Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
W 0 93/12090 2 12 S 6 ~ ~ pcr/Eps2/o2898
4-Amlno-3-acyl qulnol1ne der1vat1ves and thelr use as lnhlbltors of gastrlc
acld secret10n.
Field of use of the invention
S The invention relates to new quinoline derivatives, processes for their
preparation, their use and medicaments containing them. The compounds according to
the invention are used in the pharmaceutical industry for the preparation of medicaments. ;~
Known technical background
4-Amino-3-acyl-quinoline derivatives and their use as inhibitors of gastric acidsecretion are described in European Patent Application EP-A-330 485.
Description of the invention
It has now been found that the compounds which are described below in morc
dctail and which differ from thc compounds of the prior art in particular by the substitucnt
in the 8-position of the quinoline ring have surprising and particularly advantageous
properties.
The invention thus relates in a first aspect to compounds of the formula I:
R
, R1~ 11
~ '`NH 0
~'~
~O--C X--C--Y
.... Il 11
' O O
~ 25 (I)
,
wherein
Rl denotes hydrogen, hydroxyl (OH), halogen or Cl 4alkyl,
R2 denotes hydrogen or Cl 4alkyl,
30 R3 denotesCl 4alkyl,
WO 93t12090 212 5 6 ~ 1 PCI/EP92/02898
. .
A denotes methylene (-CH2-), ethylene (-CH2CH2-), ethylidene [-CH(CH3)-],
trimethylene (-CH2CH2CH2-), oxyethylene (-0-CH2CH2-) or oxytrimethylene
(-o-cH2cH2cH2-)~
X denotes C1 6alkylene or C2 4alkenylene and
Y denotes hydroxyl (OH) or amino (NH2),
and their salts.
.
Halogen in the sense of the present invention is bromine, chlorine and in
particular fluorine.
Cl 4alkyl represents straight-chain or branched alkyl radicals having 1 to 4
carbon atoms. Examples which may be mentioned are the butyl, iso-butyl, sec-butyl, tert-
butyl, propyl, isopropyl, ethyl and the methyl radical. The C~ 4alkyl radicals R1 and/or
R2 are preferably methyl radicals. Preferred Cl 4alkyl radicals R3 are the ethyl, the
isopropyl and in particular the propyl Mdical.
Cl 6alkylene represents straight-chain or branched alkylene radicals having 1 to 6
carbon atoms. Examples which may be mentioned are the methylene (-CH2-), ethylene
(-CH2CH2-), ethylidene 1-CH(CH3)-], isopropylidene [-CH(CH3)2-], propylidene
[-CH(C2Hs)-], trimethylene (-CH2CH2CH2-), propylene ~ H(~H3)-CH2-],
tetramethylene (-CH2CH2CH2CH~-), l,l-dimethylethylene [-C(C~13~2-CH2-], 1,2-
dimethylethylene l-CH(CH3)-CH(CH3)-], I-methyltrimethylene [-CH(CH3)-CH2CH2-],
2-methyltrimethylene [-CH2-CH(CH3)-CH2-~, pentylidene [-CH(C4Hg)-], pentan-3-
ylidene [-CH(C2Hs)2-], pentamethylene (-CH2CH2CH~CH2CH2-), and the
hexamethylene radi.cal (-CH2CH ~CH2CH2CH2CH2-), of which the ethylene radical ispreferred.
C2 4alkenylene represents straight-chain or branched, mono- or polyunsaturated
alkenylene radicals having 1 to 4 carbon atoms. Examples which may be men~ioned are
the vinylene (-CH=CH-), propenylene (-CH2-CH=CH-), isopropenylene
l-CH2-C(=CH ~)-], 2-butenylene (-CH2-CH=CH-CH2-) and the 1,3-butadienylene radical
(-CH=CH-CH=CH-), of which the vinylene radical is prefe~ed.
Since the compounds of the formula 1 are ampholytes, possible salts are both acid
addition salts and salts with bases. The pharmacologically tolerated salts of the inorganic
and organic acids and bases usually used in pharmaceutical formulations may be
mentioned in particular. Salts which are not tolerated pharmacologically and which may
initially bs obtained as process products, for example, when the compounds according to
Wo 93/12090 pcr/Ep92/o2898
' ~256~1
the invention are prepared on an industrial scale are converted into pharmacologically
tolerated salts by processes known to the expert.
Examples of such suitable salts are water-soluble and water-insoluble acid
S - addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid,
phosphoric acid, nitric acid, sulphuric acid, acetic acid, citric acid, D-gluconic acid,
- benzoic acid, 2-(4-hydroxybenzoyl)-benzoic acid, butyric acid, sulphosalicylic acid,
maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid,
embonic acid, stearic acid, toluenesulphonic acid, methanesulphonic acid or 3-hydroxy-2-
10 naphthoic acid, ~he acids being employed in the salt preparation in an equimolar ratio or aratio which deviates therefrom - depending on whether the acid is mono- or polybasic and
depending on what salt is desired. Examples of basic salts which may be mentioned are
lithium, sodium, potassium, calcium, aluminium, magnesium, titanium, ammonium orguanidinium salts, it also being possible here for the bases to be cmployed in the salt
15 preparation in an equimolar ratio or a ratio which deviates therefrom.
Compounds of the formula I which are to be singled out are those in which
Rl denotes hydrogen, hydroxyl (OH) or fluorine,
R2 denotes methyl,
20 R3 denotes ethyl, propyl or isopropyl,
A denotes methylene (-CH2-), ethylene (-CH2CH2-), ethylidene [-CH(CH3)-] or
oxyethylene (-O-CH2cH2-)~
X denotes methylene (-CH2-), ethylene (-CH2CH2-) or vinylene (-CH=CH-) and
Y denotes hydroxyl (OH),
25 and their salts.
Compounds of the formula I which are to be singled out in particular are those in
which
R 1 is in the 4-position relative to the -NH- group and denotes hydrogen, hydroxyl (OH) or
30 fluorine,
R2 is in the 2-position relative to the -NH- group and denotes methyl,
A denotes methylene (-CH2-) or oxyethylene (-O-CH2CH2-),
X denotes ethylene (-CH2CH2-) and
Y denotes hydroxyl (OH),
35 and their salts.
212 5 f~ 81 PCr/EP92/02898
One or more chiral centres may be present in the compounds of the forr.nula 1,
depending on the nature of the substituents. The invention relates to all the enantiomers
and diastereomers as well as mixtures and racemates thereof.
S Examples of compounds of the forrnula I according to the invention aresummarised in the following Table 1 with the aid of selected meanings of R1, R2, R3, A,
X and Y:
WO 93/12090 212 ~ 6 ~ ~ PCr/EP92/02898
Table 1
Rl R2 R3 A X
4-H 2-CH3 -CH2CHCH -OCH2CH2- -CH2- OH
4-H2-CH3 -CH~CHCH -OCH2CH2- -CH2CH2- OH
4-H2-CH3 -CH2CHCH -OCH2CH2- -CH2CH2- NH2
4-H 2-CH3 -CH2CHCH -OCH2CH2- -CH=CH- OH
4-H2-CH3 -CH2CHCH -OCH2CH2- -CH(CH3)- OH
4-H2-CH3 -CH2CHCH -OCH2CH2- -C(CH3)2- OH
4-H2-CH3 -CH2CHCH -OCH2CH2- -CH(CH2CH3)- OH
lo 4-H2-CH3 -CH2CHCH -OCH2CH2- -CH2CH2CH2- OH
4-H2-CH3 -CH2CHCH -OCH2CH2- -CH(CH3)CH2- OH
4-OH2-CH3 -CH2CHCH -OCH2CH2- -CH2- OH
4-OH2-CH3 -CH2CHCH -OCH2CH2- -CH2Q2- OH
4-OH 2-CH3 -CH2CHCH -OCH2CH2- -CH=CH- OH
4-F 2-CH3 -CH2CHCH -OCH2CH2- -CH2- OH
4-F 2-CH3 -CH2CHCH -OCH2CH2- -CH2CH2- OH
4-F 2-CH3 -CH2CHCH -OCH2CH2- -CH=CH- OH
4-H 2-CH3 -CH(CHCH -OCH2CH2- -CH2- OH
4-H 2-CH3 -CH(CHCH -OCH2CH2- -CH2CH2- OH
4-H 2-CH3 -CH(CHCH -OCH2CH2- -CH=CH- OH
4-H 2-CH3 -CH2CH -OCH2~H2- -CH2- OH
4-H 2-CH3 -CH~CH -OCH2CH2- -CH2CH2- OH
: 4-H 2-CH3 -CH~CH -OCH~CH2- -CH=CH- OH
4-H 2-CH3 -CH~CHCH -CH2- -CH2- OH
4-H 2-CH3 -CH2CHCH -CH2- -CH2CH2- OH
4-H 2-CH3 -CH~CHCH -CH2- -CH=CH- OH
4-H 2-CH3 -CH~CHCH -CH2CH2- -CH2- OH
4-H 2-CH3 -CH2CHCH -CH2CH2- -CH2CH2- OH
4-H 2-CH3 -CH2CHCH -CH2CH2- -CH=CH- OH
4-H 2-CH3 -CH2CHCH -CH(CH3)- -CH2- OH
4-H 2-CH3 -CH~CHCH -CH(CH3)- -CH2CH2- OH
: , 4-H 2-CH3 -CH~CHCH -CH(CH3)- -CH=CH- OH
4-OH 2-CH3 -CH2CHCH -CH2- -CH2- OH
4-OH 2-CH3 -CH~CHCH -CH2- -CH2CH2- OH
4-OH 2-CH3 -CH2CHCH -CH~- -CH=CH- OH
4-F 2-CH3 -CH2CHCH -CH2- -CH2- OH
4-F 2-CH3 -CH2CHCH -CH2- -CH2CH2- OH
4-~ 2-CH3 -CH~CHCH -CH2- -CH=CH- OH
WO 93/12090 pcr/Ep92/o2898
2 1 2 ~ 6 -
The invention furthermore relates to a process for the preparation of the
compounds according to the invention and their salts. The process is characterised in tha~ :
compounds of the f~rmula Il
1 ~
R I 11
~/~NH O
~\R3
OH
(Il)
wherein Rl, R2, R3 and A are as described for ~ormula (I), are reacted with dicarboxylic
10 acid derivatives of the formula III
Z C --X C--Y
Il 11
O
(IIl) :
wherein X is as described for formula (I), Yl is a group Y as described for formula (I) ~r a
protected group Y, and Z represents OH (hydroxyl) or a suitable leaving group, or wherein
Y and Z together denote an oxygen atom (cyclic anhydride), and in that, if desired, the
resulting compounds 1 are then converted into their salts, or in that, if desired, the
compounds I are then liberated from resulting salts of the compounds I.
Suitable protected groups Y include protec~ed hydroxy groups as known to ~hose
skilled in the art, in particular benzyloxy groups.
....
The reaction of the compounds 11 with the dicarboxylic acid derivatives III is
carried out in a r~anner which is known per se, such as is known to the expert on the basis
of his specialised knowledge of esterif~lca~ion reactions. The esterification is carried out
in inert solvents, such as, for example, dioxane or te~rahydrofuran, and, depending on the
nature of the group Z, either in the presence of a dehydrating agent or an agent which
bonds water chemically, such as, for example, dicyclohexylcarbodiimide (if Z - OH), or
WO 93/12090 2 ;L 2 ~ 6 ~ 1 pcr/Ep92/o2898
- 7 -
in the presence of an auxiliary base (e.g. triethylamine), if Z represents a leaving group,
for example a halogen atom (in particular chlorine). The leaving group Z is preferably an
alkoxycarbonyloxy radical (mixed anhydride), in particular the isobutoxycarbonyloxy
radical, in which case the reaction can be carried out without further addition of a
5 dehydrating agent. Particularly preferred is the reaction of compounds II with (cyclic)
dicarboxylic acid anhydrides III (Y and Z together denote an oxygen atom).
The compounds of the formuia II are known from EP-A-330 485.
The following examples illustrate the invention in more detail, without limiting it.
The invention preferably relates to the new compounds mentioned by name in the
examples and the salts of these compounds. M.p. denotes melting point, the abbreviation
h is used for hour(s) and the abbreviation min is used for minutes. "Ether" is understood
as meaning diethyl ether.
WO 93/12090 pcr/Ep92/o2898
8-
Example 1
Succinic acid mono-{2-[3-butyryl-4-(2-methylphenylamino)-quinolin-8-yl]-oxyethyl}
ester
.
a) 3-Butyryl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)-quinoline sodium salt
A solution of 1.83 g (5mmol) 3-butyry1-4-(2-methylphenylamino)-8-(2-
hydroxyethoxy)-quinoline in anhydrous tetrahydrofuran (50 ml) is added dropwise to a
suspension of 300 mg (10 mmol) sodium hydride in anhydrous tetrahydrofuran (10 ml) at
room temperature in the course of 30 min, while stirnng vigorously. The mixture is
subsequently stirred at room temperature for a further 2 h. The solution is then employed
directly in step b).
b) Succinic acid mono-~2-~3-butyry1-4-(2-methylphenylamino)-quinolin-8-yl]-oxyethyl
ester
A solution of 0.7 ml (6.3 mmol) N-methylmorpholine in 10 ml tetrahydrofur~n is
added to a solution of 1.49 g (12.5 mmol) succinic acid in anhydrous tetrahydrofuran
(50 ml) and the mixture is stirred at room temperature for 30 min. A solution of 0.82 ml
(6.25 mmol) isobutyl chloroformate in 10 ml te~rahydrofuran is then added dropwise in
the course of 30 min. The suspension is subsequently stir;red at room temperature for a
further 90 min. The solution prepared in a) is then added dropwise at room temperature
in the course of 30 min. The yellow suspension is stirred at room temperature for a
further 3 days. Water (150 ml) is then added and the mixture is extracted with ethyl
acetate (4 x 150 ml). The organic extracts are washed with water (200 ml), dried over
magnesium sulphate and concentrated. The residue is purifled by chromatography on
silica gel (mobile phase: methylene chloride/methanol = 9:1). The frac~ions of
mRf = 0.25 are concentrated. After crystallisation from ethyl acetate, 1.21 g (52%) of the
ti~le compound are isolated. M.p.: 146-148C.
Example 2
Succinic acid mono-~2 [3-butyryl-4 (2-methylphenylamino)-quinolin-8-yl]-oxyethyl}
ester
A mixture of 1.00 g (2.75 mmol3 3-butyryl-4-(2-methylphenylamino)-8-(2-
hydroxyethyl)-quinoline and 3.64 mg (3.57 mn~ol) 98% succinic anhydride in 12 ml
WO 93/12090 21~ ~ 6 ~ ~ PCI/EP92/02Xg8
anhydrous tetrahydrofuran is stirred under reflux for 9 h, whereupon the product begins to
crys~allise. 20 ml of diisopropyl ether are added dropwise, and the mixture is cooled and
stirred for 1.5 h in an ice bath. The yellow precipitate is ~lltered off and washed with
diisopropyl ether. 1.21 g (95.1%) of the title compound of m.p. 163-164C are obtained.
When the reaction is carried out analogously in the presence of 2.74 mmol
- potassium tert-butoxide at room temperature, the potassium salt of the title compound is
obtained.
Example 3
Glutaric acid mono-{2-[3-butyryl-4-(2-methylphenylamino)-quinolin-X-yloxy]ethyl} ester
1.00 g (2.74 mmol) 3-butyryl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)-
quinoline and 407 mg (3.57 mmol) glutaric anhydride were reacted analogously to
Example 2. The solution was concentrated in vacuo, diisopropyl ether added, and 1.22 g
(92.8%) of the title compound of m.p. 160-161~C obtained.
Example 4
3-Methylglutaric acid mono-~2-[3-butyryl-4-(2-methylphenylamino)-quinolin-8-
yloxy]ethyl} ester `~
2.00 g (5.49 mmol) 3-butyryl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)-
quinoline, 0.91 g (6.3 mmol) 99% 3-methylglutaric anhydride and 60 ml dry
tetrahydrofuran were heated under reflux for 24 h. The mixture was stirred at room
temperature for 12 h, cooled in ice, filtered and dried in vacuo at 100C. 2.40 g (88.7%)
of the title compound of m.p. 160-162C were obtained.
Example
. . .
3,3-Dimethyl~lutaric acid mono-{2-[3-butyryl-4-(2-methylphenylamino)-quinolin.8- yloxy]ethyl} ester
IJsing 3,3-dimethylglutaric anhydride analogously to Example 4, 27% of the titlecompound of m.p. 151-156C was obtained after heating under reflux for 48 h,
concentration in vacuo and chromatography on silica gel using ethyl acetate~
Wo 93/12090 PCI/EP92/02898
21~S~ - lO-
Example 6
2,2-Dimethylglutaric acid 5-mono-~2-[3-butyryl-4-(2-methylphenylamino)-quinolin- 8-yloxy]ethyl} ester
From 1.82 g (5.0 mmol) 3-butyry1-4-(2-metylphenylamino)-8-(2-hydroxyethoxy)-
quinoline and 930 mg 2,2-dimethylglutaric anhydride in 60 ml dry tetrahydrofuran, 2.14 g
(84.6%) of the title compound of m.p. 179-180C were obtained analogously ~o Example
4 and after recrystallisation from ethyl acetate (260 ml).
Example 7
Malonic acid mono-{2-13-butyryl-4-(2-methylphenylamino)-quinolin-8-yloxy]ethyl}
ester
A solution of 0.53 ml (5.5 mmol) malonic acid dichloride in 10 ml
tetrahydrofuran was added dropwise to a solution of 2.00 g (5.49 mmol) 3-butyryl~-(2-
methylphenylamino)-8-(2-hydroxyethoxy)-quinoline in 40 ml dry tetrahydrofuran at 0C -
in the course of 30 min, and the mixture stirred at room temperature for 4 h, and then
poured onto ice/water, buffered to pH 5.7 with sodium bicarbonate and extracted with
isopropyl acetate. The organic solution was dried with magnesium sulphate and
concentrated in vacuo. Column chromatography with ethyl acetate/isopropanol 2:1 over
1,600 g silica gel followed by concentration and precipitation with diisopropyl ether gave
1.7 g (68.8%) of the title compound of m.p. 18~187C (decomposition).
Example 8
Succinic acid mono-~2-(3-butyryl-4-(4-fluoro-2-methylphenylamino)-quinolin-8-
yl)oxyethyl} ester
a) Benzyl succinic acid mono- ( 2-(3-butyryl-4-(4-fluor~2-methylphenylamino)-quinolin-
8-yl)oxyethyl) ester
Isobutyl chloroformate (1.43 ml, 11 mmol) was added to a mixture of benzyl
hydrogen succinate (2.29 g, 11 mmol), triethylamine (1.53 ml, 11 mmol~, dioxan (100 ml)
and chloroform (50 ml). The resulting suspension was stirred for 30 min at room
temperature, then 3-butyryl-4-(4-fluoro-2-methylphenylamino)-8-(2-hydroxyethoxy)-
WO 93/12090 2 ~ 2 5 $`~ ~ PCI/EP92/028~8
11
quinoline (3.5 g, 9.2 mmol) and triethylamine ( 1.53 ml, 11 mmol) were added, and the
mixture was heated at reflux for 16 hours. The solvent was evaporated, and the residue
was taken up in dichloromethane, washed with aqueous sodium bicarbonate then with
water, dried, and the solvent evaporated. Chromatography (silica,
5 dichloromethane/methanol) and trituration with ether gave the product (1.77 g, 34%);
m.p. 107-111C.
.
b) Succinic acid mono- ~ 2-(3-butyry1-4-(4-fluoro-2-methylphenylamino)-quinolin-8-
yl)oxyethyll ester
A solution of benzyl succinic acid mono-~2-(3-butyryl-4-(4-fluoro-2-
methylphenylamino)-quinolin-8-yl)-oxyethyl) ester (1.7 g, 3.0 mmol) in glacial acetic
acid (100 ml) was hydrogenated at 50 psi over 10% pal!adium on charcoal (0.1 g) for 5
hours, then filtered and the solvent removed in vacuo. Recrystallisa~ion from ethyl acetate
gave the product (1.1 g, 77%); m.p. 172-174C.
Example 9
. .
Succinic acid mono-{2-(3-butyryl-4-(4-fluoro-2-methylphenylamino)-quinolin-8-
ylhxyethyl} ester
a) Benzyl succinic acid mono- l 2-(3-propanoyl-4-(2-methylphenylamino)-quinolin-8-
yl)oxyethyl) ester
Isobutyl chloroformate (1.95 ml, 15 mmol) was added to a mixture of benzyl
hydrogen succinate (3.12 g, 15 mmol), triethylamine (1.95 ml, 15 mmol), dioxan (150 ml)
and chloroform (100 ml). The resulting suspension was stirred for 30 min at roomtemperature, then 3-propanoyl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)quinoline
(3.5 g, 10 mmol) and triethylamine ( 1.95 ml, 15 mmol) were added, and the mixture was
heated at reflux for 16 hours. The solvent was evaporated, and the residue was takcn up in
dichloromethane, washed with aqueous sodium bicarbonate then with water, dricd, and the
solvent evaporatcd. Trituration with ether gave the product (1.55 g, 29%);
m.p. 108^110C.
WO 93/12090 PCI/EP92/02898
212~ 12
b) Succinic acid mono- ( 2-(3-propanoyl-4-(2-methylphenylamino)-quinolin-8-
yl)oxyethyl} ester
A solution of benzyl succinic acid mono-(2-(3-propanoyl-4-(2-
methylphenylamino)-quinolin-8-yl)oxyethyll ester (1.55 g, 2.87 mmol) in glacial acetic
acid (100 ml) was hydrogenated at 50 psi over 10% palladium on charcoal (0.1 g) for 5
- hours, then ~lltered and the solvent removed in vacuo. Recrystallisation from ethyl acetate
gave the product (1.05 g, 81%); m.p. 189rl93C (dec).
Example 10
Succ;nic acid mono-{2-(3-propanoyl-4-~4-f1uoro-2-methylphenylamino)-quinolin-8-
yl)oxyethyl} ester
a) Benzyl succinic acid mono-12-(3-propanoyl-4-(4-fluoro-2-methylphenylamino)-
quinolin-8-yl)oxyethyl ) ester
lsobutyl chloroformate (1.43 ml, 11 mmol) was added to a mixture of benzyl
hydrogen succinate (2.29 g, 11 mmol), triethylamine ( 1.53 ml, 1 1 mmol), tetrahydrofu~an
(50 ml) and chloroform (10 ml). The resulting suspension was stirred for 20 min at room
temperature, then 3-propanoyl-4-(4-fluoro-2-methylphenylamino)-8-(2-hydroxyethoxy)-
quinoline (3.68 g, 10 mmol) was added, and the mixture was heated at reflux for 16 hours.
The solvent was evaporated, and the residue was taken up in dichloromethane, washed
with aqueous sodium bicarbonate then with water, dried, and the solvent evaporated.
Chromatography (silica, dichloromethane/methanol) and recrystallisation from methanol
gave the product (2.9 g, 47%); m.p. 110-113 C.
b) Succinic acid mono- ~ 2-(3-propanoyl-4-(4-fluoro-2-methylphenylamino)-quinolin-8-
yl)oxyethyl} ester
A solution of benzyl succinic acid mono-(2-(3-propanoyl-4-(4-fluoro-2-
methylphenylamino)-quinolin-8-yl)oxyethyl ) ester (2.7 g, 4.8 mmol) in glacial acetic acid
(100 ml) was hydrogenated at S0 psi over 10% palladium on charcoal (0.2 g) for 3 hours,
then filtered and the solvent removed in v~cuo. Recrystallisation from ethyl acetate gave
the product (1.4 g, 62%); m.p. 195-197 C.
WO 93/12090 PCI/EP92/02898
? ~3
Commercia~ usefulness
The compounds of the fonnula I and their salts have valuable pharmacological
properties which render them commercially usable. They display a pronounced inhibition
S of gastric acid secretion and an excellent protective action on the stomach and intestine in
- warm-blooded animals. The comparatively good solubility of the compounds according -'
to the invention is of particular importance. On the basis of this good solubility, an even
and uniform availability which is essentially independent of the particular secretion status
is achieved - a wide range of sca~ter being avoided.
`"'"`
"Protection of the stomach and intestine" in this connection is understood as 'meaning the prevention and treatment of gastrointestinal disea~ses, in particular
gastrointestinal inflammatory diseases and lesions (such as e.g. ulcus ventriculi, ulcus
duodeni, gastritis, hyperacid irritated stomach or irritated stomach of medicamentous
15 origin) which can be caused, for example, by microorganisms (e.g. Helicobacter pylori),
bacterial toxins, medicaments (e.g. certain antiinflammatories and antirheumatics),
chemicals (e.g. ethanol), gastric acid or stress situations.
The compounds according to the invention and their salts have proved to have an
~0 excellent action on various models in which the antiulcerogenic and the antisecretory
properties are determined, and therefore to be outstandingly suitable for use in human and
veterinary medicine, in which they are used in particular for the treatment and/or
prophylaxis of diseases of the stomach and/or intestine.
The invention thus furthermore relates tO the compounds according to the
invention and their pharmacologically tolerated salts for use in the treatrnent and/or
prophylaxis of the above-mentioned diseases.
The invention also relates to the use of the compounds according to the invention
and their pharmacologically tolerated salts for the preparation of medicaments which are
employed for the treatmcnt and/or prophylaxis of the above-mentioned discases.
The invention furthermore relates to the use of the compounds according to the
invention and their salts for the treatment and/or prophylaxis of the above-mentioned
diseases.
The invention furthermore relates to medicaments which contain one or more
compounds of the formula I and/or their ph'armacological1y tolerated salts.
WO 93/12090 PCI/EP92/02898
~12~6~ - 14-
The medicaments are prepared by processes which are known per se and with
which the expert is familiar. The pharmacologically active compounds (= active
compounds) according to the invention are employed as medicaments either as such or,
preferably, in combination with suitable pharmaceutical auxiliaries or excipients, in the
form of tablets, coated tablets, capsules, suppositories, plasters (e.g. as l'rS), emulsions,
suspensions or solutions, the active compound content advantageously being between 0.1
and 95%.
~-
The expert is familiar, on the basis of his specialised knowledge, with the
auxiliaries and excipients which are suitable for the medicament formulations desired. In
addition to solvents, gel-forming agents, suppository bases, tablet auxiliaries and other
active compound excipients, it is possible to use, for example, antioxidants, dispersing
agents, emulsifiers, foam suppressants, flavour correctants, preservatives, solubilizing
lS agents, dyestuffs or, in particular, perrneation promoters and complexing agents (e.g.
cyclodextrins).
The active compounds can be administered orally, parenterally or percutaneously.
In general, in the case of oral administration, for the active compound or
compounds to be administered in a daily dose of about 0.01 to about 20, preferably 0.05 to
5, in particular 0.1 to l.S mgllcg body weight, if appropriate in the form of several,
preferably I to 4, individual doses, in order to achieve the desired results. For parenteral
treatment, similar or (especially in the case of intravenous administration of the active
compounds~ as a rule lower dosages can be used. The particular optimum dosage and
mode of administration required for the active sompounds can easily be deterr;nined by any
expert on the basis of his specialised knowledge.
If the compounds and/or salts according to the invention are to be employed for
the treatment of the above-mentioned diseases, the pharmaceutical formulations can also
contain one or rnore pharmacologically active constituents from other groups of
medicaments, such as antacids, for example aluminium hydroxide or magncsium
aluminate; tranquillisers, such as benzodiazepines, for example diazepam; spasmolytics,
such as e.g. bietamiverine or camylofin, or anticholinergics, such as e.g.
oxyphencyclimine or phencarbamide; local anaesthetics, such as c.g. tetracaine or
procaine; and, if appropriate, also enzymes, vitamins or amino acids.
WO 93/12090 PCI/EP92/02898
,.~ 2~5~ IS-
There should be singled out in this connection in particular combination of the
compounds according to the invention with drugs which inhibit acid secretion, such as for
example, H2-blockers (e.g. cimetidine or ranitidine) or furtherrnore with so-called
peripheral anticholinergics (e.g. pirenzepine or telenzepine) as well as with gastrin
S antagonists, with the aim of intensifying the main action in the additive or superadditive
sense and/or of eliminating or reducing the side effects, or furthermore combination with
antibacterial substances (such as e.g. cephalosporins, tetracyclines, nalidixic acid,
penicillins or also bismuth salts) for combating Helicobacter pylori.
