Note: Descriptions are shown in the official language in which they were submitted.
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Active substance combination
The present invention relates to an active substance combination comprising at
least
one substituted carbinol compound and at least one opioid, a medicament
comprising said active substance combination, a pharmaceutical formulation
comprising said active substance combination and the use of said active
substance
combination for the manufacture of a medicament.
Opioids such as morphine, which belong to the class of centrally acting
analgesics,
are key compounds for the treatment of moderate to very severe pain. However,
in
addition to their desired analgesic properties, these opioid analgesics show a
multifaceted spectrum of undesired side effects, when administered to the
patient in
need of treatment, ranging from unpleasant effects such as emesis, inhibition
of
gastrointestinal function, sedation or dizziness to severe, often life-
threatening effects
such as respiratory depression. Further problems associated with the
administration
of opioids are the development of tolerance, the risk of addiction as well as
the illicit
use of such substances.
WO 03/099268 discloses the use of an active substance combination comprising
at
least one compound selected from a group comprising among others opioids and
at
least one compound selected from a group comprising among others cizolirtine
for
the preparation of a drug for the treatment of urinary urgency or urinary
incontinence,
whereby said active substance combination is not to have an analgesic effect.
It was therefore an object of the present invention to provide a medicament
with
analgesic properties suitable for the treatment of moderate to very severe
pain, which
preferably does not show the undesired side effects of opioids, or at least
less
frequent and/or to a lesser extent.
It has now surprisingly been found that the pharmacological efficacy of
opioids is
enhanced by their administration in combination with one or more substituted
carbinol
compounds of general formula I given below. Consequently, the dose of the
opioid
analgesic may be reduced and fewer, less pronounced to none undesired side
effects occur.
CONFIRMATION COPY
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Thus, in one of its aspects the present invention relates to an active
substance
combination comprising
(A) at least one substituted carbinol compound of general formula I,
R~
X Y
O~ RZ
wherein
R~ represents a hydrogen atom, a linear or branched alkyl radical, a linear or
branched alkenyl radical, an optionally at least mono-substituted
cycloaliphatic
radical, which may contain at least one nitrogen atom as ring member, or a
phenyl
radical,
R2 represents a hydrogen atom, an optionally at least one nitrogen atom as
ring
member containing cycloaliphatic radical, which may be at least mono-
substituted by
a linear or branched alkyl radical and/or which may be bound via a linear or
branched
alkylene group, a NR3R4-moiety, which is bound via a linear or branched
alkylene
group, or a NR5R6-moiety, which is bound via a linear or branched alkylene
group,
R3 and R4, identical or different, represent a linear or branched alkyl
radical or an
unsubstituted benzyl radical,
R5 and R6 together with the bridging nitrogen atom represent a saturated,
unsubstituted, optionally at least one further heteroatom as ring member
containing
heterocyclic radical,
2
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X represents an optionally at least mono-substituted phenyl radical or an
optionally at
least mono-substituted thienyl radical, wherein in each case the substituents
are
selected from the group consisting of a linear or branched alkyl radical, a
linear or
branched alkoxy group, a linear or branched alkyl radical, which is at least
partially
halogenated or a halogen atom,
Y represents a heteroaryl radical, which contains one or more nitrogen atoms
as ring
members and which is unsubstituted or at least mono-substituted by one or more
substitutents independently from one another selected from the group
consisting of a
halogen atom, a linear or branched alkyl radical, an unsubstituted benzyl
radical, a
ciano group bound via a linear or branched C~_4-alkylene group, a carboxy
group
bound via a linear or branched C~_4-alkylene group, a methoxy carbonyl group
bound
via a linear or branched C~_4-alkylene group, a hydroxy group bound via a
linear or
branched C~_4-alkylene group, an amino group bound via a linear or branched
C~_4-
alkylene group, a (C~_4) dialkylamino group bound via a linear or branched
C~_4-
alkylene group and a cycloaliphatic radical, which contains one or more
nitrogen
atoms as ring members and which is bound via a linear or branched C~_4-
alkylene
group, or Y represents an unsubstituted heteroaryl radical, which contains two
nitrogen atoms as ring members and which is condensed with (annellated to) a
saturated, one methyl-substituted nitrogen atom as ring member containing
cycloaliphatic group,
optionally in form of one of its stereoisomers, preferably enantiomers or
diastereomers, its racemate or in form of a mixture of at least two of its
stereoisomers, preferably enantiomers and/or diastereomers, in any mixing
ratio, or a
corresponding salt, preferably a corresponding physiologically acceptable salt
thereof, or a corresponding solvate, and
(B) at least one opioid.
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C~_4-alkyl radical and/or which may be bound via a linear or branched C~_4-
alkyl
radical, a NR3R4-moiety, which is bound via a linear or branched C2_3 alkylene
group,
or a NR5R6-moiety, which is bound via a linear or branched C2_3 alkylene
group, and
the remaining substituents R~, R3-R6, X and Y have the meaning given above,
optionally in form of one of its stereoisomers, preferably enantiomers or
diastereomers, its racemate or in form of a mixture of at least two of its
stereoisomers, preferably enantiomers and/or diastereomers, in any mixing
ratio, or a
corresponding salt thereof, or a corresponding solvate.
In another preferred embodiment of the present invention the inventive active
substance combination comprises one or more substituted carbinol compounds of
general formula I given above, wherein R3 and R4, identical or different,
independently from one another represent a linear or branched C~_4 alkyl
radical or
an unsubstituted benzyl radical, preferably a linear or branched C~_4 alkyl
radical, and
the remaining substituents R~, R2, R5, R6, X and Y have the meaning given
above,
optionally in form of one of its stereoisomers, preferably enantiomers or
diastereomers, its racemate or in form of a mixture of at least two of its
stereoisomers, preferably enantiomers and/or diastereomers, in any mixing
ratio, or a
corresponding salt thereof, or a corresponding solvate.
Also preferred the active substance combination according to the present
invention
comprises one or more substituted carbinol compounds of general formula I
given
above, wherein R5 and R6 together with the bridging nitrogen atom represent a
saturated, unsubstituted, optionally at least one oxygen atom as ring member
containing, 5- or 6-membered heterocyclic radical, and the remaining
substituents R'-
R4, X and Y have the meaning given above, optionally in form of one of its
stereoisomers, preferably enantiomers or diastereomers, its racemate or in
form of a
mixture of at least two of its stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate.
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Also preferred the active substance combination according to the present
invention
comprises one or more substituted carbinol compounds of general formula I
given
above, wherein X represents an optionally at least mono-substituted phenyl
radical or
an optionally at least mono-substituted thienyl radical, wherein in each case
the
substituents are independently selected from the group consisting of a linear
or
branched C~_4 alkyl radical, a linear or branched C~_4 alkoxy radical, a
linear or
branched C~_4 alkyl radical, which is at least partially fluorinated, a
fluorine atom, a
chlorine atom and a bromine atom, preferably an optionally at least mono-
substituted
phenyl radical or an optionally at least mono-substituted thienyl radical,
wherein in
each case the substituents are independently selected from the group
consisting of a
methyl radical, a methoxy radical, a trifluoromethyl radical, a fluorine atom,
a chlorine
atom and a bromine atom, and the remaining substituents R~-R6 and Y have the
meaning given above, optionally in form of one of its stereoisomers,
preferably
enantiomers or diastereomers, its racemate or in form of a mixture of at least
two of
its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing
ratio,
or a corresponding salt thereof, or a corresponding solvate.
Also preferred the active substance combination according to the present
invention
comprises one or more substituted carbinol compounds of general formula I,
wherein
Y represents an azole radical selected from the group consisting of
a) a pyrazole of the general formula (a):
R8
N
'N
1 7
R
(a)
in which R7 represents a linear or branched C~-~2 alkyl radical, a benzyl
radical or a
radical of the type:
6
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N (CH2)n CHI
in which n = 1 or 2, and
R$ represents a hydrogen atom, a methyl radical or a halogen atom, preferably
a
hydrogen atom, a methyl radical, a bromine atom or a chlorine atom,
b) an imidazole of the general formula
N
N
9
R
(b)
in which R9 represents a hydrogen atom, a C~-~2 alkyl radical, a benzyl
radical or a
radical of the general formula (b1 ):
R~°_(CH2)n_
(b1)
in which n is 2, 3 or 4 and R'° represents a piperidinyl radical, a
phenyl radical, a
cyano group, a hydroxyl radical, a carboxy radical, an amino group, a
dimethylamino
group or a methyl ester group,
and
an imidazole of the following formula:
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IV
~N
N\
H3C~
and the remaining substituents R~-R6 and ?C have the meaning given above,
optionally in form of one of its stereoisomers, preferably enantiomers or
diastereomers, its racemate or in form of a mixture of at least two of its
stereoisomers, preferably enantiomers and/or diastereomers, in any mixing
ratio, or a
corresponding salt thereof, or a corresponding solvate.
In a more preferred embodiment of the present invention the inventive active
substance combination comprises one or more substituted carbinol compounds of
general formula I given above, wherein
R~ represents a hydrogen atom; a linear or branched C~_4 alkyl radical; a
linear or
branched C2_4 alkenyl radical; a 5-or 6-membered cycloaliphatic radical, which
may
contain 1 or 2 nitrogen atoms as ring members) and/or which may be substituted
by
1, 2, 3 or 4 linear or branched C~_4 alkyl radicals that may be identical or
different; or
a phenyl radical;
R2 represents a hydrogen atom; an optionally 1, 2 or 3 nitrogen atoms) as ring
members) containing, 5- or 6-membered cycloaliphatic radical, which may be
substituted by 1, 2, 3 or 4 linear or branched C~_4-alkyl radical that may be
identical or
different and/or which may be bound via a linear or branched C~_4-alkyl
radical; a
NR3R4-moiety, which is bound via a linear or branched C~_4 alkylene group; or
a
NR5R6-moiety, which is bound via a linear or branched C~_4 alkylene group;
R3 and R~, identical or different, independently from one another represent a
linear or
branched C~_4 alkyl radical; or an unsubstituted benzyl radical;
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R5 and R6 together with the bridging nitrogen atom represent a saturated,
unsubstituted, optionally one oxygen atom as ring member containing, 5- or 6-
membered heterocyclic radicals
X represents a phenyl radical, which may be substituted with 1, 2, 3, 4 or 5
substituents or a thienyl radical, which may be substituted with 1, 2 or 3
substituents,
wherein in each case the substituents may be independently selected from the
group
consisting of a linear or branched C~_4 alkyl radical, a linear or branched
C~_4 alkoxy
radical, a linear or branched C~_4 alkyl radical, which is at least partially
fluorinated, a
fluorine atom, a chlorine atom and a bromine atom; and
Y represents an azole radical selected from the group consisting of
a) a pyrazole of the general formula (a):
R8
N~
N
R
(a)
in which R' represents a linear or branched C~-~2 alkyl radical, a benzyl
radical or a
radical of the type:
N (CH2)n CH2
in which n = 1 or 2, and
R$ represents a hydrogen atom, a methyl radical or a halogen atom, preferably
a
hydrogen atom, a methyl radical, a bromine atom or a chlorine atom,
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b) an imidazole of the general formula
N
N
9
R
(b)
in which R9 represents a hydrogen atom, a C~-~2 alkyl radical, a benzyl
radical or a
radical of the general formula (b1 ):
R~°_(CH2)~_
(b1)
in which n is 2, 3 or 4 and R~° represents a piperidinyl radical, a
phenyl radical, a
cyano group, a hydroxyl radical, a carboxy radical, an amino group, a
dimethylamino
group or a methyl ester group,
and
an imidazole of the following formula:
N
'N
N
H3C~
optionally in form of one of its stereoisomers, preferably enantiomers or
diastereomers, its racemate or in form of a mixture of at least two of its
stereoisomers, preferably enantiomers and/or diastereomers, in any mixing
ratio, or a
corresponding salt thereof, or a corresponding solvate.
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In an even more preferred embodiment of the present invention the inventive
active
substance combination comprises one or more substituted carbinol compounds of
general formula I given above, wherein
R~ represents a hydrogen atom; a linear or branched C~_4 alkyl radical; a
vinyl group;
a cyclohexyl radical; an N-Methyl-piperidyl radical; or a phenyl radical;
R2 represents a hydrogen atom; an optionally 1, 2 or 3 nitrogen atoms) as ring
members) containing, 5- or 6-membered cycloaliphatic radical, which may be
substituted by 1, 2, 3 or 4 linear or branched C~_4-alkyl radicals that may be
identical
or different and/or which may be bound via a linear or branched C~_4-alkyl
radical; a
NR3R4-moiety, which is bound via a linear or branched C~_4 alkylene group; or
a
NR5R6-moiety, which is bound via a linear or branched C~_4 alkylene group;
R3 and R4, identical or different, independently from one another represent a
linear or
branched C~_4 alkyl radical;
R5 and R6 together with the bridging nitrogen atom represent a saturated,
unsubstituted, optionally one oxygen atom as ring member containing, 5- or 6-
membered heterocyclic radical;
X represents a phenyl radical that may be substituted with 1, 2, 3, 4 or 5
substituents
or a thienyl radical that may be substituted with 1, 2 or 3 substituents,
wherein in
each case the substituents may be independently selected from the group
consisting
of a methyl radical, a methoxy radical, a trifluoromethyl radical, a fluorine
atom, a
chlorine atom and a bromine atom;
Y represents an azole radical selected from the group consisting of
a) a pyrazole of the general formula (a):
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R8
N
~N
R
(a)
in which R' represents a linear or branched C~-~2 alkyl radical, a benzyl
radical or a
radical of the type:
N (CH~)n GHQ
in which n = 1 or 2, and
R$ represents a hydrogen atom, a methyl radical or a halogen atom, preferably
a
hydrogen atom, a methyl radical, a bromine atom or a chlorine atom,
b) an imidazole of the general formula
N
a
N
9
R
(b)
in which R9 represents a hydrogen atom, a C~-~~ alkyl radical, a benzyl
radical or a
radical of the general formula (b1 ):
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R~°-(CH2)n-
(b1)
in which n is 2, 3 or 4 and R~° represents a piperidinyl radical, a
phenyl radical, a
cyano group, a hydroxyl radical, a carboxy radical, an amino group, a
dimethylamino
group or a methyl ester group,
and
an imidazole of the following formula:
N
'N
N
H3C~
optionally in form of one of its stereoisomers, preferably enantiomers or
diastereomers, its racemate or in form of a mixture of at least two of its
stereoisomers, preferably enantiomers and/or diastereomers, in any mixing
ratio, or a
corresponding salt thereof, or a corresponding solvate.
In yet a more particularly preferred embodiment of the present invention the
inventive
active substance combination comprises one or more substituted carbinol
compounds of general formula I
R~
X Y
~~ R2
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wherein
R~ represents a hydrogen atom, a methyl radical, an ethyl radical, an n-propyl
radical,
an iso-propyl radical, a sec-butyl radical, a tent-butyl radical, an n-butyl
radical, a vinyl
radical, a cyclohexyl radical, an N-methyl-piperidinyl group, or a phenyl
group,
R2 represents a hydrogen atom, a dimethylaminoethyl group, a pyrrolidinylethyl
group, a piperidinylethyl group, a methyl-benzyl-aminoethyl group, a
morpholinylethyl
group, a diisopropylaminoethyl group, a dimethylaminopropyl group, a
piperidinylpropyl group, a pyrrolidinylpropyl group, a morpholinylpropyl
group, an N-
methyl-2-piperidyl group, an N-ethyl-2-piperidyl group, an N-propyl-2-
piperidyl group,
an N-methyl-2-pyrrolidinyl group, an N-ethyl-2-pyrrolidinyl group, an N-propyl-
2-
pyrrolidinyl group, or a 2-dimethylaminoethyl-1-methyl group,
X represents a phenyl radical, a 2-methyl-phenyl radical, a 3-methyl-phenyl
radical, a
4-methyl phenyl radical, a 2-chloro-phenyl radical, a 3-chloro-phenyl radical,
a 4-
chloro-phenyl radical, a 2-fluoro-phenyl radical, a 3-fluoro-phenyl radical, a
4-fluoro-
phenyl radical, a 2-trifluoromethyl-phenyl radical, a 3-trifluoromethyl-phenyl
radical, a
4-trifluoromethyl-phenyl radical, a 2-methoxy-phenyl radical, a 3-methoxy-
phenyl
radical, a 4-methoxy-phenyl radical, a 3,4,5-tris-methoxy-phenyl radical, a
3,4-
dichloro-phenyl radical, a 2,4-dichloro-phenylradical, a thien-2-yl radical, a
thien-3-yl
radical, a 3-methyl-thien-2-yl radical, a 5-methyl-thien-2-yl-radical, a 5-
bromo-thien-2-
yl radical or a 4-bromo-thien-2-yl-radical,
Y represents an azole radical selected from the group consisting of
a) a pyrazole of the general formula (a);
R~
N
~N
R
(a)
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In WIlICh
R' represents a methyl radical, an ethyl radical, an n-propyl radical, an iso-
propyl
radical, an n-butyl radical, a sec-butyl radical or a tert-butyl radical,
R$ represents a hydrogen atom, a methyl radical, a bromine atom or a chlorine
atom,
b) an imidazole of the general formula
N
N
9
R
(b)
in which R9 represents a hydrogen atom, a methyl radical, an ethyl radical, an
n-
propyl radical, an iso-butyl radical, an n-butyl radical, a sec-butyl radical
a tent-butyl
radical, an n-pentyl radical, an n-hexyl radical, an n-heptyl radical, an n-
octyl radical,
an n-nonyl radical, an n-decyl radical, an n-undecyl radical an n-dodecyl
radical, a
benzyl radical, or a radical of the general formula (b1 ):
R~0-(~H2)n_
(b1)
in which n is 2, 3 or 4 and R~° represents a piperidinyl radical, a
phenyl radical, a
cyano group, a hydroxyl radical, a carboxy radical, an amino group, a
dimethylam ino
group, or a methyl ester group,
and
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(c) an imidazole of the following formula:
N
'N
N
H3C~
In a most particularly preferred embodiment of the present invention the
inventive
active substance combination comprises one or more substituted carbinol
compounds selected from the group consisting of:
[1] 2-~a-[2-(dimethylamino)ethoxy]benzyl}-1-methyl-1H-imidazole,
[2] 2-{4-chloro-a-[2-(dimethylamino)ethoxy]-a-methylbenzyl}-1-methyl-1 H-
imidazole,
[3] 2-{4-chloro-a-[2-(dimethylamino)ethoxy]benzyl}-1-methyl-1H-imidazole,
[4] 2-~3-chloro-a-[2-(dimethylamino)ethoxy]benzyl}-1-methyl-1H-imidazole
[5] 2-~4-chloro-a-[2-(dimethylamino)ethoxy]-a-methylbenzyl)-1-methyl-1H-
imidazole,
[6] 2-~4-fluoro-a-[2-(dimethylamino)ethoxy]-a-methylbenzyl}-1-methyl-1H-
imidazole,
[7] 2-~a-[2-(dimethylamino)ethoxy]-a-methyl-3-(trifluoromethyl)benzyl}-1-
methyl-
1 H-imidazole,
[~] 2-{3-chloro-a-[2-(dimethylamino)ethoxy]-a-methylbenzyl}-1-methyl-1H-
imidazole,
[9] 2-{3-chloro-a-[2-(dimethylamino)ethoxy]-a-propylbenzyl}-1-methyl-1H-
imidazole,
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[10] 1-butyl-2-~4-chloro-a-[2-(dimethylamino)ethoxy]-a-methylbenzyl~-1H-
imidazole,
[11 ] 2-{a-[2-(dimethylamino)ethoxy]-a-methyl-4-methoxybenzyl}-1-methyl-1 H-
imidazole,
[12] 2-~3-chloro-a-methyl-a-[2-(N-pyrrolidinyl)ethoxy]benzyl}-1-methyl-1H-
imidazole,
[13] 2-{a-[2-(dimethylamino)ethoxy]-a-propyl-3,4,5-trimethoxybenzyl}-1-dodecyl-
1 H-imidazole,
[14] 1-butyl-2-~a-[2-(dimethylamino)ethoxy]-4-(trifluorornethyl)benzyl~-1H-
imidazole,
[15] 1-methyl-2-~a-methyl-a-[2-(N-piperidyl)ethoxy]-3-(trifluoromethyl)benzyl~-
1H-
imidazole,
[16] 2-{a-cyclohexyl-3,4-dichloro-a-[2-(dimethylamino)ethoxy]benzyl~-1-methyl-
1 H-
imidazole,
[17] 2-{3,4-dichloro-a-[2-(dimethylamino)ethoxy]-a-pro pylbenzyl~-1-methyl-1 H-
imidazole,
[18] 2-{3,4-dichloro-a-[2-(dimethylamino)ethoxy]-a-methylbenzyl~-1-methyl-1H-
imidazole,
[19] 2-(3,4-dichloro-a-[2-(dimethylamino)ethoxy]benzyl~-1-methyl-1H-imidazole,
[20] 2-{4-chloro-a-[2-(dimethylamino)ethoxy]-a-methylbenzyl}-1-[2-(N-
piperidyl)ethyl]-1 H-imidazole,
[21 ] 2-{4-chloro-a-[2-(dimethylamino)ethoxy]-a-methyl benzyl}-1-[2-(N-
piperidyl)propyl]-1 H-imidazole,
[22] 1-(3-cyanopropyl)-2-{4-chloro-a-[2-(dimethylamino)ethoxy]benzyl}-1H-
imidazole,
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[23] 2-{4-chloro-a-[2-(dimethylamino)ethoxy]-a-(N-methyl-4-piperidyl)benzyl}-1-
methyl-1 H-imidazole,
[24] 1-benzyl-2-{a-[2-(N-benzyl-N-methylamino)ethoxy]-4-chlorobenzyl~-1H-
imidazole,
[25] 2-~4-chloro-a-[2-(dimethylamino)ethoxy]-a-methylbenzyl}-7-methyl-6,7,8,9-
tetrahydro-1 H-imidazole[1,5-a][1,4]diazepine,
[26] 2-~4-chloro-a-[2-(dimethylamino)ethoxy]benzyl}-7-m ethyl-6,7,8,9-
tetrahydro-
1 H-imidazole[1,5-a][1,4]diazepine,
[27] 1-butyl-5-{a-[2-(dimethylamino)ethoxy]benzyl~-1H-pyrazole,
[28] 5-{a-(4-chlorophenyl)-a-[2-(dimethylamino)ethoxy]benzyl~-1-methyl-1H-
pyrazole,
[29] 1-butyl-5-(a-[2-(dimethylamino)ethoxy]-3,4,5-trimethoxybenzyl~-1H-
pyrazole,
[30] 1-butyl-5-{4-chloro-a-[2-(dimethylamino)ethoxy]-a-methylbenzyl}-1H-
pyrazole,
[31] 5-~a-[2-(dimethylamino)ethoxy]-a-methylbenzyl}-1-methyl-1H-pyrazole,
[32] 5-{a-[2-(dimethylamino)ethoxy]-3,4,5-trimethoxybenzyl}-1-methyl-1H-
pyrazole,
[33] 1-methyl-5-~a-[2-(N-pyrrolidinyl)ethoxy]benzyl}-1H-pyrazole,
[34] 1-methyl-5-~a-[2-(N-morpholinyl)ethoxy]benzyl}-1 H-pyrazole,
[35] 5-{a-[2-(dimethylamino)ethoxy]-a-methyl-3,4,5-trimethoxybenzyl}-1-methyl-
1H-
pyrazole,
[36] 4-bromo-5-~a-[2-(dimethylamino)ethoxy]benzyl~-1-methyl-1H-pyrazo1e,
[37] 1,3-dimethyl-5-{a-[2-(dimethylamino)ethoxy]-a-meth ylbenzyl}-1 H-
pyrazole,
[38] 1,3-dimethyl-5-{a-[2-(dimethylamino)ethoxy]benzyl}-1H-pyrazole,
[39] 5-{a-[2-(dimethylamino)ethoxy]-2-methylbenzyl}-1-rr~ethyl-1H-pyrazole,
[40] 4-chloro-5-{4-chloro-a-[2-(dimethylamino)ethoxy]benzyl}-1-methyl-1H-
pyrazole,
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[41] 5-{4-chloro-a-[2-(dimethylamino)ethoxy]benzyl)-1-methyl-1H-pyrazole,
[42] 5-~3-chloro-a-[2-(dimethylamino)ethoxy]benzyl)-1-methyl-1H-pyrazole,
[43] 5-{a-[2-(dimethylamino)ethoxy]-4-methylbenzyl}-1-methyl-1H-pyrazole,
[44] 5-{2-chloro-a-[2-(dimethylamino)ethoxy]benzyl}-1-methyl-1H-pyrazole,
[45] 1-methyl-5-(a-[2-(N-piperidyl)ethoxy]benzyl~-1H-pyrazole,
[46] 1-methyl-5-{a-[2-(N-propyl-2-piperidyl)ethoxy]benzyl}-1H-pyrazole,
[47] 5-{a-[2-(N-ethyl-2-piperidyl)ethoxy]benzyl}-1-methyl-1H-pyrazole,
[48] 1-methyl-5-~a-[2-(N-methyl-2-pyrrolidinyl)ethoxy]benzyl}-1H-pyrazole,
[49] 5-{a-[2-(diisopropylamino)ethoxy]benzyl)-1-methyl-1H-pyrazole,
[50] 1-methyl-5-{a-[2-(N-methyl-2-piperidyl)ethoxy]benzyl}-1H-pyrazole,
[51 ] 2-{4-chloro-a-[3-(dimethylamino)propoxy]-a-methylbenzyl}-1-methyl-1 H-
imidazole,
[52] 2-(3-chloro-a-[3-(dimethylamino)propoxy]benzyl}-1-methyl-1H-imidazole
[53] 2-(4-chloro-a-[3-(dimethylamino)propoxy]-a-ethylbenzyl)-1-methyl-1 H-
imidazole,
[54] 2-{a-butyl-3-chloro-a-[3-(dimethylamino)propoxy]benzyl)-1-methyl-1 H-
imidazole,
[55] 2-(a-cyclohexyl-4-chloro-a-[3-(dimethylamino)propoxy]benzyl)-1-m ethyl-1
H-
imidazole,
[56] 2-{a-[3-(dimethylamino)propoxy]-4-fluoro-a-methylbenzyl}-1-methyl-1H-
imidazole,
[57] 2-fa-[3-(dimethylamino)propoxy]-a-methyl-3-(trifluoromethyl)benzyl}-1-
methyl-
1 H-imidazole,
[58] 2-(2-chloro-a-[3-(dimethylamino)propoxy]-a-methylbenzyl)-1-methyl-1 H-
imidazole,
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[59] 2-~3-chloro-a-[3-(dimethylamino)propoxy]-a-methylbenzyl}-1-methyl-1 H-
imidazole,
[60] 2-{a-[3-(dimethylamino)propoxy]-a-methyl-3,4,5-trimethoxybenzyl}-1-methyl-
1 H-imidazole,
[61 ] 2-{a-[3-(dimethylamino)propoxy]-a-methyl-4-methoxybenzyl}-1-methyl-1 H-
imidazole,
[62] 2-{4-chloro-a-[3-(dimethylamino)propoxy]benzyl}-1-methyl-1H-imidazole,
[63] 2-{a-[3-(dimethylamino)propoxy]-3,4,5-trimethoxybenzyl}-1-methyl-1H-
imidazole,
[64] 2-{a-[3-(dimethylamino)propoxy]-a-methyl-4-(trifluoromethyl)benzyl}-1-
methyl-
1 H-imidazole,
[65] 2-{a-[3-(dimethylamino)propoxy]-3-(trifluoromethyl)benzyl}-1-methyl-1H-
imidazole,
[66] 2-{a-[3-(dimethylamino)propoxy]-4-(trifluoromethyl)benzyl}-1-methyl-1 H-
imidazole,
[67] 2-~a-[3-(dimethylamino)propoxy]-4-methoxybenzyl}-1-methyl-1 H-imidazole,
[68] 2-{a-butyl-a-[3-(dimethylamino)propoxy]-3-(trifluoromethyl)benzyl}-1-
methyl-
1 H-imidazole,
[69] 1-butyl-2-{4-chloro-a-[3-(dimethylamino)propoxy]-a-methylbenzyl}-1H-
imidazole,
[70] 1-butyl-2-~a-butyl-a-[3-(dimethylamino)propoxy]-3,4,5-trimethoxybenzyl}-
1H-
imidazole,
[71] 1-butyl-2-~a-butyl-2-chloro-a-[3-(dimethylamino)propoxy]benzyl}-1H-
imidazole,
[72] 1-butyl-2-{a-butyl-2,4-dichloro-a-[3-(dimethylamino)propoxy]benzyl}-1H-
imidazole,
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[73] 1-butyl-2-~a-[3-(dimethylamino)propoxy]-4-(trifluoromethyl)benzy1}-1H-
imidazole,
[74] 2-{4-chloro-a-[3-(N-piperidyl)propoxy]benzyl}-1-methyl-1H-imidazole,
[75] 1-methyl-2-~a-methyl-a-[3-(N-piperidyl)propoxy]-4-
(trifluoromethyl)benzyl}-1 H-
imidazole,
[76] 2-{a-butyl-2-chloro-a-[3-(dimethylamino)propoxy]benzyl}-1-methyl-1 H-
imidazole,
[77] 2-{a-butyl-3,4-dichloro-a-[3-(dimethylamino)propoxy]benzyl)-1-methyl-1H-
imidazole,
[78] 2-{3,4-dichloro-a-[3-(dimethylamino)propoxy]-a-methylbenzyl~-1-methyl-1H-
imidazole,
[79] 2-{3,4-dichloro-a-[3-(dimethylamino)propoxy]benzyl}-1-methyl-1H-
imidazole,
[80] 2-~a-cyclohexyl-3,4-dichloro-a-[3-(dimethylamino)propoxy]benzyl}-1-methyl-
1 H-imidazole,
[81] 2-~4-chloro-a-[3-(dimethylamino)propoxy]-a-methylbenzyl}-a-[2-(N-
piperidyl)
ethyl]-1 H-imidazole,
[82] 2-~4-chloro-a-[3-(dimethylamino)propoxy]-a-methylbenzyl~-1-[2-(N-
piperidyl)
propyl]-1 H-imidazole,
[83] 2-{4-chloro-a-[3-(dimethylamino)propoxy]-a-(N-methyl-4-piperidyl)benzyl}-
1-
methyl-1 H-imidazole,
[84] 1-butyl-5-{a-[3-(dimethylamino)propoxy]benzyl~-1H-pyrazole,
[85] 1-butyl-5-{4-chloro-a-[3-(dimethylamino)propoxy]-a-methylbenzyl~-1H-
pyrazole,
[86] 5-{a-[3-(dimethylamino)propoxy]benzyl~-1-methyl-1H-pyrazole,
[87] 5-{a-[3-(dimethylamino)propoxy]-a-methylbenzyl~-1-methyl-1H-pyrazole,
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[88] 1,3-dimethyl-5-~a-[3-(dimethylamino)propoxy]-a-methylbenzyl}-1H-pyrazole,
[89] 1,3-dimethyl-5-~a-[3-(dimethylamino)propoxy]benzyl}-1H-pyrazole,
[90] 5-~a-[3-(dimethylamino)propoxy]-2-methylbenzyl}-1-methyl-1H-pyrazole,
[91] 5-chloro-5-{4-chloro-a-[3-(dimethylamino)propoxy]benzyl~-1-methyl-1H-
pyrazole,
[92] 1-methyl-5-{a-[3-(N-piperidyl)propoxy]benzyl}-1 H-pyrazole,
[93] 1-methyl-5-{a-[3-(N-pyrrolidinyl)propoxy]benzyl)-1H-pyrazole,
[94] 4-{4-chloro-a-[2-(dimethylamino)ethoxy]benzyl}-1-methyl-1H-pyrazole,
[95] 4-{4-chloro-a-[2-(dimethylamino)ethoxy]-a-methylbenzyl}-1-methyl-1H-
pyrazole,
[96] 4-{4-chloro-a-[2-(N-propyl-2-piperidyl)ethoxy]benzyl}-1-methyl-1 H-
pyrazole,
[97] 4-~4-chloro-a-[2-(N-methyl-2-piperidyl)ethoxy]benzylj~-1-methyl-1 H-
pyrazole,
[98] 4-~4-chloro-a-[2-(N-ethyl-2-piperidyl)ethoxy]benzyl}-1-methyl-1 H-
pyrazole,
[99] 4-{4-chloro-a-[2-(diisopropylamino)ethoxy]benzyl~-1-methyl-1H-pyrazole,
[100] 4-~4-chloro-a-[2-(N-methyl-2-pyrrolidinyl)ethoxy]benzyl~-1-methyl-1H-
pyrazole,
[101] 4-~a-[3-(dimethylamino)propoxy]benzyl}-1-methyl-1H-pyrazole,
[102] 4-{4-chloro-a-[3-(N-morpholinyl)propoxy]benzyl~-1-methyl-1H-pyrazole,
[103] 4-~4-chloro-a-[3-(N-pyrrolidinyl)propoxy]benzyl}-1-methyl-1H-pyrazole,
[104] 2-(a-hydroxybenzyl)-1 H-imidazole,
[105] 2-(4-chloro-a-hydroxybenzyl)-1 H-imidazole,
[106] 2-(4-chloro-a-hydroxybenzyl)-1-methyl-1H-imidazole,
[107] 2-(3-chloro-a-hydroxybenzyl)-1-methyl-1H-imidazole,
[108] 2-(4-fluoro-a-hydroxybenzyl)-1-methyl-1H-imidazole,
[109] 2-[a-hydroxy-3-(trifluoromethyl)benzyl]-1-methyl-1 H-imidazole,
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[110] 2-[a-hydroxy-4-(trifluoromethyl)benzyl]-1-methyl-1H-imidazole,
[111 ] 2-(a-hydroxy-3,4,5-trimethoxybenzyl)-1-methyl-1 H-imidazole,
[112] 2-(3,4-dichloro-a-hydroxybenzyl)-1-methyl-1H-imidazole,
[113] 1-butyl-2-[a-hydroxy-4-(trifluoromethyl)benzyl]-1H-imidazole,
[114] 1-butyl-2-(3,4-dichloro-a-hydroxybenzyl)-1H-imidazole,
[115] 1-butyl-2-(4-chloro-a-hydroxybenzyl)-1H-imidazole,
[116] 1-butyl-2-(a-hydroxy-3,4,5-trimethoxybenzyl)-1H-imidazole,
[117] 1-dodecyl-2-(a-hydroxy-3,4,5-trimethoxybenzyl)-1H-imidazole,
[118] 2-(a-butyl-3-chloro-a-hydroxybenzyl)-1-methyl-1H-imidazole,
[119] 2-(3-chloro-a-hydroxy-a-methylbenzyl)-1-methyl-1H-imidazole,
[120] 2-(4-chloro-a -hydroxy-a-methylbenzyl)-1-methyl-1 H-imidazole,
[121] 2-[4-chloro-a-hydroxy-a-(N-methyl-4-piperidyl)benzyl]-1-methyl-1H-
imidazole,
[122] 2-(4-chloro-a-ethyl-a-hydroxybenzyl)-1-methyl-1H-imidazole,
[123] 2-(a-butyl-4-chloro-a-hydroxybenzyl)-1-methyl-1H-imidazole,
[124] 2-(a-cyclohexyl-4-chloro-a-hydroxybenzyl)-1-methyl-1H-imidazole,
[125] 2-(2-chloro-a-hydroxy-a-methylbenzyl)-1-methyl-1H-imidazole,
[126] 2-(a -butyl-2-chloro-a-hydroxybenzyl)-1-methyl-1 H-imidazole,
[127] 2-[a-hydroxy-a-methyl-3-(trifluoromethyl)benzyl]-1-methyl-1H-imidazole,
[128] 2-[a-butyl-a-hydroxy-3-(trifluoromethyl)benzyl]-1-methyl-1H-imidazole
[129] 2-[a-cyclohexyl-.a-hydroxy-3-(trifluoromethyl)benzyl]-1-methyl-1H-
imidazole,
[130] 2-[a-hydroxy-a-methyl-4-(trifluoromethyl)benzyl]-1-methyl-1H-imidazole,
[131] 2-(4-fluoro-a-hydroxy-a-methylbenzyl)-1-methyl-1H-imidazole,
[132] 2-(a-hydroxy-a-methyl-4-methoxybenzyl)-1-methyl-1H-imidazole,
[133] 2-(3,4-dichloro-a-hydroxy-a-methylbenzyl)-1-methyl-1 H-imidazole,
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[134] 2-(a-butyl-3,4-dichloro-a-hydroxybenzyl)-1-methyl-1H-imidazole,
[135] 2-(a-cyclohexyl-3,4-dichloro-a-hydroxybenzyl)-1-methyl-1H-imidazole,
[136] 2-(a -hydroxy-a-methyl-3,4,5-trimethoxybenzyl)-1-methyl-1 H-imidazole,
[137] 1-butyl-2-(4-chloro-a-hydroxy-a-methylbenzyl)-1H-imidazole,
[138] 1-butyl-2-(a-butyl-4-chloro-a-hydroxybenzyl]-1H-imidazole,
[139] 1-butyl-2-[4-chloro-a-hydroxy-a-(N-methyl-4-piperidyl)benzyl]-1H-
imidazole,
[140] 1-butyl-2-(a-butyl-a-hydroxy-3,4,5-trimethoxybenzyl)-1H-imidazole,
[141 ] 1-butyl-2-(a-butyl-2-chloro-a-hydroxybenzyl)-1 H-imidazole,
-[142] -1-butyl-2-[a-ethyl-a-hydroxy-3-(trifluoromethyl)benzyl]-1 H-imidazole,
[143] 1-butyl-2-(a-butyl-2,4-dichloro-a-hydroxybenzyl)-1H-imidazole,
[144] 2-(4-chloro-a-hydroxy-a-methylbenzyl)-1-[2-(N-piperidyl)ethyl]-1H-
imidazole,
[145] 2-(4-chloro-a-hydroxy-a-methylbenzyl)-1-(3-dimethylaminopropyl)-1H-
imidazole,
[146] 2-(a-butyl-a-hydroxy-3,4,5-trimethoxybenzyl)-1-dodecyl-1H-imidazole,
[147] 1-benzyl-2-[a-butyl-a-hydroxy-3-(trifluoromethyl)benzyl]-1H-imidazole,
[148] 1-benzyl-2-(4-chloro-a-hydroxy-a-methylbenzyl)-1H-imidazole,
[149] 1-(2-cyanoethyl)-2-(4-chloro-a-hydroxybenzyl)-1H-imidazole,
[150] 1-(3-aminopropyl)-2-(4-chloro-a-hydroxybenzyl)-1H-imidazole,
[151 ] 3-[2-(3-chloro-a-hydroxybenzyl)-1 H-imidazole-1-yl]propanoic acid
[152] 2-(4-chloro-a-hydroxybenzyl)-1-(3-hydroxypropyl)-1H-imidazole,
[153] 3-[2-(3-chloro-a-hydroxybenzyl)-1H-imidazole-1-yl]methyl-propanoate
[154] 2-(a-hydroxybenzyl)-1-(3-hydroxypropyl)-1H-imidazole,
[155] 2-(a-hydroxy-4-methylbenzyl)-1-(3-hydroxypropyl)-1H-imidazole,
[156] 2-(a-hydroxy-4-methoxybenzyl)-1-(3-hydroxypropyl)-1H-imidazole,
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[157] 2-(3,4-dichloro-a-hydroxybenzyl)-1-(3-hydroxypropyl)-1H-imidazole,
[158] 3-(2-(a-hydroxybenzyl)-1H-imidazole-1-yll}-methyl propanoate
[159] 2-(4-chloro-a-hydroxybenzyl)-1-(4-hydroxybutyl)-1H-imidazole,
[160] 1-(3-cyanopropyl)-2-(4-chloro-a-hydroxybenzyl)-1 H-imidazole,
[161] 4-[2-(4-chloro-a-hydroxybenzyl)-1H-imidazole-1-yl]butanoicacid,
[162] 4-[2-(4-chloro-a-hydroxybenzyl)-1H-imidazole-1-yl]-methyl butanoate,
[163] 1-butyl-5-(a-hydroxybenzyl)-1H-pyrazole,
[164] 5-(4-chloro-a-hydroxybenzyl)-1-methyl-1H-pyrazole,
[165] 5-(a-hydroxy-3;4,5-trimethoxybenzyl)-1-methyl-1H-pyrazole,
[166] 1-butyl-5-(a-hydroxy-3,4,5-trimethoxybenzyl)-1H-pyrazole,
[167] 4-bromo-5-(a-hydroxybenzyl)-1-methyl-1H-pyrazole,
[168] 5-[a-(4-chlorophenyl)-a-hydroxybenzyl]-1-methyl-1H-pyrazole,
[169] 1-butyl-5-(4-chloro-a-hydroxy-a-methylbenzyl)-1 H-pyrazole,
[170] 5-(oc-hydroxy-a-methylbenzyl)-1-methyl-1H-pyrazole,
[171] 5-(a-hydroxy-a-methyl-3,4,5-trimethoxybenzyl)-1-methyl-1H-pyrazo1e,
[172] 1,3-dimethyl-5-(a-hydroxy-a-methylbenzyl)-1H-pyrazole,
[173] 1-butyl-5-(a-hydroxy-a-vinylbenzyl)-1H-pyrazole,
[174] 1-butyl-5-(4-chloro-a-hydroxy-a-vinylbenzyl)-1H-pyrazole,
[175] 4-chloro-5-(a-hydroxybenzyl)-1-methyl-1H-pyrazole,
[176] 5-(oc-hydroxy-2-methylbenzyl)-1-methyl-1H-pyrazole,
[177] 5-(3-chloro-a-hydroxybenzyl)-1-methyl-1H-pyrazole,
[178] 5-(a-hydroxy-4-methylbenzyl)-1-methyl-1H-pyrazole,
[179] 5-(2-chloro-a-hydroxybenzyl)-1-methyl-1H-pyrazole,
[180] 5-(oc-hydroxy-4-methoxybenzyl)-1-methyl-1H-pyrazole,
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[181] 5-{a-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazole,
[182] 5-~a-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazole
citrate,
[183] 5-{a-[2-(dimethylamino)ethoxy]-3-thienylmethyl}-1-methyl-1H-pyrazole,
[184] 2-~a-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-imidazole,
[185] 5-{a-[2-(dimethylamino)ethoxy]-3-methyl-2-thienylmethyl}-1-methyl-1H-
pyrazole,
[186] 5-{a-[2-(dimethylamino)ethoxy]-5-methyl-2-thienylmethyl]~-1-methyl-1H-
pyrazole,
[187] 5~{5-bromo-oc-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-
pyrazole,
[188] 5-{4-bromo-oc-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-
pyrazole,
[189] 5-{a-[2-(dimethylamino)ethoxy]-a-methyl-2-thienylmethyl}-1-methyl-1H-
pyrazole,
[190] (~)-5-{a-[2-(dimethylamino)-1-(methyl)ethoxy]benzyl}-1-methyl-1H-
pyrazole,
[191] (~)-5-{a-[2-(dimethylamino)-1-(methyl)ethoxy]benzyl}-1-methyl-1H-
pyrazole,
[192] (+)-5-{a-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-
pyrazole,
[193] (-)-5-{a-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-
pyrazole,
[194] (+)-5-{a-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazole
citrate,
[195] (-)-5-{a-[2-(dimethylamino)ethoxy]-2-thienylmethyl~-1-methyl-1H-pyrazole
citrate,
[196] (+)-5-{a-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazole-
D-
ditoluyltartrat,
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[197] (-)-5-{oc-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-
pyrazole D-
ditoluyltartrat,
[198] 5-(a,-hydroxy-2-thienylmethyl)-1-methyl-1H-pyrazole,
[199] 5-(a-hydroxy-3-methyl-2-thienylmethyl)-1-methyl-1H-pyrazole,
[200] 5-(a-hydroxy-5-methyl-2-thienylmethyl)-1-methyl-1 H-pyrazole,
[201] 5-(5-bromo-a-hydroxy-2-thienylmethyl)-1-methyl-1H-pyrazole,
[202] 5-(4-bromo-a-hydroxy-2-thienylmethyl)-1-methyl-1 H-pyrazole,
[203] 5-(a-hydroxy-a-methyl-2-thienylmethyl)-1-methyl-1H-pyrazole,
[204] 5~~a-(2-(dimethylam.ino_)ethoxy]benzyl}-1-methyl-1H-pyrazole,
[205] 5-{a-[2-(dimethylamino)ethoxy]benzyl}-1-methyl-1H-pyrazole citrate,
[206] (+)-5-{a-[2-(dimethylamino)ethoxy]benzyl}-1-methyl-1H-pyrazole citrate
and
[207] (-)-5-{a,-[2-(dimethylamino)ethoxy]benzyl~-1-methyl-1H-pyrazole citrate,
as component (A).
Preferably the compounds [204], [205], (206] and [207] may be excluded from
the
afore mentioned group of compounds as component (A).
The preparation of the substituted carbinol compounds of general formula I,
their
stereoisomers, corresponding salts and corresponding solvates may be
accomplished by the reagents and methods described, for example, in EP 0289
380,
US 5,017,596, W099/52525 (US 6,410,582) and W099/07684 (US 6,118,009).
Methods for the optical resolution of said compounds, i.e. the preparation or
separation of the respective stereoisomers are described, for example, in
W099/02500 (US 6,187,930) and W097/20817 (US 5,849,931). The corresponding
parts of these publications are hereby incorporated by reference and form part
of the
present disclosure.
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Physiologically acceptable salts of the substituted carbinol compounds of
general
formula I given above may be obtained by conventional methods known to those
skilled in the art. Preferred pharmaceutically acceptable salts of these
substituted
carbinol compounds of general formula I given above are the citrate salts or
the
ditoluyltartrate salts. Generally included are also addition salts of mineral
acids or of
organic acids such as oxalate, tartrate, citrate and hydroquinonesulfate.
Additionally,
the term "salt" is to be understood as including any form of an active
compound of the
inventive active substance combination in which this is present in ionic or
charged
form and is coupled with a corresponding counter-ion (a cation or anion) or is
in
solution. The term "salt" further comprises complexes of an active compound of
the
inventive active substance combination with other ions or molecules, in
particular
complexes, which are complexed via ionic interactions.
In the context of the present invention, the term "physiologically acceptable
salt" is
understood in particular as including a salt that is formed either with a
physiologically
tolerated acid, that is to say salts of the particular active compound with
inorganic or
organic acids which are physiologically tolerated - especially if used on
humans
and/or mammals - or with at least one, preferably inorganic, ion, preferably
cation,
which are physiologically tolerated, especially if used on humans and/or
mammals.
Examples of physiologically tolerated salts of particular acids are salts of
hydrochloric
acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid,
acetic acid,
oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric
acid, lactic
acid, citric acid, glutamic acid, 1,1-dioxo-'1,2-dihydro-6-benzo(d]isothiazol-
3-one
(saccharin acid), monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic
acid,
nicotinic acid, 2-,3- or 4-aminobenzoic acid, 2,4,6-trimethyl-benzoic acid,
alpha-lipoic
acid, acetylglycine, acetylsalicylic acid, hippuric acid and/or aspartic acid.
Examples
of physiologically tolerated salts of particular bases are salts of alkali and
alkaline
earth metals and/or with ~NH,~R4_,~]+-ions, wherein x is 0, 1, 2, 3 or 4 and R
represents
a linear or branched C~_4 alkyl radical.
With regard to the compounds of component A of the inventive active substance
combination the salts that are preferred are salts of physiologically
tolerated acids.
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The salt, which is particularly preferred for the particular compound of
component A
is the citrate.
For the purposes of the present invention the term opioid includes substances
having
affinity for one or more of the opioid receptors such as the p-opioid
receptors, the ~-
opioid receptors and/or the K-opioid receptors. Preferred are opioids, which
act as
agonists or partial agonists on these receptors as well as mixed
agonists/antagonists.
Preferred are also compounds that act as antagonists, either if used alone or
in
combination with other compounds of component (B).
Suitable opioids according to component (B) of the inventive pharmacologically
active
substance combination as well as methods for their preparation are well known
to
those skilled in the art, e.g. from E. Friderichs, T. Christoph and H.
Buschmann,
"Analgesics and Antipyretics", Ullmann's Encyclopedia of Industrial Chemistry,
Sixth
Edition, Wiley-VCH Verlag GmbH, Weinheim 2000, pages 27-45. The opioid 14-
Methoxymetopon is for example described in the publication of M.A. King et
al., Eur.
J. of Pharmacology, 459 (2003), 203-209. The respective descriptions are
hereby
incorporated by reference and form part of the present disclosure, especially
as
sources for the election of the opioids according to component B of the
inventive
active substance combination.
Preferably the inventive active substance combination comprises as component
(B)
at least one opoid with weak analgesic efficacy, which may preferably be
selected
from the group consisting of codeine, dextropropoxyphene, dihydrocodeine,
diphenoxylate, ethylmorphine, loperamide, meptazinol, nalbuphine, pethidine,
tilidine,
tramadol, viminol and corresponding physiologically acceptable salts of these
compounds.
Even though neither the active substance combination of the present invention
nor
any compound according to component A do give rise to concerns regarding
addiction it may also be preferred to include either in addition to an active
substance
combination according to the present invention or as compound B an opioid
antagonist like Naloxone or Naltrexone.
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If the active substance combination of the present invention comprises as
component
(B) an opioid with weak analgesic efficacy, the molar ratio of component (B)
to
component (A) is preferably in the range of 1:1 to 1:20, preferably 1:1 to
1:10, more
preferably 1:1 to 1:5.
Also preferably, the inventive active substance combination comprises one or
more
opioid analgesics with medium to strong analgesic efficacy, which may
preferably be
selected from the group consisting of alfentanil, buprenorphine, butorphanol,
dextromoramide, dezocine, diacetylmorphine (heroine), etorphine, fentanyl,
hydrocodone, hydromorphone, ketobemidone, levomethadone, levomethadyl
acetate, levorphanol, morphine, nalorphine, oxycodone, oxymorphone,
pentazocine,
piritramide, remifentanil, sufentanil and corresponding physiologically
acceptable
salts thereof.
If the active substance combination of the present invention comprises as
component
(B) an opioid with medium to strong analgesic efficacy, the molar ratio of
component
(B) to component (A) is in the range of 1:1 to 1:400, preferably 1:1 to 1:200,
more
preferably 1:1 to 1:10, most preferably 1:1 to 1:5.
Physiologically acceptable salts of the opioid analgesics according to
component (B)
of the inventive active substance combination are also well known to those
skilled in
the art and may preferably be selected from the group consisting of
hydrochloride,
hydrobromide, sulfate, phosphate, tartrate, citrate and acetate. Generally
included
are addition salts of mineral acids or of organic acids such as oxalate,
tartrate, citrate
and hydroquinonesulfate. Additionally, the term "salt" is to be understood as
including
any form of an active compound of the inventive active substance combination
in
which this is present in ionic or charged form and is coupled with a
corresponding
counter-ion (a cation or anion) or is in solution. The term "salt" further
comprises
complexes of an active compound of the inventive active substance combination
with
other ions or molecules, in particular complexes, which are complexed via
ionic
interactions.
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In the context of the present invention, the term "physiologically acceptable
salt" is
understood in particular as including a salt that is formed either with a
physiologically
tolerated acid, that is to say salts of the particular active compound v~rith
inorganic or
organic acids which are physiologically tolerated - especially if used on
humans
and/or mam mals - or with at least one, preferably inorganic, ion, preferably
cation,
which are physiologically tolerated, especially if used on humans and/or
mammals.
Examples ofi physiologically tolerated salts of particular acids are salts of
hydrochloric
acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid,
acetic acid,
oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric
acid, lactic
acid, citric acid, glutamic acid, 1,1-dioxo-1,2-dihydro-6-benzo(d]isothiazol-3-
one
(saccharin acid), monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic
acid,
nicotinic acid, 2-,3- or 4-aminobenzoic acid, 2,4,6-trimethyl-benzoic acid,
alpha-lipoic
acid, acetylglycine, acetylsalicylic acid, hippuric acid and/or aspartic acid.
Examples
of physiolog ically tolerated salts of particular bases are salts of alkali
and alkaline
earth metals and/or with {NHXR4_~]+-ions, wherein x is 0, 1, 2, 3 or 4 and R
represents
a linear or branched C~_4 alkyl radical.
The active substance according to component (B) and/or the active substance
according to component (A) of the inventive active substance combination may
each
also be present in form of mixture of two or more different salts.
If an active substance according to component (A) is basic and an active
substance
according to component (B) is acidic group or vice versa, both components may
at
least partial 1y form a salt with one another. These salts may be prepared
according to
conventional methods well known to those skilled in the art, e.g. by
dissolution of
both components in a suitable solvent and subsequent evaporation of the
solvent.
Thus, in another preferred embodiment of the present invention com ponent (A)
and
component (B) are at least partially present in form of a salt formed between
these
two components.
The inventive active substance combination is suitable for the administration
to
humans, including infants, children and grown-ups, as well as animals.
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WO 2005/097192 PCT/EP2005/003862
Preferably the total amount of the active substances) according to component
(A),
calculated as the free compound(s), to be administered to the patient in a 24
hours
period does not exceed 800 mg.
The total amount of the active substances) according to component (B),
calculated
as the free compound(s), to be administered to the patient in a 24 hours
period does
not exceed 200 mg.
Preferably the inventive active substance combination comprises components (A)
and (B) in the above defined molar ratios and within the afore given limits
for the
maximum dosis to be administered per day.
Pharmaceutically active substances, particularly opioids, may be the subject
of
abuse. For example , a certain dose of an opioid active substance is usually
more
potent when administered parenterally, particularly intravenously, compared to
the
same dose being administered orally. Consequently, a common mode of abuse for
an oral pharmaceuti cal formulation comprising an opioid active substance
includes
the extraction of the opioid from the formulation with subsequent intravenous
injection.
Thus, in another preferred embodiment of the present invention the active
substance
combination further comprises as component (C) one or more agents that are
suitable to reduce or even prevent abuse of the active substances of component
(A)
andlor component ( B).
If such anti-abuse agents are present in the inventive active substance
combination,
they are included in such a form that they are either not liberated at all or
in such a
way that they do not develop their anti-abuse effect if the active substance
combination is administered to the patient according to its intended route of
administration.
However, if the inventive active substance combination or- after separation -
one of
its components alone is administered via a route other than the intended route
of
administration, said anti-abuse agent will exert its effect and therefore
reduce or even
prevent abuse.
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WO 2005/097192 PCT/EP2005/003862
Agents that are particularly suitable for the reduction or prevention of
opioid abuse
are, for example, opioid antagonists, which have little or no effect if taken
orally, but
which will block the effect of the opioid if administered parenterally
together with the
opioid after extraction.
Suitable opioid antagonists may preferably be selected from the group
consisting of
levallorphan, naloxone, naltrexone and corresponding physiologically
acceptable
salts thereof.
Other anti-abuse agents include aversive agents such as bittering agents,
irritants,
emetics and/or nauseants as well as gelli ng agents.
The kinds and amounts of the anti-abuse agents used as component (C) in the
inventive active substance combination as well as their mode of formulation
together
with components (A) and/or (B) depend on the kind of abuse that is to be
reduced or
prevented, e.g. parenteral, intranasal or oral misuse. Different modes of
formulations
and/or different anti-abuse agents from the same class or from different
classes may
be used to reduce or eliminate more than one kind of abuse, e.g. the inventive
active
substance combination may comprise on a agent suitable for the reduction or
prevention of parenteral abuse and one agent suitable for the reduction or
prevention
of nasal abuse.
Suitable opioid antagonists according to component (C) of the inventive
substance
combination as well as methods for their preparation are well known to those
skilled
in the art, e.g. from E. Friderichs, T. Christoph and H. Buschmann,
"Analgesics and
Antipyretics", Ullmann's Encyclopedia of Industrial Chemistry, Sixth Edition,
Wiley-
VCH Verlag GmbH, Weinheim 2000, pages 45-47.
Opioid antagonists as well as other anti-abuse agents suitable for reduction
or
prevention of different ways of abuse of active substances, suitable amounts
and
methods for their incorporation into pharmaceutical formulations are also
known to
those skilled in the art from EP 1 201 233, W003/013476 and WO 99/32120.
The respective parts of the descriptions of the afore mentioned publications
are
hereby incorporated by references and form part of the present disclosure.
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WO 2005/097192 PCT/EP2005/003862
In another aspect the present invention relates to a medicament comprising an
inventive active substance combination and optionally at least one further
active
substance and/or optionally at least one au>ciliary substahce.
Preferably the inventive medicament is suitable for the treatment of pain,
particularly
for the treatment of pain selected from the g roup consisting of neuropathic
pain,
acute pain, chronic pain, post-operative pain, chronic lower back pain,
cluster
headaches, herpes neuralgia, phantom limb pain, central pain, dental pain,
resistant
pain, visceral pain, surgical pain, bone injury pain, pain during labor and
delivery,
pain resulting from burns, pain resulting from sunburns, post partum pains,
migraine,
angiria pain, genitourinary tract-related pain , pain from cystitis and
nociceptive pain.
Also preferably the inventive medicament is suitable for the prophylaxis
and/or
treatment of urinary incontinence. Furthermore, the inventive medicament is
also
suitable for the prophylaxis and/or treatment of neurogenic inflammation.
Those skilled in the art understand that the components (A) and (B) of the
active
substance combination according to the present invention may be administered
simultaneously or sequentially to one another, whereby in each case components
(A)
and (B) may be administerd via the same or different administration pathways,
e.g.
orally or parenterally. preferably both components (A) and (B) are
administered
simultaneously in one and the same administration form.
Another aspect of the present invention relates to the use of an inventive
pharmacologically active substance combin ation for the preparation of a
medicament
for the treatment of pain, preferably for the treatment of pain selected from
the group
consisting of neuropathic pain, acute pain, chronic pain, post-operative pain,
chronic
lower back pain, cluster headaches, herpes neuralgia, phantom limb pain,
central
pain, dental pain, resistant pain, visceral pa in, surgical pain, bone injury
pain, pain
during labor and delivery, pain resulting from burns, pain resulting from
sunburns,
post partum pains, migraine, angina pain, g enitourinary tract-related pain,
pain from
cystitis and nociceptive pain. A further aspect of the present invention is
the use of an
inventive active substance combination for the preparation of a medicament for
the
prophylaxis and/or treatment of urinary incontinence. Yet another aspect of
the
present invention is the use of an inventive active substance combination for
the
34
CA 02562231 2006-10-04
WO 2005/097192 PCT/EP2005/003862
preparation of a medicament for the prophylaxis and/or lrreatment of
neurogenic
inflammation.
A further aspect of the present invention relates to pharmaceutical
formulations in
different pharmaceutical forms comprising an inventive active substance
combination
and optionally at least one further active substance andfor optionally at
least one
auxiliary substance.
Preferably the inventive pharmaceutical formulation is suitable for oral or
parenteral
administration, more preferably for oral, intravenous, intraperitoneal,
intramuscular,
subcutaneous, intrathekal, rectal, transdermal, transmucosal or nasal
administration.
Inventive pharmaceutical formulation for oral administration are preferably
selected
from the group consisting of tablets, dragees, capsules, drops, gels, juices,
sirups,
solutions and suspensions.
The pharmaceutical formulation of the present invention for oral
administration may
also be in the form of multiparticulates, preferably pellets or granules,
optionally
compressed into a tablet, filled into a capsule or suspended in a suitable
liquid.
Suitable liquids are known to those skilled in the art.
The respective pharmaceutical formulations may - depending on their route of
administration - also contain one or more auxiliary substances known to those
skilled
in the art. The pharmaceutical formulations according to the present invention
may be
produced according to standard procedures known to those skilled in the art,
e.g.
from the tables of contents from "Pharmaceutics: the Science of Dosage Forms",
Second Edition, Aulton, M.E. (Ed.) Churchill Livingstone, Edinburgh (2002);
"Encyclopedia of Pharmaceutical Technology", Second Edition, Swarbrick, J. and
Boylan J.C. (Eds.), Marcel Dekker, Inc. New York (2002); "Modern
Pharmaceutics",
Fourth Edition, Banker G.S. and Rhodes C.T. (Eds.) Marcel Dekker, Inc. New
York
2002 and "The Theory and Practice of Industrial Pharmacy", Lachman L.,
Lieberman
H. and Kanig J. (Eds.), Lea & Febiger, Philadelphia (1986). The respective
descriptions are incorporated by reference and are part of the present
disclosure.
CA 02562231 2006-10-04
WO 2005/097192 PCT/EP2005/003862
In one embodiment of the present invention the pharmaceutical formulation
comprises one or both of the components (A) and (B) at least partially in a
s~stained-
release form. Preferably the inventive pharmaceutical formulation comprises
component (B) at least partially in a sustained-release form.
By incorporating one or both of these components at least partially or compl
etely in a
sustained-release form it is possible to extend the duration of their effect,
allowing for
the beneficial effects of such a sustained release form, e.g. the maintenance
of even
concentrations in the blood.
Suitable sustained-release forms as well as materials and methods for their
preparation are known to those skilled in the art, e.g. from the tables of
contents from
"Modified-Release Drug Delivery Technology", Rathbone, M.J. Hadgraft, J. and
Roberts, M.S. (Eds.), Marcel Dekker, Inc., New York (2002); "Handbook of
Pharmaceutical Controlled Release Technology", Wise, D.L. (Ed.), Marcel
Dekker,
Inc. New York, (2000);"Controlled Drug Delivery", Vol. I, Basic Concepts,
Bruck, S.D.
(Ed.), CRC Press Inc., Boca Raton (1983) and from Takada, IC. and Yoshikawa,
H.,
"Oral Drug delivery", Encyclopedia of Controlled Drug Delivery, Mathiowitz, E.
(Ed.),
John Wiley & Sons, Inc., New York (1999), Vol. 2, 728-742; Fix, J., "Oral drug
delivery, small intestine and colon", Encylopedia of Controlled Drug Delivery,
Mathiowitz, E. (Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 2, 698-
728. The
respective descriptions are incorporated by reference and are part of the
disclosure.
If the pharmaceutical formulation according to the present invention comprises
at
least one of the components (A) and (B) at least partially in a sustained-
release form,
said sustained release may preferably be achieved by the application of at I
east one
coating or provision of a matrix comprising at least one sustained-release
material.
The sustained-release material is preferably based on an optionally modified,
water-
insoluble, natural, semisynthetic or synthetic polymer, or a natural,
semisyn~hetic or
synthetic wax or fat or fatty alcohol or fatty acid, or on a mixture of at
least two of
these afore mentioned components.
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WO 2005/097192 PCT/EP2005/003862
The water-insoluble polymers used to produce a sustained-release material are
preferably based on an acrylic resin, which is preferably selected from the
group of
poly(meth)acrylates, particularly preferably poly(C~_4)alkyl (meth)acrwlates,
poly(C~_4)dialkylamino(C~_4)alkyl (meth)acrylates and/or copolymers or
mixtures
thereof, and very particularly preferably copolymers of ethyl acrylate and
methyl
methacrylate with a monomer molar ratio of 2:1 (Eudragit NE30D~), copolymers
of
ethyl acrylate, methyl methacrylate and trimethylammonium ethyl mathacrylate-
chloride with a monomer molar ratio of 1:2:0.1 (Eudragit RS~), copolymers of
ethyl
acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate-
chloride
with a monomer molar ratio of 1:2:0.2 (Eudragit RL~), or a mixture of at least
two of
the above-mentioned copolymers. These coating materials are comnnercially
available as 30 wt.% aqueous latex dispersions, i.e. as Eudragit RS30D~,
Eudragit
NE30D° or Eudragit RL30D~, and may also be used as such for coating
purposes.
In another embodiment, the sustained-release material is based on water-
insoluble
cellulose derivatives, preferably alkyl celluloses, particularly preferably
ethyl
cellulose, or cellulose esters, e.g. cellulose acetate. Aqueous ethyl
cellulose
dispersions are commercially available, for example, under the trademarks
Aquacoat~ or Surelease°.
As natural, semisynthetic or synthetic waxes, fats or fatty alcohols, tl-~e
sustained-
release material may be based on carnauba wax, beeswax, glycerol monostearate,
glycerol monobehenate, glycerol ditripalmitostearate, microcrystalline wax,
cetyl
alcohol, cetylstearyl alcohol or a mixture of at least two of these com
ponents.
The afore mentioned polymers of the sustained-release material may also
comprise a
conventional, physiologically acceptable plasticizer in amounts known to those
skilled
in the art.
Examples of suitable plasticizers are lipophilic diesters of a C6-C4o
aliphatic or
aromatic dicarboxylic acid and a C~-C$ aliphatic alcohol, e.g. dibutyl
phthalate, diethyl
phthalate, dibutyl sebacate or diethyl sebacate, hydrophilic or lipoph ilic
citric acid
esters, e.g. triethyl citrate, tributyl citrate, acetyltributyl citrate or
acetyltriethyl citrate,
polyethylene glycols, propylene glycol, glycerol esters, e.g. triacetin,
Myvacet~
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WO 2005/097192 PCT/EP2005/003862
(acetylated mono- and diglycerides, C23H4405 to C25Hø7O7), medium-chain
triglycerides (Miglyol~), oleic acid or mixtures of at least two of said
plasticizers.
Aqueous dispersions of Eudragit RS~ and optionally Eudragit RL°
preferably contain
triethyl citrate. The sustained-release material may comprise one or more
plasticisers
in amounts of, for example, 5 to 50 wt.% based on the amount of polymers)
used.
The sustained-release material may also contain other conventional auxiliary
substances known to those skilled in the art, e.g. lubricants, coloured
pigments or
surfactants.
The pharmaceutical formulation of the present invention may also comprise at
least
one of the components (A) and (B) covered by an enteric coating form which
dissolves as a function of pH. Because of this coating, part or all of the
pharmaceutical formulation can pass through the stomach undissolved and the
components (A) and/or (B) are only released in the intestinal tract. The
enteric
coating preferably dissolves at a pH of between 5 and 7.5.
The enteric coating may be based on any enteric material known to those
skilled in
the art, e.g. on methacrylic acid/methyl methacrylate copolymers with a
monomer
molar ratio of 1:1 (Eudragit L~), methacrylic acid/methyl methacrylate
copolymers
with a monomer molar ratio of 1:2 (Eudragit S~), methacrylic acid/ethyl
acrylate
copolymers with a monomer molar ratio of 1:1 (Eudragit L30D-55~), methacrylic
acid/methyl acrylate/methyl methacrylate copolymers with a monomer molar ratio
of
7:3:1 (Eudragit FS°), shellac, hydroxypropyl methyl cellulose acetate-
succinates,
cellulose acetate-phthalates or a mixture of at least two of these components,
which
can optionally also be used in combination with the above-mentioned water-
insoluble
poly(meth)acrylates, preferably in combination with Eudragit NE30D~ and/or
Eudragit
RL~ and/or Eudragit RS~.
The coatings of the pharmaceutical formulations of the present invention may
be
applied by the conventional processes known to those skilled in the art, e.g.
from
Johnson, J.L., "Pharmaceutical tablet coating", Coatings Technology Handbook
(Second Edition), Satas, D. and Tracton, A.A. (Eds), Marvel Dekker, Inc. New
York,
(2001 ), 863-866; Carstensen, T., "Coating Tablets in Advanced Pharmaceutical
38
CA 02562231 2006-10-04
WO 2005/097192 PCT/EP2005/003862
Solids", Swarbrick, J. (Ed.), Marcel Dekker, Inc. New York (2001 ), 455-468;
Leopold,
C.S., "Coated dosage forms for colon-specific drug delivery", Pharmaceutical
Science
& Technology Today, 2(5), 197-204 (1999), Rhodes, C.T. and Porter, S.C.,
Coatings,
in Encyclopedia of Controlled Drug Delivery. Mathiowitz, E. (Ed.), John Wiley
& Sons,
Inc., New York (1999), Vol. 1, 299-311. The respective descriptions are
incorporated
by reference and are part of the present disclosure.
In another embodiment, the pharmaceutical formulation of the present invention
contains one or both of components (A) and (B) not only in sustained-release
form,
but also in non-retarded form. By combination with the immediately released
form, a
high initial dose can be achieved for the rapid onset of the beneficial
effect. The slow
release from the sustained release form then prevents the beneficial effect
from
diminishing. Such a pharmaceutical formulation is particularly useful for the
treatment
of acute health problems.
This may be achieved, for example, by a pharmaceutical formulation having at
least
one immediate-release coating comprising at least one of the components (A)
and
(B) to provide for rapid onset of the beneficial effect after administration
to the patient.
It has surprisingly been found that in the active substance combination of the
present
invention the pharmacological efficacy of the opioid component is enhanced by
their
administration in combination with one or more substituted carbinol compounds
of
general formula I given above. As a result of this synergistic effect, the
dose of the
opioid may be reduced and fewer, less pronounced to none undesired side
effects
occur and the risk of tolerance development is reduced, while the analgesic
efficacy
is at least maintained.
In addition to this, the withdrawal symptoms resulting from the administration
of such
an opioid analgesic component are reduced or entirely suppressed, even if the
amount of administered opioid analgesic is not reduced compared to the
administration of an opioid analgesic alone.
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WO 2005/097192 PCT/EP2005/003862
Pharmacological Methods:
A. Hot plate test in mice:
The analgesic activity of the inventive active substance combination is
determined in
male Swiss mice (weight 20-25 g, Harlan Iberica, S. Feliu de Codinas,
Barcelona,
Spain) as described in the publication of G. Woolfe and A. D. MacDonald, J.
Pharm.
Exp. Ther. 1944, 80, pages 300-307. The respective description of this
publication is
incorporated by reference and forms part of the present disclosure.
According to this test the mice are put onto a plate, which is heated to 55
°C and the
time is determined until the mice show signs of pain such as vigorous and
repeated
licking of the paws, jumping or pulling back the paws. The mice are kept on
the hot
plate for no longer than 40 seconds in order to avoid the development of
cutaneous
lesions. At first the untreated mice are subjected to the hot-plate test to
determine a
baseline for their pain induced behaviour. After 10 minutes the vehicle, the
active
substances and the inventive active substance combination to be tested are
administered to different groups of mice. 0.5 hours, 1 hour and 2 hours after
the
administration the animals are put onto the hot plate and the time is measured
until
they show signs of pain. The analgesic efficacy of the active substances or
active
substance combination is calculated on the basis of the values obtained for
the
comparison group of mice which is only administered the vehicle.
CA 02562231 2006-10-04
WO 2005/097192 PCT/EP2005/003862
B. Determination of withdrawal symptoms
The effect of the inventive active substance combination on withdrawal
symptoms
after treatment with an opoid is determined according to the publication of
J.K.
Saelens et al. Int. Pharmacodyn. 1971, 190, pages 213-218 in male Swiss albino
mice (weight 20-25 g, Harlan Iberica, S. Feliu de Codinas, Barcelona, Spain).
Opioid dependency is delevoped in the mice by intraperitoneal administration
of the
opioid in a suitable dose known to those skilled in the art, e.g. 5 mg/kg/day
for 4
consecutive days for morphine. Withdrawal symptoms are then induced by the
intravenous administration of a suitable opioid antagonist in a dose known to
those
skilled in the art, for example, 2 mg/kg naloxone in case of morphine, 30
minutes
after the administration of the final dose of the opioid is completed.
In the 30 minute perioid following the naloxone administration the mice show
typical
withdrawal symptoms, namely jumps and shakes (of the wet dog shake type),
which
are counted and registered.
The active substance comination is also administered to the mice for 4
consecutive
days. After the administration of 2 mg/kg naloxone 30 minutes after the
administration of the final dose of the active substance combination has been
completed, the mice are closely watched for withdrawal symptoms, namely jumps
and shakes (of the wet dog shake type), which are then counted and registered.
The present invention is illustrated below with the aid of examples. These
illustrations
are given solely by way of example and do not limit the general spirit of the
present
invention.
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WO 2005/097192 PCT/EP2005/003862
Examples:
A. Hot plate test in mice:
The analgesic efficacy of an inventive active substance combination comprising
as
component (A) the compound (~)-5-[a-[2-(Dimethylamino)ethoxy]benzyl]-1-methyl-
1 H-pyrazole citrate (hereinafter Cizolirtine Citrate) and as component (B)
Morphine in
mice has been determined as described above and compared to the administration
of vehicle, Cizolirtine Citrate and Morphine alone.
The active substance combination as well as the comparison substances, their
mode
of administration and the respective amounts are given in the following table
A
together with determined activities.
Table A:
PreparationDosis Mode of % Analgesic
activity
administered(mg/kg) administration0.5 hours'1 hour' 2 hours
vehicle2 --- s.c. 7.8 9.6 6.6
Cizolirtine320 i.p. 25.8 17.1 23.4
Morphine 5 s.c. 48.6 34.8 15.8
Cizorlitine20 i.p. 88.8 71.5 30.7
+ +
Morphine 5 s.c.
1 time after administration
2: 5 % by weight arabic gum in water for injection purposes
3: as Citrate salt
s.c.: subcutaneous
i.p.: intraperitoneal
As can be seen from table A the inventive active substance combination shows a
synergistic effect.
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WO 2005/097192 PCT/EP2005/003862
B: Determination of withdrawal symptoms
The influence of the active substance combination on withdrawal symptons has
been
determined as described above. The results are given in Table B:
Table B:
PreparationDosis mode of Number of Number of
administered(mg/kg/day)administrationjumps shakes
over 4 days
vehicle --- i.p. 0 0
Morphine 5 s.c. 6.6 16.3
Cizorlitine'40 i.p. 3.1 3.4
+ +
Morphine 5 s.c.
1: 5 % by weight arabic gum in water for injection purposes
2: as Citrate salt
i.p.: intraperitoneal
s.c. subcutaneous
As can be seen from the values given in table B the withdrawal symptoms
usually
associated with the administration of opoids (here morphine) are significantly
reduced
by its co-administration with a substituted carbinol compound - component (A) -
Cizolirtin Citrate, even if the administered amount of the opioid is not
reduced.
43
