Note: Descriptions are shown in the official language in which they were submitted.
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t5I I l -;ibZ
1
'New esters of hydroxy-substituted nitrogen heterocycles as antagonists
of the muscarinic M3 receptor, processes for the preparation thereof as
well as the use thereof as' pharmaceutical compositions
The present invention relates to new compounds of general formula 1
N
H
4Z<O~ 0
R3 A t3 R'
4 Rx Rx R4.
wherein X - and the groups A, B, R, RI, R2, R3, R3% R4, R41, RX and Rx,
are as described herein, processes for preparing them and the use thereof as
pharmaceutical compositions.
Description of the invention
The present invention relates to compounds of general formula 1
F22 f'R1 = X I
N
i
H
4zto 0
R
3 A {{ !! B
R R
f I
4
R 4 Rx Rx R
1 }
wherein
X - denotes an anion with a single negative charge, preferably an
anion selected from the group consisting of chloride, bromide,
iodide, sulphate, .phosphate, methanesulphonate, nitrate,
maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate,
benzoate and p-toluenesulphonate;
{
1
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A and B which may be identical or different, preferably identical, denote
-0, -S, -NH, -CH2, -CH=CH, or -N(C1-C4-alkyl)-;
R denotes hydrogen, hydroxy, -C1-C4-alkyl, -C1-C4-alkyloxy,
-C 1-C4-alkylene-halogen, -0-C 1-C4-alkylene-halogen,
-C1-C4-alkylene-OH, -CF3, CHF2, -C1-C4-alkylene-C1-C4-
alkyloxy, -0-COC1-C4-alkyl, -O-COCI-C4-alkylene-halogen,
-C 1-C4-alkylene-C3-C6-cycloalkyl, -0-000F3 or halogen;
R1 and R2 which may be identical or different denote -C1 -C5-alkyl, which
may optionally be substituted by -C3-C6-cycloalkyl, hydroxy or
halogen,
or
R1 and R2 together denote a -C3-C5-alkylene-bridge;
R3, R4, R3' and R4', which may be identical or different denote hydrogen,
C1-C4-alkyl, C1-C4-alkyloxy, hydroxy, -CF3, -CHF2, CN, N02
or halogen;
Rx and Rx' which may be identical or different denote hydrogen, C1-C4-
alkyl, C1-C4-alkyloxy, hydroxy, -CF3, -CHF2, CN, N02 or
halogen
or
Rx and Rx' together denote a single bond or a bridging group
selected from the bridges -0, -S, -NH, -CH2, -CH2-CH2-,
-N(C 1-C4-alkyl), -CH(C 1 -C4-alkyl)- and -C(C 1 -C4-alkyl)2.
Compounds of general formula 1 are preferred wherein
X - denotes an anion with a single negative charge selected from
among the chloride, bromide, 4-toluenesulphonate and
methanesulphonate, preferably bromide,
A and B which may be identical or different, preferably identical, denote
-0, -S, -NH or -CH=CH-;
R denotes hydrogen, hydroxy, -C1-C4-alkyl, -C1-C4-alkyloxy,
-CF3, -CHF2, fluorine, chlorine or bromine;
R1 and R2 which may be identical or different, denote C1-C4-alkyl, which
may optionally be substituted by hydroxy, fluorine, chlorine or
bromine,
or
R1 and R2 together denote a -C3-C4-alkylene-bridge;
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R3, R4, R3' and R41, which may be identical or different, denote hydrogen,
C1-C4-alkyl, C1-C4-alkyloxy, hydroxy, -CF3, -CHF2, CN, N02,
fluorine, chlorine or bromine;
Rx and Rx' which may be identical or different denote hydrogen, C1-C4-
alkyl, Cl-C4-alkyloxy, hydroxy, -CF3, -CHF2, CN, N02, fluorine,
chlorine or bromine
or
Rx and RX' together denote a single bond or a bridging group
selected from the bridges -0, -S, -NH- and -CH2-.
Particularly preferred are compounds of general formula 1 wherein
X - denotes an anion with a single negative charge selected from
among the chloride, bromide and methanesulphonate, preferably
bromide;
A and B which may be identical or different, preferably identical, denote
-S or -CH=CH-;
R denotes hydrogen, hydroxy, methyl, ethyl, methyloxy, ethyloxy,
-CF3, or fluorine;
R1 and R2 which may be identical or different denote methyl, ethyl, -CH2F
or -CH2-CH2F, preferably methyl or ethyl;
R3, R4, R3' and R4', which may be identical or different, denote hydrogen,
methyl, methyloxy, -CF3 or fluorine;
RX and RX' which may be identical or different denote hydrogen, methyl,
methyloxy, -CF3 or fluorine
or
RX and RX' together denote a single bond or the bridging group
-0-.
Of particular importance according to the invention are compounds of general
formula 1 wherein
X - denotes an anion with a single negative charge selected from
among the chloride, bromide and methanesulphonate, preferably
bromide;
A and B which may be identical or different, preferably identical, denote
-S or -CH=CH-;
R denotes hydrogen, hydroxy or methyl, preferably hydroxy;
R1 and R2 which may be identical or different denote methyl or ethyl;
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R3, R4, R3' and R4', which may be identical or different denote hydrogen,
-CF3 or fluorine, preferably hydrogen;
Rx and Rx' which may be identical or different denote hydrogen, -CF3 or
fluorine, preferably hydrogen or
Rx and Rx' together denote a single bond or the bridging group
-0, preferably a single bond.
Also preferred according to the invention are compounds of general formula I
Wherein
X - denotes bromide;
A and B which may be identical or different, preferably identical, denote
-S or -CH=CH-;
R denotes hydrogen, hydroxy or methyl, preferably hydroxy;
RI and R2 denotes methyl;
R3, R4, R3' and R4', which may be identical or different, denote hydrogen or
fluorine, preferably hydrogen;
Rx and Rx' which may be identical or different denote hydrogen or fluorine,
preferably hydrogen or
Rx and Rx' together denote a single bond or the bridging group
-0, preferably a single bond.
The invention relates to the compounds of formula 1 optionally in the form of
the individual optical isomers, mixtures of the individual enantiomers or
racemates thereof and optionally in the form of the pharmacologically
acceptable acid addition salts thereof.
In the compounds of general formula 1 the groups R3, R4, R3' and R4', if
they do not represent hydrogen, may in each case be arranged in the ortho,
meta or para position relative to the bond to the "-C- R" group. If none of
the
groups R3, R4, R3' and R4' denotes hydrogen, R3 and R3' are preferably
linked in the para position and R4 and R4' are preferably linked in the ortho
or
meta position, most preferably in the meta position. If one of the groups R3
and R4 and one of the groups R3' and R4' denotes hydrogen, the other group
in each case is preferably bonded in the meta or para position, most
preferably in the para position. If none of the groups R3, R4, R3' and R4'
denotes hydrogen, the compounds of general formula 1 wherein the groups
R3, R4, R3' and R4' have the same meaning are particularly preferred
according to the invention.
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Of particular importance according to the invention are the compounds of
general formula I wherein A denotes -CH=CH- and B denotes -CH=CH-.
These compounds correspond to general formula 1'
R2---+,R1 x N
H
4L~~, O O
R
R3 R3
R4 Rx R" R4
wherein X - and the groups R, R1, R2, R3, R3', R4, R4', Rx and Rx' may have
the meanings given above.
Also of particular importance according to the invention are the compounds of
general formula 1, wherein A denotes -S- and B denotes -S-. These
compounds correspond to general formula 1"
R2~+/R X
N
H
4L(- O O
R
R3 S I I S R3,
R4 Rx Rx Ra
1"
wherein X - and the groups R, R1, R2, R3, R3, R4, R4', Rx and Rx'may have
the meanings given above.
The following compounds are particularly important according to the invention:
- tropan-6exo-yl benzilate methobromide;
- tropan-6exo-yl 9-hydroxy-fluorene-9-carboxylate methobromide;
- tropan-6-exo-yl 2-hydroxy-2,2-dithiophene-acetate methobromide;
- tropan-6exo-yl 9-hydroxy-xanthene-9-carboxylate methobromide;
- tropan-6endo-yl benzilate methobromide;
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- tropan-6endo-yl 9-hydroxy-fluorene-9-carboxylate methobromide;
- tropan-6endo-yl 9-hydroxy-xanthene-9-carboxylate methobromide;
- tropan-6endo-yl 2-hydroxy-2,2-dithiophene-acetate methobromide.
The alkyl groups used, unless otherwise stated, are branched and
unbranched alkyl groups having I to 4 carbon atoms. Examples include:
methyl, ethyl, propyl or butyl. The groups methyl, ethyl, propyl or butyl may
optionally also be referred to by the abbreviations Me, Et, Prop or Bu. Unless
otherwise stated, the definitions propyl and butyl also include all possible
isomeric forms of the groups in question. Thus, for example, propyl includes
n-propyl and iso-propyl, butyl includes iso-butyl, sec. butyl and tert.-butyl,
etc.
The cycloalkyl groups used, unless otherwise stated, are alicyclic groups with
3 to 6 carbon atoms. These are the cyclopropyl, cyclobutyl, cyclopentyl and
cyclohexyl groups. According to the invention cyclopropyl is of particular
importance within the scope of the present invention.
The alkylene groups used, unless otherwise stated, are branched and
unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms. Examples
include: methylene, ethylene, propylene or butylene.
The alkylene-halogen groups used, unless otherwise stated, are branched
and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms which
may be mono-, di- or trisubstituted, preferably disubstituted, by a halogen.
Accordingly, unless otherwise stated, the term alkylene-OH groups denotes
branched and unbranched double-bonded alkyl bridges with 1 to 4 carbon
atoms which may be mono-, di- or trisubstituted, preferably monosubstituted,
by a hydroxy.
The alkyloxy groups used, unless otherwise stated, are branched and
unbranched alkyl groups with 1 to 4 carbon atoms which are linked via an
oxygen atom. The following may be mentioned, for example: methyloxy,
ethyloxy, propyloxy or butyloxy. The groups methyloxy, ethyloxy, propyloxy or
butyloxy may optionally also be referred to by the abbreviations MeO, EtO,
PropO or BuO. Unless otherwise stated, the definitions propyloxy and
butyloxy also include all possible isomeric forms of the groups in question.
Thus, for example, propyloxy includes n-propyloxy and iso-propyloxy, butyloxy
includes iso-butyloxy, sec. butyloxy and tert.-butyloxy, etc. The word alkoxy
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may also possibly be used within the scope of the present invention instead of
the word alkyloxy. The groups methyloxy, ethyloxy, propyloxy or butyloxy may
optionally also be referred to as methoxy, ethoxy, propoxy or butoxy.
The alkylene-alkyloxy groups used, unless otherwise stated, are branched
and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms which
may be mono-, di- or trisubstituted, preferably monosubstituted, by an
alkyloxy group.
The -0-CO-alkyl groups used, unless otherwise stated, are branched and
unbranched alkyl groups with 1 to 4 carbon atoms which are bonded via an
ester group. The alkyl groups are bonded directly to the carbonylcarbon of the
ester group. The term -0-CO-alkyl-halogen group should be understood
analogously. The group -0-CO-CF3 denotes trifluoroacetate.
Within the scope of the present invention halogen denotes fluorine, chlorine,
bromine or iodine. Unless otherwise stated, fluorine and bromine are the
preferred halogens. The group CO denotes a carbonyl group.
As explained hereinafter, the compounds according to the invention may be
prepared partly analogously to the methods already known in the art (Diagram
1).
R'
R R' 0 N
N R H
O
H + R3 A I I B R3' 4Z~O '
4 R
a
R Rx Rx R R3 A B R3
2 3 4 R4 Rx Rx R4'
R2 +,R1 X
R? X N
H
+~~O' 0
R
R3 A I I B R3,
R4 Rx R)e R4,
Diagram 1:
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The carboxylic acid derivatives of formula 3 are known in the art or may be
obtained by methods of synthesis known in the art. If only suitably
substituted
carboxylic acids are known in the art, the compounds of formula 3 may also
be obtained directly from them by acid- or base-catalysed esterification with
the corresponding alcohols or by halogenation with the corresponding
halogenation reagents.
Starting from the compounds of formula 2 the esters of general formula 4
may be obtained by reaction with the carboxylic acid derivatives of formula 3,
wherein R' denotes for example chlorine or a C 1 -C4-alkyloxy group. When R'
equals C1-C4-alkyloxy this reaction may be carried out for example in a
sodium melt at elevated temperature, preferably at about 50-150 C, more
preferably at about 90-100 C at low pressure, preferably at below 500 mbar,
most preferably at below 75 mbar. Alternatively, instead of the derivatives 3
wherein R' denotes C1-C4-alkyloxy, the corresponding acid chlorides (R = CI)
may also be used.
The compounds of formula 4 thus obtained may be converted into the target
compounds of formula I by reacting with the compounds R2-X, wherein R2
and X may have the abovementioned meanings. This synthesis step may
also be carried out analogously to the examples of synthesis disclosed in WO
92/16528. In the case wherein R1 and R2 together form an alkylene bridge
there is no need to add the reagent R2-X, as will be apparent to the skilled
man. In this case the compounds of formula 4 contain a suitably substituted
group R1 (for example -C3-C5-alkylene-halogen) according to the above
definitions and the compounds of formula 1 are prepared by intramolecular
quaternisation of the amine.
Alternatively, the compounds of formula 4 wherein R denotes halogen may
also be prepared by the method shown in Diagram 2.
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R~ R1
N' N
O H H
O O O
OH R
s A B s R3 A` B R3.
R I R
a'
Ra Rx Rx. Ra' Ra Rx Rx R
4 (mit R=OH) 4 (mit R = Halogen)
Diagram 2:
For this, the compounds of formula 4 wherein R denotes hydroxy are
converted into the compounds 4 wherein R denotes halogen using suitable
halogenation reagents. The method used for the halogenation reactions to be
carried out according to Diagram 2 is sufficiently well known in the art.
As is apparent from Diagram 1, the intermediate products of general formula
4 have a central importance. Accordingly, in another aspect, the present
invention relates to the intermediates of formula 4
R'
N
4:::~ H
0 0
R
R3 A B R31
Ra Rx Rx Ra
4
wherein the groups A, B, R, R1, R3, R31, R4, R4', Rx and Rx' may be defined
as above, optionally in the form of the acid addition salts thereof.
By acid addition salts are meant salts selected from among the hydrochloride,
hydrobromide, hydroiodide, hydrosulphate, hydrophosphate,
hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,
hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate,
hydrobenzoate and hydro-p-toluenesulphonate, preferably the hydrochloride,
hydrobromide, hydrosulphate, hydrophosphate, hydrofumarate and
hydromethanesulphonate.
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As in the compounds of general formula I the groups R3, R4, R& and R4', if
they do not represent hydrogen, may in each case be arranged in the ortho,
meta or para position relative to the bond to the "-C- R" group in the
compounds of general formula 4 as well. If none of the groups R3, R4, RS
and R4' denotes hydrogen, R3 and R3' are preferably linked in the para
position and R4 and R4' are preferably linked in the ortho or meta position,
most preferably in the meta position. If one of the groups R3 and R4 and one
of the groups R3' and R4' denotes hydrogen, the other group in each case is
preferably linked in the meta or para position, most preferably in the para
position. If none of the groups R3, R4, R3' and R4'denotes hydrogen the
compounds of general formula 4 which are particularly preferred according to
the invention are those wherein the groups R3, R4, RT and R4' have the
same meaning.
As is apparent from Diagram 1, the compounds of formula 2 are used as
starting products for preparing the compounds of formula 1. These
compounds are partly known in the prior art (Jones, J. Chem. Soc 1959, 615;
D. E. Justice, THL 1995 4689-4692). Accordingly, in another aspect, the
present invention relates to the as yet unknown use of the compounds of
general formula 2
R1
N
H
41~:r
OH 2
wherein
R1 denotes hydrogen or -C1-C5-alkyl, which may optionally be
substituted by -C3-C6-cycloalkyl, hydroxy or halogen, optionally
in the form of the acid addition salts thereof, for preparing the
compounds of general formula 4.
By the acid addition salts are meant salts selected from among the
hydrochloride, hydrobromide, sulphate, phosphate, fumarate and
methanesulphonate.
It is preferable to use the abovementioned compounds of general formula 2
wherein
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R1 denotes hydrogen or C1-C4-alkyl, which may optionally be
substituted by hydroxy, fluorine, chlorine or bromine,
optionally in the form of the acid addition salts thereof.
It is particularly preferred to use the abovementioned compounds of general
formula 2 wherein
R1 denotes hydrogen, methyl, ethyl, -CH2F or -CH2-CH2F,
preferably methyl or ethyl, optionally in the form of the acid
addition salts thereof.
Of particular importance according to the invention is the abovementioned use
of compounds of general formula 2 wherein
R1 denotes hydrogen, methyl or ethyl, optionally in the form of the
acid addition salts thereof.
Also preferred according to the invention is the abovementioned use of
compounds of general formula 2 wherein
R1 denotes hydrogen or methyl, optionally in the form of the acid
addition salts thereof.
Moreover, the present invention relates to the use of the abovementioned
compounds of general formula 2 as starting materials for preparing the
compounds of general formula 1.
The examples of synthesis described below serve to illustrate the present
invention still further. However, they are to be regarded as only examples of
the procedure, as further illustration of the invention, without restricting
the
invention to the object described below by way of example.
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Preparation of the bases 2a and 2b:
N,Me N,Me
OH H
4 ~- 4c~~
H 2a OH 2b
The compounds of formula 2a and 2b may be prepared by methods known in
the art (cf. Jones, J. Chem. Soc 1959, 615; D. E. Justice, THL 1995 4689-
4692).
Example 1: Tropan-6exo-yl benzilate methobromide :
Me\+/Me Br
N
O O
H HO
/1 /1
1.1.: methyl benzilate 3a:.
90 g (0.394 mol) benzilic acid are dissolved in 900 ml acetonitrile and at 5 C
109.6 g (0.72 mol) of DBU are added dropwise. After the addition of 204.4 g
(1.44 mol) of methyl iodide the mixture is stirred for 24 hours at ambient
temperature (about 20-23 C). The solution is evaporated down to the residue,
the residue is taken up in diethyl ether and extracted with water. The organic
phase is washed with 5% aqueous sodium carbonate solution and water,
dried and the solvent is distilled off. The product is purified by
recrystallisation
from cyclohexane. Yield: 77.19 g white crystals (= 81 % of theory)
Melting point: 74 -76 C.
1.2.: Tropan-6exo-yl benzilate 4a:
1.2 g of compound 2a are combined with 2.42 g of methyl benzylate 3a and
mg of sodium and heated to 100 C for 1 h at 70 mbar. The mixture is
cooled and 10ml acetonitrile are added to decompose any excess sodium.
Then the solvent is distilled off under reduced pressure. The residue
remaining is combined with 100ml of toluene and washed 1x with 100ml of
water. The organic phase is dried and the solvent distilled off under reduced
pressure. The product is purified by chromatography on silica gel ( about
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100ml silica gel; 150 ml ethyl acetate, then about 500m1 of a solvent mixture
consisting of dichloromethane 70: ethyl acetate 20 : methanol 10). Yield: 2.2
g (74%); Melting point: 135 C.
1.3: Tropan-6exo-yl benzilate methobromide:
2.1 g of compound 4a are dissolved in 40 mL acetonitrile and 40 mL
dichloromethane and combined with 3.42 g of a 50% solution of methyl
bromide in acetonitrile. The mixture is stirred for 24 h at RT (ambient
temperature) and the crystals precipitated are suction filtered and washed
with diethyl ether. Yield: 2.4 g (90%); Melting point: 264 C.
Example 2: tropan-6exo-yl 9-hydroxy-fluorene-9-carboxylate methobromide:
Me\+/Me Br
N
O O
H HO
2.1.: methyl 9-hydroxy-fluorene-9-carboxylate 3b:.
50.4 g (0.223 mol) 9-hydroxy-9-fluorenecarboxylic acid are dissolved in 500
ml of methanol, combined with 5 ml (0.089 mol) conc. sulphuric acid and
refluxed for 1 hour. After cooling 100 ml sodium hydrogen carbonate solution
(about pH 8) are added, and the methanol is largely distilled off under
reduced
pressure. The residue remaining is extracted with dichloromethane and water,
the organic phase is dried and evaporated to dryness.
The product is purified by recrystallisation from ethyl acetate.
Yield: 50.Og (= 93% d. Th.)
2.2: tropan-6exo-yl 9-hydroxy-fluorene-9-carboxylate 4b:
1.05 g 2a, 2.4 g methyl fluorenehydroxycarboxylate 3b and 10 mg sodium are
stirred for 1 h at 100 C and 70 mbar. The mixture is cooled and 10 ml of
acetonitrile are added to break down excess sodium. Then the solvent is
distilled off under reduced pressure. The residue is combined with 100ml of
toluene and washed 1x with 100 mI of water. The organic phase is dried, the
solvent distilled off under reduced pressure and the residue purified by
chromatography (about 100 ml silica gel; 150 ml ethyl acetate, then about
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500ml a solvent mixture consisting of dichloromethane 70 : ethyl acetate 20:
methanol 10). Yield: 1.1 g (44%); melting point 154 C.
2.3: tropan-6exo-yl 9-hydroxy-fluorene-9-carboxylate methobromide:
1.1 g 4b are dissolved in 20 mL acetonitrile and 20 mL dichloromethane,
combined with 1.82 g of a 50% solution of methylbromide in acetonitrile and
stirred for 24 h at RT. Then the solvent is distilled off under reduced
pressure
and the residue is taken up in 5 mL methanol and combined with 30 mL
acetone. After 2 h the crystals precipitated are suction filtered. Yield: 0.7
g
(50%); Melting point: > 300 C (decomposition).
Example 3: tropan-6-exo-yl 2-hydroxy-2,2-dithiophene-acetate
methobromide:
Me\+Me Sr
N
O O
H HO
S S
3.1: tropan-6-exo-yl 2-hydroxy-2, 2-dithiophene-acetate 4c:
1.05 g 2a, 2.54 g methyl dithienylglycolate 3c and 10 mg of sodium are stirred
for 1 hat 100 C and 70 mbar. The mixture is cooled and 10 ml of acetonitrile
are added to break down excess sodium. Then the solvent is distilled off
under reduced pressure. The residue is combined with 100ml of toluene and
washed 1 x with 100mI of water. The organic phase is dried and the solvent
distilled off under reduced pressure. The residue is purified by
chromatography on silica gel ( about 100ml silica gel; 150 ml ethyl acetate,
then about 500ml of a solvent mixture consisting of dichloromethane 70 : ethyl
acetate 20 : methanol 10). Yield 0.9 g (35%);
Melting point: 141 C.
3.2: tropan-6-exo-yl 2-hydroxy-2 2-dithiophen-acetate methobromide:
0.9 g 4c are dissolved in 20 mL acetonitrile and 20 mL dichloromethane,
combined with 1.42 g of a 50% solution of methylbromide in acetonitrile and
stirred for 24 h at RT. The crystals precipitated are suction filtered and
washed with ether. Yield: 0.9 g (79%); Melting point: 220 C (decomposition).
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Example 4: tropan-6exo-yl 9-hydroxy-xanthene-9-carboxylate methobromide:
Meg+/Me Br -
N
0 0
H HO
O
4.1.: methyl 9-hydroxy-xanthene-9-carboxylate 3d:.
a) methyl xanthene-9-carboxylate:
A sodium ethoxide solution is generated from 21.75 g (0.95 mol) of sodium
and 1500 ml of ethanol. 214 g (0.95 mol) of xanthene-9-carboxylic acid is
added batchwise to this solution and the suspension obtained is stirred for 1
hour at ambient temperature. Then the solid is separated off, washed with
1500 ml diethyl ether, the crystals isolated are suspended in 1500 ml of
dimethylformamide and combined with 126.73 ml (2.0 mol) methyl iodide with
stirring. The solution formed is left to stand for 24 hours at ambient
temperature, then diluted with water to a total volume of 6 I, crystallised,
suction filtered, washed with water and dried. Yield: 167 g of white crystals
7
(= 74% of theory)
Melting point: 82 C.
b) methyl 9-hydroxy-xanthene-9-carboxylate 3d:
48.05 g (0.2 mol) methyl xanthene-9-carboxylate are dissolved in 1200 ml of
tetrahydrofuran and at 0 C 23.63 g (0.2 mol) of potassium tent. butoxide are
added. Then oxygen is piped in for 2 hours at -10 to -5 C, the mixture is
acidified with 2 N aqueous hydrochloric acid and the majority of the solvent
is
distilled off. The residue remaining is extracted with ethyl acetate and
water,
the organic phase is extracted with aqueous Na2S205 solution, washed with
water, dried and the solvent is distilled off.
The product is purified by crystallisation from diisopropylether and
cyclohexane. Yield: 11.10 g of white crystals (= 22% of theory)
4.2: tropan-6exo-yl 9-hydroxy-xanthene-9-carboxylate 4d:
0.705 g 2a, 2.60 g methyl 9-hydroxy-xanthene-9-carboxylate 3d and 10 mg
sodium are stirred for 2 h at 100 C and 70mbar. The mixture is cooled and 10
ml of acetonitrile are added to break down excess sodium. Then the solvent is
distilled off under reduced pressure. The residue is combined with 100ml of
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toluene and washed 1x with 100ml of water. The organic phase is dried and
the solvent distilled off under reduced pressure. The residue is purified by
chromatography ( about 100ml silica gel; 150 ml ethyl acetate, then about
500ml of a solvent mixture consisting of dichloromethane 70: ethyl acetate 20
: methanol 10). Yield 0.45 g (25%); amorphous solid.
4.3: tropan-6exo-yl 9-hydroxy-xanthene-9-carboxylate methobromide
0.45 g of 4d are dissolved in 4.5 mL acetonitrile, combined with 0.50 g of a
50% solution of methylbromide in acetonitrile and stirred for 24 h at RT. The
crystals precipitated are suction filtered and washed with ether. Yield 0.3 g
(53%); Melting point: 255 C.
Example 5: Tropan-6endo-yl benzilate methobromide:
Meg+/Me Br
N
H
O O
41~
HO
f5.1.: methyl benzilate 3a:.
Prepared according to step 1.1.
5.2.: Tropan-6endo-yl benzilate 4e:
0.6 g 2b and 1.6 g methyl benzilate 3a are dissolved in 10 mL toluene and
combined with 20 mg NaH. The mixture is heated to 140 C while the
methanol formed is distilled off. After 2 h it is cooled, 20m1 of water are
added,
the organic phase is separated off and extracted 2x with 30 ml of 1 N
hydrochloric acid. The aqueous phase is combined with potassium carbonate
and extracted 2x with 30ml dichloromethane. The combined organic phases
are dried, the solvent distilled off under reduced pressure and the residue is
crystallised from acetone with ethereal HCI (saturated). Yield: 1.2 g; Melting
point: 265 C.
5.3: Tropan-6endo-yl benzilate methobromide:
1.2 g 4e are dissolved in 50m1 of water, combined with potassium carbonate
and extracted 2x with 30m1 of dichloromethane. The organic phase is dried
CA 02482637 2004-10-12
WO 03/087096 17 PCT/EP03/03765
and distilled off under reduced pressure. The residue is taken up in 5 mL
acetonitrile and combined with 0.5 g of a 50% solution of methylbromide in
acetonitrile. The mixture is stirred for 24h at RT, the crystals precipitated
are
suction filtered and washed with acetone and ether. Yield 1.0 g (66%); Melting
point: 229 C.
Example 6: tropan-6endo-yl 9-hydroxy-fluorene-9-carboxylate methobromide:
Meg+/Me Br
N
H
4C::(-' O O
HO
6.1.: methyl 9-hydroxy-fluorene-9-carboxylate 3b:.
Prepared as in step 2.1.
6.2: tropan-6endo-yl 9-hydroxy-fluorene-9-carboxylate 4f:
0.6 g 2b and 1.6 g methyl 9-hydroxy-f luorene-9-carboxylate 3b are dissolved
in 10 mL toluene and combined with 20 mg NaH. The mixture is heated to
140 C while the methanol formed is distilled off. After 2 h it is cooled, 20m1
of
water are added, the organic phase is separated off and extracted 2x with 30
ml of 1 N hydrochloric acid. The aqueous phase is combined with potassium
carbonate and extracted 2x with 30ml of dichloromethane. The combined
organic phase is dried, the solvent is distilled off under reduced pressure
and
the residue is crystallised from acetone with saturated ethereal HCI. Yield:
1.2
g (73%); Melting point: 261 C.
6.3: tropan-6endo-yl 9-hydroxy-fluorene-9-carboxylate methobromide:
1.2 g of 4f are dissolved in 50ml of water, combined with potassium carbonate
and extracted 2x with 30ml of dichloromethane. The organic phase is dried
and the solvent is distilled off under reduced pressure. The residue is taken
up in 5 mL acetonitrile and combined with 0.5 g of a 50% solution of
methylbromide in acetonitrile. The mixture is stirred for 24 h at RT, the
crystals precipitated are separated off and washed with acetone and ether.
Yield: (70%).
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WO 03/087096 18 PCT/EP03/03765
Example 7: tropan-6endo-y19-hydroxy-xanthene-9-carboxylate
methobrom ide:
Me\+Me Br
N
H
O O
HO
0
7.1.: methyl 9-hydroxy-xanthene-9-carboxylate 3d:.
Prepared as in step 4.1.
7.2: tropan-6endo-yl 9-hydroxy-xanthene-9-carboxylate 4g:
0.6 g of 2b and 1.6 g of methyl 9-hydroxy-xanthene-9-carboxylate 3d are
dissolved in 10 mL toluene and combined with 20 mg NaH. The mixture is
heated to 140 C while the methanol formed is distilled off. After 2 h it is
cooled, 20 ml of water are added, the organic phase is separated off and
extracted 2x with 30 ml of 1 N hydrochloric acid. The aqueous phase is
combined with potassium carbonate and extracted 2x with 30m1 of
dichloromethane. The combined organic phase is dried, the solvent is distilled
off under reduced pressure and the residue is crystallised from acetone with
saturated ethereal HCI. Yield: 1.1 g (73%); Melting point: 212 C.
7.3: tropan-6endo-yl 9-hydroxy-xanthene-9-carboxylate methobrom ide:
1.1 g of 4g are dissolved in 50m1 of water, combined with potassium
carbonate and extracted 2x with 30m1 dichloromethane. The organic phase is
dried and the solvent distilled off under reduced pressure. The residue is
taken up in 5 mL acetonitrile and combined with 0.5 g of a 50% solution of
methylbromide in acetonitrile. The mixture is stirred for 24 h at RT, the
crystals precipitated are separated off and washed with acetone and ether.
Yield: 1.0 g (72%); Melting point: 250 C.
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WO 03/087096 19 PCT/EP03/03765
Example 8: tropan-6endo-yl 2-hydroxy-2,2-dithiophene-acetate
m ethobromide:
Me\+/Me Br
N
H
41Z O O
HO
O> U
S
S
8.1: tropan-6endo-yl 2-hydroxy-2,2-dithiophene-acetate 4h:
0.6 g 2b and 1.7 g methyl di-(2-thienyl)glycolate 3c are dissolved in 10 mL
toluene and combined with 20 mg NaH. The mixture is heated to 140 C while
the methanol formed is distilled off. After 2 h it is cooled, 20ml of water
are
added, the organic phase is separated off and extracted 2x with 30 ml of 1 N
hydrochloric acid. The aqueous phase is combined with potassium carbonate
and extracted 2x with 30ml dichloromethane. The combined organic phase is
dried, the solvent is distilled off under reduced pressure and the residue is
crystallised from acetone by means of saturated ethereal HCl. Yield: 1.1 g
(65%);
Melting point: 242 C.
8.2: tropan-6endo-yl 2-hydroxy-2,2-dithiophene-acetate methobromide:
1.1 g 4h are dissolved in 50m1 of water, combined with potassium carbonate
and extracted 2x with 30ml dichloromethane. The organic phase is dried and
the solvent is distilled off under reduced pressure. The residue is taken up
in 5
mL acetonitrile and combined with 0.5 g of a 50% solution of methylbromide in
acetonitrile. The mixture is stirred for 24 h at RT, the crystals precipitated
are
separated off and washed with acetone and ether. Yield: 1.1 g (79%); Melting
point: 218 C.
It was found that the compounds according to the invention of formula 1 are
antagonists of the M3 receptor (Muscarinic Receptor subtype 3). The
compounds according to the invention have Ki values of less than 100nM in
terms of their affinity for the M3 receptor. These values were determined by
the method described below.
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WO 03/087096 20 PCT/EP03/03765
Chemicals
3H-NMS was obtained from Messrs Amersham of Braunschweig, with a
specific radioactivity of 3071 GBq/mmol (83 Ci/mmol). All the other reagents
were obtained from Serva of Heidelberg and Merck of Darmstadt.
Cell membranes:
We used cell membranes from CHO (Chinese hamster ovary) cells which
were transfected with the corresponding genes of the human muscarinic
receptor subtypes hm1 to hm5 (BONNER). The cell membranes of the
desired subtype were thawed, resuspended by hand with a glass
homogeniser and diluted with HEPES buffer to a final concentration of 20-30
mg of protein/ml.
Receptor binding studies:
The binding assay was carried out in a final volume of I ml and consisted of
100 pl of unlabelled substance in various concentrations, 100 pl of
radioligand
(3H-N-methylscopolamine 2 nmol/L (3H-NMS), 200 pl of membrane
preparation and 600 ..il of HEPES buffer (20 mmol/L HEPES, 10 mmol/L
MgC12, 100 mmol/L NaCl, adjusted with 1 mol/L NaOH to pH 7.4).
The nonspecific binding was determined using 10 pmol/I of atropine.
The preparation was incubated for 45 min. at 37 C in 96-well microtitre plates
(Beckman, polystyrene, No. 267001) as a double measurement. The
incubation was ended by filtering using an Inotech Cell Harvester (type IH
110) through Whatman G-7 filters. The filters were washed with 3 ml of ice-
cooled HEPES buffer and dried before measuring.
Determining the radioactivity:
The radioactivity of the filter mats was measured simultaneously using a two-
dimensional digital autoradiograph (Berthold, Wildbad, type 3052).
Evaluation:
The Ki values were calculated using implicit equations which were derived
directly from the mass-action law, with the model for the 1 receptor 2 ligand
reaction (SysFit software, SCHITTKOWSKI).
Literature:
BONNER TI, New subtypes of muscarinic acetylcholine receptors
Trends Pharmacol. Sci. 10, Suppl.: 11-15 (1989); SCHITTKOWSKI K
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WO 03/087096 21 PCTIEPO3/03765
Parameter estimation in systems of nonlinear equations Numer Math. 68:
129-142 (1994).
The compounds of formula I according to the invention are characterised by
their range of uses in the therapeutic field. Particular mention should be
made
of those applications for which the compounds of formula 1 according to the
invention may preferably be used on the basis of their pharmaceutical activity
as anticholinergics.
These are for example the treatment of asthma or COPD (chronic obstructive
pulmonary disease). The compounds of general formula 1 may also be used
to treat vagally induced sinus bradycardia and to treat heart rhythm
disorders.
Generally, the compounds according to the invention may also be used
therapeutically to treat spasms, for example, in the gastrointestinal tract .
They may also be used to treat spasms in the urinary tract and also to treat
menstrual pain, for example. Of the ranges of indications mentioned above,
the treatment of asthma and COPD with the compounds of formula 1
according to the invention is of particular importance.
The compounds of general formula 1 may be used on their own or in
conjunction with other active substances of formula 1. The compounds of
general formula 1 may also be used in combination with other
pharmacologically active substances. These may be, in particular,
betamimetics, antiallergics, dopamine agonists, PAF antagonists, PDE-IV
inhibitors, leukotriene antagonists, p38 kinase inhibitors, EGFR kinase
inhibitors and corticosteroids as well as combinations of active substances
thereof.
Examples of betamimetics which may be used according to the invention in
conjunction with the compounds of formula 1 include compounds selected
from among bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol,
formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol,
salmeterol, sulphonterol, terbutaline, tolubuterol, 4-hydroxy-7-[2-{[2-{[3-(2-
phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone, 1-
(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-
butylamino]ethanol, 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-
benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-
1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-
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WO 03/087096 22 PCT/EP03/03765
propylam ino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-
methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-
1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-
propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-
(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, 5-
hydroxy-8-(1 -hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one,
1-(4-amino-3-chloro-5-trifluormethylphenyl)-2-tert.-butylamino)ethanol and 1-
(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol,
optionally in the form of the racemates, the enantiomers, the diastereomers
and optionally the pharmacologically acceptable acid addition salts, the
solvates and/or the hydrates thereof. Most preferably, the betamimetics used
as active substances in conjunction with the compounds of formula I
according to the invention are selected from among fenoterol, formoterol,
salmeterol, 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-
benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-
1,4-benzoxazin-8-yl]-2-[3-(4-N, N-dimethylam inophenyl)-2-methyl-2-
propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-
methoxyphenyl)-2-methyl-2-propylam ino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-
1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-
propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-
(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylam ino}ethanol,
optionally in the form of the racemates, the enantiomers, the diastereomers
and optionally the pharmacologically acceptable acid addition salts and the
hydrates thereof. Of the betamimetics mentioned above the compounds
formoterol and salmeterol are particularly preferred, optionally in the form
of
the racemates, the enantiomers, the diastereomers and optionally the
pharmacologically acceptable acid addition salts thereof, and the hydrates
thereof. According to the invention, the acid addition salts of the
betamimetics
selected, for example, from among the hydrochloride, hydrobromide,
sulphate, phosphate, fumarate, methanesulphonate and xinafoate are
preferred. Particularly preferred in the case of salmeterol are the salts
selected from among the hydrochloride, sulphate and xinafoate, of which the
xinafoate is particularly preferred. Particularly preferred in the case of
formoterol are the salts selected from among the hydrochloride, sulphate and
fumarate, of which the hydrochloride and fumarate are particularly preferred.
According to the invention, formoterol fumarate is of exceptional importance.
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WO 03/087096 23 PCT/EP03/03765
Within the scope of the present invention, the corticosteroids which may
optionally be used in conjunction with the compounds of formula 1 may be
compounds selected from among flunisolide, beclomethasone, triamcinolone,
budesonide, fluticasone, mometasone, ciclesonide, rofleponide, GW215864,
KSR 592, ST-126 and dexamethasone. Preferably, within the scope of the
present invention, the corticosteroids are selected from among flunisolide,
beclomethasone, triamcinolone, budesonide, fluticasone, mometasone,
ciclesonide and dexamethasone, while budesonide, fluticasone, mometasone
and ciclesonide are important and budesonide and fluticasone are particularly
important. In some cases, within the scope of the present patent application,
the term steroids is used on its own instead of the word corticosteroids. Any
reference to steroids within the scope of the present invention includes a
reference to salts or derivatives which may be formed from the steroids.
Examples of possible salts or derivatives include: sodium salts,
sulphobenzoates, phosphates, isonicotinates, acetates, propionates,
dihydrogen phosphates, palmitates, pivalates or furoates. In some cases the
corticosteroids may also occur in the form of their hydrates.
Examples of PDE-IV inhibitors which may be used according to the invention
as a combination with the compound of formula 1 include compounds
selected from among enprofylline, roflumilast, ariflo, Bay-198004, CP-
325,366, BY343, D-4396 (Sch-351591), V-11294A and AWD-12-281.
Preferred PDE-IV inhibitors are selected from among enprofylline, roflumilast,
ariflo and AWD-12-281, while AWD-12-281 is particularly preferred as the
combination partner with the compound of formula I according to the
invention. Any reference to the abovementioned PDE-IV inhibitors also
includes, within the scope of the present invention, a reference to any
pharmacologically acceptable acid addition salts thereof which may exist. By
the physiologically acceptable acid addition salts which may be formed by the
abovementioned PDE-IV inhibitors are meant, for example, pharmaceutically
acceptable salts selected from among the salts of hydrochloric acid,
hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid,
acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric
acid and
maleic acid. According to the invention, the salts selected from among the
acetate, hydrochloride, hydrobromide, sulphate, phosphate and
methanesu[phonate are preferred in this context.
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WO 03/087096 24 PCT/EP03/03765
Within the scope of the present invention, the term dopamine agonists, which
may optionally be used in conjunction with the compounds of formula 1,
denotes compounds selected from among bromocriptine, cabergolin, alpha-
dihydroergocryptine, lisuride, pergolide, pramipexol, roxindol, ropinirol,
talipexol, tergurid and viozan. It is preferable within the scope of the
present
invention to use, as combination partners with the compounds of formula 1,
dopamine agonists selected from among pramipexol, talipexol and viozan,
pramipexol being of particular importance. Any reference to the
abovementioned dopamine agonists also includes, within the scope of the
present invention, a reference to any pharmacologically acceptable acid
addition salts and hydrates thereof which may exist. By the physiologically
acceptable acid addition salts thereof which may be formed by the
abovementioned dopamine agonists are meant, for example,
pharmaceutically acceptable salts selected from among the salts of
hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,
methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid,
citric acid, tartaric acid and maleic acid.
Examples of antiallergic agents which may be used according to the invention
as a combination with the compound of formula 1 include epinastin, cetirizin,
azelastin, fexofenadin, levocabastin, loratadine, mizolastin, ketotifen,
emedastin, dimetinden, clemastine, bamipin, cexchloropheniramine,
pheniramine, doxylamine, chlorophenoxamine, dimenhydrinate,
diphenhydramine, promethazine, ebastin, desloratidine and meclizine.
Preferred antiallergic agents which may be used within the scope of the
present invention in combination with the compounds of formula 1 according
to the invention are selected from among epinastin, cetirizin, azelastin,
fexofenadin, levocabastin, loratadine, ebastin, desloratidine and mizolastin,
epinastin and desloratidine being particularly preferred. Any reference to the
abovementioned antiallergic agents also includes, within the scope of the
present invention, a reference to any pharmacologically acceptable acid
addition salts thereof which may exist.
Examples of PAF antagonists which may be used according to the invention
as a combination with the compounds of formula 1 include
4-(2-chlorophenyl)-9-methyl-2-[3-(4-morpholinyl)-3-propanon-1-yl]-6H-
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WO 03/087096 25 PCT/EP03/03765
thieno-[3,2-f] [1,2,4]triazolo[4.3-a][1,4]diazepine, 6-(2-chlorophenyl)-8,9-
dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclo-penta-
[4.5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine.
Examples of EGFR kinase inhibitors which may be used as a combination
with the compounds of formula 1 according to the invention include, in
particular, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[4-((R)-6-methyl-2-oxo-
morpholin-4-yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline, 4-[(3-chloro-4-
fluoro-phenyl)amino]-7-[4-((S)-6-methyl-2-oxo-morpholin-4-yl)-butyloxy]-6-
[(vinylcarbonyl)amino]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-(2-
{4-[(S)-(2-oxo-tetrahydrofuran-5-yl)carbony!]-piperazin-1-yl}-ethoxy)-
6-[(vinylcarbonyl)amino]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-
((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-6-[(vinylcarbonyl)am ino]-
quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[2-(ethoxycarbonyl)-
ethyl]-N-[(ethoxycarbonyl)methyl]amino}-1-oxo-2-buten-1-yl)amino]-7-
cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-
(morpholin-4-yl)-1-oxo-2-buten-1-yl]am ino}-7-cyclopropylmethoxy-quinazoline
and 4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(morpholin-4-yl)-propyloxy]-7-
methoxy-quinazoline. Any reference to the abovementioned EGFR kinase
inhibitors also includes, within the scope of the present invention, a
reference
to any pharmacologically acceptable acid addition salts thereof which may
exist. By the physiologically or pharmacologically acceptable acid addition
salts thereof which may be formed by the EGFR kinase inhibitors are meant,
according to the invention, pharmaceutically acceptable salts selected from
among the salts of hydrochloric acid, hydrobromic acid, sulphuric acid,
phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic
acid, lactic acid, citric acid, tartaric acid and maleic acid. The salts of
the
EGFR kinase inhibitors selected from among the salts of acetic acid,
hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid and
methanesulphonic acid are preferred according to the invention.
Particularly preferred examples of p38 kinase inhibitors which may be used as
a combination with the compounds of formula 1 according to the invention
include 1-[5-tent-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-
ethoxy)naphthalin-1-yl]-urea; 1-[5-tent-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-
(2-
(1-oxothiomorphol in-4-yl)ethoxy)naphthalin-1-yl]-urea; 1-[5-tent-butyl-2-(2-
methyl pyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-pyridine-4-yl-ethoxy)naphthalin-
1-
yl]-urea; 1-[5-tent-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-
WU U3/087096 26 PCT/EP03/03765
morpho(in-4-yl-ethoxy)naphthalin-1-yl]-urea or 1-[5-tent-butyl-2-methyl-2H-
pyrazol-3-yl]-3-[4-(2-morphoIin-4-yl-ethoxy)naphtha len-1-yl]-urea. Any
reference to the abovementioned p38 kinase inhibitors also includes, within
the scope of the present invention, a reference to any pharmacologically
acceptable acid addition salts thereof which may exist. By the physiologically
or pharmacologically acceptable acid addition salts thereof which may be
formed by the p38 kinase inhibitors are meant, according to the invention,
pharmaceutically acceptable salts selected from among the salts of
hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,
methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid,
citric acid, tartaric acid and maleic acid.
If the compounds of formula 1 are used in conjunction with other active
substances, the combination with steroids, PDE IV inhibitors or betamimetics
is particularly preferred, of the categories of compounds mentioned above.
The combination with betamimetics, particularly with long-acting
betamimetics, is of particular importance. The combination of the compounds
of formula 1 according to the invention with salmeterol or formoterol is
particularly preferred.
Suitable preparations for administering the salts of formula 1 include for
example tablets, capsules, suppositories and solutions, etc. Administration of
the compounds according to the invention by inhalation is of particular
importance according to the invention (particularly for treating asthma or
COPD). The content of the pharmaceutically active compound(s) should be in
the range from 0.05 to 90 wt.-%, preferably 0.1 to 50 wt.-% of the
composition as a whole. Suitable tablets may be obtained, for example, by
mixing the active substance(s) with known excipients, for example inert
diluents such as calcium carbonate, calcium phosphate or lactose,
disintegrants such as corn starch or alginic acid, binders such as starch or
gelatine, lubricants such as magnesium stearate or talc and/or agents for
delaying release, such as carboxymethyl cellulose, cellulose acetate
phthalate, or polyvinyl acetate. The tablets may also comprise several layers.
Coated tablets may be prepared accordingly by coating cores produced
analogously to the tablets with substances normally used for tablet coatings,
for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
To achieve delayed release or prevent incompatibilities the core may also
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WO 03/087096 27 PCT/EP03/03765
consist of a number of layers. Similarly the tablet coating may consist of a
number or layers to achieve delayed release, possibly using the excipients
mentioned above for the tablets.
Syrups or elixirs containing the active substances or combinations thereof
according to the invention may additionally contain a sweetener such as
saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a
flavouring such as vanillin or orange extract. They may also contain
suspension adjuvants or thickeners such as sodium carboxymethyl cellulose,
wetting agents such as, for example, condensation products of fatty alcohols
with ethylene oxide, or preservatives such as p-hydroxybenzoates.
Solutions are prepared in the usual way, e.g. with the addition of isotonic
agents, preservatives such as p-hydroxybenzoates or stabilisers such as
alkali metal salts of ethylenediaminetetraacetic acid, optionally using
emulsifiers and/or dispersants, while if water is used as diluent, for
example,
organic solvents may optionally be used as solubilisers or dissolving aids,
and
the solutions may be transferred into injection vials or ampoules or infusion
bottles.
Capsules containing one or more active substances or combinations of active
substances may for example be prepared by mixing the active substances
with inert carriers such as lactose or sorbitol and packing them into gelatine
capsules.
Suitable suppositories may be made for example by mixing with carriers
provided for this purpose, such as neutral fats or polyethyleneglycol or the
derivatives thereof.
Excipients which may be used include, for example, water, pharmaceutically
acceptable organic solvents such as paraffins (e.g. petroleum fractions),
vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional
alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral
powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g.
highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose
and glucose), emulsifiers (e.g. lignin, spent sulphite liquors,
methylcellulose,
starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate,
talc,
stearic acid and sodium lauryl sulphate).
VV %j W/VS/Vyb 28 PCT/EP03/03765
For oral use the tablets may obviously contain, in addition to the carriers
specified, additives such as sodium citrate, calcium carbonate and dicalcium
phosphate together with various additional substances such as starch,
preferably potato starch, gelatin and the like. Lubricants such as magnesium
stearate, sodium laurylsulphate and talc may also be used to produce the
tablets. In the case of aqueous suspensions the active substances may be
combined with various flavour enhancers or colourings in addition to the
abovementioned excipients.
For administering the compounds of formula I for the treatment of asthma or
COPD it is particularly preferred according to the invention to use
preparations or pharmaceutical formulations which are suitable for inhalation.
Inhalable preparations include inhalable powders, propellant-containing
metering aerosols or propellant-free inhalable solutions Within the scope of
the present invention, the term propellant-free inhalable solutions also
includes concentrates or sterile inhalable solutions ready for use. The
formulations which may be used within the scope of the present invention are
described in more detail in the next part of the specification
The inhalable powders which may be used according to the invention may
contain 1 either on their own or in admixture with suitable physiologically
acceptable excipients.
If the active substances I are present in admixture with physiologically
acceptable excipients, the following physiologically acceptable excipients may
be used to prepare these inhalable powders according to the invention:
monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose,
saccharose, maltose), oligo- and polysaccharides (e.g. dextrans),
polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride,
calcium carbonate) or mixtures of these excipients. Preferably, mono- or
disaccharides are used, while the use of lactose or glucose is preferred,
particularly, but not exclusively, in the form of their hydrates. For the
purposes
of the invention, lactose is the particularly preferred excipient, while
lactose
monohydrate is most particularly preferred.
Within the scope of the inhalable powders according to the invention the
excipients have a maximum average particle size of up to 250 pm, preferably
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WO 03/087096 29 PCT/EP03/03765
between 10 and 150 pm, most preferably between 15 and 80 pm. It may
sometimes seem appropriate to add finer excipient fractions with an average
particle size of 1 to 9 pm to the excipient mentioned above. These finer
excipients are also selected from the group of possible excipients listed
hereinbefore. Finally, in order to prepare the inhalable powders according to
the invention, micronised active substance 1, preferably with an average
particle size of 0.5 to 10 pm, more preferably from 1 to 5 m, is added to the
excipient mixture. Processes for producing the inhalable powders according
to the invention by grinding and micronising and finally mixing the
ingredients
together are known from the prior art. The inhalable powders according to the
invention may be administered using inhalers known from the prior art.
The inhalation aerosols containing propellant gas according to the invention
may contain the compounds I dissolved in the propellant gas or in dispersed
form. The compounds 1 may be contained in separate formulations or in a
common formulation, in which the compounds 1 are either both dissolved,
both dispersed or in each case only one component is dissolved and the other
is dispersed. The propellant gases which may be used to prepare the
inhalation aerosols are known from the prior art. Suitable propellant gases
are selected from among hydrocarbons such as n-propane, n-butane or
isobutane and halohydrocarbons such as fluorinated derivatives of methane,
ethane, propane, butane, cyclopropane or cyclobutane. The abovementioned
propellant gases may be used on their own or in admixture. Particularly
preferred propellant gases are halogenated alkane derivatives selected from
TG134a and TG227 and mixtures thereof.
The propellant-driven inhalation aerosols may also contain other ingredients
such as co-solvents, stabilisers, surfactants, antioxidants, lubricants and pH
adjusters. All these ingredients are known in the art.
The propellant-driven inhalation aerosols according to the invention
mentioned above may be administered using inhalers known in the art (MDIs
= metered dose inhalers).
Moreover, the active substances I according to the invention may be
administered in the form of propellant-free inhalable solutions and
suspensions. The solvent used may be an aqueous or alcoholic, preferably
an ethanolic solution. The solvent may be water on its own or a mixture of
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WO 03/087096 30 PCT/EP03/03765
water and ethanol. The relative proportion of ethanol compared with water is
not limited but the maximum is up to 70 percent by volume, more particularly
up to 60 percent by volume and most preferably up to 30 percent by volume.
The remainder of the volume is made up of water. The solutions or
suspensions containing I are adjusted to a pH of 2 to 7, preferably 2 to 5,
using suitable acids. The pH may be adjusted using acids selected from
inorganic or organic acids. Examples of particularly suitable inorganic acids
include hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid
and/or
phosphoric acid. Examples of particularly suitable organic acids include
ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic
acid,
fumaric acid, acetic acid, formic acid and/or propionic acid etc. Preferred
inorganic acids are hydrochloric and sulphuric acids. It is also possible to
use
the acids which have already formed an acid addition salt with one of the
active substances. Of the organic acids, ascorbic acid, fumaric acid and
citric
acid are preferred. If desired, mixtures of the above acids may be used,
particularly in the case of acids which have other properties in addition to
their
acidifying qualities, e.g. as flavourings, antioxidants or complexing agents,
such as citric acid or ascorbic acid, for example. According to the invention,
it
is particularly preferred to use hydrochloric acid to adjust the pH.
According to the invention, the addition of editic acid (EDTA) or one of the
known salts thereof, sodium edetate, as stabiliser or complexing agent may
be unnecessary in these formulations. Other embodiments may contain this
compound or these compounds. In a preferred embodiment the content
based on sodium edetate is less than 100 mg/100ml, preferably less than
50mg/100ml, more preferably less than 20mg/100ml. Generally, inhalable
solutions in which the content of sodium edetate is from 0 to 10mg/100mI are
preferred.
Co-solvents and/or other excipients may be added to the propellant-free
inhalable solutions according to the invention. Preferred co-solvents are
those which contain hydroxyl groups or other polar groups, e.g. alcohols -
particularly isopropyl alcohol, glycols - particularly propyleneglycol,
polyethyleneglycol, polypropyleneglycol, glycolether, glycerol,
polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms
excipients and additives in this context denote any pharmacologically
acceptable substance which is not an active substance but which can be
formulated with the active substance or substances in the pharmacologically
WU 03/087096 31 PCT/EP03/03765
suitable solvent in order to improve the qualitative properties of the active
substance formulation. Preferably, these substances have no
pharmacological effect or, in connection with the desired therapy, no
appreciable or at least no undesirable pharmacological effect. The excipients
and additives include, for example, surfactants such as soya lecithin, oleic
acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other
stabilisers, complexing agents, antioxidants and/or preservatives which
guarantee or prolong the shelf life of the finished pharmaceutical
formulation,
flavourings, vitamins and/or other additives known in the art. The additives
also include pharmacologically acceptable salts such as sodium chloride as
isotonic agents.
The preferred excipients include antioxidants such as ascorbic acid, for
example, provided that it has not already been used to adjust the pH, vitamin
A, vitamin E, tocopherols and similar vitamins and provitamins occurring in
the
human body.
Preservatives may be used to protect the formulation from contamination with
pathogens. Suitable preservatives are those which are known in the art,
particularly cetyl pyridinium chloride, benzalkonium chloride or benzoic acid
or
benzoates such as sodium benzoate in the concentration known from the
prior art. The preservatives mentioned above are preferably present in
concentrations of up to 50 mg/100 ml, more preferably between 5 and 20
Mg/100 ml.
Preferred formulations contain, in addition to the solvent water and the
active
substance 1, only benzalkonium chloride and sodium edetate. In another
preferred embodiment, no sodium edetate is present.
The dosage of the compounds according to the invention is naturally highly
dependent on the method of administration and the complaint which is being
treated. When administered by inhalation the compounds of formula 1 are
characterised by a high potency even at doses in the pg range. The
compounds of formula I may also be used effectively above the pg range.
The dosage may then be in the gram range, for example.
Particularly when administered by routes other than by inhalation the
compounds according to the invention may be administered in higher doses
(for example, but not restrictively, in the range from 1 to 1000 mg).
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WO 03/087096 32 PCT/EP03/03765
The following examples of formulations illustrate the present invention
without
restricting its scope:
Examples of pharmaceutical formulations
A) Tablets per tablet
active substance 1 100 mg
lactose 140 mg
corn starch 240 mg
polyvinylpyrrolidone 15 mg
magnesium stearate 5 mg
500 mg
The finely ground active substance, lactose and some of the corn starch are
mixed together. The mixture is screened, then moistened with a solution of
polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The
granules, the remaining corn starch and the magnesium stearate are
screened and mixed together. The mixture is compressed to produce tablets
of suitable shape and size.
B) Tablets per tablet
active substance 1 80 mg
lactose 55 mg
corn starch 190 mg
microcrystalline cellulose 35 mg
polyvinylpyrrolidone 15 mg
sodium-carboxymethyl starch 23 mg
magnesium stearate 2 mg
400 mg
The finely ground active substance, some of the corn starch, lactose,
microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the
mixture is screened and worked with the remaining corn starch and water to
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form a granulate which is dried and screened. The sodium carboxymethyl
starch and the magnesium stearate are added and mixed in and the mixture is
compressed to form tablets of a suitable size.
C) Ampoule solution
active substance 1 50 mg
sodium chloride 50 mg
water for inj. 5 ml
The active substance is dissolved in water at its own pH or optionally at pH
5.5 to 6.5 and sodium chloride is added to make the solution isotonic. The
resulting solution is filtered to remove pyrogens and the filtrate is
transferred
under aseptic conditions into ampoules which are then sterilised and heat-
sealed. The ampoules contain 5 mg, 25 mg and 50 mg of active substance.
D) Metering aerosol
active substance 1 0.005
Sorbitan trioleate 0.1
Monofluorotrichloromethane and
Difluorodichloromethane 2 : 3 ad 100
The suspension is transferred into a conventional aerosol container with
metering valve. Preferably 50 pl suspension are released on each actuation.
The active substance may also be released in higher doses if desired
(e.g. 0.02 wt.-%).
E) Solutions (in mg/100ml)
active substance 1 333.3 mg
formoterol fumarate 333.3 mg
benzalkonium chloride 10.0 mg
EDTA 50.0 mg
HCI (1n) ad pH 3.4
This solution may be prepared in the usual way.
WO 03/087096 34 PCT/EP03/03765
F) Inhalable powder
active substance 1 6 pg
formoterol fumarate 6 pg
lactose monohydrate ad 25 mg
The inhalable powder is prepared in the usual way by mixing the individual
ingredients.
G) Inhalable powder
active substance 1 10 pg
lactose monohydrate ad 5 mg
The inhalable powder is prepared in the usual way by mixing the individual
ingredients.
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