Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
WO 031024440 CA 02460440 2004-03-12 PCT/EP02/09975
78626pct.209
Salicylic acid salts, processes for preparing them and their use as
s pharmaceutical compositions
The present invention relates to new substituted salicylic acid salts of
salmeterol,
processes for preparing them and their use as pharmaceutical compositions.
Detailed description of the invention
The problem of the present invention is to prepare salts of salmeterol which
are
characterised by a high degree of local compatibility, particularly when
administered
by inhalation.
~5 This problem is solved with the substituted salicylic acid salts of formula
1 shown
below. Accordingly, the present invention relates to salts of general formula
1
HO
OH
HO ~ ( N O / '00C
i v I R'
OH H H
R2
R
1
2o wherein
R~ and R2 which may be identical or different, denote hydrogen, C~-C4-alkyl,
C~-C4-alkoxy, halogen, COOH, OH, -COOC~-C4-alkyl, -CO-C~-C4-
alkyl, -NH2, -NH(C~-C4-alkyl), -N(C1-C4-alkyl)2, -S02-OH, -CF3 or
phenyl;
25 R3 denotes hydrogen, C~-C4-alkyl, C~-C4-alkoxy, halogen, -CF3 or
phenyl, while the phenyl ring may optionally be mono-, di- or
trisubstituted by one, two or three groups selected from among C~-C4-
alkyl, C~-C4-alkoxy, halogen or -CFg,
with the proviso that not all the groups R~ , R2 and R3 may
3o simultaneously represent hydrogen,
optionally in the form of the enantiomers, mixtures of enantiomers or
racemates
thereof.
CA 02460440 2004-03-12
2
Preferred are salts of formula _1, wherein
R~ and R2 which may be identical or different, denote hydrogen, methyl, ethyl,
propyl, butyl, methoxy, ethoxy, fluorine, chlorine, bromine, iodine,
COOH, OH, -COOmethyl, -CO-methyl, -NH2, -NH(methyl),
-N(methyl)2, -NH(ethyl), -N(ethyl)2, -S02-OH, -CF3 or phenyl;
R3 denotes hydrogen, methyl, ethyl, propyl, butyl, methoxy, ethoxy,
fluorine, chlorine, bromine, iodine, -CFg or phenyl, while the phenyl
ring may optionally be mono-, di- or trisubstituted by one, two or three
groups selected from among methyl, ethyl, propyl, butyl, methoxy,
ethoxy, fluorine, chlorine, bromine, iodine or -CFg,
with the proviso that not all the groups R~ , R2 and R3 may
simultaneously represent hydrogen,
optionally in the form of the enantiomers, mixtures of enantiomers or
racemates
~5 thereof.
- Particularly preferred are salts of formula 1 wherein
R~ and R2 which may be identical or different, denote hydrogen, methyl, ethyl,
propyl, methoxy, fluorine, chlorine, bromine, iodine, -COOH, OH,
20 -COOmethyl, -CO-methyl, -NH2, -S02-OH or -CF3;
R3 denotes hydrogen, methyl, ethyl, methoxy, fluorine, chlorine, -CFg or
phenyl, while the phenyl ring may optionally be mono- or disubstituted
by one or two groups selected from among fluorine, chlorine, bromine
or -CFg,
25 with the proviso that not all the groups R~, R2 and R3 may
simultaneously represent hydrogen,
optionally in the form of the enantiomers, mixtures of enantiomers or
racemates
thereof.
3o Of particular importance according to the invention are compounds of
formula 1
wherein
R~ and R2 which may be identical or different denote hydrogen, methyl, propyl,
methoxy, chlorine, iodine, -COOH, OH, -COOmethyl, -CO-methyl,
-NH2 or -S02-OH;
35 R3 denotes hydrogen or phenyl, while the phenyl ring may optionally be
mono- or disubstituted by one or two groups, preferably a group
selected from among fluorine, chlorine, bromine or-CF3,
with the proviso that not all the groups R~ , R2 and R3 may
simultaneously represent hydrogen,
CA 02460440 2004-03-12
3
optionally in the form of the enantiomers, mixtures of enantiomers or
racemates
thereof.
Especially preferred according to the invention are compounds of general
formula 1
wherein
R1 and R2 which may be identical or different, denote hydrogen, methyl,
propyl,
methoxy, chlorine, iodine, -COOH, OH, -COOmethyl, -CO-methyl,
-NH2 or -S02-OH;
R3 denotes hydrogen,
~o with the proviso that not all the groups R1, R2 and R3 may
simultaneously represent hydrogen,
optionally in the form of the enantiomers, mixtures of enantiomers or
racemates
thereof.
~5 Also of especial importance according to the invention are compounds of
formula _1
wherein
R1 and R2 denote hydrogen;
R3 denotes phenyl, while the phenyl ring may optionally be mono- or
disubstituted by one or two groups, preferably a group selected from
2o among fluorine, chlorine, bromine or -CF3, preferably fluorine,
optionally in the form of the enantiomers, mixtures of enantiomers or
racemates
thereof.
The alkyl groups used, unless otherwise stated, are branched and unbranched
alkyl
25 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 isomeric forms of the groups in question.
Thus, for
example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl,
sec. butyl
3o 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
35 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
CA 02460440 2004-03-12
4
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
To 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
the 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 R~, 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 carboxyl group. If none of the groups R~ , R2 and R3 denotes
hydrogen, the group R3 is preferably linked in the meta position and the
groups R~
2o and R2 are linked in the ortho andlor para position. If one of the groups
R~ , 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. Compounds wherein
the
group R3 does not denote hydrogen are of particular importance according to
the
invention. In these compounds the group R3 is preferably in the meta position,
in
25 relation to the carboxyl group.
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.
The preparation method comprises reacting the free base salmeterol with
carboxylic
acids of formula 2
COOH
R'
RZ 3 OH
R _2
wherein the groups R~ , R2 and R3 are as hereinbefore defined, in suitable
solvents,
preferably organic solvents.
CA 02460440 2004-03-12
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
5 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.
~o
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),
2o 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.
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
3s 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.
CA 02460440 2004-03-12
6
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
s 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
~5 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.
Within the scope of the present invention, the term dopamine agonists, which
may
20 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
2s 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
3o 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.
35 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,
CA 02460440 2004-03-12
7
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
s 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
~5 (Sch-351591 ), V-11294A and AWD-12-281. Preferred PDE-IV inhibitors are
selected
from among enprofylline, roflumilast, 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
2o 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 malefic
acid. According to the invention, the salts selected from among the acetate,
25 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
3o 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,
35 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.
CA 02460440 2004-03-12
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.
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
2o 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,
25 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).
3o 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
35 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
CA 02460440 2004-03-12
9
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.
s 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 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
~s 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 prefen-ed propellant gases
are
fluorinated alkane derivatives selected from TG134a (1,1,1,2-
tetrafluoroethane),
2o 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,
surfactants, antioxidants, lubricants and pH adjusters. All these ingredients
are
2s 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
so 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.
s5 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 andlor phosphoric acid. Examples
of
particularly suitable organic acids include ascorbic acid, citric acid, malic
acid, tartaric
CA 02460440 2004-03-12
acid, malefic acid, succinic acid, fumaric acid, acetic acid, formic acid
andlor
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
desired, mixtures of the above acids may be used, particularly in the case of
acids
5 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
~5 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
2o 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 Ng 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
3o example.
CA 02460440 2004-03-12
11
Examples of synthesis:
4-hydroxy-oc'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-5-
(2,4-difluorophenyl)salicylate-salt 1a:
HO
HO ~ ~ N O
OH H H
OOC
HO ~ ~ ~ ~ F
F
30 g of salmeterol are dissolved by refluxing in 300 ml of ethyl acetate with
heating.
To this solution are added 18.3 g of 5-(2,4-difluorophenyl)salicylic acid
(diflunisal).
The solution is left to cool to ambient temperature. The suspension is
filtered off, the
precipitate is washed with ethyl acetate and dried in vacuo at 35°C. 46
g of the title
salt are obtained as a colourless solid.
Melting point: 104°C
The following compounds were prepared analogously:
4-hydroxy-a,'-[[[6-(4-phenylbutoxy)-hexyl]-am ino]-methyl]-1,3-
benzenedimethanol-
3,5-diisopropyl-salicylate-salt 1b;
Melting point: 115°C;
20 4-hydroxy-oc'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-4-
chloro-salicylate-salt 1c;
Melting point: 123°C;
4-hydroxy-a,'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-
25 3,5-dichloro-salicylate-salt 1d;
Melting point: 108°C;
4-hydroxy-a.'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-
2,5-dihydroxyterephthalate-salt 1e; (base : acid = 1:2).
CA 02460440 2004-03-12
12
Melting point: 102°C;
4-hydroxy-a,'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-3-
methoxysalicylate-salt 1f;
Melting point: 118°C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-
4-
methoxysalicylate-salt 1~c ;
Melting point: 113°C;
~o
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-
5-
methoxysalicylate-salt 1h;
Melting point: 114°C;
~5 4-hydroxy-a.'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-4-
methylsalicylate-salt 1i;
Melting point: 116°C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-
5-
2o aminosalicylate-salt 1j;
Melting point: 146°C;
4-hydroxy-oc'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-3-
chlorosalicylate-salt 1k;
25 Melting point: 108°C;
4-hydroxy-a,'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-5-
sulpho-salicylate-salt 11;
Melting point: 129°C;
4-hydroxy-a'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-
5-
acetylsalicylate-salt 1 m;
Melting point: 80°C;
4-hydroxy-a.'-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-
benzenedimethanol-
3,5-diiodosalicylate-salt 1 n;
Melting point: 133°C;
CA 02460440 2004-03-12
13
In the abovementioned salts 1 according to the invention the base salmeterol
and
the acid of formula 2 are present in a molar ratio of salmeterol to acid of 1
: 1 unless
otherwise stated.
s 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
~o 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
2o 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
25 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).
3o The following examples of formulations illustrate the present invention
without
restricting its scope:
~
CA 02460440 2004-03-12
14
~o
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
~5 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 starch 23 mg
magnesium stearate 2 mg
330 mg
The finely ground active substance, some of the com 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.
CA 02460440 2004-03-12
C) Metering aerosol
active substance 0.005
sorbitan trioleate 0.1
5 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 NI of
9o suspension are delivered per spray. The active substance can also be in a
higher
dose if desired (e.g. 0.02 wt. °/a).
D) Inhalable powder
active substance 110 Ng
~5 lactose monohydrate ad 25 mg
The inhalable powder is prepared in the usual way by mixing the individual
ingredients together.
2o D) Inhalable powder
active substance 50 Ng
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.
