WO2005060961A2 - Treatment of transient lower esophageal sphincter relaxations (tlesrs) and gastro-esophageal reflux disease (gerd) - Google Patents

Treatment of transient lower esophageal sphincter relaxations (tlesrs) and gastro-esophageal reflux disease (gerd) 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
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Prior art keywords
pyridyl
oxadiazole
oxazole
cyanophenyl
chloro
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PCT/US2004/041133
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French (fr)
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WO2005060961A3 (en
Inventor
Anders Lehmann
Jan Mattsson
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Astrazeneca Ab
Nps Pharmaceuticals, Inc.
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Publication of WO2005060961A2 publication Critical patent/WO2005060961A2/en
Publication of WO2005060961A3 publication Critical patent/WO2005060961A3/en

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    • 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.

Abstract

The present invention relates to the use of a compound of formula (II) for the inhibition of transient lower esophageal sphincter relaxations. A further aspect of the invention is directed to the use of compounds of formula (II) for the treatment of gastro-esophageal reflux disease.

Description

NOVEL TREATMENT OF GERD
Field of the invention
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.
Background of the invention
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 (GERD) 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.
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. Outline of the invention
The present invention is directed to the use of compounds of formula π
Figure imgf000003_0001
wherein 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; Ar1 and Ar2 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, - SO2R, -SO2NRR', -OCOR, -OCONRR', -NRCOR', -NRCO2R', -CN, -NO2, -CO2R, -CONRR', -C(O)R, - ' CH(OR)R', -CH2(OR), -R, and -A-(CH2)n-NRR'; wherein R or R' is selected from the group consisting of H, CF3, Ci-C10 alkyl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, heterocycloalkyl, aryl and where R and R' may combine to form a ring, and A is defined as CH2, O, NH, S, SO, SO and n is 1, 2, 3, or 4; and wherein the 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; or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for the inhibition of transient lower esophageal sphincter relaxations (TLESRs). The Ar1 moiety is generally defined as a heterocyclic moiety, and the Ar1 moiety is 1 generally defined as a carbocylic moiety. Ar and Ar can be monocyclic or fused bicyclic groups. In one embodiment, Ar2 is defined as an aryl or alkaryl moiety. In one embodiment, Ar1 is defined as a heterocyclic, heteroaryl or heteroarylalkyl moiety. The ring systems encompassed by Ar1 can contain up to four heteroatoms, independently selected from the group consisting of N, S, and O. When Ar1 is a heteroaryl ring or ring system, it preferably contains one or two heteroatoms. At least one of the heteroatoms preferably is nitrogen (N). The 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 Ar1 groups include, but are not limited to: thiazoyl, furyl, pyranyl, 2H- pyrrolyl, thienyl, pyrroyl, imidazoyl, pyrazoyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl moieties. Monocyclic Ar2 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. Fused bicyclic Ar1 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. In one embodiment, Ar1 is a 2-pyridyl moiety. In one embodiment, Ar2 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, CrC3 O-alkyl, -OH, - OCF3, -COOR, -COR, -SOR, -SO2NRR', -NRR', -CN, -CF3, -CO-NRR', -A-(CH2)n-NRR', wherein A is C, O, N, SO, SO2, 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.
In one embodiment of the invention, 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-pyridyl)- 5-[3-(trifluoromethoxy)phenyl]-l,2,4- oxadiazole, 3-(2-pyridyl)-5-(2,3-difluorophenyl)-l,2,4-oxadiazole, 3-(2-pyridyl)-5-(2,5- difluorophenyl)- 1,2,4-oxadiazole, 3-(2-pyridyl)-5-(3,5-difluorophenyl)-l,2,4-oxadiazole, 3-(2-pyridyl)-5-(3-cyanophenyl)-l,2,4-oxadiazole, 3-(2-pyridyl)-5-(3,5-dimethoxyphenyl)- 1,2,4-oxadiazole, 3-(2-pyridyl)-5-(2,3-dichlorophenyl)-l,2,4-oxadiazole, 3-(2-pyridyl)-5- (3-chloro-5-cyanophenyl)-l,2,4-oxadiazole, 3-(2-pyridyl)-5-(3-fluoro-5-cyanophenyl)- 1,2,4-oxadiazole, 3-(2-pyridyl)-5-(3-chloro-5-fluorophenyl)-l,2,4-oxadiazole, 3~(5- chloropyrid-2-yl)-5-(3-cyanophenyl)-l,2,4-oxadiazole, 3-(5-fluoropyrid-2-yl)-5-(3- cyanophenyl)-l,2,4-oxadiazole, 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-l,2,4- oxadiazole, 3-(3-fluoropyrid-2-yl)-5-(3-cyanophenyl)-l,2,4-oxadiazole, 3-(5-fluoropyrid- 2-yl)-5-(3,5-dimethoxyphenyl)-l,2,4-oxadiazole, 3-(5-methoxypyrid-2-yl)-5-(3- cyanophenyl)- 1,2,4-oxadiazole, 3-(2-quinolinyl)-5-(3-cyanophenyl)-l,2,4-oxadiazole, 3- (3-chloro-5-trifluoromethylpyrid-2-yl)-5-(3-cyanophenyl)-l,2,4-oxadiazole, 3-(2-pyridyl)- 5-(5-chloro-2-methoxyphenyl)-l,2,4-oxadiazole, 3-(2-pyridyl)-5-(2-chloro-5- methylthiophenyl)- 1,2,4-oxadiazole, 3-(2-pyridyl)-5-(2-bromo-5-methoxyphenyl)-l,2,4- oxadiazole, 3-(2-pyridyl)-5-(2,5,6- trifluorophenyl)- 1,2,4-oxadiazole, 2-(3-chlorophenyl)- 4-(pyridin-2-yl)- 1,3-oxazole, 3-(2-pyridyl)-5-(2,5,6-trifluorophenyl)-l,2,4-oxadiazole, 3- (2-pyridyl)-5-(3-nitrophenyl)-l ,2,4-oxadiazole, 3-(2-pyridyl)-5-(3-bromophenyl)-l ,2,4- oxadiazole and pharmaceutically acceptable salts thereof.
In a further embodiment of the invention, 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- trifluoromethoxyphenyl)-4-(2-pyridyl)-l,3-oxazole, 2-(2,3-difluorophenyl)-4-(2-pyridyl)- 1,3-oxazole, 2-(2,5-difluoroρhenyl)-4-(2-pyridyl)- 1,3-oxazole, 2-(3,5-difluorophenyl)-4- (2-pyridyl)-l,3-oxazole, 2-(3-cyanophenyl)-4-(2-pyridyl)- 1,3-oxazole, 2-(3,5- dimethoxyphenyl)-4-(2-pyridyl)- 1,3-oxazole, 2-(2,3-dichlorophenyl)-4-(2-pyridyl)-l,3- oxazole, 2-(3-chloro-5-cyanophenyl)-4-(2-pyridyl)- 1,3-oxazole, 2-(3-fluoro-5- cyanophenyl)-4-(2-pyridyl)-l,3-oxazole, 2-(3-chloro-5-fluorophenyl)-4-(2-pyridyl)-l,3- oxazole, 2-(3-cyanophenyl)-4-(5-chloropyrid-2-yl)-l,3-oxazole, 2-(3-cyanophenyl)-4-(5- fluoropyrid-2-yl)- 1,3-oxazole, 2-(3-cyano-5-fluorophenyl)-4-(5-fluoropyrid-2-yl)-l,3- oxazole, 2-(3-cyanophenyl)-4-(3-fluoropyrid-2-yl)-l,3-oxazole, 2-(3,5-dimethoxyphenyl)~ 4-(5-fluoropyrid-2-yl)-l,3-oxazole, 2-(3-cyanophenyl)-4-(5-methoxypyrid-2-yl)-l,3~ oxazole, 2-(3-cyanophenyl)-4-(2-quinolinyl)-l,3-oxazole, 2-(3-cyanophenyl)-4-(3-chloro- 5-trifluoromethylpyrid-2-yl)-l ,3-oxazole, 2-(5-chloro-2-methoxyphenyl)-4-(2-pyridyl)-l ,3- oxazole, 2-(2-chloro-5-methylthiophenyl)-4-(2-pyridyl)- 1 ,3-oxazole, 2-(2-bromo-5- methoxyphenyl)-4-(2-pyridyl)-l,3-oxazole, 2-(2,5,6-trifluorophenyl)-4-(2-pyridyl)-l,3- oxazole, 2-(3-chlorophenyl)-4-(pyridin-2-yl)-l,3-oxazole, 2-(2,5,6-trifluorophenyl)-4-(2- pyridyl)- 1,3-oxazole, 2-(3-nitrophenyl)-4-(2-pyridyl)-l,3-oxazole, 2-(3-bromophenyl)-4- (2-pyridyl)-l,3-oxazole, 3-(2-pyridyl)-5-(2,3-dimethoxyphenyl)-l,2,4-oxadiazole, 3-(2- pyridyl)-5-(3-phenoxyphenyl)-l,2,4-oxadiazole, 3-(2-pyridyl)-5-(3-benzoylphenyl)-l,2,4- oxadiazole, 3-(2-pyridyl)-5-(2-chloro-5-(trifluoromethyl)phenyl)-l,2,4-oxadiazole, 3-(2- pyridyl)-5-(3,4,5-trifluorophenyl)- 1,2,4-oxadiazole, 3-(3-methoxyphenyl)-5-(2-pyridyl)- 1 ,2,4-oxadiazole, 3-(pyrid-2-yl)-5-(2-hydroxyphenyl)- 1 ,2,4-oxadiazole, 3-(2-pyridyl)-5-(5- chloro-2-hydroxyphenyl)-l,2,4-oxadiazole, 3-(2-pyridyl)-5-(2-aminophenyl)-l,2,4- oxadiazole, 2-(3-bromophenyl)-4-(pyridin-2-yl)-l ,3-oxazole, 2-(3-cyanophenyl)-4- (pyridin-2-yl)-l ,3-oxazole, 5-(3-hydroxyphenyl)-3-(pyridine-2-yl)-l ,2-oxazole, 5-(3- cyanophenyl)-3-(pyridin-2-yl)-l,2-oxazole, 3-(2-pyridyl)-5-(3-iodophenyl)-l,2,4-triazole, 3-(2-pyridyl)-5-(5-chloro-2-aminophenyl)-l,2,4-oxadiazole and pharmaceutically acceptable salts thereof.
The compounds of formula II above may be prepared as described in WOO 1/12627 Al.
A further aspect of the invention is the use of a compound formula LT for the manufacture of a medicament for the prevention of reflux. Still a further aspect of the invention is the use of a compound of formula LI for the manufacture of a medicament for the treatment of gastro-esophageal reflux disease (GERD).
Effective prevention of regurgitation would be an important way of preventing, as well as curing lung disease due to aspiration of regurgitated gastric contents, and for managing failure to thrive. Thus, 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. 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.
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.
Yet another aspect of the invention is a method for the treatment of chronic laryngitis, 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 inhibition of lung disease, 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). Yet another aspect of the invention is the use of 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.
The wording "TLESR", transient lower esophageal sphincter relaxations, is herein defined in accordance with Mittal, R.K., Holloway, R.H., Penagini, R., Blackshaw, L.A., Dent, J., 1995; Transient lower esophageal sphincter relaxation. Gastroenterology 109, pp. 601-610.
The wording "reflux" is defined as fluid from the stomach being able to pass into the esophagus, since the mechanical barrier is temporarily lost at such times.
The wording "GERD", gastro-esophageal reflux disease, is defined in accordance with van Heerwarden, M.A., Smout A. J. P.M., 2000; Diagnosis of reflux disease. Bailliere's Clin. Gastroenterol. 14, pp. 759-774.
Pharmaceutical formulations
For clinical use, 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. Thus, 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.
In the preparation of oral pharmaceutical formulations in accordance with the invention, 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. The mixture is then processed into granules or compressed into tablets.
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.
In one aspect of the present invention, the compound of formula II may be administered once or twice daily, depending on the severity of the patient's condition.
Biological evaluation
Screening for compounds active against TLESR
Adult Labrador retrievers of both genders, trained to stand in a Pavlov sling, are used. Mucosa-to-skin esophagostomies are formed and the dogs are allowed to recover completely before any experiments are done.
Motility measurement
In brief, after fasting for approximately 17 h with free supply of water, a multilumen sleeve/sidehole assembly (Dentsleeve, Adelaide, 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, Adelaide, 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.
When a baseline measurement free from fasting gastric/LES phase LTI motor activity has been obtained, placebo (0.9% NaCl) or test compound is administered intravenously (i.v., 0.5 ml/kg) in a foreleg vein. Ten min after i.v. administration, 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. Immediately following the meal, air is insufflated at 40 ml/min. 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.

Claims

Claims
Use of a compound of formula II,
Figure imgf000014_0001
wherein 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; Ar1 and Ar2 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 Ar1 and Ar2 moieties are optionally substituted with one or more moieties selected from the group consisting of -F, -Cl, -Br, -I, -OR, -SR, -SOR, -SO2R, -SO2NRR', -OCOR, - OCONRR', -NRCOR', -NRCO2R', -CN, -NO2, -CO2R, -CONRR', -C(O)R, - CH(OR)R', -CH2(OR), -R, and -A-(CH2)-NRR'; wherein R or R' is selected from the group consisting of H, CF3, Ci-Cio alkyl, cycloalkyl, alkyl-aryl, alkyl- heteroaryl, heterocycloalkyl, aryl and where R and R' may combine to form a ring, and A is defined as CH2, O, NH, S, SO, SO2 and n is 1, 2, 3, or 4, with the proviso that the compound is not 3-(2-Pyridyl)-5-(2-nitrophenyl)- 1,2,4- oxadiazole, 3-(2-Pyridyl)-5-(2-chlorophenyl)- 1,2,4-oxadiazole, 3-(2-Pyridyl)-5- (3- methoxyphenyl)- 1, 2,4-oxadiazole, 3-(2-Pyridyl)-5-[3- (trifluoromethyl)phenyl]- 1,2,4- oxadiazole, or 3-(2-Pyridyl)-5-(2-bromo-5- methoxyphenyl)- 1 ,2,4-oxadiazole; ■ or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for the inhibition of transient lower esophageal sphincter relaxations (TLESRs).
2. Use of a compound of formula II as defined in claim 1, or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for the treatment of gastro-esophageal reflux disease (GERD).
3. Use of a compound of formula II as defined in claim 1, or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for the prevention of reflux.
4. Use of a compound of formula II as defined in claim 1, or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for the treatment of, or prevention of, regurgitation.
5. Use of a compound of formula LT as defined in claim 1, or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for the treatment of, or prevention of, asthma.
6. Use according to claim 5, wherein the asthma is reflux-related asthma.
7. Use of a compound of formula LT as defined in claim 1, or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for the treatment of, or prevention of, laryngitis.
8. Use of a compound of formula LT as defined in claim 1, or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for the treatment of, or prevention of, lung disease.
9. Use of a compound of formula LT as defined in claim 1 , or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for managing failure to thrive.
10. Use according to any one of the preceding claims, wherein the compound of formula II is selected from the group of compounds consisting of 3-(2-pyridyl)-5- (3, 5-dichlorophenyl)- 1,2,4-oxadiazole, 3-(2-pyridyl)-5-(3-chlorophenyl)-l,2,4- oxadiazole, 3-(2-pyridyl)-5-(3-methoxyphenyl)-l ,2,4-oxadiazole, 3-(2-pyridyl)-5- (2-chlorophenyl)- 1,2,4-oxadiazole, 3-(2-pyridyl)-5-[3- (trifluoromethyl)phenyl]- 1,2,4-oxadiazole, 3-(2-pyridyl)-5-(3-methylphenyl)-l,2,4-oxadiazole, 3-(2- pyridyl)-5-(l-naρhthyl)-l,2,4-oxadiazole, 3-(2-pyridyl)- 5-[3- (trifluoromethoxy)phenyl]-l,2,4-oxadiazole, 3-(2-pyridyl)-5-(2,3-difluorophenyl)- 1,2,4-oxadiazole, 3-(2-pyridyl)-5-(2,5-difluorophenyl)-l,2,4-oxadiazole, 3-(2- pyridyl)-5-(3,5-difluorophenyl)-l ,2,4-oxadiazole, 3-(2-pyridyl)-5-(3- cyanophenyl)- 1,2,4-oxadiazole, 3-(2-pyridyl)-5-(3,5-dimethoxyphenyl)-l,2,4- oxadiazole, 3-(2-pyridyl)-5-(2,3-dichlorophenyl)-l,2,4-oxadiazole, 3-(2-pyridyl)- 5-(3-chloro-5-cyanophenyl)- 1,2,4-oxadiazole, 3-(2-pyridyl)-5-(3-fluoro-5- cyanophenyl)- 1,2,4-oxadiazole, 3-(2-pyridyl)-5-(3-chloro-5-fluorophenyl)-l,2,4- oxadiazole, 3-(5-chloropyrid-2-yl)-5-(3-cyanophenyl)-l,2,4-oxadiazole, 3-(5- fluoropyrid-2-yl)-5-(3-cyanophenyl)- 1 ,2,4-oxadiazole, 3-(5-fluoropyrid-2-yl)-5- (3-cyano-5-fluorophenyl)- 1,2,4-oxadiazole, 3-(3-fluoropyrid-2-yl)-5-(3- cyanophenyl)-l,2,4-oxadiazole, 3-(5-fluoropyrid-2-yl)-5-(3,5-dimethoxyphenyl)- 1,2,4-oxadiazole, 3-(5-methoxypyrid-2-yl)-5-(3-cyanophenyl)-l,2,4-oxadiazole, 3-(2-quinolinyl)-5-(3-cyanophenyl)- 1 ,2,4-oxadiazole, 3-(3-chloro-5- trifluoromethylpyrid-2-yl)-5-(3-cyanophenyl)-l,2,4-oxadiazole, 3-(2-pyridyl)-5- (5-chloro-2-methoxyρhenyl)- 1,2,4-oxadiazole, 3-(2-pyridyl)-5-(2-chloro-5- methylthiophenyl)- 1 ,2,4-oxadiazole, 3-(2-pyridyl)-5-(2-bromo-5- methoxyphenyl)-l ,2,4-oxadiazole, 3-(2-pyridyl)-5-(2,5,6- trifluorophenyl)-l ,2,4- oxadiazole, 2-(3-chlorophenyl)-4-(pyridin-2-yl)-l,3-oxazole and 3-(2-pyridyl)-5- (2,5, 6-trifluorophenyl)- 1,2,4-oxadiazole, 3-(2-pyridyl)-5-(3-nitrophenyl)- 1,2,4- oxadiazole, 3-(2-pyridyl)-5-(3-bromophenyl)- 1,2,4-oxadiazole and pharmaceutically acceptable salts or optical isomers thereof.
11. Use according to any one of the preceding claims, wherein the compound of formula LT is selected from the group of compounds consisting of 2-(3,5- dichlorophenyl)-4-(2-pyridyl)- 1,3-oxazole, 2-(3-chlorophenyl)-4-(2-pyridyl)-l,3- oxazole, 2-(3-methoxyphenyl)-4-(2-pyridyl)-l,3-oxazole, 2-(2-chlorophenyl)- 4- (2-pyridyl)-l ,3-oxazole, 2-(3-trifluorophenyl)-4- (2-pyridyl)- 1 ,3-oxazole, 2-(3- methylphenyl)-4-(2-pyridyl)-l,3-oxazole, 2-(l-naphthyl)-4-(2-pyridyl)-l,3- oxazole, 2-(3-trifluoromethoxyphenyl)-4-(2-pyridyl)-l,3-oxazole, 2-(2,3- difluorophenyl)-4-(2-pyridyl)-l ,3-oxazole, 2-(2,5-difluorophenyl)-4-(2-pyridyl)-
1,3-oxazole, 2-(3,5-difluorophenyl)-4-(2-pyridyl)-l,3-oxazole, 2-(3- cyanophenyl)-4-(2-pyridyl)-l,3-oxazole, 2-(3,5-dimethoxyphenyl)-4-(2-pyridyl)- 1 ,3-oxazole, 2-(2,3-dichlorophenyl)-4-(2-pyridyl)-l,3-oxazole, 2-(3-chloro-5- cyanophenyl)-4-(2-pyridyl)-l,3-oxazole, 2-(3-fluoro-5-cyanophenyl)-4-(2- pyridyl)- 1,3-oxazole, 2-(3-chloro-5-fluorophenyl)-4-(2-pyridyl)-l,3-oxazole, 2-(3- cyanophenyl)-4-(5-chloropyrid-2-yl)-l,3-oxazole, 2-(3-cyanophenyl)-4-(5- fluoropyrid-2-yl)-l,3-oxazole, 2-(3-cyano-5-fluorophenyl)-4-(5-fluoropyrid-2-yl)- 1,3-oxazole, 2-(3-cyanophenyl)-4-(3-fluoropyrid-2-yl)-l,3-oxazole, 2-(3,5- dimethoxyphenyl)-4-(5-fluoropyrid-2-yl)- 1,3-oxazole, 2-(3-cyanoρhenyl)-4-(5- methoxypyrid-2-yl)-l,3- oxazole, 2-(3-cyanophenyl)-4-(2-quinolinyl)-l,3-oxazole,
2-(3-cyanophenyl)-4-(3-chloro-5-trifluoromethylρyrid-2-yl)- 1 ,3-oxazole, 2-(5- chloro-2-methoxyphenyl)-4-(2-pyridyl)- 1 ,3-oxazole, 2-(2-chloro-5- methylthiophenyl)-4-(2-pyridyl)-l,3-oxazole, 2-(2-bromo-5-methoxyphenyl)-4- (2-pyridyl)- 1,3-oxazole, 2-(2,5,6-trifluorophenyl)-4-(2-pyridyl)-l,3-oxazole, 2-(3- chlorophenyl)-4-(pyridin-2-yl)- 1,3-oxazole and 2-(2,5,6-trifluorophenyl)-4-(2- pyridyl)- 1,3-oxazole, 2-(3-nitrophenyl)-4-(2-pyridyl)-l,3-oxazole, 2-(3- bromophenyl)-4-(2-pyridyl)-l,3-oxazole, 3-(2-pyridyl)-5-(2,3-dimethoxyphenyl)- 1,2,4-oxadiazole, 3-(2-pyridyl)-5-(3-phenoxyphenyl)- 1,2,4-oxadiazole, 3-(2- pyridyl)-5-(3-benzoylphenyl)-l,2,4-oxadiazole, 3-(2-pyridyl)-5-(2-chloro-5- (trifluoromethyl)phenyl)- 1,2,4-oxadiazole, 3-(2-pyridyl)-5-(3,4,5- trifluorophenyl)- 1,2,4-oxadiazole, 3-(3-methoxyphenyl)-5-(2-pyridyl)-l,2,4- oxadiazole, 3-(pyrid-2-yl)-5-(2-hydroxyphenyl)- 1,2,4-oxadiazole, 3-(2-pyridyl)-5- (5-chloro-2-hydroxyphenyl)- 1 ,2,4-oxadiazole, 3-(2-pyridyl)-5-(2-aminophenyl)- 1,2,4-oxadiazole, 2-(3-bromophenyl)-4-(pyridin-2-yl)- 1,3-oxazole, 2-(3- cyanophenyl)-4-(pyridin-2-yl)- 1 ,3-oxazole, 5-(3-hydroxyphenyl)-3-(pyridine-2- yl)-l,2-oxazole, 5-(3-cyanophenyl)-3-(pyridin-2-yl)-l,2-oxazole, 3-(2-pyridyl)-5- (3-iodophenyl)-l,2,4-triazole, 3-(2-pyridyl)-5-(5-chloro-2-aminophenyl)- 1,2,4- oxadiazole and pharmaceutically acceptable salts or optical isomers thereof.
12. A method for the inhibition of transient lower esophageal sphincter relaxations s (TLESRs), whereby a pharmaceutically and pharmacologically effective amount of a compound of formula II
Figure imgf000018_0001
wherein 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; Ar1 and Ar2o 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, I- naphthyl, 2-naphthyl, fluorenyl, anthrenyl, indenyl, phenanthrenyl, and benzonaphthenyl, wherein the Ar1 and Ar2 moietiess are optionally substituted with one or more moieties selected from the group consisting of -F, -Cl, -Br, -I, -OR, -SR, -SOR, -SO2R, -SO2NRR', -OCOR, - OCONRR', -NRCOR', -NRCO2R', -CN, -NO2, -CO2R, -CONRR', -C(O)R, - CH(OR)R', -CH2(OR), -R, and -A-(CH2)-NRR'; wherein R or R' is selected from the group consisting of H, CF3, C^ o alkyl, cycloalkyl, alkyl-aryl, alkyl-0 heteroaryl, heterocycloalkyl, aryl and where R and R' may combine to form a ring, and A is defined as CH2, 0, NH, S, SO, SO2 and n is 1, 2, 3, or 4, with the proviso that the compound is not 3-(2-Pyridyl)-5-(2-nitrophenyl)-l,2,4- oxadiazole, 3-(2-Pyridyl)-5-(2-chlorophenyl)-l,2,4-oxadiazole, 3-(2-Pyridyl)-5- (3- methoxyphenyl)- 1,2,4-oxadiazole, 3-(2-Pyridyl)-5-[3-5 (trifluoromethyl)phenyl]-l,2,4-oxadiazole, 3-(2-Pyridyl)-5-(2-bromo-5- methoxyphenyl)- 1,2,4-oxadiazole; or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such inhibition.
13. A method for the treatment of gastro-esophageal reflux disease (GERD), whereby a pharmaceutically and pharmacologically effective amount of a compound of formula II as defined in claim 12, or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such treatment.
14. A method for the prevention of reflux, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula II as defined in claim 12, or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such prevention.
15. A method for the treatment of, or prevention of, regurgitation, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula II as defined in claim 12, or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such treatment or prevention.
16. A method for the prevention of, or treatment of, lung disease, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula II as defined in claim 12, or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such treatment or prevention.
17. A method for managing failure to thrive, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula LT as defined in claim 12, or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such management.
18. A method for treatment or prevention of asthma, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula II as defined in claim 12, or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such treatment or prevention.
19. A method according to claim 18, wherein the asthma is reflux-related asthma.
20. A method for treatment or prevention of laryngitis, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula II as defined in claim 12, or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such treatment or prevention.
21. A method according to any one of claims 12-20, wherein the compound of formula II is selected from the group of compounds consisting of 3-(2-pyridyl)-5- (3,5-dichlorophenyl)-l,2,4-oxadiazole, 3-(2-pyridyl)-5-(3-chlorophenyl)-l,2,4- oxadiazole, 3-(2-pyridyl)-5-(3-methoxyphenyl)-l,2,4-oxadiazole, 3-(2-pyridyl)-5- (2-chlorophenyl)- 1 ,2,4-oxadiazole, 3-(2-pyridyl)-5-[3-(trifluoromethyl)phenyl]- 1,2,4-oxadiazole, 3-(2-pyridyl)-5-(3-methylphenyl)-l,2,4-oxadiazole, 3-(2- ρyridyl)-5-(l-naphthyl)-l,2,4-oxadiazole, 3 -(2-pyridyl)- 5-[3- (trifluoromethoxy)phenyl]-l,2,4-oxadiazole, 3-(2-pyridyl)-5-(2,3-difluorophenyl)- 1,2,4-oxadiazole, 3-(2-pyridyl)-5-(2,5-difluorophenyl)- 1,2,4-oxadiazole, 3-(2- pyridyl)-5-(3,5-difluorophenyl)-l,2,4~oxadiazole, 3-(2-pyridyl)-5-(3- cyanophenyl)- 1,2,4-oxadiazole, 3-(2-pyridyl)-5-(3,5-dimethoxyphenyl)-l,2,4- oxadiazole, 3-(2-pyridyl)-5-(2,3-dichlorophenyl)-l,2,4-oxadiazole, 3-(2-pyridyl)- 5-(3-chloro-5-cyanophenyl)-l,2,4-oxadiazole, 3-(2-pyridyl)-5-(3-fluoro-5- cyanophenyl)-l ,2,4-oxadiazole, 3-(2-pyridyl)-5-(3-chloro-5-fluorophenyl)-l ,2,4- oxadiazole, 3-(5-chloropyrid-2-yl)-5-(3-cyanophenyl)-l ,2,4-oxadiazole, 3-(5- fluoropyrid-2-yl)-5-(3-cyanophenyl)- 1 ,2,4-oxadiazole, 3-(5-fluoropyrid-2-yl)-5- (3-cyano-5-fluorophenyl)-l,2,4-oxadiazole, 3-(3-fluoropyrid-2-yl)-5-(3- cyanophenyl)- 1,2,4-oxadiazole, 3-(5-fluoropyrid-2-yl)-5-(3,5-dimethoxyphenyl)- 1,2,4-oxadiazole, 3-(5-methoxypyrid-2-yl)-5-(3-cyanophenyl)-l,2,4-oxadiazole, 3-(2-quinolinyl)-5-(3-cyanophenyl)-l,2,4-oxadiazole, 3-(3-chloro-5- trifluoromethylpyrid-2-yl)-5-(3-cyanophenyl)-l,2,4-oxadiazole, 3-(2-pyridyl)-5- (5-chloro-2-methoxyphenyl)- 1,2,4-oxadiazole, 3-(2-pyridyl)-5-(2-chloro-5- methylthiophenyl)-l ,2,4-oxadiazole, 3-(2-pyridyl)-5-(2-bromo-5- methoxyphenyl)- 1,2,4-oxadiazole, 3-(2-pyridyl)-5-(2,5,6- trifluorophenyl)-l,2,4- oxadiazole, 2-(3-chlorophenyl)-4-(pyridin-2-yl)- 1,3-oxazole and 3-(2-pyridyl)-5- (2,5, 6-trifluorophenyl)- 1,2,4-oxadiazole, 3-(2-pyridyl)~5-(3-nitrophenyl)-l,2,4- oxadiazole, 3-(2-pyridyl)-5-(3-bromophenyl)- 1,2,4-oxadiazole and pharmaceutically acceptable salts or optical isomers thereof.
22. A method according to any one of claims 12-20, wherein the compound of formula II is selected from the group of compounds consisting of 2-(3,5- dichlorophenyl)-4-(2-pyridyl)-l,3-oxazole, 2-(3-chlorophenyl)-4-(2-pyridyl)-l,3- oxazole, 2-(3-methoxyphenyl)-4-(2-pyridyl)-l,3-oxazole, 2-(2-chlorophenyl)- 4- (2-pyridyl)-l,3-oxazole, 2-(3-trifluorophenyl)-4-(2-pyridyl)- 1,3-oxazole, 2-(3- methylρhenyl)-4-(2-ρyridyl)-l ,3-oxazole, 2-(l-naphthyl)-4-(2-pyridyl)- 1 ,3- oxazole, 2-(3- trifluoromethoxyphenyl)-4-(2-pyridyl)-l,3-oxazole, 2-(2,3- difluorophenyl)- 4-(2-pyridyl)- 1,3-oxazole, 2-(2,5-difluorophenyl)-4-(2-pyridyl)- 1,3-oxazole, 2-(3,5-difluorophenyl)-4-(2- pyridyl)- 1,3-oxazole, 2-(3- cyanophenyl)-4-(2-pyridyl)-l,3-oxazole, 2-(3,5-dimethoxyphenyl)-4-(2-pyridyl)- 1 ,3-oxazole, 2-(2,3-dichlorophenyl)-4-(2-pyridyl)-l ,3-oxazole, 2-(3-chloro-5- cyanophenyl)-4-(2-pyridyl)-l,3-oxazole, 2-(3-fluoro-5-cyanophenyl)-4-(2- pyridyl)-l,3-oxazole, 2-(3-chloro-5-fluorophenyl)-4-(2-pyridyl)-l,3-oxazole, 2-(3- cyanophenyl)-4-(5-chloropyrid-2-yl)- 1 ,3-oxazole, 2-(3~cyanophenyl)-4-(5- fluoropyrid-2-yl)- 1,3-oxazole, 2-(3-cyano-5-fluorophenyl)-4-(5- fluoropyrid-2- yl)- 1,3-oxazole, 2-(3-cyanophenyl)-4-(3-fluoropyrid-2-yl)-l,3-oxazole, 2-(3,5- dimethoxyphenyl)-4-(5-fluoropyrid-2-yl)-l,3-oxazole, 2-(3-cyanophenyl)-4-(5- methoxypyrid-2-yl)-l,3-oxazole, 2-(3-cyanophenyl)-4-(2-quinolinyl)-l,3-oxazole, 2-(3-cyanophenyl)-4-(3-chloro-5- trifluoromediylpyrid-2-yl)- 1,3-oxazole, 2-(5- chloro-2-methoxyphenyl)-4-(2- pyridyl)-l,3-oxazole, 2-(2-chloro-5- methylthiophenyl)-4-(2-pyridyl)-l,3-oxazole, 2-(2- bromo-5-methoxyphenyl)-4- (2-pyridyl)- 1,3 -oxazole, 2-(2,5,6-trifluorophenyl)-4-(2- pyridyl)-l,3-oxazole, 2- [3-chlorophenyl]-4-[pyridin-2-yl]-l,3-oxazole and 2-(2,5,6- trifluorophenyl)-4-(2- pyridyl)- 1,3-oxazole, 2-(3-nitrophenyl)-4-(2-pyridyl-l,3-oxazole, 2-(3- bromophenyl)-4-(2- pyridyl)-l,3-oxazole, 3-(2-pyridyl)-5-(2,3-dimethoxyphenyl)- 1 ,2,4-oxadiazole, 3-(2-pyridyl)-5-(3-phenoxyphenyl)-l ,2,4-oxadiazole, 3-(2- pyridyl)-5-(3-benzoylphenyl)- 1 ,2,4-oxadiazole, 3-(2-pyridyl)-5-(2-chloro-5- (trifluoromethyl)phenyl)- 1,2,4-oxadiazole, 3-(2-pyridyl)-5-(3,4,5- trifluorophenyl)- 1,2,4-oxadiazole, 3-(3-methoxyphenyl)-5-(2-pyridyl)-l,2,4- oxadiazole, 3-(pyrid-2-yl)-5-(2-hydroxyphenyl)-l,2,4-oxadiazole, 3-(2-pyridyl)-5- (5-chloro-2-hydroxyphenyl)- 1 ,2,4-oxadiazole, 3-(2-pyridyl)~5-(2-aminophenyI)- 1,2,4-oxadiazole, 2-[3-bromophenyl]-4-[pyridin-2-yl]-l,3-oxazole, 2-(3- cyanophenyl)-4-(pyridin-2-yl)-l,3-oxazole, 5-[3-hydroxyphenyl]-3-[pyridine-2- yl]-l,2-oxazole, 5-[3-cyanophenyl]-3-[pyridin-2-yl]-l,2-oxazole, 3-(2-pyridyl)-5- (3-iodophenyl)-l,2,4-triazole, 3-(2-pyridyl)-5-(5-chloro-2-aminophenyl)- 1,2,4- oxadiazole and pharmaceutically acceptable salts or optical isomers thereof.
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1053825A (en) * 1963-03-22
US3647809A (en) * 1968-04-26 1972-03-07 Chinoin Gyogyszer Es Vegyeszet Certain pyridyl-1 2 4-oxadiazole derivatives
EP0328200A1 (en) * 1988-02-12 1989-08-16 Merck Sharp & Dohme Ltd. Five-membered ring systems with bonded azacyclic ring substituents
DE4320801A1 (en) * 1993-06-23 1995-01-05 Fahlberg List Pharma Gmbh 2-Hydroxyphenyl-substituted 1,2,4-triazoles and 1,2,4-oxadiazoles, their use as pharmaceutical agents and pharmaceutical compositions containing them
US5627200A (en) * 1994-09-26 1997-05-06 Pfizer Inc β3 -Adrenoceptor agonists and antagonists for the treatment of intestinal motility disorders, depression, prostate disease and dyslipidemia
EP0795328A1 (en) * 1996-03-15 1997-09-17 Pfizer Inc. Use of naphthalene derivatives in treating lung carcinoma
WO2001012627A1 (en) * 1999-08-19 2001-02-22 Nps Pharmaceuticals, Inc. Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
WO2001085723A1 (en) * 2000-05-08 2001-11-15 James Black Foundation Limited Gastrin and cholecystokinin receptor ligands (ii)
US6495578B1 (en) * 1999-04-19 2002-12-17 Shionogi & Co., Ltd. Sulfonamide derivatives having oxadiazole rings
WO2002100826A2 (en) * 2001-06-08 2002-12-19 Cytovia, Inc. Substituted 3-aryl-5-aryl-[1,2,4]-oxadiazoles and analogs
US20030055085A1 (en) * 1999-08-19 2003-03-20 Wagenen Bradford Van Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
WO2003061567A2 (en) * 2002-01-18 2003-07-31 Merck & Co., Inc. Selective s1p1/edg1 receptor agonists
US20030158155A1 (en) * 2000-04-28 2003-08-21 Yozo Hori Mmp-12 inhibitors
WO2004000316A1 (en) * 2002-06-20 2003-12-31 Astrazeneca Ab Use of mglur5 antagonists for the treatment of gerd

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4219810B2 (en) * 2001-10-26 2009-02-04 塩野義製薬株式会社 Sulfonamide derivatives having MMP inhibitory action

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1053825A (en) * 1963-03-22
US3647809A (en) * 1968-04-26 1972-03-07 Chinoin Gyogyszer Es Vegyeszet Certain pyridyl-1 2 4-oxadiazole derivatives
EP0328200A1 (en) * 1988-02-12 1989-08-16 Merck Sharp & Dohme Ltd. Five-membered ring systems with bonded azacyclic ring substituents
DE4320801A1 (en) * 1993-06-23 1995-01-05 Fahlberg List Pharma Gmbh 2-Hydroxyphenyl-substituted 1,2,4-triazoles and 1,2,4-oxadiazoles, their use as pharmaceutical agents and pharmaceutical compositions containing them
US5627200A (en) * 1994-09-26 1997-05-06 Pfizer Inc β3 -Adrenoceptor agonists and antagonists for the treatment of intestinal motility disorders, depression, prostate disease and dyslipidemia
EP0795328A1 (en) * 1996-03-15 1997-09-17 Pfizer Inc. Use of naphthalene derivatives in treating lung carcinoma
US6495578B1 (en) * 1999-04-19 2002-12-17 Shionogi & Co., Ltd. Sulfonamide derivatives having oxadiazole rings
WO2001012627A1 (en) * 1999-08-19 2001-02-22 Nps Pharmaceuticals, Inc. Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
US20030055085A1 (en) * 1999-08-19 2003-03-20 Wagenen Bradford Van Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
US20030158155A1 (en) * 2000-04-28 2003-08-21 Yozo Hori Mmp-12 inhibitors
WO2001085723A1 (en) * 2000-05-08 2001-11-15 James Black Foundation Limited Gastrin and cholecystokinin receptor ligands (ii)
WO2002100826A2 (en) * 2001-06-08 2002-12-19 Cytovia, Inc. Substituted 3-aryl-5-aryl-[1,2,4]-oxadiazoles and analogs
WO2003061567A2 (en) * 2002-01-18 2003-07-31 Merck & Co., Inc. Selective s1p1/edg1 receptor agonists
WO2004000316A1 (en) * 2002-06-20 2003-12-31 Astrazeneca Ab Use of mglur5 antagonists for the treatment of gerd

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch, Week 200339 Derwent Publications Ltd., London, GB; Class B05, AN 2003-421390 XP002324067 & WO 03/035610 A1 (SHIONOGI & CO LTD) 1 May 2003 (2003-05-01) *
PANCECHOWSKA-KSEPKO D ET AL: "ÄStudies of pyrazine derivatives. XVII. Synthesis and the tuberculostatic activity of pyrazinyl-1,3,4-oxadiazole derivativesÜ" ACTA POLONIAE PHARMACEUTICA. 1986, vol. 43, no. 2, 1986, pages 116-123, XP008045320 ISSN: 0001-6837 *
PANCECHOWSKA-KSEPKO D ET AL: "ÄStudies of pyrazine derivatives. XX. Synthesis and tuberculostatic activity of 3-pyrazinol-1,2,4-oxadiazole derivativesÜ" ACTA POLONIAE PHARMACEUTICA. 1986, vol. 43, no. 3, 1986, pages 211-217, XP008045321 ISSN: 0001-6837 *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8796322B2 (en) 2003-04-11 2014-08-05 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
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
US10071081B2 (en) 2003-04-11 2018-09-11 Ptc Therapeutics, Inc. Compositions of 1,2,4-oxadiazole benzoic acid compounds and methods for their use
US8299105B2 (en) 2003-04-11 2012-10-30 Ptc Therapeutics, Inc. 1,2,4-oxadiazole benzoic acid compositions and their use in bioassays
US8486982B2 (en) 2003-04-11 2013-07-16 Ptc Therapeutics, Inc. 1,2,4-oxadiazole benzoic acids
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
US8975287B2 (en) 2003-04-11 2015-03-10 Ptc Therapeutics, Inc. Methods for using 1,2,4-Oxadiazole benzoic acid compounds
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
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
US9861617B2 (en) 2003-04-11 2018-01-09 Ptc Therapeutics, Inc. Compositions of 1,2,4-oxadiazole benzoic acid compounds and methods for their use
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
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US10233161B2 (en) 2014-03-06 2019-03-19 Ptc Therapeutics, Inc. Pharmaceutical compositions and salts of a 1,2,4-oxadiazole benzoic acid
US10618877B2 (en) 2014-03-06 2020-04-14 Ptc Therapeutics, Inc. Pharmaceutical compositions and salts of a 1,2,4-oxadiazole benzoic acid
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