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WO2005060961A2 - Nouveau traitement du reflux gastrooesophagien pathologique - Google Patents

Nouveau traitement du reflux gastrooesophagien pathologique Download PDF

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Publication number
WO2005060961A2
WO2005060961A2 PCT/US2004/041133 US2004041133W WO2005060961A2 WO 2005060961 A2 WO2005060961 A2 WO 2005060961A2 US 2004041133 W US2004041133 W US 2004041133W WO 2005060961 A2 WO2005060961 A2 WO 2005060961A2
Authority
WO
WIPO (PCT)
Prior art keywords
pyridyl
oxadiazole
oxazole
cyanophenyl
chloro
Prior art date
Application number
PCT/US2004/041133
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English (en)
Other versions
WO2005060961A3 (fr
Inventor
Anders Lehmann
Jan Mattsson
Original Assignee
Astrazeneca Ab
Nps Pharmaceuticals, Inc.
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 Astrazeneca Ab, Nps Pharmaceuticals, Inc. filed Critical Astrazeneca Ab
Publication of WO2005060961A2 publication Critical patent/WO2005060961A2/fr
Publication of WO2005060961A3 publication Critical patent/WO2005060961A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the present invention relates to the use of certain compounds for the inhibition of transient lower esophageal sphincter relaxations.
  • a further aspect of the invention is directed to the use of certain compounds for the treatment of gastro-esophageal reflux disease.
  • the compounds of formula II have been described in WO01/12627 Al.
  • the compounds have been described as being useful in the treatment of various CNS disorders such as senile dementia, schizophrenia, Alzheimer's disease and anxiety.
  • the lower esophageal sphincter (LES) is prone to relaxing intermittently. As a consequence, fluid from the stomach can pass into the esophagus since the mechanical barrier is temporarily lost at such times, an event hereinafter referred to as "reflux".
  • Gastro-esophageal reflux disease is the most prevalent upper gastrointestinal tract disease. Current pharmacotherapy aims at reducing gastric acid secretion, or at neutralizing acid in the esophagus. The major mechanism behind reflux has been considered to depend on a hypotonic lower esophageal sphincter. However, e.g. Holloway & Dent (1990) Gastroenterol. Clin. N. Amer. 19, pp. 517-535, has shown that most reflux episodes occur during transient lower esophageal sphincter relaxations (TLESRs), i.e. relaxations not triggered by swallows. It has also been shown that gastric acid secretion usually is normal in patients with GERD.
  • TLESRs transient lower esophageal sphincter relaxations
  • the object of the present invention was to find a new way for the inhibition of transient lower esophageal sphincter relaxations (TLESRs), thereby preventing reflux. More particularly the object of the invention was to find a new way of treating gastro-esophageal reflux disease (GERD), as well as a new way for the treatment of regurgitation.
  • GENERAL gastro-esophageal reflux disease
  • the present invention is directed to the use of compounds of formula ⁇
  • X, Y, and Z are independently selected from the group consisting of N, O, S, C, and CO wherein at least one of X, Y, and Z is a heteroatom;
  • Ar 1 and Ar 2 are independently selected from the group consisting of a heterocyclic or fused heterocyclic moiety containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S and an aromatic moiety selected from the group consisting of phenyl, benzyl, 1- naphthyl, 2-naphthyl, fluorenyl, anthrenyl, indenyl, phenanthrenyl, and benzonaphthenyl, wherein the Ar and Ar moieties are optionally substituted with one or more moieties selected from the group consisting of -F, -Cl, -Br, -I, -OR, -SR, -SOR, - SO 2 R, -SO 2 NRR', -OCOR, -OCONRR
  • the Ar 1 moiety is generally defined as a heterocyclic moiety, and the Ar 1 moiety is 1 generally defined as a carbocylic moiety.
  • Ar and Ar can be monocyclic or fused bicyclic groups.
  • Ar 2 is defined as an aryl or alkaryl moiety.
  • Ar 1 is defined as a heterocyclic, heteroaryl or heteroarylalkyl moiety.
  • the ring systems encompassed by Ar 1 can contain up to four heteroatoms, independently selected from the group consisting of N, S, and O. When Ar 1 is a heteroaryl ring or ring system, it preferably contains one or two heteroatoms. At least one of the heteroatoms preferably is nitrogen (N).
  • heterocyclic or fused heterocylic moiety preferably is selected from the group consisting of quinolyl, quinazolyl, quinoxalyl, 2-pyrimidyl, 4- pyrimidyl, 5-pyrimidyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, and pyrazyl.
  • Monocyclic Ar 1 groups include, but are not limited to: thiazoyl, furyl, pyranyl, 2H- pyrrolyl, thienyl, pyrroyl, imidazoyl, pyrazoyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl moieties.
  • Monocyclic Ar 2 group include but are not limited to phenyl and benzyl.
  • Fused bicyclic Ar include, but are not limited to, naphthyl, fluorenyl, anthrenyl, indenyl, phenanthrenyl, and benzonaphthenyl.
  • Ar 1 groups include, but are not limited to: benzothiazole, benzimidazole, 3H-indolyl, indolyl, indazoyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalizinyl, naphthyridinyl, quinazolinyl, cinnolinyl, isothiazolyl, quinoxalinyl indolizinyl, isoindolyl, benzothienyl, benzofuranyl, isobenzofuranyl, and chromenyl moieties.
  • Ar 1 is a 2-pyridyl moiety.
  • Ar 2 is a substituted phenyl moiety.
  • the Ar and Ar moieties optionally may independently be substituted with one or more moieties selected from the group consisting of halogen, -Cs alkyl, CrC 3 O-alkyl, -OH, - OCF 3 , -COOR, -COR, -SOR, -SO 2 NRR', -NRR', -CN, -CF 3 , -CO-NRR', -A-(CH 2 ) n -NRR', wherein A is C, O, N, SO, SO 2 , and R and R' are independently selected from the group consisting of -C alkyl, H, cycloalkyl, heterocycloalkyl, aryl, and n is 1, 2, 3, or 4.
  • the compound is selected from the group consisting of 3-(2-pyridyl)-5-(3,5-dichlorophenyl)-l ,2,4-oxadiazole, 3-(2-pyridyl)-5-(3-chlorophenyl)- 1,2,4-oxadiazole, 3-(2-pyridyl)-5-(3-methoxyphenyl)-l,2,4-oxadiazole, 3-(2-pyridyl)-5-(2- chlorophenyl)-l,2,4-oxadiazole, 3-(2-pyridyl)-5-[3-(trifluoromethyl)phenyl]-l,2,4- oxadiazole, 3-(2-pyridyl)-5-(3-methylphenyl)-l,2,4-oxadiazole, 3-(2-pyridyl)-5-(l- naphthyl)- 1,2,4-oxadiazole, 3-(2-pyrid
  • the compound is selected from the group consisting of 2-(3 ,5-dichlorophenyl)-4-(2-pyridyl)- 1 ,3-oxazole, 2-(3-chlorophenyl)-4-(2- pyridyl)- 1,3-oxazole, 2-(3-methoxyphenyl)-4-(2-pyridyl)-l,3-oxazole, 2-(2-chlorophenyl)- 4-(2-pyridyl)-l,3-oxazole, 2-(3-trif uorophenyl)-4-(2-pyridyl)-l,3-oxazole, 2-(3- methylphenyl)-4-(2-pyridyl)-l ,3-oxazole, 2-(l-naphthyl)-4-(2-pyridyl)- 1 ,3-oxazole, 2-(3- trifluoromethoxy
  • the compounds of formula II above may be prepared as described in WOO 1/12627 Al.
  • GFD gastro-esophageal reflux disease
  • a further aspect of the invention is the use of a compound of formula II for the manufacture of a medicament for the treatment of regurgitation.
  • Still a further aspect of the invention is the use of a compound of formula II for the manufacture of a medicament for the treatment or prevention of lung disease.
  • Another aspect of the invention is the use of a compound of formula LT for the manufacture of a medicament for the management of failure to thrive.
  • Still a further aspect of the invention is the use of a compound of formula II for the manufacture of a medicament for the treatment or prevention of asthma, such as reflux-related asthma.
  • Another aspect of the invention is the use of a compound of formula II for the manufacture of a medicament for the treatment or prevention of chronic laryngitis.
  • a further aspect of the present invention is a method for the inhibition of transient lower esophageal sphincter relaxations (TLESRs), whereby a pharmaceutically and pharmacologically effective amount of a compound of formula II is administered to a subject in need of such inhibition.
  • TLESRs transient lower esophageal sphincter relaxations
  • Another aspect of the invention is a method for the prevention of reflux, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula II is administered to a subject in need of such prevention.
  • Still a further aspect of the invention is a method for the treatment of gastro-esophageal reflux disease (GERD), whereby a pharmaceutically and pharmacologically effective amount of a compound of formula II is administered to a subject in need of such treatment.
  • GSD gastro-esophageal reflux disease
  • Yet another aspect of the invention is a method for the treatment of regurgitation, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula II is administered to a subject in need of such treatment.
  • Still a further aspect of the invention is a method for the treatment or prevention of asthma, such as reflux-related asthma, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula II is administered to a subject in need of such treatment.
  • Still a further aspect of the invention is a method for the management of failure to thrive, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula II is administered to a subject in need of such treatment.
  • a further aspect of the invention is the use of a compound according to formula LI for the manufacture of a medicament for the treatment or prevention of functional gastrointestinal disorders, such as functional dyspepsia (FD).
  • a compound according to formula II for the manufacture of a medicament for the treatment or prevention of irritable bowel syndrome (LBS), such as constipation predominant IBS, diarrhea predominant IBS or alternating bowel movement predominant IBS.
  • LBS irritable bowel syndrome
  • TLESR transient lower esophageal sphincter relaxations
  • GFD gastro-esophageal reflux disease
  • the compounds of formula II are in accordance with the present invention suitably formulated into pharmaceutical formulations for oral administration. Also rectal, parenteral or any other route of administration may be contemplated to the skilled man in the art of formulations.
  • the compounds of formula II are formulated with at least one pharmaceutically and pharmacologically acceptable carrier or adjuvant.
  • the carrier may be in the form of a solid, semi-solid or liquid diluent.
  • the compound of formula LT to be formulated is mixed with solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • Soft gelatine capsules may be prepared with capsules containing a mixture of the active compound or compounds of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules.
  • Hard gelatine capsules may contain the active compound in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.
  • Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the active substance(s) mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil, or other suitable vehicle for gelatine rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
  • Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions, containing the active compound and the remainder of the formulation consisting of sugar or sugar alcohols, and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agent.
  • Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
  • Solutions for parenteral administration may be prepared as a solution of a compound of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients and/or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.
  • the compound of formula II may be administered once or twice daily, depending on the severity of the patient's condition.
  • a multilumen sleeve/sidehole assembly (Dentsleeve, Sydney, South Australia) is introduced through the esophagostomy to measure gastric, lower esophageal sphincter (LES) and esophageal pressures.
  • the assembly is perfused with water using a low-compliance manometric perfusion pump (Dentsleeve, Sydney, South Australia).
  • An air-perfused tube is passed in the oral direction to measure swallows, and an antimony electrode monitored pH, 3 cm above the LES. All signals are amplified and acquired on a personal computer at 10 Hz.
  • placebo (0.9% NaCl) or test compound is administered intravenously (i.v., 0.5 ml/kg) in a foreleg vein.
  • a nutrient meal (10% peptone, 5% D-glucose, 5% Intralipid, pH 3.0) is infused into the stomach through the central lumen of the assembly at 100 ml/min to a final volume of 30 ml/kg.
  • air is insufflated at 40 ml/min.
  • TLESRs In an alternative model (Barostat model), the infusion of the nutrient meal is followed by air infusion at a rate of 500 ml/min until a intragastric pressure of lO ⁇ l mmHg is obtained. The pressure is then maintained at this level throughout the experiment using the infusion pump for further air infusion or for venting air from the stomach. The experimental time from start of nutrient infusion to end of air insufflation is 45 min. The procedure has been validated as a reliable means of triggering TLESRs. TLESRs is defined as a decrease in lower esophageal sphincter pressure (with reference to intragastric pressure) at a rate of >1 mmHg/s.
  • the relaxation should not be preceded by a pharyngeal signal ⁇ 2s before its onset in which case the relaxation is classified as swallow- induced.
  • the pressure difference between the LES and the stomach should be less than 2 mmHg, and the duration of the complete relaxation longer than 1 s.

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  • Health & Medical Sciences (AREA)
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  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

La présente invention a trait à l'utilisation d'un composé de formule (II) pour l'inhibition des relaxations transitoires du sphincter inférieur de l'oesophage. Dans un autre aspect, l'invention a trait à l'utilisation des composés de formule (II) pour le traitement du reflux gastrooesophagien pathologique.
PCT/US2004/041133 2003-12-18 2004-12-10 Nouveau traitement du reflux gastrooesophagien pathologique WO2005060961A2 (fr)

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US53023203P 2003-12-18 2003-12-18
US60/530,232 2003-12-18

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WO2005060961A3 WO2005060961A3 (fr) 2006-01-05

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US7202262B2 (en) 2003-04-11 2007-04-10 Ptc Therapeutics, Inc. Benzoic acid or benzoate substituted 1,2,4-oxadiazole compounds and their use for the treatment of disease
US9289398B2 (en) 2006-03-30 2016-03-22 Ptc Therapeutics, Inc. Methods for the production of functional protein from DNA having a nonsense mutation and the treatment of disorders associated therewith
US9873677B2 (en) 2014-03-06 2018-01-23 Ptc Therapeutics, Inc. Pharmaceutical compositions and salts of a 1,2,4-oxadiazole benzoic acid
US10517853B2 (en) 2015-10-30 2019-12-31 Ptc Therapeutics, Inc. Methods for treating epilepsy

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US8796322B2 (en) 2003-04-11 2014-08-05 Ptc Therapeutics, Inc. Methods for using 1,2,4-oxadiazole benzoic acid compounds
US7419991B2 (en) 2003-04-11 2008-09-02 Ptc Therapeutics, Inc. 3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid, compositions, and methods for the use thereof
US7683082B2 (en) 2003-04-11 2010-03-23 Ptc Therapeutics, Inc. 1,2,4-oxadiazole benzoic acid compositions and their use in bioassays
US7772259B2 (en) 2003-04-11 2010-08-10 Ptc Therapeutics, Inc. 1,2,4-Oxadiazole benzoic acid compounds and their use for nonsense suppression and the treatment of disease
US8017636B2 (en) 2003-04-11 2011-09-13 Ptc Therapeutics, Inc. 1,2,4-Oxadiazole benzoic acid compositions and their use in bioassays
US8129540B2 (en) 2003-04-11 2012-03-06 Ptc Therapeutics, Inc. Methods for the synthesis of 1,2,4-oxadiazole benzoic acid compounds
US8163782B2 (en) 2003-04-11 2012-04-24 Ptc Therapeutics, Inc. 1,2,4-oxadiazole benzoic acid compositions
US8227494B2 (en) 2003-04-11 2012-07-24 Ptc Therapeutics, Inc. Pharmaceutical compositions of 1,2,4-oxadiazole benzoic acid and their use for the treatment of disease
US8486982B2 (en) 2003-04-11 2013-07-16 Ptc Therapeutics, Inc. 1,2,4-oxadiazole benzoic acids
US8299105B2 (en) 2003-04-11 2012-10-30 Ptc Therapeutics, Inc. 1,2,4-oxadiazole benzoic acid compositions and their use in bioassays
US9205088B2 (en) 2003-04-11 2015-12-08 Ptc Therapeutics, Inc. Compositions of 1,2,4-oxadiazol benzoic acid compounds and methods for their use
US8975287B2 (en) 2003-04-11 2015-03-10 Ptc Therapeutics, Inc. Methods for using 1,2,4-Oxadiazole benzoic acid compounds
US7202262B2 (en) 2003-04-11 2007-04-10 Ptc Therapeutics, Inc. Benzoic acid or benzoate substituted 1,2,4-oxadiazole compounds and their use for the treatment of disease
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