EP1644327A1 - Kappa agonists, especially for the treatment and/or prophylaxis of irritable bowel syndrome - Google Patents

Kappa agonists, especially for the treatment and/or prophylaxis of irritable bowel syndrome

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Publication number
EP1644327A1
EP1644327A1 EP04740074A EP04740074A EP1644327A1 EP 1644327 A1 EP1644327 A1 EP 1644327A1 EP 04740074 A EP04740074 A EP 04740074A EP 04740074 A EP04740074 A EP 04740074A EP 1644327 A1 EP1644327 A1 EP 1644327A1
Authority
EP
European Patent Office
Prior art keywords
formula
compounds
solvates
derivatives
treatment
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Withdrawn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
EP04740074A
Other languages
German (de)
French (fr)
Inventor
Wolfgang Stähle
Rudolf Gottschlich
Jürgen Harting
Christoph Seyfried
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Merck Patent GmbH
Original Assignee
Merck Patent GmbH
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Publication of EP1644327A1 publication Critical patent/EP1644327A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D207/12—Oxygen or sulfur 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics

Definitions

  • the invention relates to compounds of the formula
  • A is a mononuclear or dinuclear aromatic or not
  • RH or a C 8 -C 8 alkyl, C 3 -C 14 cycloalkyl, C 6 -C 0 aryl or C 7 - C 14 araikyl group which is substituted one or more times by R 5 and their alkyl-C Chain can be interrupted by -O-
  • n 0, 1, 2 or 3
  • IBS Intestinal peristalsis have no effect, but help to cure Irritable Bowel Syndrome. IBS is the most common cause of abdominal pain syndromes.
  • Preferred compounds of the formula I are kappa agonists, in particular peripherally acting kappa agonists, and are therefore suitable for the treatment of diseases which are known to be influenced by kappa agonists, such as, for example, Pruitus (U.S. 6,004,964).
  • the compounds are also suitable as analgelics.
  • a phenyl, pyridyl, thienyl or cyclohexyl which is unsubstituted or mono- or polysubstituted by R 1 ,
  • Y is a single bond or NH
  • Shark is preferably F, Cl or Br, especially Cl.
  • the invention thus relates, in addition to the compounds of the formula I, to the use of the compounds of the formula I as medicaments for the treatment of diseases which can be influenced by kappa agonists, and in particular of the irritable bowel syndrome.
  • Preparations which contain compounds of the formula I as a component for the treatment and / or prophylaxis of irritable bowel syndrome are also the subject of the present application.
  • mice or rats act in the "writhing test” on mice or rats (method cf. Siegmund et. Al., Proc. SOG. Exp. Biol. 95, (1957), 729-731).
  • the analgesic effect as such can also be demonstrated in the "tail-fuck test” on mice or rats (methodology cf. & Amour and Smith, J. Pharmacol. Exp. Ther. 72, (1941), 74-79), also in "Hot plate test” (cf. Schmauss and Yaksh, J. Pharmacol. Exp. Ther. 228, (1984), 1-12 and the literature cited therein).
  • Binding behavior to kappa receptors Binding behavior to kappa receptors.
  • compounds of the formula I are particularly suitable for use in pharmaceutical preparations for the treatment of irritable bowel syndrome since, in addition to the analgesic and anti-inflammatory activity, they are suitable for normalizing disorders of the intestinal motor function caused by the disease.
  • the compounds of formula I are also distinguished by the fact that, owing to their pharmacokinetic properties, e.g. a logD value ⁇ -1.5 or a very low solubility of less than 0.01 mol / I cannot be absorbed or only to an extremely small extent. They are therefore predestined for local use in the intestine.
  • the compounds of the general formula I and their physiologically acceptable salts can therefore be used for the production of pharmaceutical preparations by bringing them into the suitable dosage form together with at least one carrier or auxiliary and, if desired, with one or more further active ingredients.
  • the invention therefore also relates to a pharmaceutical preparation, characterized in that it contains at least one compound of the formula I and / or one of its physiologically acceptable salts for the treatment of irritable bowel syndrome.
  • Suitable carrier substances are organic or inorganic substances which are suitable for enteral (e.g. oral or rectal) or parenteral application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate and other fatty acid glycerides , Gelatin, soy lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc or cellulose.
  • Tablets coated tablets, capsules, syrups, juices or drops are used in particular for oral use. Of particular interest are coated tablets and capsules with enteric coatings or capsule shells. Suppositories are used for rectal administration, solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants for parenteral administration.
  • the active ingredients claimed according to the invention can also be lyophilized and the lyophilizates obtained, for. B. can be used for the preparation of injectables.
  • the specified preparations can be sterilized and / or contain auxiliaries such as preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants and / or flavorings. If desired, they can also contain one or more other active ingredients, e.g. B. one or more vitamins, diuretics, anti-inflammatory drugs.
  • the compounds of the formula I according to the invention are generally administered in analogy to other known preparations which are commercially available for the claimed indications, preferably in doses between about 1 mg and 50 mg, in particular between 5 and 30 mg per dosage unit.
  • the daily dosage is preferably between about 0.02 and 20 mg / kg, in particular 0.2 and 0.4 mg / kg body weight.
  • the specific dose for each individual patient depends on a variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of elimination, combination of drugs and The severity of the disease to which the therapy applies. Oral application is preferred.
  • customary work-up means: if necessary, water is added, and if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ethyl acetate or dichloromethane, and the mixture is dried and dried organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel and / or by crystallization.
  • solvent A water + 0.1% TFA (trifluoroacetic acid)
  • solvent B acetonitrile + 0.08% TFA
  • Example A Injection glasses
  • a solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate are adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.
  • Example B Suppositories A mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
  • Example C Solution A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g
  • Example D ointment
  • 500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
  • Example E tablets A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg
  • Example F coated tablets Analogously to Example E, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.

Abstract

The invention relates to compounds of formula (I) wherein A, R1, R2, R3, X, Y, m and n have the cited designation, said compounds being suitable for the treatment of irritable bowel syndrome.

Description

KAPPA-AGONISTEN INSBESONDERE ZUR BEHANDLUNG UND/ODER PROPHYLAXE DES IRRITABLE BOWEL SYNDROMSKAPPA AGONISTS, IN PARTICULAR FOR TREATING AND / OR PROPHYLAXIS OF THE IRRITABLE BOWEL SYNDROME
Die Erfindung betrifft Verbindungen der FormelThe invention relates to compounds of the formula
worin wherein
A ein ein- oder zweikerniges aromatisches oder nicht¬A is a mononuclear or dinuclear aromatic or not
15 aromatisches carba- oder heterozyklisches unsubstituiertes oder einfach oder mehrfach durch R1 substituiertes Ringsystem,15 carba aromatic or heterocyclic unsubstituted or mono- or polysubstituted by R 1 ring system,
Ri H, Hai, N02, NHR, NRR, OR, CO-R, S03R, S02R, SR, CF3, OCF3) SCF3) C C8 alkyl, C3-C14 cycloalkyl,Ri H, Hai, N0 2 , NHR, NRR, OR, CO-R, S0 3 R, S0 2 R, SR, CF 3 , OCF 3) SCF 3) CC 8 alkyl, C 3 -C 14 cycloalkyl,
20 R2 H, Hai, N02) NHR, NRR, OR, CO-R, S03R, S02R, SR, CF3, OCF3, SCF3, C C8 aikyl, C3-C14 cycloalkyl,20 R 2 H, shark, N0 2) NHR, NRR, OR, CO-R, S0 3 R, S0 2 R, SR, CF 3 , OCF 3 , SCF 3 , CC 8 aikyl, C 3 -C 14 cycloalkyl,
R3 C C8 alkyl,R3 CC 8 alkyl,
25 X CO, CS, S02, Y eine Einfachbindung, O, NH, CH2 25 X CO, CS, S0 2 , Y a single bond, O, NH, CH 2
30 R H oder eine Cι-C8 alkyl-, C3-C14 cycloalkyl-, C6-Cι0 aryl- oder C7- C14 araikyl-Gruppe, die ein-oder mehrfach durch R5 substituiert und deren alkyl-C-Kette durch -O- unterbrochen sein kann,30 RH or a C 8 -C 8 alkyl, C 3 -C 14 cycloalkyl, C 6 -C 0 aryl or C 7 - C 14 araikyl group which is substituted one or more times by R 5 and their alkyl-C Chain can be interrupted by -O-
Hai F, Cl, Br, oder JShark F, Cl, Br, or J
35 m 0, 1 , 2, 3 oder 4 und35 m 0, 1, 2, 3 or 4 and
n 0, 1 , 2 oder 3n 0, 1, 2 or 3
bedeuten,mean,
und/oder eines ihrer physiologisch unbedenklichen Salze und/oder eines ihrer glykosylierten Derivate.and / or one of their physiologically acceptable salts and / or one of their glycosylated derivatives.
Verbindungen mit ähnlicher Strukturformel und geeignete Verfahren zu deren Herstellung sind in der Offenlegungsschrift DE 198 49 650, DE 40 34 785 und DE 42 15 213 beschrieben. Die Verwendung ähnlicher Verbindungen zur Behandlung von entzündlichen Darmerkrankungen ist in EP 0 752 246 offenbart. Es war Aufgabe der Erfindung, pharmazeutisch wirksame Verbindungen zur Verfügung zu stellen, die insbesondere in der Behandlung und/oder Prophylaxe des Irritable Bowel Syndroms (IBS oder Colon Irritable) einsetzbar und wirksam sind, die gleichzeitig die mit dieser Erkrankung verbundenen Schmerzen lindern und die Erkrankung heilen. Gleichzeitig war es Aufgabe der Erfindung, pharmazeutisch wirksame Verbindungen zur Verfügung zu stellen, die auf eine normaleCompounds with a similar structural formula and suitable processes for their preparation are described in published patent applications DE 198 49 650, DE 40 34 785 and DE 42 15 213. The use of similar compounds for the treatment of inflammatory bowel diseases is disclosed in EP 0 752 246. It was an object of the invention to provide pharmaceutically active compounds which can be used and are particularly effective in the treatment and / or prophylaxis of Irritable Bowel Syndrome (IBS or Colon Irritable) and which simultaneously alleviate the pain associated with this disease and the disease heal. At the same time, it was an object of the invention to provide pharmaceutically active compounds which are normal
Darmperistaltik keine Auswirkungen haben, jedoch die Ausheilung des Irritable Bowel Syndroms mitbewirken. IBS ist die häufigste Ursache abdominaler Schmerzsyndrome.Intestinal peristalsis have no effect, but help to cure Irritable Bowel Syndrome. IBS is the most common cause of abdominal pain syndromes.
Bevorzugte Verbindungen der Formel I sind Kappa-Agonisten insbesondere peripher wirkende Kappa-Agonisten und eignen sich daher zur Behandlung solcher Krankheiten die sich bekanntermaßen durch Kappa-Agonisten beeinflussen lassen, wie z.B. Pruitus (U.S. 6,004,964). Ebenso eignen sich die Verbindungen als Analgelika.Preferred compounds of the formula I are kappa agonists, in particular peripherally acting kappa agonists, and are therefore suitable for the treatment of diseases which are known to be influenced by kappa agonists, such as, for example, Pruitus (U.S. 6,004,964). The compounds are also suitable as analgelics.
Es wurde nun gefunden, dass Verbindungen der Formel worin A, R1, R2, R3, X, Y, m und n die oben angegebenen Bedeutungen aufweisen und/oder ihre physiologisch unbedenklichen Salze und/oder ihre glycosylierte Derivate pharmazeutisch wirksame Verbindungen sind, die sich als Kappa-Agonisten und Wirkstoffe in Arzneimitteln zur Behandlung des Irritable Bowel Syndroms in ganz besonderer Weise eignen. Insbesondere sind Verbindungen der Formel IA bevorzugtIt has now been found that compounds of the formula wherein A, R 1 , R 2 , R 3 , X, Y, m and n have the meanings given above and / or their physiologically acceptable salts and / or their glycosylated derivatives are pharmaceutically active compounds which are kappa agonists and active ingredients in drugs for the treatment of Irritable Bowel Syndrome in a very special way. Compounds of the formula IA are particularly preferred
worin A, R1, R2, R3, X, Y, m und n die oben angegebenen Bedeutungen aufweisen. Ganz besonders bevorzugt sind Verbindungen der Formel I und IA, wherein A, R 1 , R 2 , R 3 , X, Y, m and n have the meanings given above. Compounds of the formula I and IA are very particularly preferred,
worinwherein
A unsubstituiertes oder einfach oder mehrfach durch R1 substituiertes Phenyl, Pyridyl, Thienyl oder Cyclohexyl,A phenyl, pyridyl, thienyl or cyclohexyl which is unsubstituted or mono- or polysubstituted by R 1 ,
R1 HR 1 H
R^ H oder HaiR ^ H or shark
bedeutet. Bevorzugt sind auch solche Verbindungen der Formel I und IA, worinmeans. Preferred compounds of the formula I and IA are also those in which
A Phenyl oder NaphthylA phenyl or naphthyl
und/oderand or
X CO oder S02, insbesondere S02 X CO or S0 2 , in particular S0 2
und/oderand or
Y eine Einfachbindung oder NHY is a single bond or NH
bedeutet.means.
Hai bedeutet vorzugsweise F, Cl oder Br, insbesondere Cl.Shark is preferably F, Cl or Br, especially Cl.
Gegenstand der Erfindung sind somit neben den Verbindungen der Formel I die Verwendung der Verbindungen der Formel I als Arzneimittel zur Behandlung von Krankheiten, die durch Kappa Agonisten beeinflusst werden können, und insbesondere des Irritable Bowel Syndroms. Auch Zubereitungen, die Verbindungen der Formel I als Bestandteil zur Behandlung und/oder Prophylaxe des Irritable Bowel Syndroms, erhalten sind Gegenstand der vorliegenden Anmeldung.The invention thus relates, in addition to the compounds of the formula I, to the use of the compounds of the formula I as medicaments for the treatment of diseases which can be influenced by kappa agonists, and in particular of the irritable bowel syndrome. Preparations which contain compounds of the formula I as a component for the treatment and / or prophylaxis of irritable bowel syndrome are also the subject of the present application.
Versuche haben gezeigt, dass die erfindungsgemäßen Verbindungen im "Writhing Test" an Mäusen oder Ratten wirken(Methode vgl. Siegmund et. al., Proc. SOG. Exp. Biol. 95, (1957), 729-731 ). Die analgetische Wirkung als solche lässt sich ferner im "Tail-FIick-Test" an Mäusen oder Ratten nachweisen (Methodik vgl. &Amour and Smith, J. Pharmacol. Exp. Ther. 72, (1941 ), 74-79), ferner im "Hot plate test" (vgl. Schmauss und Yaksh, J. Pharmacol. Exp. Ther. 228, (1984), 1-12 und die dort zitierte Literatur). Besonders starke Wirkungen sind an Ratten im Modell der Carrageeninin- duzierten Hyperalgesie (vgl. Bartoszyk und Wild, Neuroscience Letters 101 (1989) 95) zu beobachten. Dabei zeigen die Verbindungen keine oder nur geringe Neigung zu physischer Abhängigkeit. Außerdem wurden durch entsprechende nach geläufigen Methoden durchgeführte Versuche ausgeprägte antiinflammatorische, diuretische, antikonvulsive, neuroprotektive Wirkungen nachgewiesen. Die Verbindungen zeigen eine hohe Affinität in bezug auf dieExperiments have shown that the compounds according to the invention act in the "writhing test" on mice or rats (method cf. Siegmund et. Al., Proc. SOG. Exp. Biol. 95, (1957), 729-731). The analgesic effect as such can also be demonstrated in the "tail-fuck test" on mice or rats (methodology cf. & Amour and Smith, J. Pharmacol. Exp. Ther. 72, (1941), 74-79), also in "Hot plate test" (cf. Schmauss and Yaksh, J. Pharmacol. Exp. Ther. 228, (1984), 1-12 and the literature cited therein). Particularly strong effects can be observed in rats in the model of carrageenin-induced hyperalgesia (cf. Bartoszyk and Wild, Neuroscience Letters 101 (1989) 95). The connections show little or no tendency towards physical dependence. In addition, pronounced anti-inflammatory, diuretic, anticonvulsive, neuroprotective effects were demonstrated by appropriate tests carried out according to common methods. The compounds show a high affinity for the
Bindungsverhalten an Kappa-Rezeptoren.Binding behavior to kappa receptors.
Verbindungen der Formel I sind im Gegensatz zu anderen Verbindungen mit ähnlichem Wirkungsspektrum besonders geeignet für die Verwendung in pharmazeutischen Zubereitungen zur Behandlung des Irritable Bowel Syndroms, da sie neben der analgetischen und antiinflammatorischen Wirkung geeignet sind, durch die Erkrankung hervorgerufene Störungen der Darmmotorik zu normalisieren.Compared to other compounds with a similar spectrum of activity, compounds of the formula I are particularly suitable for use in pharmaceutical preparations for the treatment of irritable bowel syndrome since, in addition to the analgesic and anti-inflammatory activity, they are suitable for normalizing disorders of the intestinal motor function caused by the disease.
Als besonders vorteilhaft hat sich außerdem bei den erfindungsgemäßen Verbindungen erwiesen, dass sie aufgrund ihrer Struktur offenbar die Blut- Hirn-Schranke nicht passieren können und daher kein Abhängigkeitspotential aufweisen.It has also proven to be particularly advantageous in the case of the compounds according to the invention that, owing to their structure, they obviously cannot pass the blood-brain barrier and therefore have no dependency potential.
Die Verbindungen der Formel I, sie zeichnen sich außerdem dadurch aus, dass sie aufgrund ihrer pharmakokinetischen Eigenschaften, wie z.B. einem logD-Wert<-1.5 oder einer sehr geringen Löslichkeit von weniger als 0,01 mol/I nicht oder nur zu einem äußerst geringen Teil resorbierbar sind. Sie sind daher eine lokale Anwendung im Darm prädestiniert.The compounds of formula I are also distinguished by the fact that, owing to their pharmacokinetic properties, e.g. a logD value <-1.5 or a very low solubility of less than 0.01 mol / I cannot be absorbed or only to an extremely small extent. They are therefore predestined for local use in the intestine.
Auch wurden bisher keine Wirkungen gefunden, die die Nutzung der vorteilhaften Wirkungen für die beanspruchten Indikationen in irgendeiner Weise einschränken würden. Die Verbindungen der aligemeinen Formel I und ihre physiologisch unbedenklichen Salze können daher zur Herstellung pharmazeutischer Präparate verwendet werden, indem man sie zusammen mit mindestens einem Träger- oder Hilfsstoff und, falls erwünscht, mit einem oder mehreren weiteren Wirkstoffen in die geeignete Dosierungsform bringt. Gegenstand der Erfindung ist daher auch eine pharmazeutische Zubereitung, gekennzeichnet durch einen Gehalt an mindestens einer Verbindung der Formel I und/oder einem ihrer physiologisch unbedenklichen Salze zur Behandlung des Irritable Bowel Syndroms.So far, no effects have been found that would in any way restrict the use of the advantageous effects for the claimed indications. The compounds of the general formula I and their physiologically acceptable salts can therefore be used for the production of pharmaceutical preparations by bringing them into the suitable dosage form together with at least one carrier or auxiliary and, if desired, with one or more further active ingredients. The invention therefore also relates to a pharmaceutical preparation, characterized in that it contains at least one compound of the formula I and / or one of its physiologically acceptable salts for the treatment of irritable bowel syndrome.
Die so erhaltenen Zubereitungen können als Arzneimittel in der Humanoder Veterinärmedizin eingesetzt werden. Als Trägersubstanzen kommen organische oder anorganische Stoffe in Frage, die sich für die enterale (z. B. orale oder rektale) oder parenterale Applikation eignen und mit den neuen Verbindungen nicht reagieren, beispielsweise Wasser, pflanzliche Öle, Benzylalkohole, Polyethylenglykole, Glycerintriacetat und andere Fettsäureglyceride, Gelatine, Sojalecithin, Kohlenhydrate wie Lactose oder Stärke, Magnesiumstearat, Talk oder Cellulose.The preparations thus obtained can be used as pharmaceuticals in human or veterinary medicine. Suitable carrier substances are organic or inorganic substances which are suitable for enteral (e.g. oral or rectal) or parenteral application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate and other fatty acid glycerides , Gelatin, soy lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc or cellulose.
Zur oralen Anwendung dienen insbesondere Tabletten, Dragees, Kapseln, Sirupe, Säfte oder Tropfen. Von Interesse sind speziell Lacktabletten und Kapseln mit magensaftresistenten Überzügen bzw. Kapselhüllen. Zur rektalen Anwendung dienen Suppositorien, zur parenteralen Applikation Lösungen, vorzugsweise ölige oder wäßrige Lösungen, ferner Suspensionen, Emulsionen oder Implantate.Tablets, coated tablets, capsules, syrups, juices or drops are used in particular for oral use. Of particular interest are coated tablets and capsules with enteric coatings or capsule shells. Suppositories are used for rectal administration, solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants for parenteral administration.
Die erfindungsgemäß beanspruchten Wirkstoffe können auch lyophilisiert und die erhaltenen Lyophilisate z. B. zur Herstellung von Injektionspräparaten verwendet werden. Die angegebenen Zubereitungen können sterilisiert sein und/oder Hilfsstoffe wie Konservierungs-, Stabilisierungs- Und/oder Netzmittel, Emulgatoren, Salze zur Beeinflussung des osmotischen Druckes, Puffersubstanzen, Färb- und/oder Aromastoffe enthalten. Sie können, falls erwünscht, auch einen oder mehrere weitere Wirkstoffe enthalten, z. B. ein oder mehrere Vitamine, Diuretika, Antiphlogistika.The active ingredients claimed according to the invention can also be lyophilized and the lyophilizates obtained, for. B. can be used for the preparation of injectables. The specified preparations can be sterilized and / or contain auxiliaries such as preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants and / or flavorings. If desired, they can also contain one or more other active ingredients, e.g. B. one or more vitamins, diuretics, anti-inflammatory drugs.
Die erfindungsgemäßen Verbindungen gemäß Formel I werden in der Regel in Analogie zu anderen bekannten, für die beanspruchten Indikationen im Handel erhältlichen Präparaten verabreicht, vorzugsweise in Dosierungen zwischen etwa 1 mg und 50 mg, insbesondere zwischen 5 und 30 mg pro Dosierungseinheit. Die tägliche Dosierung liegt vorzugsweise zwischen etwa 0.02 und 20 mg/kg, insbesondere 0,2 und 0,4 mg/kg Körpergewicht.The compounds of the formula I according to the invention are generally administered in analogy to other known preparations which are commercially available for the claimed indications, preferably in doses between about 1 mg and 50 mg, in particular between 5 and 30 mg per dosage unit. The daily dosage is preferably between about 0.02 and 20 mg / kg, in particular 0.2 and 0.4 mg / kg body weight.
Die spezielle Dosis für jeden einzelnen Patienten hängt jedoch von den verschiedensten Faktoren ab, beispielsweise von der Wirksamkeit der eingesetzten speziellen Verbindung, vom Alter, Körpergewicht, allgemeinem Gesundheitszustand, Geschlecht, von der Kost, vom Verabfolgungszeitpunkt und -weg, von der Ausscheidungsgeschwindigkeit, Arzneistoffkombination und Schwere der jeweiligen Erkrankung, welcher die Therapie gilt. Die orale Applikation ist bevorzugt.However, the specific dose for each individual patient depends on a variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of elimination, combination of drugs and The severity of the disease to which the therapy applies. Oral application is preferred.
Im folgenden werden Beispiele gegebenen, die zur Veranschaulichung der Erfindung dienen, jedoch die Erfindung nicht auf die gegebenen Beispiele begrenzen.In the following examples are given which serve to illustrate the invention but do not limit the invention to the examples given.
In den nachfolgenden Beispielen bedeutet "übliche Aufarbeitung": Man gibt, falls erforderlich, Wasser hinzu, stellt, falls erforderlich, je nach Konstitution des Endprodukts auf pH-Werte zwischen 2 und 10 ein, extrahiert mit Ethylacetat oder Dichlormethan, trennt ab, trocknet die organische Phase über Natrium-sulfat, dampft ein und reinigt durch Chromatographie an Kieselgel und/oder durch Kristallisation.In the examples below, "customary work-up" means: if necessary, water is added, and if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ethyl acetate or dichloromethane, and the mixture is dried and dried organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel and / or by crystallization.
Nachstehend sind alle Temperaturen in °C angegeben.All temperatures are given in ° C below.
Folgende Parameter wurden für die Analytik durch HPLC MS eingehalten:The following parameters were observed for analysis by HPLC MS:
Säule: Chromolith SpeedROD, 50 x 4.6 mm2 (Best.Nr. 1.51450.0001 ) von MerckColumn: Chromolith SpeedROD, 50 x 4.6 mm 2 (Order No. 1.51450.0001) from Merck
Methode: Laufmittel A: Wasser + 0,1 % TFA (Trifluoressigsäure) Laufmittel B: Acetonitril + 0,08% TFAMethod: solvent A: water + 0.1% TFA (trifluoroacetic acid) solvent B: acetonitrile + 0.08% TFA
Gradient (linear): t = 0 min, A:B = 80:20, t = 3 bis t = 3.5 min: A:B = 0:100 Abkürzungen:Gradient (linear): t = 0 min, A: B = 80:20, t = 3 to t = 3.5 min: A: B = 0: 100 Abbreviations:
M + H: Molpeak des MassenspektrumsM + H: Molpeak of the mass spectrum
MW: MolekulargewichtMW: molecular weight
RT: RetentionszeitRT: retention time
Beispiel 1 : Example 1 :
Eine Mischung von 25,0 g aminomethyliertem Polystyrol-Harz (0,78 mMol/g), 20 mg Dimethylaminopyridin (DMAP) und 5,85 g Bernsteinsäureanhydrid in 200 ml Pyridin wird für einen Tag beiA mixture of 25.0 g of aminomethylated polystyrene resin (0.78 mmol / g), 20 mg of dimethylaminopyridine (DMAP) and 5.85 g of succinic anhydride in 200 ml of pyridine is used for one day
Raumtemperatur (RT) gerührt, wodurch nach üblicher Aufarbeitung das entsprechende Monoamid erhalten wird.Room temperature (RT) stirred, whereby the corresponding monoamide is obtained after customary working up.
Beispiel 2:Example 2:
Zu einer Mischung von 7,91 g des Monoamids aus Beispiel 1 und 4,43 g der Verbindung 1 in 120 ml Methylenchlord werden unter Rühren 3,49 g 1- (Mesitylensulfonyl)-3-nitro-1 H-1 ,2,4-triazol (MSNT) und 4 ml N- Methylimidazol gegeben. Das Gemisch wird für 2 Stunden gerührt. Nach üblicher Aufarbeitung wird Ester 2 der Verbindung 1 erhalten. Beispiel 3:3.49 g of 1- (mesitylenesulfonyl) -3-nitro-1 H-1, 2.4 are added to a mixture of 7.91 g of the monoamide from Example 1 and 4.43 g of compound 1 in 120 ml of methylene chloride with stirring -triazole (MSNT) and 4 ml of N-methylimidazole. The mixture is stirred for 2 hours. After the usual work-up, ester 2 of compound 1 is obtained. Example 3:
9,8 g des Esters 2 aus Beispiel 2 werden in 30 ml Piperidin und 70 ml Dimethylformamid (DMF) für 30 Minuten gerührt. Nach üblicher Aufarbeitung wird die Verbindung 3 erhalten.9.8 g of the ester 2 from Example 2 are stirred in 30 ml of piperidine and 70 ml of dimethylformamide (DMF) for 30 minutes. After the usual work-up, compound 3 is obtained.
Beispiel 4:Example 4:
Zu einer Mischung von 7,644 mmol der Verbindung 3 in 130 ml DMF werden 9,9 g 2-Nitro-5-chlorphenylessigsäure 14,8 g 2-(1-H-Benzotriazol- 2yl)-1 , 1 ,3,3,-tetramethyluronium tetrafluoroborate (TBTU) und 11 ,9 g9.9 g of 2-nitro-5-chlorophenylacetic acid and 14.8 g of 2- (1-H-benzotriazol-2yl) -1, 1, 3.3, - are added to a mixture of 7.644 mmol of compound 3 in 130 ml of DMF. tetramethyluronium tetrafluoroborate (TBTU) and 11.9 g
Diisopropyletylamin gegeben. Das Reaktionsgemisch wird für 5 Stunden bei RT gerührt. Nach üblicher Aufarbeitung wird das Amid 4 erhalten.Given diisopropyletylamine. The reaction mixture is stirred for 5 hours at RT. After the usual work-up, the amide 4 is obtained.
Beispiel 5:Example 5:
Eine Mischung von 9,4 g der Verbindung 4 in 130 ml DMF wird mit 24,8 g Zinn(ll)-chlorid versetzt und für 6 Stunden bei 50°C gerührt. Nach üblicher Aufarbeitung wird die Verbindung 5 erhalten. 24.8 g of stannous chloride are added to a mixture of 9.4 g of compound 4 in 130 ml of DMF and the mixture is stirred at 50 ° C. for 6 hours. After the usual work-up, compound 5 is obtained.
Beispiel 6:Example 6:
Zu einer Suspension von 0,2 g der Verbindung 5 in 2 ml Methylenchlorid wird 0,24g 4-Chlorpheylisocyanat gegeben und die Mischung für 18 Stunden bei RT gerührt. Nach üblicher Aufarbeitung wird die Verbindung 6 erhalten.0.24 g of 4-chloropheyl isocyanate is added to a suspension of 0.2 g of compound 5 in 2 ml of methylene chloride and the mixture is stirred at RT for 18 hours. After the usual work-up, compound 6 is obtained.
Eine Lösung von 200 mg der Verbindung 6 in 4 ml Dioxan und 2 ml Methanol wird mit 0,8 ml 4N Kaliumhydroxid-Lösung versetzt und für 5 Stunden bei RT gerührt. Nach üblicher Aufarbeitung wird die Verbindung 7 erhalten.A solution of 200 mg of compound 6 in 4 ml of dioxane and 2 ml of methanol is mixed with 0.8 ml of 4N potassium hydroxide solution and stirred for 5 hours at RT. After the usual work-up, compound 7 is obtained.
8 Zu 0,15 g der Verbindung 8 in 1 ml Methylenchlorid und 1 ml Pyridin werden 0,291 ml 4-Methylbenzoesäurechlorid und eine Spateispitze DMAP gegeben. Nach üblicher Aufarbeitung erhält man die Verbindung 9. 8th 0.291 ml of 4-methylbenzoic acid chloride and a spatula tip of DMAP are added to 0.15 g of compound 8 in 1 ml of methylene chloride and 1 ml of pyridine. After the usual work-up, compound 9 is obtained.
Beispiel 9:Example 9:
10 10
Eine Mischung von 150 mg der Verbindung 9, 3,5 ml Dioxan, 1 ,8 ml Methanol und 0,7 ml 4N Kaliumhydroxidlösung wird für 5 Stunden bei Raumtemperatur gerührt. Nach üblicher Aufarbeitung erhält man die Verbindung 10.A mixture of 150 mg of compound 9, 3.5 ml of dioxane, 1.8 ml of methanol and 0.7 ml of 4N potassium hydroxide solution is stirred for 5 hours at room temperature. After the usual work-up, compound 10 is obtained.
Beispiel 11 :Example 11:
12 12
Zu 0,20 g der Verbindung 11. in 1 ml Methylenchlorid und 1 ml Pyridin werden 473 mg 2,4,6-Triisopropylbenzolsulfonylchlorid und eine Spatelspitze DMAP gegeben. Die Mischung wir für 3 Stunden gerührt. Nach üblicher Aufarbeitung erhält man die Verbindung 12. Beispiel 12:473 mg of 2,4,6-triisopropylbenzenesulfonyl chloride and a spatula tip of DMAP are added to 0.20 g of compound 11 in 1 ml of methylene chloride and 1 ml of pyridine. The mixture is stirred for 3 hours. After the usual work-up, compound 12 is obtained. Example 12:
12 13 12 13
Eine Mischung von 200 mg der Verbindung 12, 4 ml Dioxan, 2 ml Methanol und 0,8 ml 4N Kaliumhydroxidlösung wird für 5 Stunden bei Raumtemperatur gerührt. Nach üblicher Aufarbeitung erhält man die Verbindung 13. A mixture of 200 mg of compound 12, 4 ml of dioxane, 2 ml of methanol and 0.8 ml of 4N potassium hydroxide solution is stirred for 5 hours at room temperature. After the usual work-up, compound 13 is obtained.
Durch Verwendung der entsprechenden Vorstufen sind die folgenden erfindungsgemäßen Verbindungen erhältlich:The following compounds according to the invention can be obtained by using the corresponding precursors:
Die pharmazeutische Wirksamkeit der erfindungsgemäßen Substanzen in der Behandlung des Irritable Bowel Syndroms kann nach der in European J. of Pharmacology 271 (1994) 245-251 beschriebenen Methode untersucht werden. Die nachfolgenden Beispiele betreffen pharmazeutische Zubereitungen: The pharmaceutical effectiveness of the substances according to the invention in the treatment of irritable bowel syndrome can be investigated by the method described in European J. of Pharmacology 271 (1994) 245-251. The following examples relate to pharmaceutical preparations:
Beispiel A: InjektionsgläserExample A: Injection glasses
Eine Lösung von 100 g eines Wirkstoffs der Formel I und 5 g Dinatriumhydrogenphosphat werden in 3 I zweifach destilliertem Wasser mit 2 n Salzsäure auf pH 6.5 eingestellt, steril filtriert, in Injektionsgläser abgefüllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jedes Injektionsglas enthält 5 mg Wirkstoff.A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate are adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.
Beispiel B: Suppositorien Man schmilz ein Gemisch von 20 g eines Wirkstoffs der Formel I mit 100 g Sojalecithin und 1400 g Kakaobutter, gießt in Formen und lässt erkalten. Jedes Suppositorium enthält 20 mg Wirkstoff.Example B: Suppositories A mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
Beispiel C: Lösung Man bereitet eine Lösung aus 1 g eines Wirkstoffs der Formel I, 9.38 gExample C: Solution A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g
NaH2P04, 2H20, 28.48 g Na2HP04, 12H20 und 0.1 g Benzalkoniumchlorid in 940 ml zweifach destilliertem Wasser. Man stellt auf pH 6.8 ein, füllt auf 1 I auf und sterilisiert durch Bestrahlung.NaH 2 P0 4 , 2H 2 0, 28.48 g Na 2 HP0 4 , 12H 2 0 and 0.1 g benzalkonium chloride in 940 ml double-distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation.
Beispiel D: SalbeExample D: ointment
Man mischt 500 mg eines Wirkstoffs der Formel I mit 99.5 g Vaseline unter aseptischen Bedingungen.500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
Beispiel E: Tabletten Ein Gemisch von 1 kg Wirkstoff der Formel I, 4 kg Laktose, 1.2 kgExample E: tablets A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg
Kartoffelstärke, 0,2 kg Talk und 0.1 kg Magnesiumstearat wird in üblicher Weise zu Tabletten verpresst, derart, dass jede Tablette 10 mg Wirkstoff enthält. Beispiel F: Dragees Analog Beispiel E werden Tabletten gepresst, die anschließend in üblicher Weise mit einem Überzug aus Saccharose, Kartoffelstärke, Talk, Tragent und Farbstoff überzogen werden. Potato starch, 0.2 kg talc and 0.1 kg magnesium stearate are pressed into tablets in the usual way, such that each tablet contains 10 mg of active ingredient. Example F: coated tablets Analogously to Example E, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.

Claims

Patentansprüche claims
1. Verbindungen Formel I1. Compounds Formula I.
worin wherein
A ein ein- oder zweikerniges aromatisches oder nichtaromatisches carba- oder heterozyklisches unsubstituiertes oder einfach oder mehrfach durch R1 substituiertes Ringsystem,A is a mono- or binuclear aromatic or non-aromatic heterocyclic carba or unsubstituted or mono- or polysubstituted by R 1 ring system,
R-, H, Hai, N02, NHR, NRR, OR, CO-R, S03R, S02R, SR, CF3, OCF3, SCF3, CrC8 alkyl, C3-C14 cycloalkyl,R-, H, Hai, N0 2 , NHR, NRR, OR, CO-R, S0 3 R, S0 2 R, SR, CF 3 , OCF 3 , SCF 3 , CrC 8 alkyl, C 3 -C 14 cycloalkyl,
R2 H, Hai, N02, NHR, NRR, OR, CO-R, S03R, S02R, SR, CF3) OCF3, SCF3, Cι-C8 alkyl, C3-C14 cycloalkyl,R 2 H, shark, N0 2 , NHR, NRR, OR, CO-R, S0 3 R, S0 2 R, SR, CF 3) OCF3, SCF 3 , Cι-C 8 alkyl, C 3 -C 14 cycloalkyl,
R3 C Cβ alkyl,R 3 C Cβ alkyl,
X CO, CS, S02,X CO, CS, S0 2 ,
Y eine Einfachbindung, O, NH, CH2 Y is a single bond, O, NH, CH 2
R H oder eine Cι-C8 alkyl-, C3-C14 cycloalkyl-, C6-Cι0 aryl- oder C - C14 araikyl-Gruppe, die ein-oder mehrfach durch R5 substituiert und deren alkyl-C-Kette durch -O- unterbrochen sein kann,RH or a C 8 -C 8 alkyl, C3-C14 cycloalkyl, C 6 -C 0 aryl or C - C 14 araikyl group which is substituted one or more times by R 5 and whose alkyl C chain by O- can be interrupted
Hai F, Cl, Br, oder J m 0, 1 , 2, 3 oder 4 und n 0, 1 , 2 oder 3 bedeuten, sowie ihre pharmazeutisch verwendbaren Derivate, Solvate und Stereoinomere, ausschließlich deren Mischungen in allen Verhältnissen.Shark F, Cl, Br, or J m 0, 1, 2, 3 or 4 and n is 0, 1, 2 or 3, and their pharmaceutically usable derivatives, solvates and stereoinomers, exclusively their mixtures in all ratios.
2. Verbindungen der Formel lA2. Compounds of the formula IA
worin R1, R2, R3, X, Y, A, m und n die in Anspruch 1 angegebene Bedeutung aufweisen sowie ihre pharmakologischen verwendbaren Derivate, Salze, Solvate und Stereoisomere sowie deren Mischungen in allen Verhältnissen. wherein R 1 , R 2 , R 3 , X, Y, A, m and n have the meaning given in claim 1 and their pharmacologically usable derivatives, salts, solvates and stereoisomers and mixtures thereof in all ratios.
3. Verbindung der Formel I und IA, gemäß Anspruch 1 oder 2 worin3. A compound of formula I and IA, according to claim 1 or 2 wherein
A unsubstituiertes oder einfach oder mehrfach durch R1 substituiertes Phenyl, Pyridyl, Thienyl oder Cyclohexyl,A phenyl, pyridyl, thienyl or cyclohexyl which is unsubstituted or mono- or polysubstituted by R 1 ,
R1 HR 1 H
R2 H oder Hai bedeuten.R 2 is H or shark.
4. Arzneimittel der Formel l gemäß einem oder mehreren der Ansprüche 1 , 2 oder 3 worin4. Medicament of formula I according to one or more of claims 1, 2 or 3 wherein
A Phenyl oder Naphthyl und/oderA phenyl or naphthyl and or
X CO oder S02 und/oderX CO or S0 2 and / or
Y eine Einfachbindung oder NH bedeuten.Y is a single bond or NH.
5. Verwendung der Verbindungen der Formel I und/oder IA nach den Ansprüchen 1-4 sowie deren physiologisch unbedenklichen Salze, Solvate und Derivate zur Herstellung von Arzneimitteln zur Behandlung und/oder Prophylaxe des Irritable Bowel Syndroms.5. Use of the compounds of formula I and / or IA according to claims 1-4 and their physiologically acceptable salts, solvates and derivatives for the manufacture of medicaments for the treatment and / or prophylaxis of irritable bowel syndrome.
6. Pharmazeutische Zubereitung, gekennzeichnet durch einen Gehalt an mindestens einer Verbindung der Formel I und/oder IA und/oder einem ihrer physiologisch unbedenklichen Salze, Solvate und Derivate nach einem der Ansprüche 1 bis 4 zur Behandlung und/oder Prophylaxe des Irritable Bowel Syndroms.6. Pharmaceutical preparation, characterized by a content of at least one compound of the formula I and / or IA and / or one of its physiologically acceptable salts, solvates and derivatives according to any one of claims 1 to 4 for the treatment and / or prophylaxis of irritable bowel syndrome.
7. Verbindungen der Formel I gemäß Anspruch 1 bis 4 sowie ihre unbedenklichen Salze, Solvate und Derivate als Arzneimittel.7. Compounds of formula I according to claim 1 to 4 and their harmless salts, solvates and derivatives as medicaments.
8. Verwendung der Verbindungen der Formel I und/oder IA nach Anspruch 1 bis 4 sowie deren physiologisch unbedenkliche Salze, Solvate und Derivate zur Herstellung von Arzneimitteln zur Behandlung und/oder Prophylaxe solcher Krankheiten, die sich durch Kappa- Agonisten beeinflussen lassen.8. Use of the compounds of formula I and / or IA according to claim 1 to 4 and their physiologically acceptable salts, solvates and derivatives for the manufacture of medicaments for the treatment and / or prophylaxis of such diseases which can be influenced by kappa agonists.
9. Arzneimittelformulierung enthaltend mindestens eine Verbindung der Formel I und oder IA gemäß einem oder mehreren der vorhergehenden Ansprüche und/oder ihre pharmazeutisch verwendbaren Derivate, Solvate und Stereo-isomere, einschließlich deren Mischungen in allen Verhältnissen. 9. Pharmaceutical formulation containing at least one compound of formula I and or IA according to one or more of the preceding claims and / or their pharmaceutically usable derivatives, solvates and stereo-isomers, including their mixtures in all ratios.
EP04740074A 2003-07-11 2004-06-18 Kappa agonists, especially for the treatment and/or prophylaxis of irritable bowel syndrome Withdrawn EP1644327A1 (en)

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