Note: Descriptions are shown in the official language in which they were submitted.
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1
New fluorenecarboxylic acid esters, process for the manufacture thereof
and use thereof as medicaments
The present invention relates to new fluorenecarboxylic acid esters
of general formula 1
i
R\+ /R
N X-
/ H
A O O
R3 R R3'
R4 R 4
1
wherein
A denotes a double-bonded group which is
or
H2 H2 H H H O H ;
X- denotes an anion with a single negative charge,
R denotes hydroxy, methyl, ethyl, -CF3, CHF2 or fluorine;
R1 and R2 which may be identical or different denote Cl-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, NO2 or
halogen.
The present invention further relates to processes for preparing the
compounds of general formula 1 as described herein and their use as
pharmaceutical compositions.
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la
Hence, in another aspect, the invention relates to the use of a
compound of formula 1 as described herein as a medicament.
In another aspect, the invention relates to the use of a compound of
formula 1 as described herein for preparing a pharmaceutical composition for
the
treatment of a disease in which an anticholinergic can develop a therapeutic
benefit.
In another aspect, the invention relates to the use of a compound of
formula 1 as described herein for preparing a pharmaceutical composition for
the
treatment of asthma, COPD, vagally induced sinus bradycardia, heart rhythm
disorders, a spasm in the gastrointestinal tract, a spasm in the urinary tract
or
menstrual pain.
In another aspect, the invention relates to a pharmaceutical
preparation containing one or more compounds of formula 1 as described herein
in combination with a conventional excipient and/or carrier.
The invention further relates to a compound of formula 4
R1
N
H
A O O
R3 R R3'
R4 \ \ 4
R 4
wherein the groups A, R, R1, R3, R3' , R4 and R4, have the meanings
as described above, optionally in the form of an acid addition salt thereof.
The invention further relates to the use of a compound of formula 2
Ri
N
P/:~~ H
A OH 2
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lb
wherein the groups A and R1 have the meanings as described
above, optionally in the form of an acid addition salt thereof, for preparing
a
compound of general formula 1 as described above.
Description of the invention
The present invention relates to compounds of general formula 1
i
R2+'R
N X-
/ H
A O O
R3 R R3
R4 R 4,
wherein
A denotes a double-bonded group selected from among
H2 H2 H H and H O H.
X- denotes an anion with a single negative charge, preferably an
anion selected from among chloride, bromide, iodide, sulphate, phosphate,
methanesuIphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate,
oxalate,
succinate, benzoate and p-toluenesuIphonate;
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R denotes hydrogen, hydroxy, methyl, ethyl, -CF3, CHF2 or
fluorine;
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, NO2 or halogen.
Preferred compounds of general formula 1 are those wherein
A denotes a double-bonded group selected from among
C-C C=C and ;
H2 H2 H H H O H
X - denotes an anion with a single negative charge selected from
among chloride, bromide, 4-toluenesulphonate and
methanesulphonate, preferably bromide;
R denotes hydroxy, methyl or fluorine;
R1 and R2 which may be identical or different denote methyl, ethyl or
fluoroethyl;
R3, R4, R3' and R4' which may be identical or different represent hydrogen,
methyl, methyloxy, hydroxy, -CF3, -CHF2 or fluorine.
Particularly preferred compounds of general formula 1 are those wherein
A denotes a double-bonded group selected from among
C=C H H and
H O H '
X - denotes an anion with a single negative charge selected from
among chloride, bromide and methanesulphonate, preferably
bromide;
R denotes hydroxy, methyl or fluorine, preferably methyl or hydroxy;
R1 and R2 which may be identical or different represent methyl or ethyl,
preferably methyl;
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R3, R4, R3' and R4' which may be identical or different represent hydrogen,
-CF3, -CHF2 or fluorine, preferably hydrogen or fluorine.
Of particular importance according to the invention are compounds of general
formula 1 wherein
A denotes a double-bonded group selected from among
C=G H H and
H O H
X - denotes bromide;
R denotes hydroxy or methyl, preferably methyl;
R1 and R2 which may be identical or different represent methyl or ethyl,
preferably methyl;
R3, R4, R3' and R4' which may be identical or different represent hydrogen or
fluorine.
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.
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.
Also of particular importance according to the invention are those compounds
of general formula I wherein the ester substituent is in the a configuration
on
the nitrogen bicyclic group. These compounds correspond to general formula
1-a
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4
R2+~R~
N X
H
A
O O
R
R3 R3'
R4 R4'
1-a
The following compounds are of particular importance according to the
invention:
tropenol 9-hydroxy fluorene-9-carboxylate methobromide ;
tropenol 9-fluoro-fluorene-9-carboxylate methobromide ;
scopine 9-hydroxy-fluorene-9-carboxylate methobromide ;
- scopine 9-fluoro-fluorene-9-carboxylate methobromide ;
tropenol 9-methyl-fluorene-9-carboxylate methobromide ;
- scopine 9-methyl-fluorene-9-carboxylate methobromide .
The alkyl groups used, unless otherwise stated, are branched and
unbranched alkyl groups having 1 to 5 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 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
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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
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). 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
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6
esterification with the corresponding alcohols or by halogenation with the
corresponding halogenation reagents.
R4 R3
R R'
R O R R\+ R' x
N- 3 N- N
R '
R3. R? X
H H _ H
A OH A O O A O O
R R
R3 R R3 R3
2 R 4 R4, R4 R4,
Diagram 1:
As can be seen from Diagram 1, the compounds of formula 2 may be used
as starting products for preparing the compounds of formula 1. These
compounds are known in the art.
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 C1-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 1 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.
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Alternatively to the method of synthesising the compounds of formula 4
shown in Diagram 1 the derivatives 4, wherein the nitrogen bicyclic group
denotes a scopine derivative may be obtained by oxidising (epoxidising)
compounds of formula 4 wherein the nitrogen bicyclic group is a tropenyl
group. According to the invention the following procedure may be used.
The compound 4 wherein A denotes -CH=CH- is suspended in a polar organic
solvent, preferably in a solvent selected from among N-methyl-2-pyrrolidone
(NMP), dimethylacetamide and dimethylformamide, preferably
dimethylformamide and then heated to a temperature of about 30-90 C,
preferably 40-70 C. Then a suitable oxidising agent is added and the mixture
is stirred at constant temperature for 2 to 8 hours, preferably 3 to 6 hours.
The
oxidising agent is preferably vanadium pentoxide mixed with H202, most
preferably H202-urea complex combined with vanadium pentoxide. The
mixture is worked up in the usual way. The products may be purified by
crystallisation or chromatography depending on their tendency to crystallise.
Alternatively, the compounds of formula 4 wherein R denotes halogen may
also be prepared by the method shown in Diagram 2.
R R'
N N
H H
A O O A O O
HO R
R3 R3' R3 R3,
R4 R 4, R4 R4.
4 (wherein R= OH) 4 (wherein 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
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8
R'
N
H
A O O
R
R3 R3,
R4 4.
R 4
wherein the groups A, R, R1, R3, R3', R4 and R4' 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.
As in the compounds of general formula I 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 of the "-C- R" group in the
compounds of general formula 4 as well. 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 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, R3' and R4' have the
same meaning.
According to the invention, the compounds of formula 4 in the a-configured
form are preferably used as the starting materials. These a-configured
compounds are therefore of particularly importance according to the invention
and correspond to general formula 4-a
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R
N
H
A
O O
R
R3 R3,
R4 \ a.
R 4-a.
In another aspect the present invention relates to the use of compounds of
general formula 2 for preparing the compounds of general formula 4.
Moreover the present invention relates to the use of the compounds of
general formula 2 as starting materials for preparing the compounds of
general formula 1. Moreover the present invention relates to the use of the
compounds of general formula 4 as an intermediate product in the preparation
of the compounds of general formula 1.
The examples of synthesis described below serves to illustrate the present
invention still further. However, they are to be regarded as only an example
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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Example 1: tropenol 9-hydroxy-fluorene-9-carboxylate methobromide :
Me\+/Me Sr -
N
H
O O
HO
1.1.: methyl 9-hydroxy-fluorene-9-carboxylate 3a:.
50.4 g (0.223 mol) of 9-hydroxy-9-fluorenecarboxylic acid are dissolved in 500
ml of methanol, combined with 5 ml (0.089 mol) of conc. sulphuric acid and
refluxed for 1 hour. After cooling, 100 ml of sodium hydrogen carbonate
solution (about pH 8) are added and the methanol is largely evaporated down.
The mixture 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 of white crystals (= 93% of theory).
1.2: tropenol 9-hydroxy-fluorene-9-carboxylate 4a:
13.4 g (0.056 mol) of methylester 3a, 11.65 g (0.084 mol) of tropenol and 0.3
g of sodium are heated as a melt at 75 mbar for 4 h over a bath of boiling
water with occasional agitation. After cooling the sodium residues are
dissolved with acetonitrile, the solution is evaporated to dryness and the
residue is extracted with dichloromethane/water. The organic phase is
washed with water, dried over MgSO4 and the solvent is distilled off. The
product is purified by recrystallisation from diethyl ether.
Yield: 11.40 g of white crystals (= 29 % of theory).
1.3: tropenol 9-hydroxy-fluorene-9-carboxylate methobromide :
1.75 g (0.005 mol) of 4a are taken up in 30 ml dichloromethane and 15 ml
acetonitrile and combined with 2.85 g (0.015 mol) of 50% methylbromide
solution in acetonitrile. The reaction mixture is left to stand for 3 days at
ambient temperature, during which time the product crystallises. The crystals
precipitated are separated off and recrystallised from diethyl ether to purify
them.
Yield: 1.95 g of white crystals (= 88 % of theory); Melting point: 250 C.
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Elemental analysis: calculated: C (62.45) H (5.47) N (3.17)
found: C (61.53) H (5.84) N (3.22).
Example 2: tropenol 9-fl uoro-fluorene-9-ca rboxv late methobromide
Mel+/Me
N
Br
yH
O O
F
\ ( \
2.1: tropenol 9-fluoro-fluorene-9-carboxvlate 4b:
1.66 ml (0.009 mol) of bis-(2-methoxyethyl)-aminosulphur trifluoride are
placed in 10 ml dichloromethane and within 20 minutes at 15 -20 C a
solution of 2.4g (0.007 mol) of 4a in 25 ml dichloromethane is added dropwise
thereto.
The mixture is stirred for 20 h at ambient temperature, cooled to 0 C and
carefully combined with 80 ml of water with thorough stirring. Then the
mixture
is carefully adjusted to pH 8 with aqueous NaHCO3 solution, the organic
phase is separated off, the aqueous phase is extracted again with
dichloromethane, the combined organic phases are washed with water, dried
over MgSO4 and evaporated to dryness. The hydrochloride is precipitated and
recrystallised from acetonitrile/diethyl ether. Then the free base is
liberated
again using 10% aq. sodium carbonate solution. Yield: 1.05 g bright yellow
crystals (= 53 % of theoretical)
2.2: tropenol 9-fluoro-fluorene-9-carboxvlate methobromide :
1.05 g (0.003 mol) of 4b are taken up in 20 ml acetonitrile and reacted with
1.71 g (0.009 mol) of 50% methyl bromide solution in acetonitrile analogously
to step 1.3. To purify it the product is recrystallised from acetonitrile.
Yield: 0.80 g of white crystals (= 60 % of theoretical); melting point: 252 C.
Elemental analysis: calculated: C (62.17) H (5.22) N (3.15)
found: C (62.04) H (5.23) N (3.15).
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Example 3: scopine 9-hydroxy-fluorene-9-carboxylate methobromide
Mew+/Me Br
N
0 H
O O
HO
3.1: scopine 9-hydroxy-fluorene-9-carboxylate 4c:
9.0 g (0.026 mol) of tropenol ester 4a are suspended in 90 ml of
dimethylformamide and combined with 0.47 g (0.003 mol) of vanadium-(V)-
oxide. At 60 C a solution of 4.89 g (0.052 mol) of H202-urea in 20 ml of water
is added dropwise and stirred for 6 hours at 60 C. After cooling to 20 C the
precipitate formed is suction filtered, the filtrate is adjusted to pH 2 with
4 N
hydrochloric acid and combined with Na2S2O5 dissolved in water. The
resulting solution is evaporated to dryness, the residue is extracted with
dichloromethane/water. The acidic aqueous phase is made basic with
Na2CO3, extracted with dichloromethane and the organic phase is dried over
Na2SO4 and concentrated.
Then 1 ml of acetylchioride is added at ambient temperature and the mixture
is stirred for 1 hour. After extraction with 1 N hydrochloric acid the aqueous
phase is made basic, extracted with dichloromethane, the organic phase is
washed with water and dried over Na2SO4. Then the solvent is removed by
distillation. The crude product is purified by recrystallisation from diethyl
ether.
Yield: 2.8 g of white crystals (= 30 % of theoretical).
3.2: scopine 9-hydroxy-fluorene-9-carboxylate methobromide :
1.3 g (0.004 mol) 4c are taken up in 20 ml chloroform and 20 ml acetonitrile
and reacted with 2.279 g (0.012 mol) of 50% methylbromide solution in
acetonitrile analogously to step 1.3. To purify it the product is
recrystallised
from acetonitrile.
Yield: 1.25 g of light beige crystals (= 68 % of theoretical); melting point:
243-
244 C.
Elemental analysis: calculated: C (60.27) H (5.28) N (3.06)
found: C (60.03) H (5.35) N (3.55).
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Example 4: scopine 9-fluoro-fluorene-9-carboxylate methobromide:
Me\+/Me Br -
N
O H
O O
F
4.1: scopine 9-fluoro-fluorene-9-carboxylate 4d:
0.885 ml (0.005 mol) of bis-(2-methoxyethyl)-aminosulphur trifluoride are
placed in 25 ml of dichloromethane and reacted with 1.42 g (0.004 mol) of 4c
analogously to the procedure according to 2.1.
Yield: 1.1 g beige crystals (= 75 % of theoretical)
4.2: scopine 9-fluoro-fluorene-9-carboxylate methobromide :
1.1 g (0.003 mol) of 4d are taken up in 30 mI acetonitrile and reacted with
1.71 g (0.009 mol) of 50% methyl bromide solution in acetonitrile analogously
to step 1.3. To purify it the product is recrystallised from isopropanol.
Yield: 0.45 g of white crystals (= 33 % of theoretical); melting point: 200-
201 C.
Elemental analysis: calculated: C (60.01) H (5.04) N (3.04)
found: C (59.91) H (5.18) N (3.10).
Example 5: tropenol 9-methyl-fluorene-9-carboxylate methobromide :
Mew+/Me Br
N
H
O O
Me
\ I \
5.1.: 9-methyl-fluorene-9-carboxylic acid 3b:.
a) methyl 9-methyl-fluorene-9-carboxylate:
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From 7.6 g (0.33 mol) of sodium and 300 ml of ethanol a sodium ethoxide
solution is prepared, to which 69.6 g (0.33 mol) of 9-fluorenecarboxylic acid
are added batchwise. After the addition has ended the mixture is stirred for
2.5 hours at ambient temperature. Then it is evaporated to dryness, the
residue is suspended in 600 ml of dimethylformamide and 93.96 g (0.662 mol)
of methyl iodide are added dropwise. The mixture is stirred for 3 hours at
constant temperature. The cloudy solution is stirred into 500 ml of water and
300 ml of diethyl ether with cooling and extracted, the organic phase is
washed with water and 10% sodium carbonate solution, dried and evaporated
to dryness. The residue is purified by column chromatography, eluant:
cyclohexane / ethyl acetate 96:4.
Yield: 12.61 g of white crystals (= 16% of theoretical); melting point: 108 -
109 C.
b) 9-methyl-fluorene-9-carboxylic acid 3b:
12.6 g (0.053 mol) of methyl 9-methyl-fluorene-9-carboxylate and 53 ml of 2
molar, aqueous sodium hydroxide solution are stirred in 120 ml of 1,4-dioxane
for 24 hours at ambient temperature. The dioxane is distilled off, made up to
a
total volume of 300 ml with water and extracted with diethyl ether. The
aqueous phase is acidified with 3 molar, aqueous HCI, crystallised and
filtered.
Yield: 11.25 g of white crystals (= 95% of theoretical); melting point: 168 -
169 C.
5.2: tropenol 9-methyl-fluorene-9-carboxylate 4e:
6.73 g (0.03 mol) of 3b are suspended in 60 ml dichloromethane, combined
with 5.0 g of oxalyl chloride and 1 drop of dimethylformamide, then stirred
for
one hour at ambient temperature and finally the solvent is distilled off. The
acid chloride remaining is used in the next step without any further
purification.
4.18 g (0.03 mol) of tropenol and 4.27 g (0.033 mol) of diisopropylethylamine
are suspended in 100 ml of dichloroethane, the acid chloride is added
dropwise to 30 ml of dichloroethane at 35-40 C and then stirred for 24 hours
at 40 C. The suspension is diluted with dichloromethane and extracted with
dilute hydrochloric acid. The organic phase is then washed with water, dried
over MgSO4 and the product is converted into its hydrochloride with a solution
of HCI in diethyl ether. The solvent is then removed. To purify it the
precipitated hydrochloride is taken up in water and extracted with diethyl
CA 02472149 2004-06-29
ether. The aqueous phase is made basic with 10% aq. sodium carbonate
solution and extracted with dichloromethane. The organic phase is dried over
MgSO4 and the solvent is distilled off.
Yield: 4.40 g of yellow oil (= 42% of theoretical);
5.3: tropenol 9-methyl-fluorene-9-carboxylate methobromide :
1.8 g (0.005 mol) of the free base 4e are reacted analogously to the method in
step 1.3. The product is purified by recrystallisation from acetone.
Yield: 1.80 g of white crystals (= 82 % of theoretical); melting point: 258-
259 C;
Elemental analysis: calculated: C (65.46) H (5.95) N (3.18)
found: C (64.15) H (5.95) N (3.18).
Example 6: scopine 9-methyl-fluorene-9-carboxylate methobromide :
Me\+/Me Br
N
O H
O O
Me
6.1: scopine 9-methyl-fluorene-9-carboxylate 4f:
2.5 g (0.007 mol) of tropenol ester 4e are reacted with 0.13 g (0.001 mol) of
vanadium-(V)-oxide and 1.43 g (0.015 mol) of H202-urea analogously to the
process according to step 3.1.
Yield: 1.8 g of white crystals (= 71 % of theoretical).
6.2: scopine 9-methyl-fluorene-9-carboxylate methobromide :
1.8 g (0.005 mol) of 4f are taken up in 30 ml acetonitrile and reacted with
2.848 g (0.015 mol) of 50% methyl bromide solution in acetonitrile
analogously to step 1.3.
Yield: 1.6 g of white crystals (= 70 % of theoretical); melting point: 214 C.
Elemental analysis: calculated: C (62.13) H (5.93) N (4.26)
found: C (62.23) H (6.05) N (4.32).
CA 02472149 2004-06-29
16
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 10nM in
terms of their affinity for the M3 receptor. These values were determined by
the method described below.
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 hml 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 1 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 pl of HEPES buffer (20 mmol/L HEPES, 10 mmol/L
MgCI2, 100 mmol/L NaCl, adjusted with 1 mol/L NaOH to pH 7.4).
The nonspecific binding was determined using 10 pmol/l 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).
CA 02472149 2004-06-29
17
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
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 I may also be used in combination with other
pharmacologically active substances. These may be, in particular,
betamimetics, antiallergics, PAF antagonists, PDE IV inhibitors, leukotriene
antagonists, p38 kinase inhibitors, EGFR- kinase inhibitors and
corticosteroids
as well as combinations of active substances.
Examples of betamimetics which may be used according to the invention in
conjunction with the compounds of formula 1 include compounds selected
CA 02472149 2004-06-29
18
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-m ethyl-2-
butylam ino]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-
propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-
m ethoxyphenyl)-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-m ethoxyphenyl)-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-am ino-3-chloro-5-trifluormethylphenyl)-2-tert.-butylam ino)ethanol and 1-
(4-ethoxycarbonylam ino-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 and 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-dim ethylaminophenyl)-2-methyl-2-propylamino]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-
4 H-1, 4-benzoxazi n-8-yl]-2-{4-[3-(4-methoxyphenyl)-1, 2, 4-triazol-3-yl]-2-
methyl-2-butylamino}ethanol, optionally in the form of the racemates, the
enantiomers, the diastereomers and optionally the pharmacologically
acceptable acid addition salts thereof, 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
CA 02472149 2004-06-29
19
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.
Within the scope of the present invention, the corticosteroids which may
optionally be used in conjunction with the compounds of formula I may be
compounds selected from among flunisolide, beclomethasone, triamcinolone,
budesonide, fluticasone, mometasone, ciclesonide, rofleponide, GW 215864,
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 for
combining with the compounds of general formula 1 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,
CA 02472149 2004-06-29
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
methanesulphonate are preferred.
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, Ioratadine, 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.
CA 02472149 2004-06-29
21
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-morphoIinyl)-3-propanon-1-yl]-6H-
thieno-[3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepine and
6-(2-chlorophenyl)-8, 9-d ihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cy
clo-penta-[4,5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine.
Especially preferred examples of EGFR-kinase inhibitors which may be used
according to the invention as a combination with the compounds of formula 1
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)am ino]-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)carbonyl]-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)amino]-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, 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 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.
CA 02472149 2004-06-29
22
Particularly preferred examples of p38 kinase inhibitors which may be used
according to the invention as a combination with the compounds of formula 1
include, in particular, 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-oxothiomorpholin-4-yl)ethoxy)naphthalin-1-yl]-urea; 1-
[5-tent-butyl-2-(2-methylpyridin-5-yl)-2 H-pyrazol-3-yl]-3-[4-(2-pyridine-4-yl-
ethoxy)naphthalin-1-yl]-urea; 1-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-
pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphtha Iin-1-yl]-urea or 1-[5-
tert-
butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-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, 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.
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 I 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
CA 02472149 2004-06-29
23
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
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),
CA 02472149 2004-06-29
24
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,
methylceIlulose,
starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate,
talc,
stearic acid and sodium lauryl sulphate).
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.
When the compounds of formula 1 are used for the treatment of asthma or
COPD they are preferably administered as preparations or pharmaceutical
formulations for inhalation. For inhalation the compounds may be in the form
of 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 detail in the next part of
the specification.
The inhalable powders which may be used according to the invention may
contain the compounds 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. dextrane), polyalcohols (e.g. sorbitol, mannitol,
xylitol),
salts (e.g. sodium chloride, calcium carbonate) or mixtures of these
excipients
with one another. Preferably, mono- or disaccharides are used, while the use
of lactose or glucose is preferred, particularly, but not exclusively, in the
form
CA 02472149 2004-06-29
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
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 excipients 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 m, 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 by 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 which may be used
according to the invention may contain the compounds 1 dissolved in the
propellant gas or in dispersed form. The compounds 1 may be present in
separate preparations or in a combined preparation, while the compounds 1
may either both be dissolved, both dispersed or only one component is
dissolved and the other may be 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 propellant gases
mentioned above may be used on their own or in mixtures thereof.
Particularly preferred propellant gases are fluorinated 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.
CA 02472149 2004-06-29
26
The propellant-driven inhalation aerosols mentioned above may be
administered using inhalers known in the art (MDIs = metered dose inhalers).
Moreover, the active substances 1 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
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 1 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 already form an acid addition salt. 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.
In these formulations it may be possible to do without the addition of editic
acid (EDTA) or one of the known salts thereof, sodium edetate, as stabiliser
or complexing agent. Other embodiments contains this compound (these
compounds. In a preferred embodiment the content, based on sodium
edetate, is less than 100 mg/100 ml, preferably less than 50 mg/100 ml, most
preferably less than 20 mg/100ml. Generally, inhalable solutions in which the
content of sodium edetate is from 0 to 10 mg/100 ml are preferred.
Cosolvents and/or other excipients may be added to the propellent-free
inhalable solutions. Preferred cosolvents are those which contain hydroxyl
groups or other polar groups, such as alcohols - particularly
isopropylalcohol,
glycols - particularly propyleneglycol, polyethyleneglycol,
polypropyleneglycol,
CA 02472149 2004-06-29
27
glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty
acid esters. By excipients and additives are meant, in this context, any
pharmacologically acceptable substance which is not an active substance, but
can be formulated together with the active substance(s) in the
pharmacologically suitable solvent to improve the qualitative properties of
the
active substance formulation. Preferably, these substances have no
noticeable or at least no unwanted pharmacological activity in the context of
the desired therapy. The excipients and additives include e.g. surfactants
such as soya lecithin, oleic acid, sorbitan esters such as polysorbates,
polyvinylpyrrolidone, other stabilisers, complexing agents, antioxidants
and/or
preservatives which guarantee or extend 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 for example sodium chloride as isotonic agents.
The preferred excipients include antioxidants, such as for example ascorbic
acid, unless already used to adjust the pH, vitamin A, vitamin E, tocopherols
and similar vitamins or provitamins which occur in the human body.
Preservatives may be used to protect the formulation from contamination with
pathogens. Suitable preservatives are those known in the art, particularly
cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates
such as sodium benzoate in the concentration known from the prior art. The
abovementioned preservatives are preferably present in concentrations of up
to 50mg/100m1, most preferably between 5 and 20 mg/100m1.
Preferred formulations contain only benzalkonium chloride and sodium
edetate, in addition to the solvent water and the active substance 1 .
In another preferred embodiment, no sodium edetate is used.
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.
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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28
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
form a granulate which is dried and screened. The sodium carboxymethyl
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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 (1 n) ad pH 3.4
This solution may be prepared in the usual way.
F) Inhalable powder
active substance 1 6 pg
formoterol fumarate 6 pg
lactose monohydrate ad 25 mg
CA 02472149 2004-06-29
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.
