EP1644327A1 - Agonistes kappa notamment destines au traitement et/ou a la prophylaxie du syndrome du colon irritable - Google Patents

Agonistes kappa notamment destines au traitement et/ou a la prophylaxie du syndrome du colon irritable

Info

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Withdrawn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)
English (en)
Inventor
Wolfgang Stähle
Rudolf Gottschlich
Jürgen Harting
Christoph Seyfried
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.)
Merck Patent GmbH
Original Assignee
Merck Patent 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 Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1644327A1 publication Critical patent/EP1644327A1/fr
Withdrawn legal-status Critical Current

Links

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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Pain & Pain Management (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des composés représentés par la formule (I) dans laquelle A, R<1>, R<2>, R<3>, X, Y, m et n ont les significations données dans le descriptif. Lesdits composés servent au traitement et/ou à la prophylaxie du syndrome du côlon irritable.
EP04740074A 2003-07-11 2004-06-18 Agonistes kappa notamment destines au traitement et/ou a la prophylaxie du syndrome du colon irritable Withdrawn EP1644327A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10331723A DE10331723A1 (de) 2003-07-11 2003-07-11 Kappa-Agonisten
PCT/EP2004/006630 WO2005007626A1 (fr) 2003-07-11 2004-06-18 Agonistes kappa notamment destines au traitement et/ou a la prophylaxie du syndrome du colon irritable

Publications (1)

Publication Number Publication Date
EP1644327A1 true EP1644327A1 (fr) 2006-04-12

Family

ID=34071646

Family Applications (1)

Application Number Title Priority Date Filing Date
EP04740074A Withdrawn EP1644327A1 (fr) 2003-07-11 2004-06-18 Agonistes kappa notamment destines au traitement et/ou a la prophylaxie du syndrome du colon irritable

Country Status (14)

Country Link
US (1) US20060178426A1 (fr)
EP (1) EP1644327A1 (fr)
JP (1) JP2007506677A (fr)
KR (1) KR20060030895A (fr)
CN (1) CN1819994A (fr)
AR (1) AR046153A1 (fr)
AU (1) AU2004256892A1 (fr)
BR (1) BRPI0412451A (fr)
CA (1) CA2531817A1 (fr)
DE (1) DE10331723A1 (fr)
MX (1) MXPA06000366A (fr)
RU (1) RU2006104024A (fr)
WO (1) WO2005007626A1 (fr)
ZA (1) ZA200601228B (fr)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2527360B1 (fr) 2007-06-04 2015-10-28 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
US20100120694A1 (en) 2008-06-04 2010-05-13 Synergy Pharmaceuticals, Inc. Agonists of Guanylate Cyclase Useful for the Treatment of Gastrointestinal Disorders, Inflammation, Cancer and Other Disorders
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
ES2624828T3 (es) 2008-07-16 2017-07-17 Synergy Pharmaceuticals Inc. Agonistas de la guanilato ciclasa útiles para el tratamiento de trastornos gastrointestinales, inflamación, cáncer y otros
US20100221329A1 (en) 2008-12-03 2010-09-02 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase c agonists and methods of use
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
AU2012223337C1 (en) 2011-03-01 2016-11-10 Bausch Health Ireland Limited Process of preparing guanylate cyclase C agonists
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
US10011637B2 (en) 2013-06-05 2018-07-03 Synergy Pharmaceuticals, Inc. Ultra-pure agonists of guanylate cyclase C, method of making and using same
JP6577943B2 (ja) * 2013-06-28 2019-09-18 ネクター セラピューティクス κオピオイド作動薬及びその使用
US20150080466A1 (en) * 2013-09-19 2015-03-19 Allergan, Inc. Diphenyl urea derivatives as formyl peptide receptor modulators

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4034785A1 (de) * 1990-11-02 1992-05-07 Merck Patent Gmbh 1-(2-arylethyl)-pyrrolidine
US6303611B1 (en) * 1996-03-08 2001-10-16 Adolor Corporation Kappa agonist compounds and pharmaceutical formulations thereof
US6133307A (en) * 1997-04-30 2000-10-17 Warner-Lambert Company Certain benzofuranyl-N-[pyrrolidin-1-YL]-N-methyl-acetamide derivatives useful as opioid agonists
DE19849650A1 (de) * 1998-10-29 2000-05-04 Merck Patent Gmbh Kappa-Opiatagonisten für die Behandlung des Irritable Bowel Syndroms (IBS)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2005007626A1 *

Also Published As

Publication number Publication date
AU2004256892A1 (en) 2005-01-27
AR046153A1 (es) 2005-11-30
CN1819994A (zh) 2006-08-16
MXPA06000366A (es) 2006-03-28
DE10331723A1 (de) 2005-06-16
JP2007506677A (ja) 2007-03-22
BRPI0412451A (pt) 2006-09-19
WO2005007626A1 (fr) 2005-01-27
ZA200601228B (en) 2007-05-30
US20060178426A1 (en) 2006-08-10
KR20060030895A (ko) 2006-04-11
CA2531817A1 (fr) 2005-01-27
RU2006104024A (ru) 2006-07-27

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