WO1996005199A1 - Imidazopyridine salt - Google Patents

Imidazopyridine salt Download PDF

Info

Publication number
WO1996005199A1
WO1996005199A1 PCT/EP1995/003139 EP9503139W WO9605199A1 WO 1996005199 A1 WO1996005199 A1 WO 1996005199A1 EP 9503139 W EP9503139 W EP 9503139W WO 9605199 A1 WO9605199 A1 WO 9605199A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound according
salt
compound
methoxycarbonylamino
dimethylimidazo
Prior art date
Application number
PCT/EP1995/003139
Other languages
German (de)
French (fr)
Inventor
Georg Rainer
Jörg Senn-Bilfinger
Gerhard Grundler
Richard Riedel
Stefan Postius
Wolfgang-Alexander Simon
Original Assignee
Byk Gulden Lomberg Chemische Fabrik Gmbh
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 filed Critical Byk Gulden Lomberg Chemische Fabrik Gmbh
Priority to AU33432/95A priority Critical patent/AU3343295A/en
Publication of WO1996005199A1 publication Critical patent/WO1996005199A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention relates to a new imidazopyridine salt which is used in the pharmaceutical industry as an active ingredient for the production of pharmaceuticals.
  • European patent application EP-A-0033 094 describes imidazo [1,2-a] pyridines which bear an aryl substituent in the 8-position, which is preferably a phenyl, thienyl, pyridyl or chlorine or fluorine group , Methyl, tert-butyl, trifluoromethyl, ethoxy or cyano substituted phenyl radical.
  • aryl radicals in EP-A-0033 094 are the phenyl, o- or p-fluorophenyl, p-chlorophenyl and 2,4,6-trimethylphenyl radicals, of which the phenyl, o- or p-fluorophenyl radicals and 2,4,6-tri ethylphenyl are particularly preferred.
  • EP-A-0 204 285 EP-A-0 228006, EP-A-0 268989 and EP-A-0308917 imidazo [1,2-a] pyridines are described which are described in 3- Position carry an unsaturated aliphatic radical, in particular a (substituted) alkynyl radical.
  • European patent application EP-A-0 266890 describes imidazo [1,2-a] pyridines which are substituted in the 8-position by an alkenyl, alkyl or cycloalkylalkyl radical.
  • the invention relates to the salt of the compound 8- (2-methoxycarbonylamino-6-methylbenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine with D, L-apple acid, ie the 8- (2- Methoxycarbonylamino-6-methylbenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine-D, L-hemimalate and its enantiomers.
  • the 8- (2-methoxycarbonylamino-6-methylbenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine can be prepared as described in the examples below.
  • the preparation of the malate is also described in the examples.
  • RT room temperature
  • h hour (s)
  • min minute (s)
  • mp melting point
  • dec. decomposition
  • the compound is known from EP-A-0 299470 or it can be prepared analogously to that described there.
  • the 8- (2-methoxycarbonylamino-6-methylbenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine-D, L-hemimalate has valuable pharmacological properties which make it commercially usable. In particular, it has a pronounced inhibition of gastric acid secretion and an excellent gastric and intestinal protective action in warm-blooded animals.
  • the compound according to the invention is distinguished by a high selectivity of action, a comparatively long duration of action, good enteral effectiveness, the absence of essential side effects, a large therapeutic breadth and, in particular, excellent bioavailability.
  • “Stomach and intestinal protection” in this context means the prevention and treatment of gastrointestinal diseases, in particular gastrointestinal inflammatory diseases and lesions (such as, for example, ulcer ventriculi, duodenal ulcer, gastritis, hyperacid or drug-induced irritable stomach), which are caused, for example, by microorganisms (eg Helicobacter pylori), bacterial toxins, medications (eg certain anti-inflammatory drugs and anti-rheumatic drugs), chemicals (eg ethanol), gastric acid or stressful situations.
  • the compound according to the invention also has an intrinsic effect against the Helicobacter pylori germ.
  • the compound according to the invention surprisingly proves to be clearly superior to the compounds known from the prior art on various models in which the antiulcerogenic and the antisecretory properties are determined.
  • the compound according to the invention is outstandingly suitable for use in human and veterinary medicine, it being used in particular for the treatment and / or prophylaxis of diseases of the stomach and / or intestine.
  • the invention therefore furthermore relates to the compound according to the invention for use in the treatment and / or prophylaxis of the abovementioned diseases.
  • the invention also encompasses the use of the compound according to the invention for the production of medicaments which are used for the treatment and / or prophylaxis of the abovementioned diseases.
  • the invention further comprises the use of the compound according to the invention for the treatment and / or prophylaxis of the abovementioned diseases.
  • the invention further relates to medicaments which contain the compound according to the invention.
  • the pharmaceuticals are produced by methods known per se and familiar to the person skilled in the art.
  • suitable pharmaceutical auxiliaries or carriers in the form of tablets, dragées, capsules, suppositories, plasters (for example as TTS), emulsions Sions, suspensions or solutions are used, the active ingredient content advantageously being between 0.1 and 95% and the galenic dosage form being precisely adapted to the active ingredient and / or the desired
  • auxiliaries and excipients suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge.
  • active ingredient carriers for example antioxidants, dispersants, emulsifiers, defoamers, taste correctives, preservatives, solubilizers, dyes or in particular permeation promoters and complexing agents (e.g. cyclodextrins) can be used.
  • the active ingredients can be administered orally, parenterally or percutaneously.
  • the active ingredient in general, it has proven to be advantageous in human medicine for the active ingredient to be administered orally 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 of body weight, optionally in the form of several, preferably 1 to 4, individual doses to achieve the desired result.
  • a daily dose of about 0.01 to about 20, preferably 0.05 to 5, in particular 0.1 to 1.5 mg / kg of body weight, optionally in the form of several, preferably 1 to 4, individual doses to achieve the desired result.
  • similar or generally lower doses in particular when the active ingredient is administered intravenously
  • the optimum dosage and type of application of the active ingredient required in each case can easily be determined by any person skilled in the art on the basis of his specialist knowledge.
  • the pharmaceutical preparations can also contain one or more pharmacologically active constituents of other groups of medicaments, such as antacids, for example aluminum hydroxide, magnesium aluminate; Tranquilizers, such as benzodiazepines, for example diazepam; Spasmolytics, e.g. Bietamiverin, Camylofin, Anticholinergica, e.g. Oxyphencyclimine, phencarbamide; Local anesthetics, e.g. Tetracaine, procaine; optionally also contain ferments, vitamins or amino acids.
  • antacids for example aluminum hydroxide, magnesium aluminate
  • Tranquilizers such as benzodiazepines, for example diazepam
  • Spasmolytics e.g. Bietamiverin, Camylofin, Anticholinergica, e.g. Oxyphencyclimine, phencarbamide
  • Local anesthetics e.
  • the combination of the compound according to the invention with pharmaceuticals which inhibit acid secretion should be emphasized in particular So-called peripheral anticholinergics (eg pirenzepin, telenzepin) and with gastrin antagonists with the aim of strengthening the main effect in an additive or superadditive sense and / or eliminating or reducing the side effects, or further the combination with antibacterially active substances ⁇ zen (such as cephalosporins, tetracyclines, nalidixic acid, penicillins or bismuth salts) to combat Helicobacter pylori. pharmacology
  • H blockers for example ci-etidine, ranitidine
  • H / K -ATPase inhibitors for example omeprazole, pantoprazole
  • gastrin antagonists with the aim of strengthening the main effect in an additive or superadditive sense and / or eliminating or reducing the side effects
  • antibacterially active substances ⁇ zen such as cephalosporins, tetracyclines
  • Table 1 below shows the influence of the compound according to the invention after intraduodenal administration on the acid secretion of the perfused rat stomach stimulated by pentagastrin in vivo.
  • anesthetized rats (CD rat, female, 200-250 g * 1.5 g / kg in urethane) were opened with a median upper abdominal incision and a PVC catheter transorally in the esophagus and another one after tracheotomy fixed via the pylorus in such a way that the tube ends just protruded into the stomach lumen.
  • the catheter leading out of the pylorus led outwards through a lateral opening in the right abdominal wall.
  • the body temperature of the animals was kept at a constant 37.8-38 ° C. by means of infrared radiation and heating pads (automatic, stepless regulation via rectal temperature sensors).

Abstract

The invention concerns the compound 8-(2-methoxycarbonylamino-6-methyl-benzylamino)-2,3-dimethylimidazo-[1,2-a]pyridine-D,L-hemimalate and the therapeutic use of the compound.

Description

Imidazopyridinsalz Imidazopyridine salt
Anwendungsgebiet der ErfindungField of application of the invention
Die Erfindung betrifft ein neues Imidazopyridinsalz, das in der pharmazeu¬ tischen Industrie als Wirkstoff für die Herstellung von Arzneimitteln ver¬ wendet werden so l .The invention relates to a new imidazopyridine salt which is used in the pharmaceutical industry as an active ingredient for the production of pharmaceuticals.
Bekannter technischer HintergrundKnown technical background
In der europäischen Patentanmeldung EP-A-0033 094 werden Imidazo[l,2-a]py- ridine beschrieben, die in 8-Position einen Arylsubstituenten tragen, der bevorzugt ein Phenyl-, Thienyl-, Pyridyl- oder ein durch Chlor, Fluor, Me¬ thyl, tert.-Butyl, Trifluormethyl , ethoxy oder Cyan substituierter Phenyl- rest ist. Als besonders interessante Arylreste sind in der EP-A-0033 094 die Reste Phenyl, o- oder p-Fluorphenyl, p-Chlorphenyl und 2,4,6-Trimethyl- phenyl genannt, wovon die Reste Phenyl, o- oder p-Fluorphenyl und 2,4,6- Tri ethylphenyl besonders bevorzugt sind. - In den europäischen Patentan¬ meldungen EP-A-0 204 285, EP-A-0 228006, EP-A-0 268989 und EP-A-0308917 werden Imidazo[l,2-a]pyridine beschrieben, die in 3-Position einen ungesät¬ tigten aliphatischen Rest, insbesondere einen (substituierten) Alkinylrest tragen. - In der europäischen Patentanmeldung EP-A-0 266890 werden Imida- zo[l,2-a]pyridine beschrieben, die in 8-Position durch einen Alkenyl-, Al- kyl- oder Cycloalkylalkylrest substituiert sind.European patent application EP-A-0033 094 describes imidazo [1,2-a] pyridines which bear an aryl substituent in the 8-position, which is preferably a phenyl, thienyl, pyridyl or chlorine or fluorine group , Methyl, tert-butyl, trifluoromethyl, ethoxy or cyano substituted phenyl radical. Particularly interesting aryl radicals in EP-A-0033 094 are the phenyl, o- or p-fluorophenyl, p-chlorophenyl and 2,4,6-trimethylphenyl radicals, of which the phenyl, o- or p-fluorophenyl radicals and 2,4,6-tri ethylphenyl are particularly preferred. - In the European patent applications EP-A-0 204 285, EP-A-0 228006, EP-A-0 268989 and EP-A-0308917 imidazo [1,2-a] pyridines are described which are described in 3- Position carry an unsaturated aliphatic radical, in particular a (substituted) alkynyl radical. - European patent application EP-A-0 266890 describes imidazo [1,2-a] pyridines which are substituted in the 8-position by an alkenyl, alkyl or cycloalkylalkyl radical.
Beschreibung der ErfindungDescription of the invention
Es wurde nun gefunden, daß das Äpfelsäuresalz der nachfolgend näher be¬ schriebenen Verbindung überraschende und be-sonders vorteilhafte Eigenschaf¬ ten besitzt. Gegenstand der Erfindung ist das Salz der Verbindung 8-(2-Methoxycarbonyl- amino-6-methylbenzylamino)-2,3-dimethylimidazo[l,2-a]pyridin mit D,L-Äpfel säure, also das 8-(2-Methoxycarbonylamino-6-methylbenzylamino)-2,3-dime- thylimidazo[l,2-a]pyridin-D,L-hemimalat und seine Enantiomeren.It has now been found that the malic acid salt of the compound described in more detail below has surprising and particularly advantageous properties. The invention relates to the salt of the compound 8- (2-methoxycarbonylamino-6-methylbenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine with D, L-apple acid, ie the 8- (2- Methoxycarbonylamino-6-methylbenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine-D, L-hemimalate and its enantiomers.
Das 8-(2-Methoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo- [l,2-a]pyridin kann so wie in den nachfolgenden Beispielen beschrieben hergestellt werden. Die Herstellung des Malats ist ebenfalls in den Bei¬ spielen beschrieben.The 8- (2-methoxycarbonylamino-6-methylbenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine can be prepared as described in the examples below. The preparation of the malate is also described in the examples.
Die Abkürzung RT steht für Raumtemperatur, h steht für Stunde(n), min für Minute(n), Schmp. für Schmelzpunkt, Zers. für Zersetzung. The abbreviation RT stands for room temperature, h stands for hour (s), min for minute (s), mp for melting point, dec. for decomposition.
BeispieleExamples
EndproduktEnd product
1. 8-(2-Methoxycarbonylamino-6-methv1benzv1amino)-2.3-dimethylimida- zoπ.2-alDyridin-D,L-hemimalat1. 8- (2-methoxycarbonylamino-6-methv1benzv1amino) -2,3-dimethylimidazo.2-alDyridine-D, L-hemimalate
a) Man trägt 5,0 g 8-(2-Methoxycarbonylamino-6-methylbenzylamino)-2,3-di- methylimidazo[l,2-a]pyridin in kleinen Portionen bei 40*C unter Rühren in eine Lösung von 1,04 g D,L-Äpfelsäure in 35 ml Wasser ein, rührt noch 2 h bei 40'C und über Nacht bei RT. Man stellt mit Natronlauge auf pH 4,7 und läßt unter Rühren im Eisbad kristallisieren. Man erhält 5,85 g (97,7 %) der TitelVerbindung vom Schmp. 174-175'C (Zers.).a) 5.0 g of 8- (2-methoxycarbonylamino-6-methylbenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine are carried in small portions at 40 ° C. with stirring in a solution of 1. 04 g of D, L-malic acid in 35 ml of water, stirring for 2 h at 40'C and overnight at RT. The pH is adjusted to 4.7 with sodium hydroxide solution and the mixture is left to crystallize in an ice bath with stirring. 5.85 g (97.7%) of the title compound of mp 174-175'C (dec.) Are obtained.
b) Man verfährt analog, wie nachfolgend unter A. beschrieben, und versetzt anstelle von Fu arsäure mit einer konzentrierten Lösung von 2,0 g D,L-Äpfelsäure in Wasser. Das schwer lösliche Salz wird abgesaugt und aus Isopropanol/Wasser umkristall isiert. Man erhält die Titelverbindung vom Schmp. 174-175'C (Zers.).b) The procedure is analogous to that described below under A., and a concentrated solution of 2.0 g of D, L-malic acid in water is added instead of fu aric acid. The sparingly soluble salt is suctioned off and recrystallized from isopropanol / water. The title compound of mp 174-175'C (dec.) Is obtained.
2. 8-(2-Methoxycarbonv1amino-6-methylbenzylamino)-2.3-dimethv1imidazo- π,2-a1pyridiπ-L(-)-hemimalat2. 8- (2-Methoxycarbonv1amino-6-methylbenzylamino) -2.3-dimethv1imidazo- π, 2-a1pyridiπ-L (-) - hemimalate
Verfährt man analog Beispiel l.a) und verwendet L(-)-Äpfelsäure, erhält man die Titelverbindung vom Schmp. 174-175'C (Zers.). AusoangsverbindungenIf the procedure is analogous to example la) and L (-) - malic acid is used, the title compound of mp 174-175'C (decomp.) Is obtained. External connections
A. 8-(2-Methoxycarbonylamino-6-methylbenzylamino)-2.3-dimethylimidazo- ri.2-a1pyridinA. 8- (2-methoxycarbonylamino-6-methylbenzylamino) -2,3-dimethylimidazori.2-a1pyridine
Eine Lösung von 4,1 g 8-Amino-2,3-dimethylimidazo[l,2-a]pyridin und 6,0 g (2-Chlormethyl-3-methylphenyl)carbamidsäuremethylester in 100 ml Aceton wird mit 1,1 g Natriumjodid und 6,7 g pulverisiertem, wasserfreiem Natrium- carbonat versetzt und 24 h bei RT gerührt. Man filtriert die anorganischen Salze ab, wäscht gut mit Aceton aus, engt das Filtrat im Rotationsverdamp¬ fer ein, versetzt mit Wasser und schüttelt mit Ethylacetat aus. Man engt im Rotationsverdampfer ein, löst den Rückstand in 50 ml Aceton und setzt eine Lösung von 1,8 g Fumarsäure in 180 ml Aceton zu. Aus der auf die Hälfte konzentrierten Lösung filtriert man 8,5 g Hemifumarat der TitelVerbindung ab. Das Salz wird in einer Mischung von 40 ml Aceton und 100 ml Wasser bei 40'C mit verdünnter Natronlauge bis pH 9,5 neutralisiert und die ausgefal¬ lene freie Base aus Ethylacetat/Petrolether umkristallisiert. Man erhält 5,6 g (65 %) der Titelverbindung vom Schmp. 136-138'C.A solution of 4.1 g of 8-amino-2,3-dimethylimidazo [1,2-a] pyridine and 6.0 g of (2-chloromethyl-3-methylphenyl) carbamic acid methyl ester in 100 ml of acetone is mixed with 1.1 g of sodium iodide and 6.7 g of powdered, anhydrous sodium carbonate were added and the mixture was stirred at RT for 24 h. The inorganic salts are filtered off, washed well with acetone, the filtrate is concentrated in a rotary evaporator, water is added and the mixture is shaken with ethyl acetate. It is concentrated in a rotary evaporator, the residue is dissolved in 50 ml of acetone and a solution of 1.8 g of fumaric acid in 180 ml of acetone is added. 8.5 g of hemifumarate of the title compound are filtered off from the solution, which is concentrated in half. The salt is neutralized in a mixture of 40 ml of acetone and 100 ml of water at 40'C with dilute sodium hydroxide solution to pH 9.5 and the free base which has precipitated is recrystallized from ethyl acetate / petroleum ether. 5.6 g (65%) of the title compound of mp 136-138'C are obtained.
B. 8-Amino-2.3-dimethylimidazori,2-alpyridinB. 8-amino-2,3-dimethylimidazori, 2-alpyridine
Die Verbindung ist aus EP-A-0 299470 bekannt bzw. sie kann analog dazu wie dort beschrieben hergestellt werden.The compound is known from EP-A-0 299470 or it can be prepared analogously to that described there.
C. 2-Methoxycarbonylamino-6-methylbenzylchloridC. 2-Methoxycarbonylamino-6-methylbenzyl chloride
Die Verbindung ist aus EP-A-0308917 bekannt bzw. sie kann analog dazu wie dort beschrieben hergestellt werden. Gewerbliche AnwendbarkeitThe compound is known from EP-A-0308917 or it can be prepared analogously to that described there. Industrial applicability
Das 8-(2-Methoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo- [l,2-a]pyridin-D,L-hemimalat besitzt wertvolle pharmakologische Eigenschaf¬ ten, die es gewerblich verwertbar machen. Es weist insbesondere eine ausge¬ prägte Magensäuresekretionshemmung und eine ausgezeichnete Magen- und Darm¬ schutzwirkung bei Warmblütern auf. Hierbei zeichnet sich die erfindungsge¬ mäße Verbindung durch eine hohe Wirkungsselektivität, eine vergleichsweise lange Wirkungsdauer, eine gute enterale Wirksamkeit, das Fehlen wesentli¬ cher Nebenwirkungen, eine große therapeutische Breite und insbesondere eine ausgezeichnete Bioverfügbarkeit aus.The 8- (2-methoxycarbonylamino-6-methylbenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine-D, L-hemimalate has valuable pharmacological properties which make it commercially usable. In particular, it has a pronounced inhibition of gastric acid secretion and an excellent gastric and intestinal protective action in warm-blooded animals. Here, the compound according to the invention is distinguished by a high selectivity of action, a comparatively long duration of action, good enteral effectiveness, the absence of essential side effects, a large therapeutic breadth and, in particular, excellent bioavailability.
Unter "Magen- und Darmschutz" wird in diesem Zusammenhang die Verhütung und Behandlung gastrointestinaler Krankheiten, insbesondere gastrointestinaler entzündlicher Krankheiten und Läsionen (wie z.B. Ulcus ventriculi, Ulcus duodeni, Gastritis, hyperazider oder medikamentös bedingter Reizmagen) ver¬ standen, die beispielsweise durch Mikroorganismen (z.B. Helicobacter pylo- ri), Bakterientoxine, Medikamente (z.B. bestimmte Antiphlogistika und Anti- rheumatika), Chemikalien (z.B. Ethanol), Magensäure oder Streßsituationen verursacht werden können. Die erfindungsgemäße Verbindung besitzt hierbei auch eine Eigenwirkung gegen den Keim Helicobacter pylori."Stomach and intestinal protection" in this context means the prevention and treatment of gastrointestinal diseases, in particular gastrointestinal inflammatory diseases and lesions (such as, for example, ulcer ventriculi, duodenal ulcer, gastritis, hyperacid or drug-induced irritable stomach), which are caused, for example, by microorganisms ( eg Helicobacter pylori), bacterial toxins, medications (eg certain anti-inflammatory drugs and anti-rheumatic drugs), chemicals (eg ethanol), gastric acid or stressful situations. The compound according to the invention also has an intrinsic effect against the Helicobacter pylori germ.
In ihren ausgezeichneten Eigenschaften erweist sich die erfindungsgemäße Verbindung an verschiedenen Modellen, in denen die antiulcerogenen und die antisekretorischen Eigenschaften bestimmt werden, überraschenderweise den aus dem Stand der Technik bekannten Verbindungen deutlich überlegen. Auf¬ grund dieser Eigenschaften ist die erfindungsgemäße Verbindung für den Einsatz in der Human- und Veterinärmedizin hervorragend geeignet, wobei sie insbesondere zur Behandlung und/oder Prophylaxe von Erkrankungen des Magens und/oder Darms verwendet wird.In its excellent properties, the compound according to the invention surprisingly proves to be clearly superior to the compounds known from the prior art on various models in which the antiulcerogenic and the antisecretory properties are determined. On the basis of these properties, the compound according to the invention is outstandingly suitable for use in human and veterinary medicine, it being used in particular for the treatment and / or prophylaxis of diseases of the stomach and / or intestine.
Ein weiterer Gegenstand der Erfindung ist daher die erfindungsgemäße Ver¬ bindung zur Anwendung bei der Behandlung und/oder Prophylaxe der vorstehend genannten Krankheiten. Ebenso umfaßt die Erfindung die Verwendung der erfindungsgemäßen Verbindung zur Herstellung von Arzneimitteln, die zur Behandlung und/oder Prophylaxe der vorstehend genannten Krankheiten eingesetzt werden.The invention therefore furthermore relates to the compound according to the invention for use in the treatment and / or prophylaxis of the abovementioned diseases. The invention also encompasses the use of the compound according to the invention for the production of medicaments which are used for the treatment and / or prophylaxis of the abovementioned diseases.
Weiterhin umfaßt die Erfindung die Verwendung der erfindungsgemäßen Verbin¬ dung zur Behandlung und/oder Prophylaxe der vorstehend genannten Krankhei¬ ten.The invention further comprises the use of the compound according to the invention for the treatment and / or prophylaxis of the abovementioned diseases.
Ein weiterer Gegenstand der Erfindung sind Arzneimittel, die die erfin¬ dungsgemäße Verbindung enthalten.The invention further relates to medicaments which contain the compound according to the invention.
Die Arzneimittel werden nach an sich bekannten, dem Fachmann geläufigen Verfahren hergestellt. Als Arzneimittel wird die erfindungsgemäße Verbin¬ dung (= der Wirkstoff) entweder als solche, oder vorzugsweise in Kombina¬ tion mit geeigneten pharmazeutischen Hilfs- oder Trägerstoffen in Form von Tabletten, Dragees, Kapseln, Suppositorien, Pflastern (z.B. als TTS), Emul¬ sionen, Suspensionen oder Lösungen eingesetzt, wobei der Wirkstoffgehalt vorteilhafterweise zwischen 0,1 und 95 % beträgt und wobei durch die ent¬ sprechende Wahl der Hilfs- und Trägerstoffe eine auf den Wirkstoff und/oder auf den gewünschten Wirkungseintritt genau angepaßte galenische Darrei¬ chungsform (z.B. eine Retardform oder eine magensaftresistente Form) er¬ zielt werden kann.The pharmaceuticals are produced by methods known per se and familiar to the person skilled in the art. The compound according to the invention (= the active ingredient) is used as a medicament either as such, or preferably in combination with suitable pharmaceutical auxiliaries or carriers in the form of tablets, dragées, capsules, suppositories, plasters (for example as TTS), emulsions Sions, suspensions or solutions are used, the active ingredient content advantageously being between 0.1 and 95% and the galenic dosage form being precisely adapted to the active ingredient and / or the desired onset of action due to the appropriate choice of auxiliaries and carriers ( For example, a prolonged release form or an enteric form) can be achieved.
Welche Hilfs- bzw. Trägerstoffe für die gewünschten Arzneimittelformu- lierungen geeignet sind, ist dem Fachmann aufgrund seines Fachwissens ge¬ läufig. Neben Lösemitteln, Gelbildnern, Suppositoriengrundlagen, Tabletten- hilfsstoffen und anderen Wirkstoffträgem können beispielsweise Antioxidan- tien, Dispergiermittel, Emulgatoren, Entschäumer, Geschmackskorrigentien, Konservierungsmittel, Lösungsvermittler, Farbstoffe oder insbesondere Per- meationspromotoren und Komplexbildner (z.B. Cyclodextrine) verwendet wer¬ den.The person skilled in the art is familiar with the auxiliaries and excipients suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge. In addition to solvents, gel formers, suppository bases, tablet excipients and other active ingredient carriers, for example antioxidants, dispersants, emulsifiers, defoamers, taste correctives, preservatives, solubilizers, dyes or in particular permeation promoters and complexing agents (e.g. cyclodextrins) can be used.
Die Wirkstoffe können oral, parenteral oder percutan appliziert werden.The active ingredients can be administered orally, parenterally or percutaneously.
Im allgemeinen hat es sich in der Humanmedizin als vorteilhaft erwiesen, den Wirkstoff bei oraler Gabe in einer Tagesdosis von etwa 0,01 bis etwa 20, vorzugsweise 0,05 bis 5, insbesondere 0,1 bis 1,5 mg/kg Körpergewicht, gegebenenfalls in Form mehrerer, vorzugsweise 1 bis 4 Einzelgaben zur Er¬ zielung des gewünschten Ergebnisses zu verabreichen. Bei einer parenteralen Behandlung können ähnliche bzw. (insbesondere bei der intravenösen Verab¬ reichung des Wirkstoffs) in der Regel niedrigere Dosierungen zur Anwendung kommen. Die Festlegung der jeweils erforderlichen optimalen Dosierung und Applikationsart des Wirkstoffs kann durch jeden Fachmann aufgrund seines Fachwissens leicht erfolgen.In general, it has proven to be advantageous in human medicine for the active ingredient to be administered orally 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 of body weight, optionally in the form of several, preferably 1 to 4, individual doses to achieve the desired result. In the case of parenteral treatment, similar or generally lower doses (in particular when the active ingredient is administered intravenously) can be used. The optimum dosage and type of application of the active ingredient required in each case can easily be determined by any person skilled in the art on the basis of his specialist knowledge.
Soll die erfindungsgemäße Verbindung zur Behandlung der oben genannten Krankheiten eingesetzt werden, so können die pharmazeutischen Zubereitungen auch einen oder mehrere pharmakologisch aktive Bestandteile anderer Arznei- mittelgruppen, wie Antacida, beispielsweise Aluminiumhydroxyd, Magnesium- aluminat; Tranquilizer, wie Benzodiazepine, beispielsweise Diazepam; Spas- molytika, wie z.B. Bietamiverin, Camylofin, Anticholinergica, wie z.B. Oxyphencyclimin, Phencarbamid; Lokalanaesthetika, wie z.B. Tetracain, Procain; gegebenenfalls auch Fermente, Vitamine oder Aminosäuren enthalten.If the compound according to the invention is to be used for the treatment of the abovementioned diseases, the pharmaceutical preparations can also contain one or more pharmacologically active constituents of other groups of medicaments, such as antacids, for example aluminum hydroxide, magnesium aluminate; Tranquilizers, such as benzodiazepines, for example diazepam; Spasmolytics, e.g. Bietamiverin, Camylofin, Anticholinergica, e.g. Oxyphencyclimine, phencarbamide; Local anesthetics, e.g. Tetracaine, procaine; optionally also contain ferments, vitamins or amino acids.
Hervorzuheben ist in diesem Zusammenhang insbesondere die Kombination der erfindungsgemäßen Verbindung mit Pharmaka, die die Säuresekretion hemmen, wie beispielsweise H--Blockern (z.B. Ci etidin, Ranitidin), H /K -ATPase- Hemmstoffen (z.B. Omeprazol , Pantoprazol ) , oder ferner mit sogenannten pe- ripheren Anticholinergika (z.B. Pirenzepin, Telenzepin) sowie mit Gastrin- Antagonisten mit dem Ziel, die Hauptwirkung in additivem oder überadditivem Sinn zu verstärken und/oder die Nebenwirkungen zu eliminieren oder zu ver¬ ringern, oder ferner die Kombination mit antibakteriell wirksamen Substan¬ zen (wie z.B. Cephalosporinen, Tetracyclinen, Nalidixinsäure, Penicillinen oder auch Wismutsalzen) zur Bekämpfung von Helicobacter pylori. PharmakologieIn this context, the combination of the compound according to the invention with pharmaceuticals which inhibit acid secretion, such as, for example, H blockers (for example ci-etidine, ranitidine), H / K -ATPase inhibitors (for example omeprazole, pantoprazole), or also with, should be emphasized in particular So-called peripheral anticholinergics (eg pirenzepin, telenzepin) and with gastrin antagonists with the aim of strengthening the main effect in an additive or superadditive sense and / or eliminating or reducing the side effects, or further the combination with antibacterially active substances ¬ zen (such as cephalosporins, tetracyclines, nalidixic acid, penicillins or bismuth salts) to combat Helicobacter pylori. pharmacology
Die ausgezeichnete Magenschutzwirkung und die magensäuresekretionshemmende Wirkung der erfindungsgemäßen Verbindung kann in Untersuchungen an tier¬ experimentellen Modellen nachgewiesen werden.The excellent gastric protective effect and the gastric acid secretion-inhibiting effect of the compound according to the invention can be demonstrated in studies on animal experimental models.
Prüfung der sekretionshemmenden Wirkung am perfundierten RattenmagenTesting the secretion-inhibiting effect on the perfused rat stomach
In der folgenden Tabelle 1 ist der Einfluß der erfindungsgemäßen Verbindung nach intraduodenaler Gabe auf die durch Pentagastrin stimulierte Säurese¬ kretion des perfundierten Rattenmagens in vivo dargestellt.Table 1 below shows the influence of the compound according to the invention after intraduodenal administration on the acid secretion of the perfused rat stomach stimulated by pentagastrin in vivo.
Tabelle 1Table 1
Dosis Hemmung der Säureausscheidung
Figure imgf000010_0001
i .d.Dose inhibition of acid excretion
Figure imgf000010_0001
i .d.
3 953 95
Methodikmethodology
Narkotisierten Ratten (CD-Ratte, weiblich, 200-250 g* 1,5 g/kg i.m. Ure- than) wurde nach Tracheotomie das Abdomen durch einen medianen Oberbauch¬ schnitt eröffnet und ein PVC-Katheter transoral im Ösophagus sowie ein wei¬ terer via Pylorus derart fixiert, daß die Schlauchenden eben noch in das Magenlumen hineinragten. Der aus dem Pylorus führende Katheter führte über eine seitliche Öffnung in der rechten Bauchwand nach außen.After tracheotomy, anesthetized rats (CD rat, female, 200-250 g * 1.5 g / kg in urethane) were opened with a median upper abdominal incision and a PVC catheter transorally in the esophagus and another one after tracheotomy fixed via the pylorus in such a way that the tube ends just protruded into the stomach lumen. The catheter leading out of the pylorus led outwards through a lateral opening in the right abdominal wall.
Nach gründlicher Spülung (ca. 50-100 ml) wurde der Magen mit 37*C warmer physiologischer NaCl-Lösung kontinuierlich durchströmt (0,5 ml/min, pH 6,8-6,9; Braun-Unita I). In dem jeweils im 15 Minuten-Abstand aufgefangenen Effluat wurde der pH-Wert (pH-Meter 632, Glaselektrode EA 147; <p =- 5 m, Metrohm) sowie durch Titration mit einer frisch zubereiteten 0,01 N NaOH bis pH 7 (Dosimat 665 Metrohm) die sezernierte HC1 bestimmt.After thorough rinsing (about 50-100 ml) of the stomach with 37 * C, warm physiological NaCl solution was continuously passed through (0.5 ml / min, pH 6.8-6.9; Braun-Unita I). The pH value (pH meter 632, glass electrode EA 147; <p = - 5 m, Metrohm) and the titration with a freshly prepared 0.01 N NaOH to pH 7 (Dosimat 665 Metrohm) determines the secreted HC1.
Die Stimulation der Magensekretion erfolgte durch Dauerinfusion von 1 μg/kg (- 1,65 ml/h) i.v. Pentagastrin (V. fern, sin.) ca. 30 min nach Operations¬ ende (d.h. nach Bestimmung von 2 Vorfraktionen). Die zu prüfende Substanz wurden intraduodenal in 1 ml/kg Flüssigkeitsvolumen 60 min nach Beginn der Pentagastrin-Dauerinfusion verabreicht.Gastric secretion was stimulated by continuous infusion of 1 μg / kg (- 1.65 ml / h) IV. Pentagastrin (V. fern, sin.) Approx. 30 min after the end of the operation (i.e. after the determination of 2 pre-fractions). The substance to be tested was administered intraduodenally in 1 ml / kg liquid volume 60 min after the start of the continuous pentagastrin infusion.
Die Körpertemperatur der Tiere wurde durch Infrarot-Bestrahlung und Heiz¬ kissen (automatische, stufenlose Regelung über rektalen Temperaturfühler) auf konstant 37,8 - 38'C gehalten. The body temperature of the animals was kept at a constant 37.8-38 ° C. by means of infrared radiation and heating pads (automatic, stepless regulation via rectal temperature sensors).

Claims

Patentansprüche claims
1. 8-(2-Methoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo- [l,2-a]pyridin-D,L-hemimalat und seine Enantiomeren.1. 8- (2-methoxycarbonylamino-6-methylbenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine-D, L-hemimalate and its enantiomers.
2. Arzneimittel enthaltend die Verbindung nach Anspruch 1 zusammen mit üblichen pharmazeutischen Hilfs- und/oder Trägerstoffen.2. Medicament containing the compound of claim 1 together with conventional pharmaceutical auxiliaries and / or carriers.
3. Verbindung nach Anspruch 1 zur Anwendung bei der Verhütung und Behand¬ lung gastrointestinaler Krankheiten.3. A compound according to claim 1 for use in the prevention and treatment of gastrointestinal diseases.
4. Verwendung der Verbindung nach Anspruch 1 zur Herstellung von Arznei¬ mitteln für die Verhütung und Behandlung gastrointestinaler Krankheiten. 4. Use of the compound according to claim 1 for the manufacture of medicaments for the prevention and treatment of gastrointestinal diseases.
PCT/EP1995/003139 1994-08-12 1995-08-08 Imidazopyridine salt WO1996005199A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU33432/95A AU3343295A (en) 1994-08-12 1995-08-08 Imidazopyridine salt

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH249994 1994-08-12
CH2499/94-7 1994-08-12

Publications (1)

Publication Number Publication Date
WO1996005199A1 true WO1996005199A1 (en) 1996-02-22

Family

ID=4235181

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1995/003139 WO1996005199A1 (en) 1994-08-12 1995-08-08 Imidazopyridine salt

Country Status (2)

Country Link
AU (1) AU3343295A (en)
WO (1) WO1996005199A1 (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007115305A2 (en) 2006-04-04 2007-10-11 Cogentus Pharmaceuticals, Inc. Oral dosage forms including an antiplatelet agent and an acid inhibitor
WO2009105568A1 (en) 2008-02-20 2009-08-27 The Curators Of The University Of Missouri Composition comprising a combination of omeprazole and lansoprazole, and a buffering agent, and methods of using same
EP2486910A2 (en) 2006-10-27 2012-08-15 The Curators Of The University Of Missouri Multi-chambered apparatus comprising a dispenser head
US8852636B2 (en) 2001-06-01 2014-10-07 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US8945621B2 (en) 2009-06-25 2015-02-03 Pozen Inc. Method for treating a patient at risk for developing an NSAID-associated ulcer
US9220698B2 (en) 2008-09-09 2015-12-29 Pozen Inc. Method for delivering a pharmaceutical composition to patient in need thereof
US9539214B2 (en) 2011-12-28 2017-01-10 Pozen Inc. Compositions and methods for delivery of omeprazole plus acetylsalicylic acid
WO2018209150A1 (en) 2017-05-10 2018-11-15 Axsome Therapeutics, Inc. Pharmaceutical compositions comprising meloxicam
EP3789016A1 (en) 2017-01-04 2021-03-10 Axsome Therapeutics, Inc. Pharmaceutical compositions comprising meloxicam and rizatriptan
EP4008319A1 (en) 2015-11-25 2022-06-08 Axsome Therapeutics, Inc. Pharmaceutical compositions comprising meloxicam

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0033094A1 (en) * 1980-01-23 1981-08-05 Schering Corporation Imidazo(1,2-a)pyridines, processes for their preparation and pharmaceutical compositions containing them
WO1994018199A1 (en) * 1993-02-15 1994-08-18 Byk Gulden Lomberg Chemische Fabrik Gmbh Imidazopyridines and their use in treating gastrointestinal diseases

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0033094A1 (en) * 1980-01-23 1981-08-05 Schering Corporation Imidazo(1,2-a)pyridines, processes for their preparation and pharmaceutical compositions containing them
WO1994018199A1 (en) * 1993-02-15 1994-08-18 Byk Gulden Lomberg Chemische Fabrik Gmbh Imidazopyridines and their use in treating gastrointestinal diseases

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9345695B2 (en) 2001-06-01 2016-05-24 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US9161920B2 (en) 2001-06-01 2015-10-20 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US8852636B2 (en) 2001-06-01 2014-10-07 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US8858996B2 (en) 2001-06-01 2014-10-14 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDS
US9364439B2 (en) 2001-06-01 2016-06-14 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US8865190B2 (en) 2001-06-01 2014-10-21 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US9198888B2 (en) 2001-06-01 2015-12-01 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US9707181B2 (en) 2001-06-01 2017-07-18 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
WO2007115305A2 (en) 2006-04-04 2007-10-11 Cogentus Pharmaceuticals, Inc. Oral dosage forms including an antiplatelet agent and an acid inhibitor
EP2486910A2 (en) 2006-10-27 2012-08-15 The Curators Of The University Of Missouri Multi-chambered apparatus comprising a dispenser head
WO2009105568A1 (en) 2008-02-20 2009-08-27 The Curators Of The University Of Missouri Composition comprising a combination of omeprazole and lansoprazole, and a buffering agent, and methods of using same
US9220698B2 (en) 2008-09-09 2015-12-29 Pozen Inc. Method for delivering a pharmaceutical composition to patient in need thereof
US9393208B2 (en) 2008-09-09 2016-07-19 Pozen Inc. Method for delivering a pharmaceutical composition to patient in need thereof
US9801824B2 (en) 2008-09-09 2017-10-31 Pozen Inc. Method for delivering a pharmaceutical composition to patient in need thereof
US8945621B2 (en) 2009-06-25 2015-02-03 Pozen Inc. Method for treating a patient at risk for developing an NSAID-associated ulcer
US9539214B2 (en) 2011-12-28 2017-01-10 Pozen Inc. Compositions and methods for delivery of omeprazole plus acetylsalicylic acid
US9987231B2 (en) 2011-12-28 2018-06-05 Pozen Inc. Compositions and methods for delivery of omeprazole plus acetylsalicylic acid
US10603283B2 (en) 2011-12-28 2020-03-31 Genus Lifesciences, Inc. Compositions and methods for delivery of omeprazole plus acetylsalicylic acid
EP4008319A1 (en) 2015-11-25 2022-06-08 Axsome Therapeutics, Inc. Pharmaceutical compositions comprising meloxicam
EP3789016A1 (en) 2017-01-04 2021-03-10 Axsome Therapeutics, Inc. Pharmaceutical compositions comprising meloxicam and rizatriptan
WO2018209150A1 (en) 2017-05-10 2018-11-15 Axsome Therapeutics, Inc. Pharmaceutical compositions comprising meloxicam

Also Published As

Publication number Publication date
AU3343295A (en) 1996-03-07

Similar Documents

Publication Publication Date Title
EP0683780B1 (en) Imidazopyridines and their use in treating gastrointestinal diseases
EP0723544B1 (en) ALKOXY ALKYL CARBAMATES OF IMIDAZO[1,2-a]PYRIDINES
DE60208385T2 (en) ANTINEOPLASTIC COMBINATION PREPARATES
DE60002855T2 (en) Haloalkoxy IMIDAZONAPHTHYRIDINE
DE3240248A1 (en) SUBSTITUTED BENZIMIDAZOLES, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AND MEDICINAL PRODUCTS CONTAINING THE SAME
EP0127763B1 (en) Tricyclic ethers, process for their preparation, their use and medicaments containing them
DE60121345T2 (en) ALKYLATED IMIDAZOPYRIDINE DERIVATIVES
DE60115466T2 (en) ACTIVE PROCESSORS OF IMIDAZOPYRIDINE DERIVATIVES
DE69921483T2 (en) Imidazo [1,2-a] pyridine compounds which inhibit gastric acid secretion, pharmaceutical compositions containing them and processes for their preparation
DE60127131T2 (en) TRICYCLIC IMIDAZOPYRIDINE
DE69823493T2 (en) TETRAHYDROPYRIDOVERBINDUNGEN
WO1996005199A1 (en) Imidazopyridine salt
DE19513048C2 (en) New 5-pyrrolyl-6-halogen-2-pyridylmethylsulfinylbenzimidazole derivatives
WO1991017164A1 (en) Novel pyridazines
DE60131968T2 (en) PYRANOE2,3-CIMIDAZOÄ1,2-ATPYRIDINE DERIVATIVES FOR THE TREATMENT OF GASTROINTESTINAL DISEASES
EP0773946B1 (en) Imidazopyridine-azolidinones
EP0213474B1 (en) Substituted toluidines, process for their preparation, pharmaceutical compositions containing them and their use as gastric secretion inhibitors
EP0006114A1 (en) 7-Methoxy-5-oxo-5H-thiazolo(2,3-b)quinazolin-2-carboxylic acid and its pharmaceutically acceptable salts, process for their preparation and medicines containing them
EP0138034B1 (en) Substituted pyrido[1,2-c]imidazo[1,2-a]benzimidazoles, process for their preparation, their use and pharmaceutical preparations containing them
EP0882048B1 (en) 3-alkylimidazopyridines
WO1996003402A1 (en) Halogenated imidazopyridines
WO1989011479A1 (en) New fluoralkoxy compounds
WO1996003404A1 (en) Acyl imidazopyridines
WO1996003403A1 (en) Benzyl-imidazopyridines
DE3639926A1 (en) SUBSTITUTED THIENOIMIDAZOLTOLUIDINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS CONTAINING IT AND THEIR USE AS AN INGESTIC ACID INHIBITOR

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BG BR BY CA CN CZ EE FI HU JP KR LT LV MX NO NZ PL RO RU SG SI SK UA US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA