EP0642500A1 - Derives de 4-amino-3-acyle quinoline et leur utilisation comme inhibiteurs de secretion d'acide gastrique - Google Patents

Derives de 4-amino-3-acyle quinoline et leur utilisation comme inhibiteurs de secretion d'acide gastrique

Info

Publication number
EP0642500A1
EP0642500A1 EP93900050A EP93900050A EP0642500A1 EP 0642500 A1 EP0642500 A1 EP 0642500A1 EP 93900050 A EP93900050 A EP 93900050A EP 93900050 A EP93900050 A EP 93900050A EP 0642500 A1 EP0642500 A1 EP 0642500A1
Authority
EP
European Patent Office
Prior art keywords
denotes
methylphenylamino
ester
quinolin
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.)
Withdrawn
Application number
EP93900050A
Other languages
German (de)
English (en)
Inventor
Gerhard Grundler
Georg Rainer
Robert John Ife
Colin Andrew Leach
Stefen Postius
Richard Riedel
Hartmann Schaefer
Jörg Senn-Bilfinger
Wolfgang Alexander Simon
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda GmbH
Original Assignee
Byk Gulden Lomberg Chemische Fabrik GmbH
SmithKline Beecham Intercredit BV
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Byk Gulden Lomberg Chemische Fabrik GmbH, SmithKline Beecham Intercredit BV filed Critical Byk Gulden Lomberg Chemische Fabrik GmbH
Publication of EP0642500A1 publication Critical patent/EP0642500A1/fr
Withdrawn legal-status Critical Current

Links

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

Definitions

  • 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.
  • the invention thus relates in a first aspect to compounds of the formula I:
  • R! denotes hydrogen, hydroxyl (OH), halogen or C ⁇ alkyl
  • R.2 denotes hydrogen or Cj ⁇ alkyl
  • R 3 denotes C ⁇ _4alkyl
  • A denotes methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), ethylidene [-CH(CH3)-], trimethylene (-CH2CH2CH2-), oxyethylene (-O-CH2CH2-) or oxytrimethylene (-O-CH 2 CH 2 CH 2 -),
  • 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.
  • C ⁇ _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 R 3 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(C 2 H 5 )-], trimethylene (-CH2CH 2 CH 2 -), propylene [-CH(CH 3 )-CH 2 -], tetramethylene (-CH2CH2CH2CH2-), 1,1-dimethylethylene [-C(CH3)2-CH2-], 1,2- dimethylethylene [-CH(CH 3 )-CH(CH 3 )-], 1-methyltrimethylene [-CH(CH 3 )-CH2CH 2 -], 2-methyItrimethylene [-CH2-CH(CH 3 )-CH 2 -], pentylidene [-CH(C4H 9 )-], pentan-3
  • 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.
  • 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.
  • acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid
  • 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.
  • A denotes methylene (-CH2-), ethylene (-CH2CH2-), ethylidene [-CH(CH3)-j or oxyethylene (-O-CH 2 CH 2 -),
  • Y denotes hydroxyl (OH), and their salts.
  • 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.
  • 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 that compounds of the formula II
  • X is as described for formula (I)
  • Y is a group Y as described for formula (I) or a protected group Y
  • 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.
  • inert solvents such as, for example, dioxane or tetrahydrofuran
  • Z either in the presence of a dehydrating agent or an agent which • bonds water chemically, such as, for example, dicyclohexyl
  • 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.
  • an alkoxycarbonyloxy radical mixed anhydride
  • 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 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)
  • the abbreviation min is used for minutes.
  • "Ether” is understood as meaning diethyl ether.
  • 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.
  • 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.
  • gastrointestinal inflammatory diseases and lesions such as e.g. ulcus ventriculi, ulcus duodeni, gastritis, hyperacid irritated stomach or irritated stomach of medicamentous origin
  • microorganisms e.g. Helicobacter pylori
  • medicaments e.g. certain antiinflammatories and antirhe
  • 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.
  • auxiliaries and excipients which are suitable for the medicament formulations desired.
  • auxiliaries and excipients which are suitable for the medicament formulations desired.
  • the active compounds can be administered orally, parenterally or percutaneously.
  • 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.
  • 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.
  • 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
  • anticholinergics such as e.g. oxy
  • H2-blockers e.g. cimetidine or ranitidine
  • peripheral anticholinergics e.g. pirenzepine or telenzepine
  • gastrin antagonists e.g. pirenzepine or telenzepine
  • antibacterial substances such as e.g. cephalosporins, tetracyclines, nalidixic acid, penicillins or also bismuth salts

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (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

Composé de la formule (I), dans laquelle R1 représente hydrogène, hydroxyle (OH), halogène ou alkyle C¿1-4, R?2 représente hydrogène ou alkyle C¿1-4, R?3 représente alkyle C¿1-4?, A représente méthylène(-CH2-), éthylène(-CH2CH2-), éthylidène [-CH(CH3)-], triméthylène(-CH2CH2CH2-), oxyéthylène (-O-CH2CH2-) ou oxytriméthylène (-O-CH2CH2CH2-), X représente alkylène C1-6 ou alcénylène C2-4 et Y représente hydroxyle (OH) ou amino (NH2), ou sel de ce composé. Des procédés pour la préparation de ces composés, de compositions pharmaceutiques les contenant et leur utilisation en thérapie comme inhibiteurs de sécrétion d'acide gastrique sont également décrits.
EP93900050A 1991-12-12 1992-12-10 Derives de 4-amino-3-acyle quinoline et leur utilisation comme inhibiteurs de secretion d'acide gastrique Withdrawn EP0642500A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB919126438A GB9126438D0 (en) 1991-12-12 1991-12-12 New quinoline derivatives
GB9126438 1991-12-12
PCT/EP1992/002898 WO1993012090A1 (fr) 1991-12-12 1992-12-10 Derives de 4-amino-3-acyle quinoline et leur utilisation comme inhibiteurs de secretion d'acide gastrique

Publications (1)

Publication Number Publication Date
EP0642500A1 true EP0642500A1 (fr) 1995-03-15

Family

ID=10706172

Family Applications (1)

Application Number Title Priority Date Filing Date
EP93900050A Withdrawn EP0642500A1 (fr) 1991-12-12 1992-12-10 Derives de 4-amino-3-acyle quinoline et leur utilisation comme inhibiteurs de secretion d'acide gastrique

Country Status (8)

Country Link
EP (1) EP0642500A1 (fr)
JP (1) JPH07501812A (fr)
AU (1) AU665223B2 (fr)
CA (1) CA2125681A1 (fr)
GB (1) GB9126438D0 (fr)
MX (1) MX9207162A (fr)
WO (1) WO1993012090A1 (fr)
ZA (1) ZA929568B (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
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 (is) * 1993-06-11 1994-12-12 Ab Astra Efnasambönd sem hindra flæði magasýru
UA80393C2 (uk) 2000-12-07 2007-09-25 Алтана Фарма Аг Фармацевтична композиція, яка містить інгібітор фде 4, диспергований в матриці
MY140561A (en) 2002-02-20 2009-12-31 Nycomed Gmbh Dosage form containing pde 4 inhibitor as active ingredient

Family Cites Families (4)

* Cited by examiner, † Cited by third party
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
CA2099117A1 (fr) * 1991-01-29 1992-07-30 Robert John Ife Sels d'un derive de la 4-amino-3-acylquinoline et leur utilisation comme inhibiteurs de la secretion acide gastrique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9312090A1 *

Also Published As

Publication number Publication date
GB9126438D0 (en) 1992-02-12
WO1993012090A1 (fr) 1993-06-24
AU3158593A (en) 1993-07-19
AU665223B2 (en) 1995-12-21
CA2125681A1 (fr) 1993-06-24
ZA929568B (en) 1994-06-10
JPH07501812A (ja) 1995-02-23
MX9207162A (es) 1994-08-31

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