Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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80089pct.210
New cinnamic acid salts, processes for the preparation thereof and
use thereof as medicament
The present invention relates to new cinnamic acid salts of salmeterol,
processes for the preparation thereof as well as the use thereof as
pharmaceutical compositions.
Detailed description of the invention
The aim of the present invention is to prepare salts of salmeterol which are
characterised by being very well tolerated locally, particularly when
administered by inhalation.
This aim is achieved by means of the following cinnamic acid salts of formula
1.
Accordingly the present invention relates to salts of general formula 1
HO
HO ~ ~ N O / -OOC
w I R
OH H H
Rz
R
1
wherein
R1 and R2 which may be identical or different denote hydrogen, C1-C4-
alkyl, C1-C4-alkoxy, halogen, -CFg or phenyl
or
if R1 and R2 are adjacent, together they represent a -CH=CH-
CH=CH- bridge;
R3 represents hydrogen, C 1-C4-alkyl, C 1-C4-alkoxy, halogen or -
CF3,
optionally in the form of the enantiomers thereof, mixtures of the enantiomers
or racemates thereof.
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Preferred salts of formula _1 are those wherein
R1 and R2 which may be identical or different denote hydrogen, methyl,
ethyl, propyl, butyl, methoxy, fluorine, chlorine, bromine, -CFg or
phenyl,
or
if R1 and R2 are adjacent, together they represent a -CH=CH-
CH=CH- bridge;
R3 represents hydrogen, methyl, ethyl, methoxy, fluorine, chlorine,
bromine or -CFg, preferably hydrogen or fluorine,
optionally in the form of the enantiomers thereof, mixtures of the enantiomers
or racemates thereof.
Particularly preferred are salts of formula _1 wherein
R1 and R2 which may be identical or different denote hydrogen, fluorine,
chlorine, -CFg or phenyl
R3 denotes hydrogen or fluorine, preferably hydrogen,
optionally in the form of the enantiomers thereof, mixtures of the enantiomers
or racemates thereof.
Of particular importance according to the invention are compounds of formula
1, wherein
R1 denotes hydrogen;
R2 denotes -CFg or phenyl;
R3 denotes hydrogen,
optionally in the form of the enantiomers thereof, mixtures of the enantiomers
or racemates thereof.
Also particularly important are compounds of formula _1 wherein
R1 and R2 denotes chlorine;
R3 denotes hydrogen,
optionally in the form of the enantiomers thereof, mixtures of the enantiomers
or racemates thereof.
The alkyl groups used, unless otherwise stated, are branched and
unbranched alkyl groups having 1 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
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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 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.
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.
The salts of formula 1 are new acid addition salts of salmeterol, which is
known from the prior art. Salmeterol has a chiral centre. The present
invention relates to the salts of formula 1 in racemic or enantiomerically
pure
form. Both the (R)- and the (S)-enantiomer are of particular importance.
Moreover the present invention relates to salts of formula 1 in the form of
the
non-racemic mixtures of the two enantiomers.
In the compounds of general formula 1 the groups R1, R2 and R3, if they do
not represent hydrogen, may each be in the ortho, meta or para position
relative to the linking to the ethylene bridge. If none of the groups R1, R2
and
R3 denotes hydrogen, the group R3 is preferably linked in the para position
and the groups R1 and R2 are linked in the ortho and/or meta position. If one
of the groups R1, R2 and R3 denotes hydrogen, preferably at least one of the
other groups is linked in the meta or para position, most preferably in the
para
position. If none of the groups R1, R2 and R3 denotes hydrogen, compounds
of general formula 1 wherein the groups R1, R2 and R3 have the same
meaning are particularly preferred according to the invention.
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The salts 1 according to the invention may be prepared starting from the free
base of salmeterol analogously to processes known in the art for forming acid
addition salts from secondary amines.
This preparation comprises reacting the free base salmeterol with carboxylic
acids of formula _2
\ \ COOH
2
wherein the groups R~, R2 and R3 may be defined as hereinbefore, in
suitable solvents, preferably organic solvents.
For this purpose the acid 2 is taken up in a suitable solvent, preferably an
organic solvent, most preferably a solvent selected from among ethyl acetate,
methanol, ethanol, iso-propanol and diethylether or mixtures thereof. If
desired the abovementioned solvents may also be used in admixture with
tert.-butylmethylether or cyclohexane. The acids 2 taken up in one of the
abovementioned solvents are optionally dissolved with heating, preferably to
the boiling temperature of the solvent. Salmeterol, optionally dissolved in
one
of the abovementioned solvents, is added to this solution. The salts 1 are
crystallised and isolated from the resulting solution, optionally with
cooling.
As has been found, the compounds of general formula 1 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 betamimetics.
These include, for example, the treatment of bronchial asthma (normally
irritation-induced attacks of bronchial spasm with swelling of the mucosa and
increased production of mucus), the treatment of COPD (chronic obstructive
bronchitis), the inhibition of premature labour and threatened miscarriage in
midwifery (tocolysis), the restoration of the sinus rhythm in the heart in
cases
of atrio-ventricular block as well as the correcting of bradycardiac heart
rhythm disorders (antiarrhythmic agent), the treatment of circulatory shock
(vasodilatation and increasing the heart-time volume) as well as the treatment
of itching and skin inflammation. The salts of formula 1 are preferably used
in
the treatment of asthma or COPD.
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The salts of general formula 1 may be used on their own or in conjunction with
other active substances. These may be, in particular, anticholinergics,
antiallergics, leukotriene antagonists, dopamine agonists, PDEIV inhibitors
and corticosteroids as well as combinations of active substances.
Examples of anticholinergics which may be mentioned include ipratropium
bromide, oxitropium bromide and particularly tiotropium bromide. Drug
combinations which contain tiotropium bromide as an additional active
substance as well as the compound of formula 1 according to the invention
are particularly preferred according to the invention. Combinations which
contain, in addition to the compound of formula 1, crystalline tiotropium
bromide monohydrate which may be obtained by the experimental procedure
described in the experimental section are of particular importance.
This combination is particularly important in the treatment of asthma or
COPD, particularly COPD.
Within the scope of the present invention, the corticosteroids which may
optionally be used in conjunction with the compound of formula 1 may be
compounds selected from among flunisolide, beclomethasone, triamcinolone,
budesonide, fluticasone, mometasone, ciclesonide, rofleponide 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 orfuroates. In some cases the corticosteroids may also
occur in the form of their hydrates.
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Within the scope of the present invention, the term dopamine agonists, which
may optionally be used in conjunction with the compound 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 compound 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 malefic 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 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,
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ariflo and AWD-12-281. 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 rnaleic acid. According to the invention, the
salts
selected from among the acetate, hydrochloride, hydrobromide, sulphate,
phosphate and methanesulphonate are preferred.
Suitable preparations for administering the salts of formula 1 include for
example tablets, capsules, suppositories and powders, etc. The content of the
pharmaceutically active compounds) 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 substances) 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
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,
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wetting agents such as, for example, condensation products of fatty alcohols
with ethylene oxide, or preservatives such as p-hydroxybenzoates.
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).
The preparations are administered by the usual methods, preferably by
inhalation in the treatment of asthma or COPD.
For inhalation the compounds may be in the form of inhalable powders,
propellant-containing inhalable solutions or suspensions or propellant-free
inhalable solutions or suspensions.
The inhalable powders which may be used and are preferred within the scope
of the invention may contain the salts 1 either on their own or in admixture
with suitable physiologically acceptable excipients. If the salts 1 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
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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
of their hydrates. For the purposes of the invention, lactose is the
particularly
preferred excipient, while lactose monohydrate is most particularly preferred.
The inhalation aerosols containing propellant gas which may be used
according to the invention may contain the salts 1 dissolved in the propellant
gas or in dispersed form. 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 preferably 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 (1,1,1,2-tetrafluoroethane), TG227
(1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof.
The propellant-driven inhalation aerosols which may be used according to the
invention may also contain other ingredients such as co-solvents, stabilisers,
surtactants, antioxidants, lubricants and pH adjusters. All these ingredients
are known in the art.
If the salts 1 according to the invention are 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,
malefic
acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic
acid
etc. Preferred inorganic acids are hydrochloric and sulphuric acids. Of the
organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If
WO 03/074469 10 PCT/EP03/01644
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.
For oral administration the tablets may, of course contain, apart from the
abovementioned carriers, additives such as sodium citrate, calcium carbonate
and dicalcium phosphate together with various additives such as starch,
preferably potato starch, gelatine and the like. Moreover, lubricants such as
magnesium stearate, sodium lauryl sulphate and talc may be used at the
same time for the tabletting process. In the case of aqueous suspensions the
active substances may be combined with various flavour enhancers or
colourings in addition to the excipients mentioned above.
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 Ng range. The
compounds of formula 1 may also be used effectively above the pg range.
The dosage may then be in the gram range, for example.
The example of synthesis described below serves to illustrate the present
invention still further. However, it is to be regarded as only an example of a
procedure, illustrating one possible method of obtaining the compound
according to the invention, without restricting the invention to the object
described below by way of example.
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Examples of synthesis:
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-4-phenylcinnamate salt 1a:
HO
HO \ ( O
N'
OH H H
-OOC
1.35 g (6 mmol) of 4-phenylcinnamic acid is dissolved in 75 mL of ethyl
acetate while refluxing. To this solution is added a warm solution of 2.5 g (6
mmol) of salmeterol in 25 mL of ethyl acetate. The solution is left to cool
and
stirred for 16 h at ambient temperature. The suspension is filtered, the
precipitate is washed with ethyl acetate and tert.-butylmethyl ether and dried
in vacuo at 25-30°C. 3.47 g of the title compound are obtained as a
colourless
solid. Melting point: 109°C;
The following compounds were prepared analogously:
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-4-trifluoromethyl-cinnamate salt 1b;
melting point: 125°C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-3,4-dichloro-cinnamate salt 1c;
melting point: 116 °C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-2,4-dichloro-cinnamate salt 1d;
melting point: 183°C;
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4-hydroxy-a,'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-cinnamate salt 1e;
melting point: 89°C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-3-(2-naphthyl)acrylate salt 1f;
melting point: 97°C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-3-(1-naphthyl)acrylate salt 1~c;
melting point: 77°C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-2,6-dichloro-cinnamate salt 1h;
melting point: 82°C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedirnethanol-2,5-dimethoxy-cinnamate salt 1i;
melting point: 88°C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1, 3-
benzenedimethanol-2-trifluoromethyl-cinnamate salt ~;
melting point: 94°C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-3-trifluoromethyl-cinnamate salt 1k;
melting point: 92°C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-3-chloro-cinnamate salt 11;
melting point: 90°C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-4-bromo-cinnamate salt 1m;
melting point: 127°C;
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4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-4-chloro-cinnamate salt 1 n;
melting point: 123°C;
7
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-4-methoxy-cinnamate salt 10;
melting point: 98°C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-4-fluoro-cinnamate salt 1~;
melting point: 113°C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-4-isopropyl-cinnamate salt 1~c ;
melting point: 82°C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-4-tert-butyl-cinnamate salt 1 r;
melting point: 93°C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-2,4-difluoro-cinnamate salt 1s;
melting point: 121 °C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-3,4-difluoro-cinnamate salt 1t;
melting point: 102°C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-2,4,5-trifluoro-cinnamate salt 1u;
melting point: 120°C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-3,4,5-trifluoro-cinnamate salt 1v;
melting point: 107°C;
In the abovementioned salts 1 according to the invention the base salmeterol
and the acid of formula 2 are in a molar ratio of salmeterol:acid of 1:1.
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The identity of the abovementioned compounds was confirmed by 1 H-NMR
spectroscopy and ESI mass spectrometry.
The salts of formula 1 according to the invention may optionally be used in
combination with for example crystalline tiotropium bromide monohydrate. In
so far as the latter is not yet known in the art its preparation is described
hereinafter.
Tiotropium bromide may be obtained as described in European Patent
Application EP 418 716 A1. Crystalline tiotropium bromide monohydrate may
be obtained therefrom by the following method.
In a suitable reaction vessel 15.0 kg of tiotropium bromide are added to 25.7
kg of water. The mixture is heated to 80-90°C and stirred at constant
temperature until a clear solution is formed. Activated charcoal (0.8 kg),
moistened with water, is suspended in 4.4 kg of water, this mixture is added
to
the solution containing tiotropium bromide and rinsed with 4.3 kg of water.
The resulting mixture is stirred for at least 15 min at 80-90°C and
then filtered
through a heated filter into an apparatus which has been preheated to an
outer temperature of 70°C. The filter is rinsed with 8.6 kg of water.
The
contents of the apparatus are cooled to a temperature of 20-25°C at a
rate of
3-5°C per 20 minutes. The apparatus is further cooled to 10-15°C
by cold
water cooling and the crystallisation is completed by stirring for at least
one
hour. The crystals are separated off using a suction drier, the isolated
crystal
slurry is washed with 9 litres of cold water (10-15°C) and cold acetone
(10-
15°C). The crystals obtained are dried at 25°C for 2 hours in a
nitrogen
current.
Yield : 13.4 kg of crystalline tiotropium bromide monohydrate (86 % of
theory).
The following examples of formulations illustrate the present invention
without
restricting its scope:
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Examples of pharmaceutical formulations
A) Tablets per tablet
active substance 5 mg
lactose 140 mg
corn starch 240 mg
polyvinylpyrrolidone 10 mg
magnesium stearate 5 mg
400 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 10 mg
lactose 55 mg
corn starch 190 mg
microcrystalline cellulose 35 mg
polyvinylpyrrolidone 15 mg
sodium-carboxymethyl starch23 mg
magnesium stearate 2 mg
330 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
starch and the magnesium stearate are added and mixed in and the mixture is
compressed to form tablets of a suitable size.
WO 03/074469 16 PCT/EP03/01644
C) Metering aerosol
active substance 0.005
sorbitan trioleate 0.1
monofluorotrichloromethane and
difluorodichloromethane 2 : 3 ad 100
The percentages specified are percent by weight. The suspension is
transferred into a conventional aerosol container with a metering
valve. Preferably, 50 pl of suspension are delivered per spray. The active
substance can also be in a higher dose if desired (e.g. 0.02 wt.-%).
D) Inhalable powder
active substance 110 Ng
lactose monohydrate ad 25 mg
The inhalable powder is prepared in the usual way by mixing the individual
ingredients together.
E) Inhalable~~owder
active substance 50 pg
tiotropium bromide monohydrate 22.5 Ng
lactose monohydrate ad 25 mg
The inhalable powder is prepared in the usual way by mixing the individual
ingredients together.
CA 02477714 2004-08-30
