WO1993012090A1 - 4-amino-3-acyl quinoline derivatives and their use as inhibitors of gastric acid secretion - Google Patents
4-amino-3-acyl quinoline derivatives and their use as inhibitors of gastric acid secretion Download PDFInfo
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- WO1993012090A1 WO1993012090A1 PCT/EP1992/002898 EP9202898W WO9312090A1 WO 1993012090 A1 WO1993012090 A1 WO 1993012090A1 EP 9202898 W EP9202898 W EP 9202898W WO 9312090 A1 WO9312090 A1 WO 9312090A1
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- Prior art keywords
- denotes
- methylphenylamino
- ester
- quinolin
- butyryl
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
Abstract
A compound of formula (I), wherein R1 denotes hydrogen, hydroxyl (OH), halogen or C¿1-4?alkyl, R?2¿ denotes hydrogen or C¿1-4?alkyl, R?3¿ denotes C¿1-4?alkyl, A denotes methylene(-CH2-), ethylene (-CH2CH2-), ethylidene [-CH(CH3)-], trimethylene (-CH2CH2CH2-), oxyethylene (-O-CH2CH2-) or oxytrimethylene (-O-CH2CH2CH2-), X denotes C1-6alkylene or C2-4alkenylene and Y denotes hydroxyl (OH) or amino (NH2), or a salt thereof, processes for their preparation, pharmaceutical compositions containing them and their use in therapy as inhibitors of gastric acid secretion.
Description
4-Am1no-3-acyl quinol lne derivatives and thei r use as I nhibitors of gastr add secretion .
Field of use of the invention
5 - 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
10
4-Amino-3-acyl-quinoline derivatives and their use as inhibitors of gastric acid secretion are described in European Patent Application EP-A-330 485.
Description of the invention
15
It has now been found that the compounds which are described below in more detail and which differ from the compounds of the prior art in particular by the substituent in the 8-position of the quinoline ring have surprising and particularly advantageous properties.
20
The invention thus relates in a first aspect to compounds of the formula I:
25 (I)
A wherein
R! denotes hydrogen, hydroxyl (OH), halogen or C^alkyl, R.2 denotes hydrogen or Cj^alkyl, 30 R3 denotes Cι_4alkyl,
A denotes methylene (-CH2-), ethylene (-CH2CH2-), ethylidene [-CH(CH3)-], trimethylene (-CH2CH2CH2-), oxyethylene (-O-CH2CH2-) or oxytrimethylene (-O-CH2CH2CH2-),
X denotes Cj_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.
Cι_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^alkyl radicals R* and/or R^ are preferably methyl radicals. Preferred C^alkyl radicals R3 are the ethyl, the isopropyl and in particular the propyl radical.
Ci.galkylene 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 [-CH(CH3)-J, isopropylidene [-CH(CH3)2-], propylidene [-CH(C2H5)-], trimethylene (-CH2CH2CH2-), propylene [-CH(CH3)-CH2-], tetramethylene (-CH2CH2CH2CH2-), 1,1-dimethylethylene [-C(CH3)2-CH2-], 1,2- dimethylethylene [-CH(CH3)-CH(CH3)-], 1-methyltrimethylene [-CH(CH3)-CH2CH2-], 2-methyItrimethylene [-CH2-CH(CH3)-CH2-], pentylidene [-CH(C4H9)-], pentan-3- ylidene [-CH C2H5)2-], pentamethylene (-CH2CH2CH2CH2CH2-), and the hexamethylene radical (-CH2CH2CH2CH2CH2CH2-), of which the ethylene radical is preferred.
C2-4alkenylene represents straight-chain or branched, mono- or polyunsaturated alkenylene radicals having 1 to 4 carbon atoms. Examples which may be mentioned are the vinylene (-CH=CH-), propenylene (-CH2-CH=CH-), isopropenylene
[-CH2-C(=CH2)-], 2-butenylene (-CH2-CH=CH-CH2-) and the 1,3-butadienylene radical (-CH=CH-CH=CH-), of which the vinylene radical is preferred.
Since the compounds of the formula I 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 be obtained as process products, for example, when the compounds according to
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 - 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- naphthoic acid, the acids being employed in the salt preparation in an equimolar ratio or a ratio 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 or guanidinium salts, it also being possible here for the bases to be employed in the salt 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 R- denotes hydrogen, hydroxyl (OH) or fluorine, R2 denotes methyl, R denotes ethyl, propyl or isopropyl,
A denotes methylene (-CH2-), ethylene (-CH2CH2-), ethylidene [-CH(CH3)-j or oxyethylene (-O-CH2CH2-), X denotes methylene (-CH2-), ethylene (-CH2CH2-) or vinylene (-CH=CH-) and
Y denotes hydroxyl (OH), and their salts.
Compounds of the formula I which are to be singled out in particular are those in which
R! is in the 4-position relative to the -NH- group and denotes hydrogen, hydroxyl (OH) or fluorine,
R 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), and their salts.
One or more chiral centres may be present in the compounds of the formula I, depending on the nature of the substituents. The invention relates to all the enantiomers and diastereomers as well as mixtures and racemates thereof.
Examples of compounds of the formula I according to the invention are summarised in the following Table 1 with the aid of selected meanings of R-, R^5 R3, A, X and Y:
wherein R , R^, R3 and A are as described for formula (I), are reacted with dicarboxylic acid derivatives of the formula III
Z — C X — -C— Y
II II o o
(HI)
wherein X is as described for formula (I), Y is a group Y as described for formula (I) or 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 I 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 protected hydroxy groups as known to those skilled in the an, in particular benzyloxy groups.
The reaction of the compounds II with the dicarboxylic acid derivatives HI is carried out in a manner which is known per se, such as is known to the expert on the basis of his specialised knowledge of esterification reactions. The esterification is carried out in inert solvents, such as, for example, dioxane or tetrahydrofuran, 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
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 - 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 formula 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.
Example 1
Succinic acid mono-{2-[3-butyryl-4-(2-methylphenylamino)-quinolin-8-yI]-oxyethyl} ester . a) 3-Butyryl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)-quinoline sodium salt
A solution of 1.83 g (5mmol) 3-butyryl-4-(2-methylphenylamino)-8-(2- hydroxyethoxy)-quinoIine 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 stirring 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-butyryl-4-(2-methylphenylamino)-quinolin-8-yl]-oxyethyl ester}
A solution of 0.7 ml (6.3 mmol) N-methylmorpholine in 10 ml tetrahydrofuran 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 tetrahydrofuran is then added dropwise in the course of 30 min. The suspension is subsequently stirred 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 purified by chromatography on silica gel (mobile phase: methylene chloride/methanol = 9:1). The fractions of mRf = 0.25 are concentrated. After crystallisation from ethyl acetate, 1.21 g (52%) of the title compound are isolated. M.p.: 146-148°C.
Example 2
Succinic acid mono-{2-[3-butyryI-4-(2-methyIphenyIamino)-quinoIin-8-yI]-oxyethyl} ester
A mixture of 1.00 g (2.75 mmol) 3-butyryl-4-(2-methylphenylamino)-8-(2- hydroxyethyl)-quinoline and 3.64 mg (3.57 mmol) 98% succinic anhydride in 12 ml
anhydrous tetrahydrofuran is stirred under reflux for 9 h, whereupon the product begins to crystallise. 20 ml of dusopropyl ether are added dropwise, and the mixture is cooled and stirred for 1.5 h in an ice bath. The yellow precipitate is filtered off and washed with dusopropyl ether. 1.21 g (95.1 %) of the title compound of m.p. 163- 164°C 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)-quinoIin-8-yloxy]ethyI} 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, dusopropyl 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)-quinoIin-8- yloxyjethyl} 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 100°C. 2.40 g (88.7%) of the title compound of m.p. 160-162°C were obtained.
Example 5
3,3-Dimethylglutaric acid mono-{2-[3-butyryl-4-(2-methylphenylamino)-quinoIin-8- yloxy]ethyl} ester
Using 3,3-dimethylglutaric anhydride analogously to Example 4, 27% of the title compound of m.p. 151-156°C was obtained after heating under reflux for 48 h, concentration in vacuo and chromatography on silica gel using ethyl acetate.
Example 6
2,2-DimethyIgIutaric acid 5-mono-{2-[3-butyryl-4-(2-methyIphenylamino)-quinoIin- - 8-yloxy]ethyI} ester
From 1.82 g (5.0 mmol) 3-butyryl-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. 179-180°C were obtained analogously to Example 4 and after recrystallisation from ethyl acetate (260 ml).
Example 7
MaIonic acid mono-{2-[3-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-4-(2- methylphenylamino)-8-(2-hydroxyethoxy)-quinoline in 40 ml dry tetrahydrofuran at 0°C 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 dusopropyl ether gave 1.7 g (68.8%) of the title compound of m.p. 186-187°C (decomposition).
Example 8
Succinic acid mono-{2-(3-butyryI-4-(4-fiuoro-2-methylphenylamino)-quinoIin-8- y oxyethyl} ester
a) Benzyl succinic acid mono-{2-(3-butyryl-4-(4-fluoro-2-methylphenylamino)-quinoIin- 8-yl)oxyethyl} ester
Isobutyl chloroformate (1.43 ml, 11 mmol) was added to a mixture of benzyl hydrogen succinate (2.29 g, II mmol), triethylamϊne (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)-
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, "" dichloromethane/methanol) and trituration with ether gave the product (1.77 g, 34%); m.p. 107-111°C.
b) Succinic acid mono-{2-(3-butyryl-4-(4-fluoro-2-methylphenylamino)-quinolin-8- yl)oxyethyl} 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% palladium on charcoal (0.1 g) for 5 hours, then filtered and the solvent removed in vacuo. Recrystallisation from ethyl acetate gave the product (1.1 g, 77%); m.p. 172-174°C.
Example 9
Succinic acid mono-{2-(3-butyryl-4-(4-fluoro-2-methyIphenylamino)-quinolin-8- yl)oxyethyl} ester
a) Benzyl succinic acid mono-{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 room temperature, 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 taken up in dichloromethane, washed with aqueous sodium bicarbonate then with water, dried, and the solvent evaporated. Trituration with ether gave the product (1.55 g, 29%); m.p. 108-110°C.
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)-quinoIin-8-yl)oxyethyl] 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 filtered and the solvent removed in vacuo. Recrystallisation from ethyl acetate gave the product (1.05 g, 81%); m.p. 189-193°C (dec).
Example 10
Succinic acid mono-{2-(3-propanoyl-4-(4-fluoro-2-methylphenylamino)-quinolin-8- yl)oxyethyI} ester
a) Benzyl succinic acid mono-{2-(3-propanoyl-4-(4-fluoro-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), tetrahydrofuran (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- yI)oxyethyl} ester
A solution of benzyl succinic acid mono-{2-(3-propanoyl-4-(4-fluoro-2- methyIphenylamino)-quinolin-8-yl)oxyethyl} ester (2.7 g, 4.8 mmol) in glacial acetic acid (100 ml) was hydrogenated at 50 psi over 10% palladium on charcoal (0.2 g) for 3 hours, then filtered and the solvent removed in vacuo. Recrystallisation from ethyl acetate gave the product (1.4 g, 62%); m.p. 195-197 C.
Commercial usefulness
The compounds of the formula I and their salts have valuable pharmacological properties which render them commercially usable. They display a pronounced inhibition " 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 scatter being avoided.
"Protection of the stomach and intestine" in this connection is understood as meaning the prevention and treatment of gastrointestinal diseases, in particular gastrointestinal inflammatory diseases and lesions (such as e.g. ulcus ventriculi, ulcus duodeni, gastritis, hyperacid irritated stomach or irritated stomach of medicamentous 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 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 treatment 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 treatment and/or prophylaxis of the above-mentioned diseases.
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 pharmacologically tolerated salts.
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 TTS), 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, emulsifϊers, foam suppressants, flavour correctants, preservatives, solubilizing agents, dyestuffs or, in particular, permeation 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 1.5 mg/kg body weight, if appropriate in the form of several, preferably 1 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 compounds can easily be determined 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 more pharmacologically active constituents from other groups of medicaments, such as antacids, for example aluminium hydroxide or magnesium aluminate; tranquillisers, such as benzodiazepines, for example diazep am; spasmolytics, such as e.g. bietamiverine or camylofin, or anticholinergics, such as e.g. oxyphencyclimine orphencarbamide; local anaesthetics, such as e.g. tetracaine or procaine; and, if appropriate, also enzymes, vitamins or amino acids.
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 furthermore with so-called peripheral anticholinergics (e.g. pirenzepine or telenzepine) as well as with gastrin 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.
Claims
A compound of formula I,
(I)
wherein R! denotes hydrogen, hydroxyl (OH), halogen or Cι_4alkyl,
R2 denotes hydrogen or C].4alkyl,
R3 denotes Cι_4alkyl,
A denotes methylene (-CH2-), ethylene (-CH2CH2-), ethylidene [-CH(CH3)-], trimethylene (-CH2CH2CH2-), oxyethylene (-O-CH2CH2-) or oxytrimethylene (-O-CH2CH2CH2-),
X denotes Cχ_galkylene or C _4alkenylene and
Y- denotes hydroxyl (OH) or amino (NH2), or a salt thereof.
2. A compound of formula I according to claim I, wherein
R- denotes hydrogen, hydroxyl (OH) or fluorine,
R2 denotes methyl,
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), or a salt thereof.
3. A compound of formula I according to claim 1, wherein
R! is in the 4-position relative to the -NH- group and denotes hydrogen, hydroxyl (OH) or 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), or a salt thereof.
4. A compound according to claim 1 which is succinic acid mono- {2-[3-butyryl-4-(2-methylphenylamino)-quinolin-8-yl]-oxyethyl} ester, succinic acid mono- {2-[3-butyryl-4-(2-methylphenylamino)-quinolin-8-yl]-oxyethyl} ester, glutaric acid mono-{2-[3-butyryl-4-(2-methylphenylamino)-quinolin-8-yloxy]ethyl} ester,
3-methylglutaric acid mono-{2-[3-butyryl-4-(2-methylphenylamino)-quinolin-8- yloxy]ethyl) ester,
3,3-dimethylglutaric acid mono- {2-[3-butyryl-4-(2-methylphenylamino)-quinolin-8- yloxy] ethyl} ester, 2,2-dimethylglutaric acid 5-mono-{2-[3-butyryl-4-(2-methylphenylamino)-quinolin-8- yloxy} ethyl} ester, malonic acid mono-{2-[3-butyryl-4-(2-methylphenylamino)-quinolin-8-yloxy]ethyl} ester, succinic acid mono- {2-(3-butyryl-4-(4-fluoro-2-methylphenylamino)-quinolin-8- yl)oxyethyl} ester, succinic acid mono-{2-(3-butyryl-4-(4-fluoro-2-methylphenylamino)-quinolin-8- yl)oxyethyl} ester, or succinic acid mono-{2-(3-propanoyl-4-(4-fluoro-2-methylphenylamino)-quinolin-8- yl)oxyethyl} ester or a salt thereof.
5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
6. A compound according to any one of claims 1 to 4 for use in therapy.
7. A compound according to any one of claims 1 to 4 for use in the inhibition of gastric secretion.
8. A process for the preparation of a compound according to claim 1 which comprises reacting a compound of formula π,
wherein R , R^, R? and A have the meanings given in claim 1, with a dicarboxylic acid derivative of formula III
Z — C- -C— Y
II o
(in)
wherein X is as described for formula (I), Y- is a group Y as described for formula (I) or 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 I are then converted into their salts, or in that, if desired, the compounds I are then liberated from resulting salts of the compounds I.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU31585/93A AU665223B2 (en) | 1991-12-12 | 1992-12-10 | 4-amino-3-acyl quinoline derivatives |
| JP5510627A JPH07501812A (en) | 1991-12-12 | 1992-12-10 | 4-Amino-3-acylquinoline derivatives and their use as gastric acid secretion inhibitors |
| EP93900050A EP0642500A1 (en) | 1991-12-12 | 1992-12-10 | 4-amino-3-acyl quinoline derivatives and their use as inhibitors of gastric acid secretion |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9126438.2 | 1991-12-12 | ||
| GB919126438A GB9126438D0 (en) | 1991-12-12 | 1991-12-12 | New quinoline derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1993012090A1 true WO1993012090A1 (en) | 1993-06-24 |
Family
ID=10706172
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1992/002898 WO1993012090A1 (en) | 1991-12-12 | 1992-12-10 | 4-amino-3-acyl quinoline derivatives and their use as inhibitors of gastric acid secretion |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0642500A1 (en) |
| JP (1) | JPH07501812A (en) |
| AU (1) | AU665223B2 (en) |
| CA (1) | CA2125681A1 (en) |
| GB (1) | GB9126438D0 (en) |
| MX (1) | MX9207162A (en) |
| WO (1) | WO1993012090A1 (en) |
| ZA (1) | ZA929568B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994029274A1 (en) * | 1993-06-11 | 1994-12-22 | Astra Aktiebolag | New active compounds |
| US5556863A (en) * | 1993-06-11 | 1996-09-17 | Astra Aktiebolag | Compound for gastric acid secretion inhibition |
| US7175854B2 (en) | 2000-12-07 | 2007-02-13 | Altana Pharma Ag | Pharmaceutical preparation comprising an active dispersed on a matrix |
| US7951397B2 (en) | 2002-02-20 | 2011-05-31 | Nycomed Gmbh | Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0259174A1 (en) * | 1986-09-05 | 1988-03-09 | Smith Kline & French Laboratories Limited | Derivatives of 4-aminoquinoline and their use as medicaments |
| EP0330485A1 (en) * | 1988-02-25 | 1989-08-30 | SmithKline Beecham Intercredit B.V. | 4-Amino-3-acyl quinoline derivatives and their use as inhibitors of gastric acid secretion |
| EP0416749A2 (en) * | 1989-08-10 | 1991-03-13 | Smithkline Beecham Intercredit B.V. | Substituted 4-aminoquinolines |
| WO1992012969A1 (en) * | 1991-01-29 | 1992-08-06 | Smithkline Beecham Intercredit B.V. | Salts of a 4-amino-3-acyl quinoline derivative and their use as inhibitors of gastric acid secretion |
-
1991
- 1991-12-12 GB GB919126438A patent/GB9126438D0/en active Pending
-
1992
- 1992-12-10 ZA ZA929568A patent/ZA929568B/en unknown
- 1992-12-10 EP EP93900050A patent/EP0642500A1/en not_active Withdrawn
- 1992-12-10 JP JP5510627A patent/JPH07501812A/en active Pending
- 1992-12-10 WO PCT/EP1992/002898 patent/WO1993012090A1/en not_active Application Discontinuation
- 1992-12-10 MX MX9207162A patent/MX9207162A/en unknown
- 1992-12-10 AU AU31585/93A patent/AU665223B2/en not_active Ceased
- 1992-12-10 CA CA002125681A patent/CA2125681A1/en not_active Abandoned
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0259174A1 (en) * | 1986-09-05 | 1988-03-09 | Smith Kline & French Laboratories Limited | Derivatives of 4-aminoquinoline and their use as medicaments |
| EP0330485A1 (en) * | 1988-02-25 | 1989-08-30 | SmithKline Beecham Intercredit B.V. | 4-Amino-3-acyl quinoline derivatives and their use as inhibitors of gastric acid secretion |
| EP0416749A2 (en) * | 1989-08-10 | 1991-03-13 | Smithkline Beecham Intercredit B.V. | Substituted 4-aminoquinolines |
| WO1992012969A1 (en) * | 1991-01-29 | 1992-08-06 | Smithkline Beecham Intercredit B.V. | Salts of a 4-amino-3-acyl quinoline derivative and their use as inhibitors of gastric acid secretion |
Non-Patent Citations (2)
| Title |
|---|
| ANN. REP. MED. CHEM. vol. 10, 1975, pages 306 - 316; SINKULA, A.A.: 'Chapter 31. Prodrug approach in drug design' * |
| C. HANSCH "COMPREHENSIVE MEDICINAL CHEMISTRY ", FIRST EDITION, VOLUME 5, CHAPTER 23.4 1990, PERGAMON PRESS, LONDON pages 111 - 142; C. M. MACDONALD & R.G. TURCAN: 'Sites of drug metabolism, prodrugs and bioactivation.' * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994029274A1 (en) * | 1993-06-11 | 1994-12-22 | Astra Aktiebolag | New active compounds |
| US5556863A (en) * | 1993-06-11 | 1996-09-17 | Astra Aktiebolag | Compound for gastric acid secretion inhibition |
| AU680516B2 (en) * | 1993-06-11 | 1997-07-31 | Astra Aktiebolag | New active compounds |
| US5889021A (en) * | 1993-06-11 | 1999-03-30 | Astra Aktiebolag | Active Compounds |
| US7175854B2 (en) | 2000-12-07 | 2007-02-13 | Altana Pharma Ag | Pharmaceutical preparation comprising an active dispersed on a matrix |
| US7951398B2 (en) | 2000-12-07 | 2011-05-31 | Nycomed Gmbh | Pharmaceutical preparation comprising an active dispersed on a matrix |
| US7951397B2 (en) | 2002-02-20 | 2011-05-31 | Nycomed Gmbh | Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient |
| US8431154B2 (en) | 2002-02-20 | 2013-04-30 | Takeda Gmbh | Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidone as excipient |
| US9468598B2 (en) | 2002-02-20 | 2016-10-18 | Astrazeneca Ab | Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient |
Also Published As
| Publication number | Publication date |
|---|---|
| AU665223B2 (en) | 1995-12-21 |
| ZA929568B (en) | 1994-06-10 |
| AU3158593A (en) | 1993-07-19 |
| GB9126438D0 (en) | 1992-02-12 |
| CA2125681A1 (en) | 1993-06-24 |
| MX9207162A (en) | 1994-08-31 |
| JPH07501812A (en) | 1995-02-23 |
| EP0642500A1 (en) | 1995-03-15 |
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