof according to claim 2, wherein R.sup.17-R.sup.20 represent
deuterium (D); and all of R.sup.1-R.sup.16 and R.sup.21-R.sup.23
represent hydrogen (H).
20. A pharmaceutical composition according to claim 12, wherein in
the deuterated analog of
4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine or a
pharmaceutically acceptable salt thereof, R.sup.1-R.sup.2 represent
deuterium (D); and all of R.sup.3-R.sup.23 represent hydrogen
(H).
21. A pharmaceutical composition according to claim 12, wherein in
the deuterated analog of
4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine or a
pharmaceutically acceptable salt thereof, at least one of
R.sup.1-R.sup.7 represents deuterium (D); and the remaining of
R.sup.1-R.sup.23 represent hydrogen (H).
22. A pharmaceutical composition according to claim 12, wherein in
the deuterated analog of
4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine or a
pharmaceutically acceptable salt thereof, all of R.sup.1-R.sup.7
represent deuterium (D); and all of R.sup.8-R.sup.23 represent
hydrogen (H).
23. A pharmaceutical composition according to claim 12, wherein in
the deuterated analog of
4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine or a
pharmaceutically acceptable salt thereof, R.sup.8, R.sup.9,
R.sup.10 and R.sup.11 represent deuterium (D); and all of
R.sup.1-R.sup.7 and R.sup.12-R.sup.23 represent hydrogen (H).
24. A pharmaceutical composition according to claim 12, wherein in
the deuterated analog of 4-(3-methanesulfonyl-phenyl)-1
-propyl-piperidine or a pharmaceutically acceptable salt thereof,
R.sup.12 represents deuterium (D); and all of R.sup.1-R.sup.11 and
R.sup.13-R.sup.23 represent hydrogen (H).
25. A pharmaceutical composition according to claim 12, wherein in
the deuterated analog of
4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine or a
pharmaceutically acceptable salt thereof, R.sup.17-R.sup.20
represent deuterium (D); and all of R.sup.1-R.sup.16 and
R.sup.21-R.sup.23 represent hydrogen (H).
26. A method according to claim 13, wherein in the deuterated
analog of 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine or a
pharmaceutically acceptable salt thereof, R.sup.1-R.sup.2 represent
deuterium (D); and all of R.sup.3-R.sup.23 represent hydrogen
(H).
27. A method according to claim 13, wherein in the deuterated
analog of 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine or a
pharmaceutically acceptable salt thereof, at least one of
R.sup.1-R.sup.7 represents deuterium (D); and the remaining of
R.sup.1-R.sup.23 represent hydrogen (H).
Description
FIELD OF THE INVENTION
[0001] The present invention provides novel deuterated analogs of
Pridopidine, i.e. 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine.
Pridopidine is a drug substance currently in clinical development
for the treatment of Huntington's disease.
[0002] In other aspects the invention relates to pharmaceutical
compositions comprising a deuterated analog of Pridopidine of the
invention, and to therapeutic applications of these analogs.
BACKGROUND OF THE INVENTION
[0003] Deuterium, also called "heavy hydrogen", is a stable isotope
of hydrogen with a natural abundance in the oceans of Earth of
approximately one atom in 6,500 of hydrogen (.about.154 ppm).
Deuterium thus accounts for approximately 0.0154% (alternately, on
a mass basis: 0.0308%) of all naturally occurring hydrogen in the
oceans on Earth. The nucleus of deuterium, called a deuteron,
contains one proton and one neutron, whereas the hydrogen nucleus
contains no neutron.
[0004] Deuterium forms bonds with carbon that vibrate at a lower
frequency and are thus stronger than C--H bonds. Therefore "heavy
hydrogen" versions of drugs may be more stable towards degradation
and last longer in the organism. Incorporating deuterium in place
of hydrogen thus may improve the pharmacodynamic and
pharmacokinetic profiles of drugs, thus modifying the metabolic
fate, while retaining the pharmacologic activity and selectivity of
physiologically active compounds. Deuterated drugs thus may
positively impact safety, efficacy and/or tolerability.
[0005] Pridopidine, i.e.
4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine, a dopaminergic
stabilizer currently in clinical development for the treatment of
Huntington's disease. The compound is described in e.g. WO
01/46145, and in e.g. WO 2006/040155 an alternative method for its
synthesis is described.
SUMMARY OF THE INVENTION
[0006] The object of the present invention is to provide analogs of
Pridopidine with improved pharmacodynamic and pharmacokinetic
profiles.
[0007] Therefore, in its first aspect the invention provides a
partially or fully deuterated analog of
4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine as represented by
Formula 1, below.
[0008] In another aspect the invention provides a pharmaceutical
composition, comprising a therapeutically effective amount of a
deuterated analog of
4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine of the invention,
or a pharmaceutically acceptable salt thereof, together with at
least one pharmaceutically acceptable carrier, excipient or
diluent.
[0009] Viewed from another aspect the invention relates to the use
of the deuterated analog of
4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine of the invention
as a medicament, or for the manufacture of a medicament.
[0010] In a further aspect the invention provides a method for
treatment, prevention or alleviation of a dopamine mediated
disorder of a living animal body, including a human, which method
comprises the step of administering to such a living animal body in
need thereof a therapeutically effective amount of a deuterated
analog of 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine
according to the invention, or a pharmaceutically acceptable salt
thereof.
[0011] Other aspects of the invention will be apparent to the
person skilled in the art from the following detailed description
and examples.
DETAILED DESCRIPTION OF THE INVENTION
Deuterated Analogs of Pridopidine
[0012] In its first aspect the present invention provides
deuterated analogs of Pridopidine. The deuterated analog of the
invention may be a fully or partially deuterium substituted
derivative. The deuterated analog of the invention may in
particular be characterised by Formula I
##STR00001##
[0013] or a pharmaceutically acceptable salt thereof, wherein
[0014] at least one of R.sup.1-R.sup.23 represents deuterium (D);
and
[0015] the remaining of R.sup.1-R.sup.23 represent hydrogen
(H).
[0016] In the context of this invention, when a particular position
is designated as holding deuterium, it is understood that the
abundance of deuterium at that position is substantially greater
than the natural abundance of deuterium, which is about 0.015%.
[0017] In a preferred embodiment the abundance of deuterium at that
position is at least 3340 times greater (i.e. at least 50.1%
incorporation of deuterium) than the natural abundance of
deuterium. In other preferred embodiments of the invention the
abundance of deuterium at that position is at least 3500 (52.5%
deuterium incorporation), at least 4000 (60% deuterium
incorporation), at least 4500 (67.5% deuterium incorporation), at
least 5000 (75% deuterium), at least 5500 (82.5% deuterium
incorporation), at least 6000 (90% deuterium incorporation), at
least 6333.3 (95% deuterium incorporation), at least 6466.7 (97%
deuterium incorporation), at least 6600 (99% deuterium
incorporation), or at least 6633.3 (99.5% deuterium
incorporation).
[0018] In a preferred embodiment the deuterated analog of the
invention is a compound of Formula I, or a pharmaceutically
acceptable salt thereof, wherein
[0019] R.sup.1-R.sup.2 represent deuterium (D); and
[0020] all of R.sup.3-R.sup.23 represent hydrogen (H).
[0021] In another preferred embodiment the deuterated analog of the
invention is a compound of Formula I, or a pharmaceutically
acceptable salt thereof, wherein
[0022] at least one of R.sup.1-R.sup.7 represents deuterium (D);
and
[0023] the remaining of R.sup.1-R.sup.23 represent hydrogen
(H).
[0024] In a third preferred embodiment the deuterated analog of the
invention is a compound of Formula I, or a pharmaceutically
acceptable salt thereof, wherein
[0025] all of R.sup.1-R.sup.7 represent deuterium (D); and
[0026] all of R.sup.8-R.sup.23 represent hydrogen (H).
[0027] In a fourth preferred embodiment the deuterated analog of
the invention is a compound of Formula I, or a pharmaceutically
acceptable salt thereof, wherein
[0028] R.sup.8, R.sup.9, R.sup.10 and R.sup.11 represent deuterium
(D); and
[0029] all of R.sup.1-R.sup.7 and R.sup.12-R.sup.23 represent
hydrogen (H).
[0030] In a fifth preferred embodiment the deuterated analog of the
invention is a compound of Formula I, or a pharmaceutically
acceptable salt thereof, wherein
[0031] R.sup.12 represents deuterium (D); and
[0032] all of R.sup.1-R.sup.11 and R.sup.13-R.sup.23 represent
hydrogen (H).
[0033] In a sixth preferred embodiment the deuterated analog of the
invention is a compound of Formula I, or a pharmaceutically
acceptable salt thereof, wherein
[0034] R.sup.17-R.sup.20 represent deuterium (D); and
[0035] all of R.sup.1-R.sup.16 and R.sup.21-R.sup.23 represent
hydrogen (H).
[0036] Any combination of two or more of the embodiments described
herein is considered within the scope of the present invention.
Pharmaceutically Acceptable Salts
[0037] The deuterated analog of the invention may be provided in
any form suitable for the intended administration. Suitable forms
include pharmaceutically (i.e. physiologically) acceptable salts,
and pre- or prodrug forms of the deuterated analog of the
invention.
[0038] Examples of pharmaceutically acceptable salts include,
without limitation, the non-toxic inorganic and organic acid
addition salts such as the hydrochloride, the hydrobromide, the
nitrate, the perchlorate, the phosphate, the sulphate, the formate,
the acetate, the aconate, the ascorbate, the benzenesulphonate, the
benzoate, the cinnamate, the citrate, the embonate, the enantate,
the fumarate, the glutamate, the glycolate, the lactate, the
maleate, the malonate, the mandelate, the methanesulphonate, the
naphthalene-2-sulphonate, the phthalate, the salicylate, the
sorbate, the stearate, the succinate, the tartrate, the
toluene-p-sulphonate, and the like. Such salts may be formed by
procedures well known and described in the art.
[0039] Other acids such as oxalic acid, which may not be considered
pharmaceutically acceptable, may be useful in the preparation of
salts useful as intermediates in obtaining a deuterated analog of
the invention and its pharmaceutically acceptable acid addition
salt.
[0040] Examples of pharmaceutically acceptable cationic salts of a
deuterated analog of the invention include, without limitation, the
sodium, the potassium, the calcium, the magnesium, the zinc, the
aluminium, the lithium, the choline, the lysinium, and the ammonium
salt, and the like, of a deuterated analog of the invention
containing an anionic group. Such cationic salts may be formed by
procedures well known and described in the art.
[0041] The deuterated analog of the invention may be provided in
dissoluble or indissoluble forms together with a pharmaceutically
acceptable solvent such as water, ethanol, and the like. Dissoluble
forms may also include hydrated forms such as the monohydrate, the
dihydrate, the hemihydrate, the trihydrate, the tetrahydrate, and
the like. In general, the dissoluble forms are considered
equivalent to indissoluble forms for the purposes of this
invention.
Methods of Preparation
[0042] The deuterated analog of the invention may be prepared by
conventional methods for chemical synthesis, e.g. those described
in the working examples. The starting materials for the processes
described in the present application are known or may readily be
prepared by conventional methods from commercially available
chemicals.
[0043] Also one compound of the invention may be converted to
another compound of the invention using conventional methods.
[0044] The end products of the reactions described herein may be
isolated by conventional techniques, e.g. by extraction,
crystallisation, distillation, chromatography, etc.
Biological Activity
[0045] WO 01/46145, WO 01/46146, WO 2005/121087, WO 2007/042295 WO
2008/127188 and WO 2008/155357 all describe substituted
4-phenyl-N-alkyl-piperazines and 4-phenyl-N-alkyl-piperidines,
reported to be modulators of dopamine neurotransmission, and to be
useful in treatment of symptoms of various disorders of the central
nervous system. The deuterated analog of the invention is
considered useful for the same medical indications as described in
these publications, and these publications therefore are
incorporated by reference.
[0046] Neurological indications contemplated according to these
publications include the treatment of Huntington's disease and
other movement disorders, as well as movement disorders induced by
drugs.
[0047] Therefore, in a preferred embodiment, the invention relates
to the use of the deuterated analog of the invention for use as a
medicament for the treatment of Huntington's disease.
Pharmaceutical Compositions
[0048] Viewed from another aspect the invention provides deuterated
analogs for use as medicaments. Therefore, in another aspect, the
invention provides novel pharmaceutical compositions comprising a
therapeutically effective amount of the compound of the
invention.
[0049] While a deuterated analog of the invention for use in
therapy may be administered in the form of the raw compound, it is
preferred to introduce the active ingredient, optionally in the
form of a physiologically acceptable salt, in a pharmaceutical
composition together with one or more adjuvants, excipients,
carriers, buffers, diluents, and/or other customary pharmaceutical
auxiliaries.
[0050] Pharmaceutical compositions of the invention may in
particular be formulated as described in WO 01/46145.
[0051] Further details on techniques for formulation and
administration may be found in the latest edition of Remington's
Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa.).
[0052] The dose administered must of course be carefully adjusted
to the age, weight and condition of the individual being treated,
as well as the route of administration, dosage form and regimen,
and the result desired, and the exact dosage should of course be
determined by the practitioner.
[0053] The actual dosage depends on the nature and severity of the
disease being treated, and is within the discretion of the
physician, and may be varied by titration of the dosage to the
particular circumstances of this invention to produce the desired
therapeutic effect. However, it is presently contemplated that
pharmaceutical compositions containing of from about 1 to about 500
mg of active ingredient per individual dose, preferably of from
about 10 to about 100 mg, most preferred of from about 25 to about
50 mg, are suitable for therapeutic treatments. The daily dose will
preferably be administered in individual dosages 1 to 4 times
daily.
Methods of Therapy
[0054] In another aspect the invention provides a method for the
treatment, prevention or alleviation of a dopamine mediated
disorder of a living animal body, including a human, which method
comprises the step of administering to such a living animal body in
need thereof a therapeutically effective amount of the deuterated
analog of the invention.
[0055] In a preferred embodiment the dopamine mediated disorder is
Huntington's disease.
EXAMPLES
[0056] The invention is further illustrated in the examples below,
which in no way are intended to limit the scope of the
invention.
Example 1
Preparatory Example
[0057] 4-(3-Methanesulfonyl-phenyl)-1-propyl-d7-piperidine x
HCl
[0058] 4-(3-Methanesulfonyl-phenyl)-piperidine (0.43 g), CH3CN (4
ml), K.sub.2CO.sub.3 (0.49 g), and 1-lodopropane-d7 (0.19 g) are
mixed and heated in microwave oven for 30 min at 120.degree. C. The
mixture is filtered and evaporated to dryness and purified on
silica column using iso-octane:EtOAc (1:1) containing 5% NEt.sub.3
as eluent. After evaporation of the fractions with pure product,
the residue is re-dissolved in EtOAc and washed with a 10%
Na.sub.2CO.sub.3 solution. The organic phase is separated and dried
with Na.sub.2SO.sub.4, filtered and evaporated to yield pure
product (0.33 g). The amine is then converted to the HCl salt, and
re-crystallized from EtOH:Et.sub.2O. M.p. 198-199.degree. C.
* * * * *