CA2125681A1 - 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 secretionInfo
- Publication number
- CA2125681A1 CA2125681A1 CA002125681A CA2125681A CA2125681A1 CA 2125681 A1 CA2125681 A1 CA 2125681A1 CA 002125681 A CA002125681 A CA 002125681A CA 2125681 A CA2125681 A CA 2125681A CA 2125681 A1 CA2125681 A1 CA 2125681A1
- Authority
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- Canada
- Prior art keywords
- denotes
- methylphenylamino
- quinolin
- ester
- butyryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
A compound of formula (I), wherein R1 denotes hydrogen, hydroxyl (OH), halogen or C1-4alkyl, R2 denotes hydrogen or C1-4alkyl, R3 denotes C1-4alkyl, 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
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-H2-CH3 -CH~CHCH -OCH2CH2- -CH2CH2- OH
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-OH 2-CH3 -CH2CHCH -OCH2CH2- -CH=CH- 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 -CH~CHCH -CH2- -CH=CH- OH
4-H 2-CH3 -CH~CHCH -CH2CH2- -CH2- 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 -CH~CHCH -CH2- -CH2CH2- OH
4-OH 2-CH3 -CH2CHCH -CH~- -CH=CH- 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 ~
~/~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 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 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 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.
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.
? ~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.
~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.
,.~ 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.
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-H2-CH3 -CH~CHCH -OCH2CH2- -CH2CH2- OH
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-OH 2-CH3 -CH2CHCH -OCH2CH2- -CH=CH- 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 -CH~CHCH -CH2- -CH=CH- OH
4-H 2-CH3 -CH~CHCH -CH2CH2- -CH2- 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 -CH~CHCH -CH2- -CH2CH2- OH
4-OH 2-CH3 -CH2CHCH -CH~- -CH=CH- 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 ~
~/~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 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 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 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.
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.
? ~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.
~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.
,.~ 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.
Claims (8)
1. A compound of formula I, (I) wherein R1 denotes hydrogen, hydroxyl (OH), halogen or C1-4alkyl, R2 denotes hydrogen or C1-4alkyl, R3 denotes C1-4alkyl, 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.
2. A compound of formula I according to claim 1, wherein R1 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 R1 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-dimethylglutanc 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.
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-dimethylglutanc 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 II, (II) wherein R1, R2, R3 and A have the meanings given in claim 1, with a dicarboxylic acid derivative of formula III
(III) wherein X is as described for formula (I), Y1 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.
(III) wherein X is as described for formula (I), Y1 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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB919126438A GB9126438D0 (en) | 1991-12-12 | 1991-12-12 | New quinoline derivatives |
| GB9126438.2 | 1991-12-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2125681A1 true CA2125681A1 (en) | 1993-06-24 |
Family
ID=10706172
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002125681A Abandoned CA2125681A1 (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) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5556863A (en) * | 1993-06-11 | 1996-09-17 | Astra Aktiebolag | Compound for gastric acid secretion inhibition |
| IS4164A (en) * | 1993-06-11 | 1994-12-12 | Ab Astra | Compounds that inhibit gastric acid flow |
| UA80393C2 (en) | 2000-12-07 | 2007-09-25 | Алтана Фарма Аг | Pharmaceutical preparation comprising an pde inhibitor dispersed on a matrix |
| MY140561A (en) | 2002-02-20 | 2009-12-31 | Nycomed Gmbh | Dosage form containing pde 4 inhibitor as active ingredient |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8621425D0 (en) * | 1986-09-05 | 1986-10-15 | Smith Kline French Lab | Compounds |
| GB8804444D0 (en) * | 1988-02-25 | 1988-03-23 | Smithkline Beckman Intercredit | Compounds |
| GB8918265D0 (en) * | 1989-08-10 | 1989-09-20 | Smithkline Beckman Intercredit | Compounds |
| CZ153293A3 (en) * | 1991-01-29 | 1993-12-15 | Smithkline Beecham Intercredit | Salts of 4-amino-acylquinoline derivative |
-
1991
- 1991-12-12 GB GB919126438A patent/GB9126438D0/en active Pending
-
1992
- 1992-12-10 CA CA002125681A patent/CA2125681A1/en not_active Abandoned
- 1992-12-10 EP EP93900050A patent/EP0642500A1/en not_active Withdrawn
- 1992-12-10 MX MX9207162A patent/MX9207162A/en unknown
- 1992-12-10 WO PCT/EP1992/002898 patent/WO1993012090A1/en not_active Application Discontinuation
- 1992-12-10 AU AU31585/93A patent/AU665223B2/en not_active Ceased
- 1992-12-10 ZA ZA929568A patent/ZA929568B/en unknown
- 1992-12-10 JP JP5510627A patent/JPH07501812A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| AU665223B2 (en) | 1995-12-21 |
| MX9207162A (en) | 1994-08-31 |
| ZA929568B (en) | 1994-06-10 |
| GB9126438D0 (en) | 1992-02-12 |
| AU3158593A (en) | 1993-07-19 |
| WO1993012090A1 (en) | 1993-06-24 |
| EP0642500A1 (en) | 1995-03-15 |
| JPH07501812A (en) | 1995-02-23 |
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| FZDE | Dead |