Note: Descriptions are shown in the official language in which they were submitted.
WO 03/105844 CA 02485751 2004-11-12 PCT/EP03/05813
81054pct.211
MEDICAMENT COMBINATIONS OF SODIUM CHANNEL BLOCKERS AND
FIBRINOLYTICS FOR TREATING ISCHAEMIC CONDITIONS
The invention relates to new drug combinations based on sodium channel
blockers 1 and fibrinolytics 2, processes for the preparation thereof as well
as
the use thereof for preparing pharmaceutical compositions for the treatment of
ischaemic conditions.
Description of the invention
The invention relates to drug combinations containing one or more, preferably
one sodium channel blocker 1 and one or more, preferably one fibrinolytic 2
optionally in the presence of conventional excipients or carriers.
A~ Sodium channel blockers 1 which may be used according to the invention:
Within the scope of the present invention preferred sodium channel blockers 1
are those selected from the group consisting of pirmencol, sipatrigine,
irampanel, pilsicainide, oxcarbazepine, topiramate, fosphenytoin, flunarizin,
ropivacaine, levobupivacaine, zonisamide, mexiletine, bipridil, bisaramil,
milacainide, safinamide, bupivacaine, tetrodotoxin, NS 7, the compounds of
general formula 1a
R$
H, RZ
X~R'
R'
R4
R
5
R
1a
wherein
X denotes a single bond, -O, C1-C4-alkylene, an alkylene bridge
with 1 to 8 carbon atoms which may be branched or unbranched
and may have at any point in the bridge one or two oxygen atoms)
or a nitrogen atom, preferably O-C1-Cg-alkylene or -O-CH2-CH2-
O, -O-CH2-CH2-NH-;
R1 denotes hydrogen, methyl, ethyl, phenyl;
R2 denotes hydrogen, methyl;
CA 02485751 2004-11-12
2
~R3 denotes hydrogen, fluorine, chlorine, bromine, hydroxy, methyl,
methoxy;
R4 denotes hydrogen, methyl, ethyl;
R5 denotes hydrogen, methyl, ethyl;
R6 denotes hydrogen, methyl, ethyl;
R7 denotes tert.-butyl, cyclohexyl or phenyl, while phenyl may
optionally be substituted by R9 and R10, which may be identical or
different;
R$ denotes hydrogen, C1-C4-alkyl;
R9 denotes hydrogen, methyl, fluorine, chlorine, bromine, methoxy;
R10 denotes hydrogen, methyl, fluorine, chlorine, bromine, methoxy;
optionally in the form of the individual optical isomers, mixtures of
the individual enantiomers or racemates as well as in the form of
the free bases or the corresponding acid addition salts with
pharmacologically acceptable acids;
and the compounds of genera! formula 1 b.
R3,
O
R9 ~ R2,
4
F R6' R
i5'
1b
wherein
R1 ~, R2~ and R3~ which may be identical or different, denote hydrogen,
methyl or ethyl;
R4~ denotes hydrogen, methyl ar ethyl;
RS~, R6~ and R7~ which may be identical or different, denote hydrogen,
methyl or ethyl;
R8~ and R9~ which may be identical or different, denote hydrogen,
fluorine, chlorine, bromine, methyl, ethyl, hydroxy or
methoxy,
optionally in the form of the racemates, the enantiomers, the diastereomers
and the mixtures thereof, and optionally the pharmacologically acceptable
acid addition salts thereof.
Particularly preferred within the scope of the present invention is or are the
sodium channel blocker(s) 1 selected from the group consisting of pirmencol,
CA 02485751 2004-11-12
3
pilsicainide, sipatrigine, irampanel, fosphenytoin, zonisamide, mexiletine,
bipridil, bisaramil, milacainide, NS 7, the compounds of general formula 1a
wherein
X denotes C1-C3-alkylene, -O-CH2-CH2-O or -O-CH2-CH2-NH-;
R1 denotes hydrogen or
methyl;
R2 denotes hydrogen or
methyl;
R3 denotes hydrogen or
chlorine;
R4 denotes hydrogen or
methyl;
R5 denotes hydrogen or methyl;
R6 denotes methyl or ethyl;
R7 denotes tert.-butyl, cyclohexyl or phenyl, while phenyl may
optionally be substituted by R9 and R10, which may be identical or
different;
R$ denotes hydrogen;
Rg denotes hydrogen, methyl, fluorine or chlorine;
R10 denotes hydrogen, methyl, fluorine or chlorine;
optionally in the form of the individual optical isomers, mixtures of
the individual enantiomers or racemates as well as in the form of
the free bases or the corresponding acid addition salts with
pharmacologically acceptable acids;
and the compounds of general formula 1b, wherein
R1 ~, R2~ and R3~ which may be identical or different, denote hydrogen or
methyl;
R4~ denotes hydrogen or methyl;
RS~, R6~ and R7~ which may be identical or different, denote hydrogen or
methyl, preferably methyl;
R8~ denotes hydrogen, methyl, hydroxy or methoxy,
preferably hydrogen or methyl,
Rg~ denotes hydrogen or methyl,
optionally in the form of the racemates, the enantiomers, the diastereomers
and the mixtures thereof, and optionally the pharmacologically acceptable
acid addition salts thereof.
Particularly preferred within the scope of the present invention is or are the
sodium channel blocker(s) 1 selected from the group consisting of
fosphenytoin, zonisamide, sipatrigine, irampanel, mexiletine, NS 7, the
compounds of general formula 1a wherein
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'X 'denotes C1-C3-alkylene or -O-CH2-CH2-O-;
R1 denotes hydrogen or methyl;
R2 denotes hydrogen or methyl;
R3 denotes hydrogen;
R4 denotes hydrogen or methyl;
R5 denotes hydrogen or methyl;
R6 denotes methyl;
R~ denotes phenyl, the phenyl may optionally be substituted by R9
and R10, which may be identical or different;
R8 denotes hydrogen;
R9 denotes hydrogen, methyl, fluorine or chlorine;
R10 denotes hydrogen, methyl, fluorine or chlorine;
optionally in the form of the individual optical isomers, mixtures of
the individual enantiomers or racemates as well as in the form of
the free bases or the corresponding acid addition salts with
pharmacologically acceptable acids;
and the compounds of general formula _1b, wherein
R1 ~, R2~ and R3~ which may be identical or different, denote hydrogen or
methyl;
R4~ denotes hydrogen or methyl;
RS~, R6~ and R7~ denote methyl;
R8~ denotes hydrogen or methyl, preferably hydrogen;
Rg~ denotes hydrogen or methyl,
optionally in the form of the racemates, the enantiomers, the diastereomers
and the mixtures thereof, and optionally the pharmacologically acceptable
acid addition salts thereof.
C1-C4-alkyl or C1-Cg-alkyl generally denotes a branched or unbranched
hydrocarbon group with 1 to 4 or 1 to 8 carbon atom(s), which may
optionally be substituted by one or more halogen atoms - preferably
fluorine - which may be identical to or different from one another. The
following hydrocarbon groups are mentioned by way of example: methyl,
ethyl, propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl, 2-
methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-
methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-
ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-
methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2,-
CA 02485751 2004-11-12
dimetiiylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-
ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-
methylpropyl and 1-ethyl-2-methylpropyl. Unless otherwise stated, lower
alkyl groups with 1 to 4 carbon atoms, such as methyl, ethyl, propyl, iso-
5 propyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl, are
preferred.
Accordingly, alkylene denotes a branched or unbranched double-bonded
hydrocarbon bridge with 1 to 8 carbon atoms, which may optionally be
substituted by one or more halogen atoms - preferably fluorine - which
may be identical to or different from one another.
Alkoxy generally denotes a straight-chain or branched hydrocarbon group
bonded via an oxygen atom - a lower alkoxy group with 1 to 4 carbon
atoms) is preferred. The methoxy group is particularly preferred.
A particularly preferred compound of formula 1a is (-)-(1 R,2"S)-2-(2"-
benzyloxy)propyl-4'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan in the form of
the free bases or the corresponding acid addition salts with pharmacologically
acceptable acids. This compound is also known by the name crobenetine.
Of particular interest are the following compounds of general formula 1b:
(2R)-N-allyloxyethyl-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-
benzazocin-10-ol-hydrochloride and (2R,2"S)-N-(2-allyloxy-propyl)-
1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocin-10-0l-
hydrochloride.
Accordingly, within the scope of the present invention, the component 1 is
most preferably selected from the group consisting of fosphenytoin,
zonisamide, sipatrigine, irampanel, mexiletine, NS 7, crobenetine, (2R)-N-
allyloxyethyl-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-
benzazocin-10-ol-hydrochloride and (2R,2"S)-N-(2-allyloxy-propyl)-
1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocin-10-0l-
hydrochloride, most preferably crobenetine, (2R)-N-allyloxyethyl-1,2,3,4,5,6-
hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocin-10-ol-hydrochloride
and (2R,2"S)-N-(2-allyloxy-propyl)-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-
2,6-methano-3-benzazocin-10-ol-hydrochloride, while crobenetine is of
exceptional importance.
CA 02485751 2004-11-12
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The compounds 1 may optionally be used in the form of their salts, and,
particularly for pharmaceutical use, in the form of the pharmacologically
acceptable acid addition salts with an inorganic or organic acid. Suitable
acids
for this include for example succinic acid, hydrobromic acid, acetic acid,
fumaric acid, malefic acid, methanesulphonic acid, lactic acid, phosphoric
acid,
hydrochloric acid, sulphuric acid, tartaric acid or citric acid. It is also
possible
to use mixtures of the above acids.
The compounds of formula 1a are known from WO 99114199. The
compounds of formula 1 b are not yet known in the prior art.
The compounds of formula 1 b which may be used according to the invention
and are not yet known in the prior art may be prepared analogously to
methods of synthesis known per se. Possible methods of synthesising the
compounds of formula 1 b are described by way of example hereinafter.
S~~nthesis Example 1: (2R~N-allylox~iethyl-1,2,3,4,5,6-hexahydro-6,11,11-
trimethyl-2, 6-methano-3-benzazocin-10-ol-hydrochloride
1.8 g of allyloxyacetic acid are placed in 15 ml dichloromethane, combined
with 4.8 g of TBTU and 7.5 ml of ethyldiisopropylamine and stirred at RT for
15 min.. Then the mixture is cooled to -5°C and 3.1 g of 1,2,3,4,5,6-
hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocin-10-of are added. The
mixture is stirred for 30 min at 0°C, and 1 h at RT. Then it is washed
once with
100m1 of 2N HCL and once with 100m1 10% potassium carbonate solution,
dried and evaporated dawn in vacuo. The residue is taken up in 50 ml of THF
and added dropwise under nitrogen to a suspension of 1.0 g of lithium
aluminium hydride in 50m1 THF. (Temp. rises to 35°C). It is then heated
to
50°C, stirred for 1 h, cooled and at 0 -10°C 1 ml of water is
added dropwise,
the mixture is stirred for 30 min, 3ml of NaOH are added and the mixture is
stirred for 30 min. The precipitate is suction filtered, the mother liquor
evaporated down in vacuo and the residue is filtered through a short column
approx. 75 ml silica gel; dichloromethane 70, ethyl acetate 20, methanol 10).
The appropriate fractions are evaporated down in vacuo and crystallised from
acetone + eth.HCl.
Yield 2.8 g of (77%), melting point: 236 °C; [a]p2°= -78,3
° (c = 1; methanol).
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7
Synthesis Example 2: (2R 2"S)-N-(2-allyloxy-propyl)-1,2,3,4,5,6-hexahydro-
6,11 L11-trimeth~~l-2,6-methano-3-benzazocin-10-ol-hydrochloride
This is prepared analogously to the method according to Example 1.
Yield 56%, melting point: 239 °C; [a]p2°= -33,9 ° (c
= 1; methanol).
Synthesis Example 3' (2R 2"SAN-(2-but-2-enoxy-propYl)-1,2,3,4,5,6-
hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocin-10-ol-hydrochloride
This is prepared analogously to the method according to Example 1.
Yield 47%, melting point: 205 °C
Synthesis Example 4~ (2R,2"S)-N~2-(2-methyl-propenoxy)-propyl]-1,2,3,4,5,6-
hexahydro-6 11,11-trimethy-2,6-methano-3-benzazocin-10-ol-hydrochloride
This is prepared analogously to the method according to Example 1.
Yield 12%, melting point: 240 °C; [a)p2°= -29,6 ° (c
= 1; methanol).
Synthesis Example 5: (2R)-N j2-allyloxy-propyll-1,2,3,4,5,6-hexahydro-
6,11,11-trimethyl-2,6-methano-3-benzazocin-10-ol-hydrochloride
1,9 g of (2R)-N-allyloxyethyl-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-
methano-3-benzazocin-10-ol-hydrochloride (Example 1 ) are dissolved in 40
ml of methanol and combined with 3 g of 30% formalin solution and 3 ml of 4
N NaOH. The mixture is heated to 50 °C for 12 hours, the solvent is
removed
in vacuo, 100 ml of water are added to the residue and it is extracted twice
with 200 ml of ether. The organic phase is washed with water, dried and
evaporated down in vacuo. The residue is dissolved in 20 ml of
dichloromethane and at RT 1.5 g of SOC12 added dropwise. After 30 min. it is
evaporated down in vacuo, the residue is taken up in 20 ml THF and under
nitrogen added dropwise to a suspension of 0.5 g of lithium aluminium hydride
in 20m1 of tetrahydrofuran. Then it is heated to 50 °C for 2 h, cooled,
1.5 ml of
4N NaOH are added dropwise and the mixture is stirred for 30 min. The
precipitate is suction filtered and the mother liquor is evaporated down in
vacuo. The residue is filtered through a short silica gel column (approx 30 ml
of silica gel, approx 250 ml of ethyl acetate). ). The appropriate fractions
are
evaporated down in vacuo and crystallised from acetone + eth.HCl.
Yield 1.1 g of (56%), melting point: 212 °C, [a]o °_ - 71.6
° (c = 1; methanol).
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Synthesis Example 6: ~2R,2"S)-N-t2-allyloxy-propyll-1,2,3,4,5,6-hexahydro-
6,9,11,11-tetramethyl-2,6-methano-3-benzazocin-10-ol-hydrochloride
This is prepared analogously to the method according to Example 5 starting
from Example 2. Yield 60%, melting point: 215 °C; [aJp °_ -29,3
° (c = 1;
methanol).
B) Fibrinolytics 2 which may be used according to the invention:
Within the scope of the present invention the fibrinolytics 2 selected from
among the plasminogen activators are preferred. Of particular interest are
alteplase (human tissue plasminogen activator, t-PA), tenecteplase, reteplase,
streptokinase, urokinase, anistreplase, monteplase, nateplase, duteplase,
lanoteplase, silteplase, amediplase and desmoteplase. All these fibrinolytics
are known in the art.
Alteplase (amino acid sequence: GenBank Accession No. AAB59510) is a
fibrinolytic licensed for use as a drug, the preparation of which by
recombinant
expression, preferably in cell lines of the Chinese hamster Cricetulus griseus
(CHO cells), as well as its pharmaceutical formulation and medicinal use have
been described in detail in the prior art (Pennica et al., Nature 301, 214-221
(1983); EP 0 093 619; Andersen et al., Biotechnol Bioeng 70 (1 ), 25-31
(2000); Dowd et al., Biotechnol Prog 16 (5), 786-794 (2000); Fann et al.,
Biotechnol Bioeng 69 (2), 204-212 (2000); Werner et al.,
Arzneimittelforschung 48 (8), 870-880 (1998); Wernicke et Will, Anal Biochem
203 (1 ), 146-150 (1992); Bos et al., Biochim Biophys Acta 1117 (2), 188-192
(1992); Dodd et al., FEBS Lett 209 (1 ), 13-17 (1986); Matsuo et al., J
Chromatogr 369 (2), 391-397 (1986); Einarsson et al., Biochim Biophys Acta
830 (1), 1-10 (1985); Kruithof et al., Biochem J 226 (3), 631-636 (1985);
Nguyen et al., Pharm Biotechnol. 5, 91-134 (1993); The Gusto III
Investigators, N Engl J Med. 1997 Oct 16;337(16):1118-23; EP 0 239 292;
WO 86/05514).
Tenecteplase (TNK-tPA; T103N,N117Q,KHRR(296-299)AAAA-tPA) is also a
fibrinolytic licensed for use as a drug. Its preparation and use is described
in
detail in the references WO 93/24635; Keyt et al., Proc Natl Acad Sci U S A.
1994 Apr 26;91 (9):3670-4; Turcasso et Nappi, Ann Pharmacother. 2001
Oct;35(10):1233-40; MacGahan, Issues Emerg Health Technol. 2001
Jan ;(13):1-6; Davydov et Cheng, Clin Ther. 2001 Ju1;23(7):982-97; The
Assent II investigators, Lancet. 1999 Aug 28;354(9180):716-22.
CA 02485751 2004-11-12
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The preparation of reteplase, which is also licensed for drug use, and its
pharmaceutical formulations and uses are described in the literature in WO
90/03497; WO 91/08765, WO 91/08766, and Noble et McTavish, Drugs. 1996
Oct;52(4):589-605. The preparation, pharmaceutical formulation and medical
use of lanoteplase are described in the literature in WO 87104722 and WO
90/08557. The preparation, pharmaceutical formulation and medical use of
desmoteplase are described in the literature in WO 90/09438 and WO
97/29188. The preparation, pharmaceutical formulation and medical use of
anistreplase, which is licensed for drug use, is described in the literature
in
EP 0 028 489, Fears, Semin Thromb Hemost 15 (2), 129-139 (1989);
Anderson et al., Circulation. 1991 Jan ;83(1 ):126-40; Been et al., Int J
Cardiol.
1986 Apr;11 (1 ):53-61; Marder et al., Ann Intern Med. 1986 Mar;104(3):304-
10; Walker et al, Thromb Haemost. 1984 Apr 30;51 (2):204-6, and Matsuo et
al, Thromb Res Suppl. 1981 Nov 15;24(4):347-58. Urokinase is described in
EP 0 143 949, EP 0 154 272, EP 0 303 028, and EP 0 620 279.
A large number of other plasminogen activators which may be used as
component 2 for the combination according to the invention are described in
the literature.
Particularly preferred within the scope of the present invention are the
fibrinolytics 2 selected from the group consisting of alteplase (t-PA),
tenecteplase, reteplase, streptokinase, urokinase, anistreplase, monteplase
and nateplase. Particularly preferred fibrinolytics 2 according to the
invention
are selected from among alteplase (t-PA), tenecteplase, reteplase, urokinase
and anistreplase, while alteplase, tenecteplase and reteplase and most
preferably alteplase are of exceptional importance according to the invention.
C~ Use of the drugs combinations of 1 and 2 according to the invention:
The present invention further relates to the use of the combinations according
to the invention of one or more, preferably one sodium channel blocker 1 and
one or more, preferably one fibrinolytic 2 for preparing a pharmaceutical
composition for the treatment of ischaemic conditions of various origins.
Preferably, the present invention relates to the use of the combinations
according to the invention of one or more, preferably one sodium channel
blocker 1 and one or more, preferably one fibrinolytic 2 for preparing a
pharmaceutical composition for the treatment of cardiac or cerebral
CA 02485751 2004-11-12
ischaemias, most preferably for the treatment of stroke. Of particular
importance within the scope of the present invention is the use of the
combinations according to the invention of one or more, preferably one
sodium channel blocker 1 and one or more, preferably one fibrinolytic 2 for
the
5 treatment of ischaemic stroke, most preferably acute ischaemic stroke.
The present invention further relates to a process for treating ischaemic
conditions of various origins which is characterised in that a combination
according to the invention of one or more, preferably one sodium channel
10 blocker 1 and one or more, preferably one fibrinolytic 2 is administered.
The
present invention preferably relates to a method of treating cardiac or
cerebral
ischaemias, most preferably stroke, and more preferably according to the
invention ischaemic stroke, most preferably acute ischaemic stroke, which is
characterised in that a combination according to the invention of one or more,
preferably one sodium channel blocker 1 and one or more, preferably one
fibrinolytic 2 is administered.
The present invention further relates to the use of one or more, preferably
one
sodium channel blocker 1 for preparing a pharmaceutical composition for the
combined treatment of ischaemic conditions of various origins with one or
more, preferably one fibrinolytic 2. The present invention preferably relates
to
the abovementioned use for preparing a pharmaceutical composition for the
combined treatment of cardiac or cerebral ischaemias, most preferably for the
treatment of stroke with one or more, preferably one fibrinolytic 2. Of
particular
importance within the scope of the present invention is the present use for
the
combined treatment of ischaemic stroke, most preferably acute ischaemic
stroke with one or more, preferably one fibrinolytic 2.
The present invention further relates to a method of treating ischaemic
conditions of various origins which is characterised in that one or more,
preferably one sodium channel blocker 1 and one or more, preferably one
fibrinolytic 2 are administered simultaneously or sequentially in one single
or
two separate, preferably in two separate preparations. The present invention
preferably relates to a method of treating cardiac or cerebral ischaemias,
most
preferably stroke, and more preferably according to the invention ischaemic
stroke, most preferably acute ischaemic stroke, which is characterised in that
one or more, preferably one sodium channel blocker 1 and one or more,
CA 02485751 2004-11-12
11
preferably one fibrinolytic 2 are administered simultaneously or sequentially
in
one single or two separate, preferably in two separate preparations.
D.11 Administration of the drug combinations of 1 and 2 according to the
invention:
The drug combinations according to the invention may contain the active
ingredients 1 and 2 in one single or two separate preparations. In the
combinations of zonisamide, mexiletine, NS 7, crobenetine, (2R)-N-
allyloxyethyl-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-
benzazocin-10-ol-hydrochloride or (2R,2"S)-N-(2-allyloxy-propyl)-1,2,3,4,5,6-
hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocin-10-ol-hydrochloride
as component 1 with alteplase (t-PA), tenecteplase, reteplase, urokinase or
anistreplase as component 2 which are of particular importance according to
the invention, the two components are preferably contained in two separate
preparations, for example in the form of a so-called kit. Separate
formulations
of the two components 1 and 2 are described in detail in the following
paragraphs.
The combination of 1 and 2 according to the invention may be administered,
within the scope of the abovementioned use and within the scope of the
abovementioned process by simultaneously administering the combination of
1 and 2 or, when 1 and 2 are present in different preparations, by
administering components 1 and 2 simultaneously or sequentially. The term
sequentially within the scope of the present invention refers to any method of
administering components 1 or 2 which does not take place simultaneously.
By simultaneous administration is meant the method of administration in
which at least one of components 1 and 2 is administered for example by
infusion over a longer period and the other component is also used during this
period. If the two components 1 and 2 are both administered by infusion over
a longer period of time, the word simultaneously for the purposes of the
present invention means that the infusion periods overlap for at least a short
time.
Particularly when treating ischaemic stroke, which is the preferred indication
within the scope of the present invention, most preferably when treating acute
ischaemic stroke, components 1 and 2 are preferably given simultaneously or
at least within a short time of each other, i.e. for example within one hour.
Treatment with the drug combinations according to the invention is
particularly
CA 02485751 2004-11-12
12
effective when it is given as quickly as possible after the stroke takes
place.
Preferably, the treatment starts at the latest within about 5 hours, most
preferably within 4 hours, more preferably still within 3 hours after the
stroke
occurs.
D.2) Pharmaceutical formulation and administration of component 1:
Within the scope of the present invention the compounds 1 may be
administered orally, transdermally, by inhalation or parenterally. The
compounds 1 occur as active ingredients in conventional preparations, for
example in compositions which consist essentially of an inert pharmaceutical
carrier and an effective dose of the active substance, such as for example
tablets, coated tablets, capsules, lozenges, powders, solutions, suspensions,
emulsions, syrups, suppositories, transdermal systems etc.. An effective dose
of the compounds 1 , particularly the compounds of formulae 1a and 1b, is
between 1 and 1000, preferably between 1 and 500, most preferably between
5-300 mg/dose for oral administration, and between 0.001 and 100, preferably
between 0.1 and 70 mg/dose for intravenous or intramuscular administration.
It is particularly possible to use the component 1 according to the invention
as a solution for infusion, preferably in a physiological saline or nutrient
saline
solution. In an infusion, for example 10-100 mg/h, preferably 25-60 mg/h of
the compound 1 may be used. This latter method of administration is
exceptionally important according to the invention.
The compound 1 crobenetine, which is particularly preferred according to the
invention, is most preferably administered intravenously by infusion.
Preferably between 10 and 60 mg (based on the free base crobenetine) are
administered per dose. It is also possible to administer crobenetine as
component 1 of the drug combination according to the invention at different
time intervals in different doses for each therapy. For example, crobenetine
may be given as component 1 first of all in a dosage of 20-70 mg, preferably
30 to 60 mg, most preferably 50 mg over a period of about 30 minutes to 2
hours, preferably over 45 to 90 minutes, most preferably over one hour. This
first administration of component 1 crobenetine may then be followed by
further administrations in doses of for example 5 to 50 mg, preferably 10 to
40
mg, most preferably 20 to 30 mg over a period of 2 to 8 hours, preferably 3 to
7 hours, most preferably 4 to 6 hours. If desired this second administration
of
component 1 crobenetine may be followed others.
CA 02485751 2004-11-12
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Some particular embodiments of formulations for parenteral administration are
described hereinafter which may be used in particular for the compounds of
formulae 1a and 1b which are particularly preferably used as sodium channel
blockers 1.
These formulations contain at least one compound of formula 1a or 1b or one
of the pharmaceutically acceptable salts thereof and a cyclodextrin
derivative,
particularly gamma-cyclodextrin (y-CD), hydroxypropyl-gamma-cyclodextrin
(HP-y-CD), hydroxypropyl-beta-cyclodextrin (HP-~3-CD) or sulphobutylether-
beta-cyclodextrin (SBE-~i-CD). The preferred cyclodextrin derivative is
hydroxypropyl~y-cyclodextrin. Hydroxypropyl-'y-cyclodextrin with a molar
substitution level of 0.5 to 0.7 is sold for example by Messrs Wacker-Chemie
GmbH, D-Burghausen, under the name "CAVASOL ~ W8 HP Pharma".
"CAVASOL ~ W8 HP Pharma" is particularly preferred for these
pharmaceutical compositions.
Apart from the compound of formula 1a or 1b and the cyclodextrin derivative
the pharmaceutical compositions intended for parenteral use according to the
invention may contain hydroxy acids such as for example malic acid, lactic
acid, tartaric acid or citric acid. They may also optionally contain
conventional
excipients and carriers such as for example the isotonic agents glucose,
mannitol or sodium chloride or sodium acetate or sodium acetate trihydrate as
buffer combined with acetic acid or a citric acid/phosphate buffer consisting
of
e.g. citric acid and disodium hydrogen phosphate or disodium hydrogen
phosphate dihydrate. The solvent used is normally water for injections.
The molar ratio of the compound of formula 1a or 1b to cyclodextrin is
between 1:1 and 1:5 for example in these formulations. A molar ratio of 1 :
2.5
to 1 : 3.5 is preferred. In the presence of hydroxy acid this molar ratio is
preferably between 1 : 0.5 and 1 : 3 according to the invention; a molar ratio
of 1 : 0.5 to 1 : 1.5 is particularly preferred. These formulations are most
preferably used with crobenetine as component 1.
Apart from the formulations described above containing at least one
compound of formula 1a or 1b or one of the pharmaceutically acceptable salts
thereof and a cyclodextrin derivative, equally preferred formulations for
parenteral use according to the invention are those which contain mannitol as
CA 02485751 2004-11-12
14
excipi~nt, in addition to a compound of formula 1a or 1b or one of the
pharmaceutically acceptable salts thereof. The amount of mannitol is
preferably chosen so as to obtain an isotonic solution. These pharmaceutical
compositions may optionally also contain other conventional excipients and
carriers such as for example an acetic acid/acetate buffer consisting of
acetic
acid and sodium acetate or sodium acetate-trihydrate or a citric
acid/phosphate buffer consisting for example of citric acid and disodium
hydrogen phosphate or disodium hydrogen phosphate dihydrate. Usually, the
quantity of the buffer components is selected so as to obtain a particular pH
value and a particular buffer capacity. The solvent used is normally water for
injections.
Preferably, the pharmaceutical composition contains an acetic acid/acetate
buffer in addition to the isotonic agent mannitol. A 0.005 to 0.05 molar,
preferably a 0.005 to 0.02 molar acetic acid/ acetate buffer with a pH of 3.8
to
5 is particularly preferred while a 0.01 molar acetic acid/acetate buffer with
a
pH value of about 4 is most particularly preferred. The concentration
specified
relates to the total concentration of acetic acid and acetate; the ratio of
acetic
acid to acetate results from the desired pH. The pH specified is measured
both in the pure buffer solution and in the finished solution for injection of
infusion.
These formulations are particularly preferably used when crobenetine is used
as component 1.
D.2.1) Examples of pharmaceutical formulations of component 1:
Formulation Example 1:
crobenetine hydrochloride 767 mg
HpyCD*)
10000 mg
mannitol 11000 mg
acetic acid 99% 125.25 mg
sodium acetate trihydrate 56.5 mg
water for injections ad 250 ml
*) for example "CAVASOL ~ W8 HP Pharma" made by Wacker
CA 02485751 2004-11-12
Formulation Example 2:
crobenetine hydrochloride 383.5 mg
yCD 5000 mg
NaCI 2250 mg
5 water for injections ad 250 ml
Formulation Example 3:
crobenetine hydrochloride 767 mg
HPaCD 7500mg
10 mannitol 12500 mg
acetic acid 99% 125.25 mg
sodium acetate trihydrate 56.5 mg
water for injections ad 250 ml
15 Formulation Example 4:
crobenetine hydrochloride 767 mg
SBE~CD 5000 mg
mannitol 12500 mg
acetic acid 99% 125.25 mg
sodium acetate trihydrate 56.5 mg
water for injections ad 250 ml
Formulation Example 5:
crobenetine hydrochloride 767 mg
HPyCD 2500 mg
citric acid 708 mg
mannitol 12500 mg
acetic acid 99% 125.25 mg
sodium acetate trihydrate 56.5 mg
water for injections ad 250 ml
Formulation Example 6:
crobenetine hydrochloride 767 mg
yCD 2500 mg
tartaric acid 138,25 mg
NaCI 2250 mg
water for injections ad 250 ml
CA 02485751 2004-11-12
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FormulationExample 7 (solution for infusion (acetate buffer off 4
crobenetine hydrochloride 274 mg
mannitol 25000 mg
acetic acid 99% 250,5 mg
sodium acetate trihydrate 113,0 mg
water for injections ad 500 ml
Formulation Example 8 (solution for infusion (acetate buffer pH 4.5))
crobenetine hydrochloride 274 mg
mannitol 25000 mg
acetic acid 99% 180,0 mg
sodium acetate trihydrate 265,0 mg
water for injections ad 500 ml
Formulation Example 9 (solution for infusion (acetate buffer ~H 4
crobenetine hydrochloride 383,6 mg
mannitol 25000 mg
acetic acid 99% 501,0 mg
sodium acetate trihydrate 226,0 mg
water for injections ad 500 ml
Formulation Example 10 (solution for infusion (acetate buffer pH 4))
crobenetine hydrochloride 767 mg
mannitol 11000 mg
acetic acid 9% 125.25 mg
sodium acetate trihydrate 56.5 mg
water for injections ad 250 ml
Formulation Example 11 (solution for infusion (acetate buffer pH 4.5))
crobenetine hydrochloride 767 mg
mannitol 25000 mg
acetic acid 99% 90.0 mg
sodium acetate trihydrate 132.5 mg
water for injections ad 500 ml
CA 02485751 2004-11-12
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Formulation Example 12 (solution for infusion (acetate buffer pH 4))
crobenetine hydrochloride 219.1 mg
mannitol 5000 mg
acetic acid 99% 50.1 mg
sodium acetate trihydrate 22.6 mg
water for injections ad 100 ml
The amount of active substance given can be controlled by administering a
particular volume of one of the solutions described above. For example the
daily administration of 100 ml of a solution according to Example 1
corresponds to a dose of 280 mg of crobenetine a day.
D.3) Pharmaceutical formulation and administration of component 2'
The fibrinolytic 2 used within the scope of the drug combination according to
the invention is generally a polypeptide which has to be given parenterally.
It
may be given particularly by intravenous, intraarterial, intramuscular, intra-
or
subcutaneous injection, but may also be administered by inhalation of a
powder or aerosol. Typical formulations are freeze-dried preparations
(lyophilisates) of the polypeptide, which are reconstituted immediately before
administration with a solution for injection or infusion. The reconstituting
solution may be water or a buffered aqueous solution. The formulation may,
however, also consist of an aqueous solution which is preferably buffered with
a physiologically acceptable buffer and may additionally contain conventional
stabilisers, solubilisers and preservatives. Examples of conventional
adjuvants for liquid or solid formulations of this kind are alkali metal
hydrogen
phosphate/alkali metal dihydrogen phosphate, sodium chloride, serum
albumin, polyoxyethylenesorbitan-monolaurate (Tween~ 20),
polyoxyethylenesorbitan-monooleate (Tween~ 80), ethylenediamine-
tetraacetate (EDTA), sucrose, mannitol, dextran, amino acid and
benzylalcohol (the latter only for liquid formulations). They are generally
administered parenterally, preferably by intravenous injection or infusion.
The
mode of application and dosage preferably depend on the fibrinolytic selected,
particularly its specific biological activity and half-life in the blood
plasma.
Thus, alteplase, which has a relatively short half-life, is typically
administered
in a total dosage of 100 mg as follows: 10-15 mg as an intravenous bolus,
followed by an intravenous infusion of 50 mg over a period of 30 to 60
minutes, followed by another infusion of 60-180 minutes up to the maximum
dose. Tenecteplase has a longer half-life and can therefore be administered
CA 02485751 2004-11-12
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as a single bolus, based on body weight, up to a maximum dose of 50 mg.
Reteplase, which has a moderate half-life and low specific activity, is
administered as an intravenous double bolus at an interval of 30 minutes in a
dosage of 10 units (560 mg) per bolus. The skilled man knows how to
determine the correct dosage for a new pharmaceutical composition. For the
plasminogen activators mentioned by name, the skilled man can find
information as to formulations and dosages in the literature mentioned above.
D.3.1 ) Pharmaceutical formulation examples of component 2:
Formulations of component 2 are known in the prior art and may be obtained
commercially. Some commercially available formulations which may be used
according to the invention are mentioned below by way of example and as an
illustration.
Alteplase: (powder and solvent for preparing a solution for
injection/infusion)
Composition: Alteplase 10 mg/ 20 mg/ 50 mg/ 100 mg.
Other ingredients: Arginine, phosphoric acid, Polysorbate 80.
water for injections.
Tenecteplase: (powder and solvent for preparing an injectable solution)
Composition: Tenecteplase 8 000 U/ 10 000 U (40 mg/50 mg).
Other ingredients: Arginine, phosphoric acid, Polysorbate 20.
water for injections 8 ml/ 10 ml.
Reteplase: (powder and solvent for preparing an injectable solution)
Composition: Reteplase 0.56 g (corresponds to10 units).
Other ingredients: Tranexamic acid, potassium monohydrogen phosphate,
phosphoric acid, sucrose, polysorbate 80.
water for injections 10 ml.
Streptokinase: (Dry substance for a solution for infusion)
Composition: highly-purified streptokinase 250000 I.U./ 750000 I.U./
1500000 I.U. as dry substance.
Other ingredients: Human albumin, sodium-L-hydrogen glutamate
1 H20, Polygelin.
Streptokinase: (oral tablets)
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Composition: Streptokinase 10,000 I.U., Streptodornase 2500-
10,000 I.U.
Other ingredients: Magnesium stearate, calcium hydrogen phosphate,
maize starch, gum arabic.
Urokinase: (dry substance)
Composition: Urokinase 500,000 I.U.
Other ingredients: sodium monohydrogen phosphate, sodium
dihydrogen phosphate, human albumin.
Urokinase: (dry substance)
Composition: Urokinase (human) 500,000 I.U.
Other ingredients: sodium dihydrogen phosphate, sodium
monohydrogen phosphate, sodium chloride,
Dextran 40.
Anistreplase: (dry substance and solvent for i.v. injection)
Composition: 209-230 mg of dry substance with anistreplase
29.55-30.03 mg.
Other ingredients: 4-amidinophenyl (p-anisate)-HCI 0.15-0.17 mg,
dimethylsulphoxide 1-2 mg, aminocaproic acid 1.2-
1.6 mg, D-mannitol, human albumin, lysine-1 HCI,
sodium hydroxide, glycerol, water for injections.
