WO2005077368A2 - Treatment of gastro-esophageal reflux disease (gerd) - Google Patents

Treatment of gastro-esophageal reflux disease (gerd) Download PDF

Info

Publication number
WO2005077368A2
WO2005077368A2 PCT/US2005/000334 US2005000334W WO2005077368A2 WO 2005077368 A2 WO2005077368 A2 WO 2005077368A2 US 2005000334 W US2005000334 W US 2005000334W WO 2005077368 A2 WO2005077368 A2 WO 2005077368A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
oxadiazol
ylmethyl
benzonitrile
piperidin
Prior art date
Application number
PCT/US2005/000334
Other languages
French (fr)
Other versions
WO2005077368A3 (en
Inventor
Anders Lehmann
Jan Mattsson
Karolina Nilsson
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 WO2005077368A2 publication Critical patent/WO2005077368A2/en
Publication of WO2005077368A3 publication Critical patent/WO2005077368A3/en

Links

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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • 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
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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

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 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.
  • GGERD gastro-esophageal reflux disease
  • the present invention is directed to the use of compounds of formula I
  • P is selected from the group consisting of C 3 . 7 alkyl and a 3- to 8-membered ring containing one or more atoms independently selected from C, N, O or S, wherein said ring may be fused with a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S;
  • R 1 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, - ⁇ alkylhalo, Q£ ⁇ . 6 alkylhalo, C . 6 alkenyl, OC 2 . 6 alkenyl, C 2 . 6 alkynyl, OC 2 . 6 alkynyl, C 0 - 6 alkylC 3 .
  • M 1 is selected from the group consisting of a bond, d ⁇ alkyl, C 2 . 3 alkenyl, C 2 - 3 alkynyl, C 0 - 4 alkyl(CO)C 0 . 4 alkyl, C 0 . 3 alkylOCo- 3 alkyl, C 0 . 3 alkyl(CO)NR 8 , C 0 .
  • R is selected from the group consisting of hydrogen, C 0 - 3 alkyl, halo, Co- 3 alkylOR 5 , C 0 . 3 alkylNR 5 R 6 , C 0 . 3 alkyl(CO)OR 5 , C 0 . 3 alkylNR 5 R 6 and C 0 . 3 alkylaryl;
  • M 2 is selected from the group consisting of a bond, C M alkyl, C 2 . 3 alkenyl, C 2 . 3 alkynyl 5 C 0 .
  • Q is a 4-, 5-, 6- or 7-membered ring containing one or more heteroatoms independently selected from N, O or S, wherein said ring may be fused with a 3-, 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S, and wherein the fused ring may be substituted by one or more A;
  • X is selected from the group consisting of C, CR and N;
  • M 3 is selected from the group consisting of a bond, C 1 . 4 alkyl, Co- 4 alkyl(CO)C 0 . 4 alkyl, C 0 .
  • G is selected from the group consisting of R and R ;
  • R 6 is selected from the group consisting of hydrogen and a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S, wherein said ring may be fused with a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S, and wherein any of the rings may be substituted by one or more A;
  • R 8 and R 9 are independently selected from hydrogen, d. 6 alkyl, Co- 6 alkylC 3 _ 6 cycloalkyl, C 0 .
  • 6 alkylheteroary and 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S as defined under R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 may be substituted by one or more A;
  • A is selected from the group consisting of hydrogen, hydroxy, oxo, halo, nitro, d- ⁇ alkyl, Cn. 6 alkylC 3 . 6 cycloalkyl, d- 6 alkylhalo, Od- ⁇ alkylhalo, C 2 . 6 alkenyl, Od- 6 alkyl, Co.
  • TLESRs transient lower esophageal sphincter relaxations
  • alkyl includes both straight and branched chain alkyl groups and may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl or i-hexyl, t-hexyl.
  • d- 3 alkyl refers to an alkyl group having 1 to 3 carbon atoms, and may be methyl, ethyl, n-propyl or i-propyl.
  • cycloalkyl refers to an optionally substituted, saturated cyclic hydrocarbon ring system.
  • C 3 . cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • alkenyl includes both straight and branched chain alkenyl groups.
  • C 2 - 6 alkenyl refers to an alkenyl group having 2 to 6 carbon atoms and one or two double bonds, and may be, but is not limited to vinyl, allyl, propenyl, i-propenyl, butenyl, i-butenyl, crotyl, pentenyl, i-pentenyl or hexenyl.
  • alkynyl includes both straight and branched chain alkynyl groups.
  • C 2 - 6 alkynyl refers to a group having 2 to 6 carbon atoms and one or two triple bonds, and may be, but is not limited to ethynyl, propargyl, butynyl, i-butynyl, pentynyl, i-pentynyl or hexynyl.
  • aryl refers to an optionally substituted monocyclic or bicyclic hydrocarbon ring system containing at least one unsaturated aromatic ring. Examples and suitable values of the term “aryl” are phenyl, naphthyl, 1,2,3, 4-tetrahydronaphthyl, indyl and indenyl.
  • heteroaryl refers to an optionally substituted, unsaturated cyclic hydrocarbon ring system comprising at least one heteroatom and includes, but is not limited to furyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, imidazolyl, imidazolinyl, pyrazolinyl, tetrahydropyranyl.
  • the term "5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S” includes aromatic and heteroaromatic rings as well as carbocyclic and heterocyclic rings which may be saturated or unsaturated.
  • Such rings may be, but are not limited to furyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl, imidazolyl, imidazohdinyl, imidazolinyl, triazolyl, morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, thiomorpholinyl, phenyl, cyclohexyl, cyclopentyl or cyclohexenyl.
  • 3- to 8-membered ring containing one or more atoms independently selected from C, N, O or S includes aromatic and heteroaromatic rings as well as carbocyclic and heterocyclic rings which may be saturated or unsaturated.
  • rings may be, but are not limited to imidazohdinyl, imidazolinyl, morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl or thiomorpholinyl, tetrahydrothiopyranyl, furyl, pyrrolyl, isoxazolyl, isothiazolyl, oxazolyl, oxazolidinonyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl, imidazolyl, triazolyl, phenyl, cyclopropyl, aziridinyl, cyclobutyl, azetidinyl, cyclopent,
  • the term "3- to 8-membered ring containing one or more atoms independently selected from C, N, O or S, which group may optionally be fused with a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S” includes aromatic and heteroaromatic rings as well as carbocyclic and heterocyclic rings which may be saturated or unsaturated.
  • rings may be, but are not limited to naphthyl, norcaryl, chromyl, isochromyl, indanyl, benzoimidazol or tetralinyl, benzooxazolyl, benzothiazolyl, benzofuryl, benzothienyl, benzotriazolyl, indolyl, azaindolyl, indazolyl, indolinyl, isoindolinyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, quinolinyl, quinoxalinyl, benzotriazolyl.
  • the term "4-, 5-, 6- or 7-membered ring containing one or more heteroatoms independently selected from N, O or S, wherein said ring may be fused with a 3-, 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S” includes aromatic and heteroaromatic rings as well as carbocyclic and heterocyclic rings which may be saturated or unsaturated.
  • Such rings may be, but are not limited ' to pyridinyl, thiazolyl, benzoimidazolyl, quinolinyl, imidazolyl, oxadiazolyl, benzothiazolyl, pyrimidinyl, isoxazole, pyrazine, imidazolidinyl, imidazolinyl, morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, thiomorpholinyl, naphthyl, indanyl or tetralinyl, phenyl, cyclohexyl, cyclopentyl, cyclohexenyl, cycloheptyl, cycloheptenyl, azetidinyl, homopiperazinyl or azepany
  • a subscript is the integer 0 (zero) the group to which the subscript refers to indicates that the group is absent, i.e. there is a direct bond between the groups.
  • bond may be a saturated or unsaturated bond.
  • halo may be fluoro, chloro, bromo or iodo.
  • alkylhalo means an alkyl group as defined above, which is substituted with one or more halo.
  • C ⁇ alkylhalo may include, but is not limited to fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, bromopropyl.
  • OC ⁇ alkylhalo may include, but is not limited to fluoromethoxy, difluororhethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy.
  • the compounds of formula I useful in accordance with the present invention may also be used as pharmaceutically acceptable salts, but also other salts may be useful in accordance with the present invention.
  • Examples of pharmaceutically acceptable salts useful in accordance with the present invention are, but are not limited to, hydrochloride, 4-aminobenzoate, anthranilate, 4-aminosalicylate, 4- hydroxybenzoate, 3,4-dihydroxybenzoate, 3-hydroxy-2-naphthoate, nitrate and trifluoroacetate.
  • Some compounds of formula I may have chiral centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses the use of all such optical, diastereoisomers and geometric isomers.
  • the invention also relates to the use of any and all tautomeric forms of the compounds of formula I.
  • a further aspect of the invention is the use of a compound formula I for the manufacture of a medicament for the prevention of reflux.
  • a further aspect of the invention is the use of a compound of formula I 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 I 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 I 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 I for the manufacture of a medicament for the treatment or prevention of asthma, such as reflux-related asthma.
  • a further aspect of the invention is the use of a compound according to formula I for the manufacture of a medicament for the treatment or prevention of functional gastrointestinal disorders, such as functional dyspepsia (FD).
  • FD functional dyspepsia
  • Yet another aspect of the invention is the use of a compound according to formula I for the manufacture of a medicament for the treatment or prevention of irritable bowel syndrome (IBS), such as constipation predominant IBS, diarrhea predominant IBS or alternating bowel movement predominant IBS.
  • IBS irritable bowel syndrome
  • 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 I is administered to a subject in need of such inliibition.
  • 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 I 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 I is administered to a subject in need of such treatment.
  • GFD 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 I 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 I is administered to a subject in need of such treatment.
  • TLESR transient lower esophageal sphincter relaxations
  • GFD gastro-esophageal reflux disease
  • the compounds of formula I are in accordance with the present invention suitably formulated into pharmaceutical foraiulations 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 I 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 I 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 I may be administered once or twice daily, depending on the severity of the patient's condition.
  • the compounds of formula I can be prepared as described in WO2004/014902 A2.
  • 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 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 (I) for the inhibition of transient lower esophageal sphincter relaxations. A further aspect of the invention is directed to the use of compounds of formula (I) for the treatment of gastro-esophageal reflux disease.

Description

NEW TREATMENT OF GERD III
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 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 I
Figure imgf000003_0001
(I) wherein:
P is selected from the group consisting of C3.7alkyl and a 3- to 8-membered ring containing one or more atoms independently selected from C, N, O or S, wherein said ring may be fused with a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S; R1 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, -βalkylhalo, Q£\. 6alkylhalo,
Figure imgf000003_0002
C .6alkenyl, OC2.6alkenyl, C2.6alkynyl, OC2.6alkynyl, C0- 6alkylC3.6cycloalkyl, OCo-6alkylC3.6cycloalkyl, C0-6alkylaryl, OC0.6alkylaryl, (CO)R8, O(CO)R8, O(CO)OR8, d.6alkylOR8, OC2.6alkylOR8, C1.6alkyl(CO)R8, OC1.6alkyl(CO)R8, C0.6alkylCO2R8, OC1.6alkylCO2R8, C0.6alkylcyano, OC2.6alkylcyano, C0.6alkylNR8R9, OC2.6alkylNR8R9, Cι_ 6alkyl(CO)NR8R9, OC1.6alkyl(CO)NR8R9, C0.6alkylNR8(CO)R9, OC2.6alkylNR8(CO)R9, C0. 6alkylNR8(CO)NR8R9, C0.6alkylSR8, OC2.6alkylSR8, C0.6alkyl(SO)R8, OC2.6alkyl(SO)R8, C0. 6alkylSO2R8, OC2.6alkylSO2R8, C0.6alkyl(SO2)NR8R9, OC2.6alkyl(SO2)NR8R9, C0. 6alkylNR8(SO2)R9, OC2.6alkylNR8(SO2)R9, C0.6alkylNR8(SO2)NR8R9, OC2. 6alkylNR8(SO2)NR8R9, (CO)NR8R9, O(CO)NR8R9, r 8OR9, C0.6alkylNR8(CO)OR9, OC0. 6alkylNR8(CO)OR9, SO3R8 and a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S, wherein said ring may be substituted by one or more A; M1 is selected from the group consisting of a bond, d^alkyl, C2.3alkenyl, C2-3alkynyl, C0- 4alkyl(CO)C0.4alkyl, C0.3alkylOCo-3alkyl, C0.3alkyl(CO)NR8, C0.3alkyl(CO)NR8C1.3alkyl, C0. 4alkylNR8R9, C0.3alkylSC0.3 alkyl, C0.3alkyl(SO)C0-3alkyl and C0.3alkyl(SO2)C0.3alkyl; R2 is selected from the group consisting of hydrogen, hydroxy, oxo, =NR8, =NOR8, Cj. 4alkylhalo, halo, CMalkyl, O(CO)C1.4alkyl, C1.4alkyl(SO)C0.4alkyl, C1.4alkyl(SO2)C0-4alkyl,
(SO)C0.4alkyl, (SO2)C0.4alkyl, OC1. alkyl, C0.4alkylcyano, C1.4alkylOR8 and C0.4alkyl R8R9;
X1, X2 and X3 are independently selected from N, NR, O, CR, =O and S;
R is selected from the group consisting of hydrogen, C0-3alkyl, halo, Co-3alkylOR5, C0. 3alkylNR5R6, C0.3alkyl(CO)OR5, C0.3alkylNR5R6 and C0.3alkylaryl;
M2 is selected from the group consisting of a bond, CMalkyl, C2.3alkenyl, C2.3alkynyl5 C0.
4alkyl(CO)C0.4alkyl, C0.3alkylOC0.3alkyl, C0.3alkylNR8C1-3alkyl, C0-3alkyl(CO)NR8, C0.
4alkylNR8R9, C0-3alkylSC0.3alkyl, C0.3alkyl(SO)C0.3 alkyl and Co-3alkyl(SO2)Co.3alkyl;
R3 is selected from the group consisting of hydrogen, hydroxy, oxo, =NR8, =NOR8, Q. 4alkylhalo, halo, C1.4alkyl, O(CO)C1.4alkyl, C1.4alkyl(SO)C0.4alkyl, C1.4alkyl(SO2)C0.4alkyl,
(SO)C0. alkyl, (SO2)C0.4alkyl, Od^alkyl, C0.4alkylcyano, C alkylOR8 and C0.4alkylNR8R9;
Q is a 4-, 5-, 6- or 7-membered ring containing one or more heteroatoms independently selected from N, O or S, wherein said ring may be fused with a 3-, 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S, and wherein the fused ring may be substituted by one or more A;
X is selected from the group consisting of C, CR and N;
R4 is selected from the group consisting of hydrogen, hydroxy, oxo, =NR8, =NOR8, Ci.
4alkylhalo, halo, CMalkyl, OC0.6alkylaryl, O(CO)C1.4alkyl, C1.4alkyl(SO)C0.4alkyl, d.
4alkyl(SO2)C0.4alkyl, (SO)C0. alkyl, (SO2)C0.4alkyl, OC^alkyl, C1.4alkylOR8, C0.4alkylcyano and C0.4alkylNR8R9;
M3 is selected from the group consisting of a bond, C1.4alkyl, Co-4alkyl(CO)C0.4alkyl, C0.
3alkylOC0-3alkyl, C0-4alkylNR8R9, Co.3alkylNR8C1.3alkyl, C0-3alkyl(CO)NR8, C0.3alkylSCo.3alkyl,
C0.3alkyl(SO)Co.3alkyl and C0.3alkyl(SO2)Co.3alkyl;
R5 is selected from the group consisting of hydrogen, hydroxy, oxo, =NR8, =NOR8, Cμ 4alkylhalo, halo, CMalkyl, O(CO)C1.4alkyl, CMalkyl(SO)C0-4alkyl, C1.4alkyl(SO2)C0.4alkyl,
(SO)C0.4alkyl, (SO2)C0.4alkyl, OC^alkyl, C0.4alkylcyano, Cι.4alkylOR8 and C0.4alkylNR8R9;
G is selected from the group consisting of R and R ;
R6 is selected from the group consisting of hydrogen and a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S, wherein said ring may be fused with a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S, and wherein any of the rings may be substituted by one or more A;
R7 is selected from the group consisting of hydrogen, C0.4alkylcyano, C=NR8(NR8R9),
C=NOR8(NR8R9), NR8C=NR8(NR8R9), NR8(C=CCN)(NR8R9), NR8(C=CNO2)(NR8R9), NR8(C=NCN)(NR8R9), CONR8R9 and NR8(CO)NR8R9; R8 and R9 are independently selected from hydrogen, d.6alkyl, Co-6alkylC3_6cycloalkyl, C0.6alkylaryl, Co-6alkylheteroaryl and a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S, and wherein R8 and R9 may together form a 5- or 6- membered ring containing one or more atoms independently selected from C, N, O or S; wherein any CMalkyl, C2.6alkenyl, C2.6alkynyl, Co-6alkylC3.6cycloalkyl, C0.6alkylaryl, C0.
6alkylheteroary and 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S as defined under R1, R2, R3, R4, R5, R6, R7, R8, and R9 may be substituted by one or more A; A is selected from the group consisting of hydrogen, hydroxy, oxo, halo, nitro, d-βalkyl, Cn. 6alkylC3.6cycloalkyl, d-6alkylhalo, Od-βalkylhalo, C2.6alkenyl, Od-6alkyl, Co.3alkylaryl, d- ealkylOR8, OC2.6alkylOR8, d-ealkylSR8, OC2.6alkylSR8, (CO)R8, O(CO)R8, OC2.6alkylcyano, C0.6alkylcyano, C0.6alkylCO2R8, Od.6alkylCO2R8, O(CO)OR8, Od.6alkyl(CO)R8, d- 6alkyl(CO)R8, NR8OR9, C0.6alkylNR8R9, OC2.6alkylNR8R9, C0.6alkyl(CO)NR8R9, Od- 6alkyl(CO)NR8R9, OC2.6alkylNR8(CO)R9, C0.6alkylNR8(CO)R9, C0.6alkylNR8(CO)NR8R9, O(CO)NR8R9, NR8(CO)OR9, C0.6alkyl(SO2)NR8R9, OC2.6alkyl(SO2)NR8R9, C0. 6alkyMR8(SO2)R9, OC2.6alkylNR8(SO2)R9, SO3R8, d.6alkylNR8(SO2)NR8R9, OC2. 6alkyl(SO2)R8, C0.6alkyl(SO2)R8, C0.6alkyl(SO)R8 and OC2-6alkyl(SO)R8; m is selected from 0, 1, 2, 3 or 4; and n is selected from 0, 1, 2 or 3;
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).
Listed below are definitions of various terms used in the specification and claims to describe the present invention.
For the avoidance of doubt it is to be understood that in this specification 'd-δ' means a carbon group having 1, 2, 3, 4, 5 or 6 carbon atoms.
In this specification, unless stated otherwise, the term "alkyl" includes both straight and branched chain alkyl groups and may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl or i-hexyl, t-hexyl. The term "d- 3alkyl" refers to an alkyl group having 1 to 3 carbon atoms, and may be methyl, ethyl, n-propyl or i-propyl. In this specification, unless stated otherwise, the term "cycloalkyl" refers to an optionally substituted, saturated cyclic hydrocarbon ring system. The term "C3. cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
In this specification, unless stated otherwise, the term "alkenyl" includes both straight and branched chain alkenyl groups. The term "C2-6alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms and one or two double bonds, and may be, but is not limited to vinyl, allyl, propenyl, i-propenyl, butenyl, i-butenyl, crotyl, pentenyl, i-pentenyl or hexenyl.
In this specification, unless stated otherwise, the term "alkynyl" includes both straight and branched chain alkynyl groups. The term "C2-6alkynyl" refers to a group having 2 to 6 carbon atoms and one or two triple bonds, and may be, but is not limited to ethynyl, propargyl, butynyl, i-butynyl, pentynyl, i-pentynyl or hexynyl.
The term "aryl" refers to an optionally substituted monocyclic or bicyclic hydrocarbon ring system containing at least one unsaturated aromatic ring. Examples and suitable values of the term "aryl" are phenyl, naphthyl, 1,2,3, 4-tetrahydronaphthyl, indyl and indenyl.
In this specification, unless stated otherwise, the term "heteroaryl" refers to an optionally substituted, unsaturated cyclic hydrocarbon ring system comprising at least one heteroatom and includes, but is not limited to furyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, imidazolyl, imidazolinyl, pyrazolinyl, tetrahydropyranyl.
In this specification, unless stated otherwise, the term "5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S" includes aromatic and heteroaromatic rings as well as carbocyclic and heterocyclic rings which may be saturated or unsaturated. Examples of such rings may be, but are not limited to furyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl, imidazolyl, imidazohdinyl, imidazolinyl, triazolyl, morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, thiomorpholinyl, phenyl, cyclohexyl, cyclopentyl or cyclohexenyl. In this specification, unless stated otherwise, the terms "3- to 8-membered ring containing one or more atoms independently selected from C, N, O or S" includes aromatic and heteroaromatic rings as well as carbocyclic and heterocyclic rings which may be saturated or unsaturated. Examples of such rings may be, but are not limited to imidazohdinyl, imidazolinyl, morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl or thiomorpholinyl, tetrahydrothiopyranyl, furyl, pyrrolyl, isoxazolyl, isothiazolyl, oxazolyl, oxazolidinonyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl, imidazolyl, triazolyl, phenyl, cyclopropyl, aziridinyl, cyclobutyl, azetidinyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl.
In this specification, unless stated otherwise, the term "3- to 8-membered ring containing one or more atoms independently selected from C, N, O or S, which group may optionally be fused with a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S" includes aromatic and heteroaromatic rings as well as carbocyclic and heterocyclic rings which may be saturated or unsaturated. Examples of such rings may be, but are not limited to naphthyl, norcaryl, chromyl, isochromyl, indanyl, benzoimidazol or tetralinyl, benzooxazolyl, benzothiazolyl, benzofuryl, benzothienyl, benzotriazolyl, indolyl, azaindolyl, indazolyl, indolinyl, isoindolinyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, quinolinyl, quinoxalinyl, benzotriazolyl.
In this specification, unless stated otherwise, the term "4-, 5-, 6- or 7-membered ring containing one or more heteroatoms independently selected from N, O or S, wherein said ring may be fused with a 3-, 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S" includes aromatic and heteroaromatic rings as well as carbocyclic and heterocyclic rings which may be saturated or unsaturated. Examples of such rings may be, but are not limited ' to pyridinyl, thiazolyl, benzoimidazolyl, quinolinyl, imidazolyl, oxadiazolyl, benzothiazolyl, pyrimidinyl, isoxazole, pyrazine, imidazolidinyl, imidazolinyl, morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, thiomorpholinyl, naphthyl, indanyl or tetralinyl, phenyl, cyclohexyl, cyclopentyl, cyclohexenyl, cycloheptyl, cycloheptenyl, azetidinyl, homopiperazinyl or azepanyl.
In this specification, unless stated otherwise, the term "=NR5" and "=NOR5" include imino- and oximogroups carrying an R5 substituent and may be, or be part of, groups including, but not limited to iminoalkyl, iminohydroxy, iminoalkoxy, amidine, hydroxyamidine, alkoxyamidine.
In the case where a subscript is the integer 0 (zero) the group to which the subscript refers to indicates that the group is absent, i.e. there is a direct bond between the groups.
In this specification, unless stated otherwise, the term "bond" may be a saturated or unsaturated bond.
In this specification, unless stated otherwise, the term "halo" may be fluoro, chloro, bromo or iodo.
In this specification, unless stated otherwise, the term "alkylhalo" means an alkyl group as defined above, which is substituted with one or more halo. The term "C ^alkylhalo" may include, but is not limited to fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, bromopropyl. The term "OC ^alkylhalo" may include, but is not limited to fluoromethoxy, difluororhethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy.
Specific examples of compounds useful according to the present invention include
3 - [5 -( 1 -Pyridin-2-ylmethyl-piperidin-2-yl)- [ 1 ,2,4] oxadiazol-3 -yl] -benzonitrile,
3-[3-(l-Pyridin-2-ylmethyl-piperidn-2-yl)-[l,2,4]oxadiazol-5-yl]-benzonitrile,
3-[5-(l-Thiazol-2-ylmethyl-piperidin-2-yl)-[l,2,4]oxadiazol-3-yl]-benzonitrile,
3 - { 5 - [ 1 -( 1 -Methyl- 1 H-imidazol-2-ylmethyl)-piperidin-2yl] -[1,2,4] oxadiazol-3 -yl } -benzonitrile, 3 - { 5-[ 1 -(6-Methyl-pyridin-2-ylmethyl)-piperidin-2-yl] - [ 1 ,2,4] oxadiazol-3 -yl} -benzonitrile, 3 - [3 -( 1 -Thiazol-2-ylmethyl-piperidin-2-yl)- [ 1,2,4] oxadiazol-5 -yl] -benzonitrile, 3 - [5 -( 1 -Thiazol-2-ylmethyl-pyrrolidin-2-yl)- [ 1,2,4] oxadiazol-3 -yl] -benzonitrile, 3- { 5-[ 1 -(5-Chloro-pyridin-2-ylmethyl)-piperidin-2-yl] - [ 1 ,2,4] oxadiazol-3 -yl } -benzonitrile, 2- [2-(5 -m-Tolyl- [ 1 ,2,4] oxadiazol-3 -yl)-piperidin- 1 -ylmethyl] -pyridine, 3-{5-[l-(5-Fluoro-pyridin-2-ylmethyl)-piperidin-2-yl]-[l,2,4]oxadiazol-3-yl}-benzonitrile, 3-[5S-(3-Pyridin-2-ylmethyl-thiazolidin-4-yl)-[l,2,4]oxadiazol-3-yl]-benzonitrile, 3 - { 5- [ 1 -(3 -Methyl-pyridin-2-ylmethyl)-piperidin-2-yl] -[1,2,4] oxadiazol-3 -yl } -benzonitrile, 3-{5-[l-(4-Methyl-pyridin-2-ylmethyl)-piperidin-2-yl]-[l,2,4]oxadiazol-3-yl}- benzonitrile, 3-{5-[l-(5-Methyl-pyridin-2-ylmethyl)-piperidin-2-yl]-[l,2,4]oxadiazol-3-yl}-benzonitrile3 3-{5-[l-(l-Methyl-lH-benzoimidazol-2-ylmethyl)-piperidin-2-yl]-[l,2,4]oxadiazol-3-yl}- benzonitrile,
3-[5-(6-Methyl-l-pyridin-2-ylmethyl-piperidin-2-yl)-[l,2,4]oxadiazol-3-yl]-benzonitrile, 3-[5-(4,4-Difluoro-l -pyridin-2-ylmethyl-piperidin-2-yl)-[l ,2,4] oxadiazol-3 -yl] -benzonitrile, 3-[5-(4,4-Difluoro-l-thiazol-2-ylmethyl-piperidin-2-yl)-[l,2,4]oxadiazol-3-yl]-benzonitrile, 3-[5-(l-Quinolin-2-ylmethyl-piperidin-2-yl)-[l,2,4]oxadiazol-3-yl]-benzonitrile, 3-{5-[l-(lH- Benzimidazole -2-ylmethyl)-piperidin-2-yl]-[l,2,4]oxadiazol-3-yl}-benzonitrile, 3-{5-[l-(2-Methyl-thiazol-4-ylmethyl)-piperidin-2-yl]-[l,2,4]oxadiazol-3-yl}-benzonitrile, 3-{5-[l-(l -Benzyl- 1 H-imidazol-2-ylmethyl)-piperidin-2-yl] -[1,2,4] oxadiazol-3 -yl } -benzonitrile, 3-[5-(4-Pyridine-2-ylmethyl-morpholin-3-yl)-[l,2,4]oxadiazol-3-yl)-berizonitrile, 3 - { 5 - [ 1 -(6-Bromo-pyridin-2-ylmethyl)-piperidin-2-yl] -[1,2,4] oxadiazol-3 -yl } -benzonitrile, 3 - { 5- [ 1 -(4-Methoxy-3 , 5 -dimethyl-pyridin-2-ylmethyl)-piperidin-2-yl] -[1,2,4] oxadiazol-3 -yl } - benzonitrile, 3 - { 5 - [ 1 -(6-Chloro-pyridin-2-ylmethyl)-piperidin-2-yl] -[1,2,4] oxadiazol-3 -yl } -benzonitrile, 3 - [5 -( 1 -Pyrazin-2-ylmethyl~piperidin-2-yl)- [ 1 ,2,4] oxadiazol-3 -yl] -benzonitrile, 3-[5-(l-Pyrimidin-4-ylmethyl-piperidin-2-yl)-[l,2,4]oxadiazol-3-yl]-benzonitrile, 3 - { 5 - [ 1 -(5-Methyl- [ 1 ,2,4] oxadiazol-3 -ylmethyl)-piρeridin-2-yl] -[1,2,4] oxadiazol-3 -yl} - benzonitrile, 3-{5-[l -(4-Chloro-pyridin-2-ylmethyl)-piperidin-2-yl] - [ 1 ,2,4] oxadiazol-3 -yl } -benzonitrile,
2-{2-[3-(3-Cyano-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-ylmethyl}-thiazole-4-carbonitrile, 3-[5-(l-Benzothiazol-2-ylmethyl-piperidin-2-yl)-[l,2,4]oxadiazol-3-yl]benzonitrile, 6- {2-[3-(3-Cyano-phenyl)-[ 1 ,2,4]oxadiazol-5-yl]-piperidin- 1 -ylmethyl} -nicotinonitrile, 3-{5-[l-(5 -Methyl-isoxazol-3 -ylmethyl)-piperidin-2-yl] -[1,2,4] oxadiazol-3 -yl} -benzonitrile, 3-Methoxy-5-[3-(l -pyridin-2-ylmethyl-piperidin-2-yl)-[l ,2,4]oxadiazol-5-yl]-benzonitrile, 2- {2- [5-(3-Methoxy-phenyI)- [ 1 ,2,4]oxadiazol-3 -yl] -piperidin- 1 -ylmethyl} -pyridine, 3 - [5 -( 1 -Pyridin-2-ylmethyl-pyrrolidin-2-yl)- [1,2,4] oxadiazol-3 -yl] -benzonitrile, 2- { 2- [3 -(3 -Methoxy-phenyl)- [1,2,4] oxadiazol-5-yl] -piperidin- 1 -ylmethyl } -pyridine, (RS)-2- [2-(3 -Thiophen-2-yl-[ 1 ,2,4] oxadiazol-5-yl)-piperidin- 1 -ylmethyl] -pyridine, 2- [2-(3 -Phenyl- [1,2,4] oxadiazol-5 -yl)-piperidin- 1 -ylmethyl] -pyridine, 2-[2-(3-m-Tolyl-[l,2,4]oxadiazol-5-yl)-piperidin-l-ylmethyl]-pyridine, (RS)-2-[2-(3 -m-Tolyl- [ 1 ,2,4]oxadiazol-5-yl)-piperidin- 1 -ylmethyl] -pyridine, (RS)-2-{2-[3-(3-Fluoro-5-imidazol- 1 -yl-phenyl)-[ 1 ,2,4]oxadiazol-5-yl]-piρeridin- 1 -ylmethyl} - pyridine or
2-{2-[3-(3-Ethyl-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-ylmethyl}-pyridine, or salt thereof. (R)- and (S)-3-[5-(l-Pyridin-2-ylmethyl-piperidin-2-yl)-[l,2,4]oxadiazol-3-yl]-benzonitrile;
(S)-3 - [5 -( 1 -Thiazol-2-ylmethyl-piρeridin-2-yl [1,2,4] oxadiazol-3 -yl] -benzonitrile;
3 - [5 S -(3 -Thiazol-2-ylmethyl-thiazolidin-4-yl)- [ 1 ,2,4] oxadiazol-3 -yl] -benzonitrile;
(S)-3-[5-(l -Thiazol-2-ylmethyl-pyrrolidin-2-yl)- [ 1,2,4] oxadiazol-3 -yl] -benzonitrile;
(S)-3-[5-(l -Pyridin-2-ylmethyl-pyrrolidin-2-yl)- [ 1 ,2,4] oxadiazol-3 -yl] -benzonitrile; (S)-3-[5-(l -Pyridin-2-ylmethyl-2,5-dihydro- 1 H-pyrrol-2-yl)- [ 1 ,2,4] oxadiazol-3 -yl] -benzonitrile;
Trans-3-[5-(5-methyl-l-pyridin-2-ylmethyl-piperidin-2-yl)-[l,2,4]oxadiazol-3-yl]-benzonitrile;
Cis-3-[5-(5 -methyl- 1 -pyridin-2-ylmethyl-piperidin-2-yl)- [ 1 ,2,4] oxadiazol-3 -yl] -benzonitrile;
Cis-3-[5-(5-methyl-l-thiazol-2-ylmethyl-piperidin-2-yl)-[l,2,4]oxadiazol-3-yl]-benzonitrile;
Cis-2-{2-[3-(3 -chloro-phenyl)- [ 1 ,2,4] oxadiazol-5 -yl] -4-methyl-piperidin- 1 -ylmethyl } -pyridine; Cis-3-[5-(3-Methyl-l-pyridin-2-ylmethyl-piperidin-2-yl)-[l,2,4]oxadiazol-3-yl]-benzonitrile;
Trans-3-[5-(3-Methyl-l-pyridin-2-ylmethyl-piperidin-2-yl)-[l,2,4]oxadiazol-3-yl]-benzonitrile;
Cis-3-[5-(3 -Methyl- 1 -thiazol-2-ylmethyl-piperidin-2-yl)- [1,2,4] oxadiazol-3 -yl] -benzonitrile ;
3-[5-(4-Thiazol-2-ylmethyl-mo holin-3-yl)-[l,2,4]oxadiazol-3-yl]-benzonitrile;
3 - { 5 - [4-(4-Methyl-pyridin-2-ylmethyl)-morpholin-3 -yl] -[1,2,4] oxadiazol-3 -yl } -benzonitrile ; 3 - [3 -(3 -Chloro-phenyl)- [1,2,4] oxadiazol-5 -yl] -4-pyridin-2-ylmethyl-morpholine ;
3 - [3 -(3 -Chloro-phenyl)- [1,2,4] oxadiazol-5 -yl] -4-thiazol-2-ylmethyl-morpholine;
2-{2-[3-(3 -Chloro-phenyl)- [1,2,4] oxadiazol-5 -yl] -piperidin- 1 -ylmethyl } -pyridine ;
2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-l-thiazol-2-ylmethyl-piperidine; or a salt thereof.
The compounds of formula I useful in accordance with the present invention, may also be used as pharmaceutically acceptable salts, but also other salts may be useful in accordance with the present invention.
Examples of pharmaceutically acceptable salts useful in accordance with the present invention are, but are not limited to, hydrochloride, 4-aminobenzoate, anthranilate, 4-aminosalicylate, 4- hydroxybenzoate, 3,4-dihydroxybenzoate, 3-hydroxy-2-naphthoate, nitrate and trifluoroacetate. Some compounds of formula I may have chiral centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses the use of all such optical, diastereoisomers and geometric isomers.
The invention also relates to the use of any and all tautomeric forms of the compounds of formula I.
A further aspect of the invention is the use of a compound formula I 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 I 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 I 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 I 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 I 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 I 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 I for the manufacture of a medicament for the treatment or prevention of chronic laryngitis.
A further aspect of the invention is the use of a compound according to formula I 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 I for the manufacture of a medicament for the treatment or prevention of irritable bowel syndrome (IBS), such as constipation predominant IBS, diarrhea predominant IBS or alternating bowel movement predominant IBS.
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 I is administered to a subject in need of such inliibition.
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 I 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 I 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 I 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 I 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 I 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 I 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 I is administered to a subject in need of such treatment.
The wording "TLESR", transient lower esophageal sphincter relaxations, is herein defined in accordance vάth 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 I are in accordance with the present invention suitably formulated into pharmaceutical foraiulations 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 I 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 I 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 I may be administered once or twice daily, depending on the severity of the patient's condition.
Methods of Preparation
The compounds of formula I can be prepared as described in WO2004/014902 A2.
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 III 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
1. Use of a compound formula I
Figure imgf000017_0001
5 (I) wherein: P is selected from the group consisting of C3.7alkyl and a 3- to 8-membered ring containing one or more atoms independently selected from C, N, O or S, wherein said ring may be fused with a 5- or 6-membered ring containing one or more atoms0 independently selected from C, N, O or S; R1 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, d-6alkylhalo, OCi-βalkylhalo, d-6aιkyl, Od-6alkyl, C2.6alkenyl, OC .6alkenyl, C2.6alkynyl, OC2. 6alkynyl, Co-6alkylC3.6cycloalkyl, OC0.6alkylC3.6cycloalkyl, Co-6alkylaryl, OC0.6alkylaryl, (CO)R8, O(CO)R8, O(CO)OR8, d.6alkylOR8, OC2.6alkylOR8, d.6alkyl(CO)R8, OCj.s 6alkyl(CO)R8, C0.6alkylCO2R8, Od.6alkylCO2R8, C0.6alkylcyano, OC2.6alkylcyano, C0. 6alkylNR8R9, OC2.6alkylNR8R9, d.6alkyl(CO)NR8R9, Od.6alkyl(CO)NR8R9, C0. 6alkylNR8(CO)R9, OC2.6alkylNR8(CO)R9, C0.6alkylNR8(CO)NR8R9, C0.6alkylSR8, OC2. 6alkylSR8, C0.6alkyl(SO)R8, OC2.6alkyl(SO)R8, C0.6alkylSO2R8, OC2.6alkylSO2R8, C0. 6alkyl(SO2)NR8R9, OC2.6alkyl(SO2)NR8R9, C0.6alkylNR8(SO2)R9, OC2.6alkylNR8(SO2)R9,0 Co-6alkylNR8(SO2)NR8R9, OC2.6alkylNR8(SO2)NR8R9, (CO)NR8R9, O(CO)NR8R9, NR8OR9, C0.6alkylNR8(CO)OR9, OC0.6alkylNR8(CO)OR9, SO3R8 and a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S, wherein said ring may be substituted by one or more A; M1 is selected from the group consisting of a bond, d^alkyl, C2_3alkenyl, C2.3alkynyl, C0.s 4alkyl(CO)C0.4alkyl, C0.3alkylOC0.3alkyl, C0.3alkyl(CO)NR8, C0-3alkyl(CO)NR8C1.3alkyl, C0. alkylNR8R9, C0.3alkylSC0.3alkyl, C0-3alkyl(SO)C0.3alkyl and C0.3alkyl(SO2)Co.3alkyl; R2 is selected from the group consisting of hydrogen, hydroxy, oxo, =NR8, =NOR8, d.4alkylhalo, halo, d.4alkyl, O(CO)d.4alkyl, d.4alkyl(SO)C0. 4alkyl, d.4alkyl(SO2)C0.4alkyl, (SO)C0.4alkyl, (SO2)C0.4alkyl, Od.4alkyl, C0.4alkylcyano, d.4alkylOR8 and C0.4alkylNR8R9;
X1, X2 and X3 are independently selected from N, NR, O, CR, =O and S;
R is selected from the group consisting of hydrogen, C0.3alkyl, halo, Co-3alkylOR5, C0. 3alkylNR5R6, C0.3alkyl(CO)OR5, C0.3alkylNR5R6 and C0.3alkylaryl;
M2 is selected from the group consisting of a bond, d^alkyl, C2.3alkenyl, C2.3alkynyl, C0.
4alkyl(CO)C0- alkyl, C0.3alkylOCo.3 alkyl, C0-3alkylNR8C1.3alkyl, C0.3alkyl(CO)NR8, C0.
4alkylNR8R9, Co-3alkylSCo.3alkyl, Co-3alkyl(SO)C0-3alkyl and C0.3alkyl(SO2)Co-3alkyl;
R3 is selected from the group consisting of hydrogen, hydroxy, oxo, =NR8, =NOR8, Ci. 4alkylhalo, halo, C alkyl, O(CO)d.4alkyl, CMalkyl(SO)C0-4alkyl, d.4alkyl(SO2)C0-
4alkyl, (SO)C0.4alkyl, (SO2)C0.4alkyl, Od.4alkyl, C0.4alkylcyano, C!.4alkylOR8 and C0.
4alkylNR8R9;
Q is a 4-, 5-, 6- or 7-membered ring containing one or more heteroatoms independently selected from N, O or S, wherein said ring may be fused with a 3-, 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S, and wherein the fused ring may be substituted by one or more A;
X is selected from the group consisting of C, CR and N;
R4 is selected from the group consisting of hydrogen, hydroxy, oxo, =NR8, =NOR8, d-
4alkylhalo, halo, d.4alkyl, OC0-6alkylaryl, O(CO)d.4alkyl, d. alkyl(SO)C0.4alkyl, d- 4alkyl(SO2)C0-4alkyl, (SO)C0.4alkyl, (SO2)C0.4alkyl, OC1.4alkyl, d.4alkylOR8, C0.
4alkylcyano and Co-4alkylNR8R9;
M3 is selected from the group consisting of a bond, d_4alkyl, Co-4alkyl(CO)Co-4alkyl, C0.
3alkylOC0.3alkyl, C0.4alkyl R8R9, Co.3alkylNR8C1.3alkyl, C0.3alkyl(CO)NR8, C0.
3alkylSCo- alkyl, C0-3alkyl(SO)C0-3alkyl and C0.3alkyl(SO2)Co-3alkyl; R5 is selected from the group consisting of hydrogen, hydroxy, oxo, =NR8, =NOR8, Ci.
4alkylhalo, halo, C1.4alkyl, O(CO)d.4alkyl, d.4alkyl(SO)Co-4alkyl, CMalkyl(SO2)C0.
4alkyl, (SO)C0.4alkyl, (SO2)C0. alkyl, OC1.4alkyl, C0-4alkylcyano, C1.4alkylOR8 and C0.
4alkylNR8R9;
G is selected from the group consisting of R6 and R7; R6 is selected from the group consisting of hydrogen and a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S, wherein said ring may be fused with a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S, and wherein any of the rings may be substituted by one or more A; R7 is selected from the group consisting of hydrogen, C0.4alkylcyano, C=NR8(NR8R9), C=NOR8(NR8R9), NR8C=NR8(NR8R9), NR8(C=CCN)(NR8R9), NR8(C=CNO2)(NR8R9), NR8(C=NCN)(NR8R9), CONR8R9 and NR8(CO)NR8R9; R8 and R9 are independently selected from hydrogen, d-6alkyl, Co.6alkylC3.6cycloalkyl, Co-6alkylaryl, Co-6alkylheteroaryl and a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S, and wherein R8 and R9 may together form a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S; wherein any d-6alkyl, C2.6alkenyl, C2.6alkynyl, Co-6alkylC3_6cycloalkyl, Co-6alkylaryl, Co- 6alkylheteroary and 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S as defined under R1, R2, R3, R4, R5, R6, R7, R8, and R9 may be substituted by one or more A; A is selected from the group consisting of hydrogen, hydroxy, oxo, halo, nitro, d-6alkyl, Co-6alkylC3-6cycloalkyl, d.6aιkylhalo, Od.6alkylhalo, C2.6alkenyl, Od-6alkyl, Co- 3alkylaryl, d.6alkylOR8, OC2.6alkylOR8, d.6alkylSR8, OC2.6alkylSR8, (CO)R8, O(CO)R8, OC2.6alkylcyano, C0-6alkylcyano, C0.6alkylCO2R8, Od.6alkylCO2R8, O(CO)OR8, OC1.6alkyl(CO)R8, d.6alkyl(CO)R8, NR8OR9, C0.6alkylNR8R9, OC2. 6alkylNR8R9, C0.6alkyl(CO)NR8R9, Od.6alkyl(CO)NR8R9, OC2.6alkylNR8(CO)R9, C0. 6alkylNR8(CO)R9, C0.6alkylNR8(CO)NR8R9, O(CO)NR8R9, NR8(CO)OR9, Co. 6alkyl(SO2)NR8R9, OC2-6alkyl(SO2)NR8R9, C0-6alkylNR8(SO2)R9, OC2. 6alkylNR8(SO2)R9, SO3R8, d.6alkylNR8(SO2)NR8R9, OC2.6alkyl(SO2)R8, C0. 6alkyl(SO2)R8, C0.6alkyl(SO)R8 and OC2.6alkyl(SO)R8; m is selected from 0, 1, 2, 3 or 4; and n is selected from 0, 1, 2 or 3; 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 I 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 I as defined in claim 1, or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for the prevention I of reflux.
4. Use of a compound of formula I 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 I 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 I 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 I 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 I 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.
i
10. Use according to any one of the preceding claims, wherein the compound of formula I is selected from the group of compounds consisting of 3-[5-(l-Pyridin-2-ylmethyl- piperidin-2-yl)- [1,2,4] oxadiazol-3 -yl] -benzonitrile, 3-[3-(l-Pyridin-2-ylmethyl-piperidn-2-yl)-[l,2,4]oxadiazol-5-yl]-benzonitrile, 3 - [5-( 1 -Thiazol-2-ylmethyl-piperidin-2-yl)- [ 1,2,4] oxadiazol-3 -yl] -benzonitrile, 3-{5-[l-(l-Methyl-lH-imidazol-2-ylmethyl)-piperidin-2yl]-[l,2,4]oxadiazol- 3 -yl } -benzonitrile, 3 - { 5- [ 1 -(6-Methyl-pyridin-2-ylmethyl)-piperidin-2-yl] - [ 1 ,2,4] oxadiazol-3 -yl } - benzonitrile,
3-[3-(l-Thiazol-2-ylmethyl-piperidin-2-yl)-[l,2,4]oxadiazol-5-yl]-benzonitrile,
3-[5-(l-Thiazol-2-ylmethyl-pyrrolidin-2-yl)-[l,2,4]oxadiazol-3-yl]-benzonitrile, 3-{5-[l-(5-Chloro-pyridin-2-ylmethyl)-piperidin-2-yl]-[l,2,4]oxadiazol-3-yl}- benzonitrile,
2-[2-(5-m-Tolyl-[l,2,4]oxadiazol-3-yl)-piperidin-l-ylmethyl]-pyridine,
3-{5-[l-(5-Fluoro-pyridin-2-ylmethyl)-piperidin-2-yl]-[l,2,4]oxadiazol-3-yl}- benzonitrile, 3 - [5 S -(3 -Pyridin-2-ylmethyl-thiazolidin-4-yl)- [ 1 ,2,4] oxadiazol-3 -yl] -benzonitrile,
3 - { 5- [ 1 -(3 -Methyl-pyridin-2-ylmethyl)-piperidin-2-yl] -[1,2,4] oxadiazol-3 -yl } - benzonitrile,
3-{5-[l-(4-Methyl-pyridin-2-ylmethyl)-piperidin-2-yl]-[l,2,4]oxadiazol-3-yl}- benzonitrile, 3 - { 5 - [ 1 -(5-Methyl-pyridin-2-ylmethyl)-piperidin-2-yl] -[1,2,4] oxadiazol-3 -yl } - benzonitrile,
3-{5-[l-(l -Methyl- 1 H-benzoimidazol-2-ylmethyl)-piperidin-2-yl] -[1,2,4] oxadiazol-3 - yl} -benzonitrile,
3-[5-(6-Methyl-l-pyridin-2-ylmethyl-piperidin-2-yl)-[l,2,4]oxadiazol-3-yl]-benzonitrile, 3-[5-(4,4-Difluoro-l -pyridin-2-ylmethyl-piperidin-2-yl)-[l ,2,4] oxadiazol-3 -yl]- benzonitrile,
3 - [5 -(4,4-Difluoro- 1 -thiazol-2-ylmethyl-piperidin-2-yl)- [ 1,2,4] oxadiazol-3 -yl] - benzonitrile,
3 - [5 -( 1 -Quinolin-2-ylmethyl-piperidin-2-yl)- [1,2,4] oxadiazol-3 -yl] -benzonitrile, 3-{5-[l-(lH- Benzimidazole -2-ylmethyl)-piperidin-2-yl]-[l,2,4]oxadiazol-3-yl}- benzonitrile,
3-{5-[l-(2-Methyl-thiazol-4-ylmethyl)-piperidin-2-yl]-[l,2,4]oxadiazol-3-yl}- benzonitrile,
3 - { 5 - [ 1 -( 1 -Benzyl- 1 H-imidazol-2-ylmethyl)-piperidin-2-yl] -[1,2,4] oxadiazol-3 -yl } - benzonitrile,
3 - [5-(4-Pyridine-2-ylmethyl-morpholin-3 -yl)- [1,2,4] oxadiazol-3 -yl)-benzonitrile, 3 - { 5- [ 1 -(6-Bromo-pyridin-2-ylmethyl)-piperidin-2-yl] - [ 1 ,2,4] oxadiazol-3 -yl} - benzonitrile, 3 - { 5- [ 1 -(4-Methoxy-3 ,5-dimethyl-pyridin-2-ylmethyl)-piperidin-2-yl] - [ 1 ,2,4] oxadiazol-
3-yl}~benzonitrile,
3-{5-[l-(6-Chloro-pyridin-2-ylmethyl)-piperidin-2-yl]-[l,2,4]oxadiazol-3-yl}- benzonitrile, 3 - [5 -( 1 -Pyrazin-2-ylmethyl-piperidin-2-yl)- [1,2,4] oxadiazol-3 -yl] -benzonitrile,
3 - [5 -( 1 -Pyrimidin-4-ylmethyl-piperidin-2-yi)- [1,2,4] oxadiazol-3 -yl] -benzonitrile,
3-{5-[l-(5-Methyl-[l,2,4]oxadiazol-3-ylmethyl)-piperidin-2-yl]-[l,2,4]oxadiazol-3-yl}- benzonitrile,
3 - { 5 - [ 1 -(4-Chloro-ρyridin-2-ylmethyl)-piperidin-2-yl] - [ 1 ,2,4] oxadiazol-3 -yl } - benzonitrile,
2-{2-[3-(3-Cyano-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-ylmethyl}-thiazole-4- carbonitrile,
3-[5-(l-Benzothiazol-2-ylmethyl-piperidin-2-yl)-[l,2,4]oxadiazol-3-yl]benzonitrile,
6- {2-[3 -(3-Cyano-phenyl)-[ 1 ,2,4] oxadiazol-5-yl] -piperidin- 1 -ylmethyl} -nicotinonitrile, 3 - { 5- [ 1 -(5-Methyl-isoxazol-3 -ylmethyl)-piperidin-2-yl] -[1,2,4] oxadiazol-3 -yl } - benzonitrile,
3-Methoxy-5-[3-(l-pyridin-2-ylmethyl-piperidin-2-yl)-[l,2,4]oxadiazol-5-yl]- benzonitrile,
2-{2-[5-(3 -Methoxy-phenyl)- [ 1 ,2,4] oxadiazol-3 -yl] -piperidin- 1 -ylmethyl } -pyridine, 3-[5-(l -Pyridin-2-ylmethyl-pyrrolidin-2-yl)- [1,2,4] oxadiazol-3 -yl] -benzonitrile,
2- {2-[3-(3-Methoxy-phenyl)-[ 1 ,2,4]oxadiazol-5-yl]-piperidin- 1 -ylmethyl} -pyridine,
(RS)-2- [2-(3 -Thiophen-2-yl- [ 1 ,2,4] oxadiazol-5-yl)-piperidin- 1 -ylmethyl] -pyridine,
2-[2-(3-Phenyl-[l,2,4]oxadiazol-5-yl)-piperidin-l-ylmethyl]-pyridine,
2-[2-(3-m-Tolyl-[l,2,4]oxadiazol-5-yl)-piperidin-l-ylmethyl]-pyridine, (RS)-2- [2-(3 -m-Tolyl- [ 1 ,2,4] oxadiazol-5 -yl)-piperidin- 1 -ylmethyl] -pyridine,
(RS)-2-{2-[3-(3-Fluoro-5-imidazol-l-yl-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l- ylmethyl} -pyridine or
2-{2-[3-(3 -Ethyl-phenyl)- [1,2,4] oxadiazol-5 -yl] -piperidin- 1 -ylmethyl } -pyridine, or salt thereof. (R)- and (S)-3-[5-(l -Pyridin-2-ylmethyl-piρeridin-2-yl)-[l ,2,4] oxadiazol-3 -yl]- benzonitrile; (S)-3-[5-(l-Thiazol-2-ylmethyl-piρeridin-2-yl)-[l,2,4]oxadiazol-3-yl]- benzonitrile; 3-[5S-(3-Thiazol-2-ylmethyl-thiazolidin-4-yl)-[l,2,4]oxadiazol-3-yl]-benzonitrile; (S)-3-[5-(l-Thiazol-2-ylmethyl-pyrrolidin-2-yl)-[l,2,4]oxadiazol-3-yl]-benzonitrile; (S)-3-[5-(l-Pyridin-2-ylmethyl-pyrrolidin-2-yl)-[l,2,4]oxadiazol-3-yl]-benzonitrile; (S)-3-[5-(l-Pyridin-2-ylmethyl-2,5-dihydro-lH-pyrrol-2-yl)-[l,2,4]oxadiazol-3-yl]- benzonitrile; Trans-3 - [5 -(5 -methyl- 1 -pyridin-2-ylmethyl-piperidin-2-yι)- [1,2,4] oxadiazol-3 -yl] - benzonitrile; Cis-3-[5-(5-methyl-l-pyridin-2-ylmethyl-piperidin-2-yl)-[l,2,4]oxadiazol-3-yl]- benzonitrile; Cis-3-[5-(5-methyl-l-thiazol-2-ylmethyl-piperidin-2-yl)-[l,2,4]oxadiazol-3-yl]- benzonitrile; ι Cis-2-{2-[3-(3 -chloro-phenyl)- [ 1,2,4] oxadiazol-5 -yl] -4-methyl-piperidin- 1 -ylmethyl } - pyridine; Cis-3-[5-(3 -Methyl- 1 -pyridin-2-ylmethyl-piperidin-2-yl)- [ 1 ,2,4] oxadiazol-3 -yl] - benzonitrile; Trans-3 - [5 -(3 -Methyl- 1 -pyridin-2-ylmethyl-piperidin-2-yl)- [1,2,4] oxadiazol-3 -yl] - benzonitrile; Cis-3-[5-(3-Methyl-l-thiazol-2-ylmethyl-piperidin-2-yl)-[l,2,4]oxadiazol-3-yl]- benzonitrile; 3-[5-(4-Thiazol-2-ylmethyl-moφholin-3-yl)-[l,2,4]oxadiazol-3-yl]-benzonitrile; 3-{5-[4-(4-Methyl-pyridin-2-ylmethyl)-morpholin-3-yl]-[l,2,4]oxadiazol-3-yl}- benzonitrile; 3-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-4-pyridin-2-ylmethyl-morpholine; 3 - [3 -(3 -Chloro-phenyl)- [ 1 ,2,4] oxadiazol-5 -yl] -4-thiazol-2-ylmethyl-morpholine ; 2- { 2- [3 -(3 -Chloro-phenyl)- [ 1 ,2,4] oxadiazol-5-yl] -piperidin- 1 -ylmethyl } -pyridine ; 2- [3 -(3 -Chloro-phenyl)-[ 1 ,2,4] oxadiazol-5 -yl] - 1 -thiazol-2-ylmethyl-piperidine; or a pharmaceutically acceptable salt or an optical isomer thereof.
11. A method for the inhibition of transient lower esophageal sphincter relaxations (TLESRs), whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I
Figure imgf000024_0001
(I) wherein:
P is selected from the group consisting of C3- alkyl and a 3- to 8-membered ring containing one or more atoms independently selected from C, N, O or S, wherein said ring may be fused with a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S;
R1 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, d-6alkylhalo, Od-6alkylhalo, d.6alkyl, Od-6aιkyl, C2.6alkenyl, OC2.6alkenyl, C2.6alkynyl, OC2. 6alkynyl, Co-6alkylC3-6cycloalkyl, OCo-6alkylC3.6cycloalkyl, Co-6alkylaryl, OCo-βalkylaryl,
(CO)R8, O(CO)R8, O(CO)OR8, d.6alkylOR8, OC2.6alkylOR8, d.6alkyl(CO)R8, Od- 6alkyl(CO)R8, C0.6alkylCO2R8, Od-6alkylCO2R8, C0.6alkylcyano, OC2.6alkylcyano, C0. 6alkylNR8R9, OC2.6alkylNR8R9, d.6alkyl(CO)NR8R9, Od-6alkyl(CO)NR8R9, C0. 6alkylNR8(CO)R9, OC2.6alkylNR8(CO)R9, C0.6alkylNR8(CO)NR8R9, C0.6alkylSR8, OC2. 6alkylSR8, C0.6alkyl(SO)R8, OC2.6alkyl(SO)R8, C0.6alkylSO2R8, OC2.6alkylSO2R8, C0.
6alkyl(SO2)NR8R9, OC2.6alkyl(SO2)NR8R9, C0.6alkylNR8(SO2)R9, OC2.6alkylNR8(SO2)R9, C0-6alkylNR8(SO2)NR8R9, OC2.6alkylNR8(SO2)NR8R9, (CO)NR8R9, O(CO)NR8R9, NR8OR9, C0-6alkylNR8(CO)OR9, OC0-6alkylNR8(CO)OR9, SO3R8 and a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S, wherein said ring may be substituted by one or more A;
M1 is selected from the group consisting of a bond, d^alkyl, C2.3alkenyl, C2.3alkynyl, Co- 4alkyl(CO)C0.4alkyl, Co-3alkylOCo.3alkyl, C0-3alkyl(CO)NR8, C0.3alkyl(CO)NR8C1.3alkyl, C0.4alkylNR8R9, C0.3alkylSCo-3alkyl, Co-3alkyl(SO)Co-3alkyl and Co.3alkyl(SO2)C0-3alkyl; R2 is selected from the group consisting of hydrogen, hydroxy, oxo, =NR8, =NOR8, d- 4alkylhalo, halo, CMalkyl, O(CO)d.4alkyl, C1.4alkyl(SO)C0.4alkyl, d.4alkyl(SO2)C0-
4alkyl, (SO)C0-4alkyl, (SO2)C0.4alkyl, OC1.4alkyl, C0.4alkylcyano, d.4alkylOR8 and C0. 4alkylNR8R9; X1, X2 and X3 are independently selected from N, NR, O, CR, =O and S; R is selected from the group consisting of hydrogen, C0-3alkyl, halo, C0-3alkylOR5, C0.
3alkylNR5R6, C0.3alkyl(CO)OR5, C0-3alkylNR5R6 and C0.3alkylaryl;
M2 is selected from the group consisting of a bond, d.3alkyl, C2.3alkenyl, C2.3alkynyl, C0.
4alkyl(CO)C0-4alkyl, C0-3alkylOCo-3 alkyl, C0-3alkylNR8C1.3alkyl, C0-3alkyl(CO)NR8, C0. 4alkylNR8R9, C0-3alkylSCo-3alkyl, Co-3alkyl(SO)C0-3alkyl and Co-3alkyl(SO2)Co-3alkyl;
R3 is selected from the group consisting of hydrogen, hydroxy, oxo, =NR8, =NOR8, d.
4alkylhalo, halo, d-4alkyl, O(CO)d.4alkyl, d.4alkyl(SO)C0.4alkyl, d.4alkyl(SO2)C0.
4alkyl, (SO)C0.4alkyl, (SO2)C0 alkyl, Od.4alkyl, C0-4alkylcyano, d.4alkylOR8 and Co-
4alkylNR8R9; Q is a 4-, 5-, 6- or 7-membered ring containing one or more heteroatoms independently selected from N, O or S, wherein said ring may be fused with a 3-, 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S, and wherein the fused ring may be substituted by one or more A;
X4 is selected from the group consisting of C, CR, N; R4 is selected from the group consisting of hydrogen, hydroxy, oxo, =NR8, =NOR8, d-
4alkylhalo, halo, C alkyl, OC0.6alkylaryl, O(CO)C1.4alkyl, d.4alkyl(SO)Co. alkyl, d.
4alkyl(SO2)C0.4alkyl, (SO)C0- alkyl, (SO2)C0-4alkyl, Od-4alkyl, d_4alkylOR8, C0.
4alkylcyano and Co.4alkylNR R ;
M3 is selected from the group consisting of a bond, d.4alkyl, Co- alkyl(CO)Co-4alkyl, C0. 3alkylOC0.3alkyl, C0.4alkylNR8R9, C0.3alkylNR8C1.3alkyl, C0.3alkyl(CO)NR8, C0.
3alkylSCo-3alkyl, Co-3alkyl(SO)Co-3alkyl and C0-3alkyl(SO2)Co.3alkyl;
R » 5 is selected from the group consisting of hydrogen, hydroxy, oxo, =NR , =NOR , C
4alkylhalo, halo, d-4alkyl, O(CO)d-4alkyl, d.4alkyl(SO)C0.4alkyl, C1.4alkyl(SO2)C0- 4alkyl, (SO)C0.4alkyl, (SO2)C0-4alkyl, OCMalkyl, C0-4alkylcyano, C1.4alkylOR8 and C0. 4alkylNR8R9;
G is selected from the group consisting of R6 and R7;
R6 is selected from the group consisting of hydrogen and a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S, wherein said ring may be fused with a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S, and wherein any of the rings may be substituted by one or more A;
R7 is selected from the group consisting of hydrogen, Co-4alkylcyano, C=NR8(NR8R9), C=NOR8(NR8R9), NR8C=NR8(NR8R9), NR8(C=CCN)(NR8R9), NR8(C=CNO2)(NR8R9), NR8(C=NCN)(NR8R9), CONR8R9 and NR8(CO)NR8R9; R8 and R9 are independently selected from hydrogen, Chalky!, C0-6alkylC3-6cycloalkyl, C0.6alkylaryl, C0-6alkylheteroaryl and a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S, and wherein R8 and R9 may together I form a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S; wherein any d.6alkyl, C2.6alkenyl, C2.6alkynyl, Co-6alkylC3.6cycloalkyl, Co-6alkylaryl, Co- 6alkylheteroary and 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S as defined under R1, R2, R3, R4, R5, R6, R7, R8, and R9 may be substituted by one or more A; A is selected from the group consisting of hydrogen, hydroxy, oxo, halo, nitro, d-6alkyl, Co.6alkylC3.6cycloalkyl, d-δaikylhalo, Od.6alkylhalo, C2.6alkenyl, Od-6alkyl, Co- 3alkylaryl, d-6alkylOR8, OC2.6alkylOR8, d-ealkylSR8, OC2.6alkylSR8, (CO)R8, O(CO)R8, OC2.6alkylcyano, C0.6alkylcyano, C0.6alkylCO2R8, Od.6alkylCO2R8, O(CO)OR8, OC1.6alkyl(CO)R8, Ci-6alkyl(CO)R8, NR8OR9, C0.6alkylNR8R9, OC2. 6alkylNR8R9, C0.6alkyl(CO)NR8R9, Od.6alkyl(CO)NR8R9, OC2.6alkylNR8(CO)R9, C0. 6alkylNR8(CO)R9, C0.6alkylNR8(CO) R8R9, O(CO)NR8R9, NR8(CO)OR9, C0. 6alkyl(SO2)NR8R9, OC2.6alkyl(SO2)NR8R9, C0.6alkylNR8(SO2)R9, OC2. 6alkylNR8(SO2)R9, SO3R8, d-6alkylNR8(SO2)NR8R9, OC2.6alkyl(SO2)R8, C0. 6alkyl(SO2)R8, C0.6alkyl(SO)R8 and OC2.6alkyl(SO)R8; m is selected from 0, 1, 2, 3 or 4; and n is selected from 0, 1, 2 or 3; or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such prevention. I
12. A method for the treatment of gastro-esophageal reflux disease (GERD), whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I as defined in claim 1 1, or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such treatment.
13. A method for the prevention of reflux, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I as defined in claim 11, or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such prevention.
14. A method for the treatment of, or prevention of, regurgitation, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I as defined in claim 11, or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such treatment or prevention.
15. A method for the prevention of, or treatment of, lung disease, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I as defined in claim 11, 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 managing failure to thrive, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I as defined in claim 11, or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such management.
17. A method for treatment or prevention of asthma, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I as defined in claim 11, or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such treatment or prevention.
18. A method according to claim 17, wherein the asthma is reflux-related asthma.
19. A method for treatment or prevention of laryngitis, whereby a pharmaceutically and pharmacologically effective amount of a compound of fonnula I as defined in claim 11, or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such treatment or prevention.
20. A method according to any one of claims 11-19, wherein the compound of formula I is selected from the group of compounds consisting of 3-[5-(l-Pyridin-2-ylmethyl- piperidin-2-yl)-[l,2,4]oxadiazol-3-yl]-benzonitrile, 3-[3-(l-Pyridin-2-ylmethyl-piperidn-2-yl)-[l,2,4]oxadiazol-5-yl]-benzonitrile, 3-[5-(l-Thiazol-2-ylmethyl-piperidin-2-yl)-[l,2,4]oxadiazol-3-yl]-benzonitrile, 3-{5-[l-(l-Methyl-lH-imidazol-2-ylmethyl)-piperidin-2yl]-[l,2,4]oxadiazol- 3-yl} -benzonitrile, 3 - { 5 - [ 1 -(6-Methyl-pyridin-2-ylmethyl)-ρiperidin-2-yl] - [ 1 ,2,4] oxadiazol-3 -yl } - benzonitrile,
3-[3-(l-Thiazol-2-ylmethyl-ρiperidin-2-yl)-[l,2,4]oxadiazol-5-yl]-benzonitrile,
3-[5-(l-Thiazol-2-ylmethyl-pyrrolidin-2-yl)-[l,2,4]oxadiazol-3-yl]-benzonitrile, 3-{5-[l-(5-Chloro-pyridin-2-ylmethyl)-piρeridin-2-yl]-[l,2,4]oxadiazol-3-yl}- benzonitrile,
2-[2-(5-m-Tolyl-[l,2,4]oxadiazol-3-yl)-piperidin-l-ylmethyl]-pyridine,
3 - { 5- [ 1 -(5 -Fluoro-pyridin-2-ylmethyl)-piperidin-2-yl] - [ 1 ,2,4] oxadiazol-3 -yl } - benzonitrile, 3-[5S-(3-Pyridin-2-ylmethyl-thiazolidin-4-yl)-[l,2,4]oxadiazol-3-yl]-benzonitrile,
3-{5-[l-(3-Methyl-pyridin-2-ylmethyl)-piperidin-2-yl]-[l,2,4]oxadiazol-3-yl}- benzonitrile,
3-{5-[l-(4-Methyl-pyridin-2-ylmethyl)-piperidin-2-yl]-[l,2,4]oxadiazol-3-yl}- benzonitrile, 3-{5-[l-(5 -Methyl-pyridin-2-ylmethyl)-piperidin-2-yl] - [ 1 ,2,4] oxadiazol-3 -yl } - benzonitrile,
3-{5-[l-(l -Methyl- 1 H-benzoimidazol-2-ylmethyl)-piperidin-2-yl] -[1,2,4] oxadiazol-3 - yl} -benzonitrile,
3-[5-(6-Methyl-l-pyridin-2-ylmethyl-piperidin-2-yl)-[l,2,4]oxadiazol-3-yl]-benzonitrile, 3 - [5-(4,4-Difluoro- 1 -pyridin-2-ylmethyl-piperidin-2-yl)- [1,2,4] oxadiazol-3 -yl] - benzonitrile,
3-[5-(4,4-Difluoro-l-thiazol-2-ylmethyl-piperidin-2-yl)-[l,2,4]oxadiazol-3-yl]- benzonitrile,
3 - [5 -( 1 -Quinolin-2-ylmethyl-piperidin-2-yl)- [1,2,4] oxadiazol-3 -yl] -benzonitrile, 3-{5-[l-(lH- Benzimidazole -2-ylmethyl)-piperidin-2-yl]-[l,2,4]oxadiazol-3-yl}- benzonitrile,
3-{5-[l-(2-Methyl-thiazol-4-ylmethyl)-piperidin-2-yl]-[l,2,4]oxadiazol-3-yl}- benzonitrile,
3-{5-[l-(l-Benzyl-lH-imidazol-2-ylmethyl)-piperidin-2-yl]-[l,2,4]oxadiazol-3-yl}- benzonitrile,
3-[5-(4-Pyridine-2-ylmethyl-morpholin-3-yl)-[l,2,4]oxadiazol-3-yl)-benzonitrile, 3-{5-[l-(6-Bromo-pyridin-2-ylmethyl)-piperidin-2-yl]-[l,2,4]oxadiazol-3-yl}- benzonitrile, 3-{5-[l-(4-Methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-piperidin-2-yl]-[l,2,4]oxadiazol-
3 -yl} -benzonitrile,
3 - { 5 - [ 1 -(6-Chloro-ρyridin-2-ylmethyl)-ρiperidin-2-yl] -[1,2,4] oxadiazol-3 -yl } - benzonitrile, 3 - [5-( 1 -Pyrazin-2-ylmethyl-piperidin-2-yl)- [1,2,4] oxadiazol-3 -yl] -benzonitrile,
3-[5-(l-Pyrimidin-4-ylmethyl-piperidin-2-yl)-[l,2,4]oxadiazol-3-yl]-benzonitrile,
3-{5-[l -(5-Methyl-[l ,2,4]oxadiazol-3-ylmethyl)-ρiperidin-2-yl]-[l ,2,4] oxadiazol-3 -yl}- benzonitrile,
3 - { 5 - [ 1 -(4-Chloro-pyridin-2-ylmethyl)-piperidin-2-yl] -[1,2,4] oxadiazol-3 -yl } - benzonitrile,
2-{2-[3-(3 -Cyano-phenyl)- [ 1,2,4] oxadiazol-5 -yl] -piperidin- 1 -ylmethyl } -thiazole-4- carbonitrile,
3 - [5 -( 1 -Benzothiazol-2-ylmethyl-piperidin-2-yl)- [1,2,4] oxadiazol-3 -yl] benzonitrile,
6-{2-[3-(3-Cyano-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-ylmethyl}-nicotinonitrile, 3 - { 5 - [ 1 -(5-Methyl-isoxazol-3 -ylmethyl)-piperidin-2-yl] -[1,2,4] oxadiazol-3 -yl } - benzonitrile,
3 -Methoxy-5- [3-( 1 -pyridin-2-ylmethyl-piperidin-2-yl)- [ 1 ,2,4] oxadiazol-5-yl] - benzonitrile,
2- {2- [5 -(3 -Methoxy-phenyl)- [ 1 ,2,4] oxadiazol-3 -yl] -piperidin- 1 -ylmethyl } -pyridine, 3-[5-(l-Pyridin-2-ylmethyl-pyrrolidin-2-yl)-[l,2,4]oxadiazol-3-yl]-benzonitrile,
2- {2- [3 -(3 -Methoxy-phenyl)- [ 1 ,2,4] oxadiazol-5-yl] -piperidin- 1 -ylmethyl} -pyridine,
(RS)-2- [2-(3 -Thioρhen-2-yl- [ 1 ,2,4]oxadiazol-5-yl)-piperidin- 1 -ylmethyl] -pyridine,
2-[2-(3-Phenyl-[l,2,4]oxadiazol-5-yl)-piperidin-l-ylmethyl]-pyridine,
2-[2-(3-m-Tolyl-[l,2,4]oxadiazol-5-yl)-piperidin-l-ylmethyl]-pyridine, (RS)-2-[2-(3 -m-Tolyl- [ 1 ,2,4] oxadiazol-5-yl)-piperidin- 1 -ylmethyl] -pyridine,
(RS)-2-{2-[3-(3-Fluoro-5-imidazol-l-yl-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l- ylmethyl} -pyridine or
2- {2-[3-(3-Ethyl-phenyl)-[ 1 ,2,4]oxadiazol-5-yl]-piperidin- 1 -ylmethyl} -pyridine, or salt thereof. (R)- and (S)-3-[5-(l-Pyridin-2-ylmethyl-piperidin-2-yl)-[l,2,4]oxadiazol-3-yl]- benzonitrile; (S)-3-[5-(l-Thiazol-2-ylmethyl-piperidin-2-yl)-[l,2,4]oxadiazol-3-yl]- benzonitrile; 3-[5S-(3-Thiazol-2-ylmethyl-thiazolidin-4-yl)-[l,2,4]oxadiazol-3-yl]-benzonitrile;
(S)-3-[5-(l-Thiazol-2-ylmethyl-pyrrolidin-2-yl)-[l,2,4]oxadiazol-3-yl]-benzonitrile;
(S)-3 - [5-(l -Pyridin-2-ylmethyl-pyrrolidin-2-yl)- [ 1 ,2,4] oxadiazol-3 -yl] -benzonitrile;
(S)-3-[5-(l-Pyridin-2-ylmethyl-2,5-dihydro-lH-pyrrol-2-yl)-[l,2,4]oxadiazol-3-yl]- benzonitrile;
Trans-3 - [5 -(5 -methyl- 1 -pyridin-2-ylmethyl-piperidin-2-yl)- [ 1 ,2,4] oxadiazol-3 -yl] - benzonitrile;
Cis-3-[5-(5-methyl-l-pyridin-2-ylmethyl-piperidin-2-yl)-[l,2,4]oxadiazol-3-yl]- benzonitrile; Cis-3-[5-(5-methyl-l-thiazol-2-ylmethyl-piperidin-2-yl)-[l,2,4]oxadiazol-3-yl]- benzonitrile;
Cis-2-{2-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-4-methyl-piperidin-l-ylmethyl}- pyridine;
Cis-3 - [5 -(3 -Methyl- 1 -pyridin-2-ylmethyl-piperidin-2-yl)- [ 1,2,4] oxadiazol-3 -yl] - benzonitrile;
Trans-3-[5-(3-Methyl-l-pyridin-2-ylmethyl-piperidin-2-yl)-[l,2,4]oxadiazol-3-yl]- benzonitrile;
Cis-3-[5-(3-Methyl-l-thiazol-2-ylmethyl-piρeridin-2-yl)-[l,2,4]oxadiazol-3-yl]- benzonitrile; 3 - [5 -(4-Thiazol-2-ylmethyl-morpholin-3 -yl)- [1,2,4] oxadiazol-3 -yl] -benzonitrile;
3 - { 5 - [4-(4-Methyl-ρyridin-2-ylmethyl)-morpholin-3 -yl] - [ 1 ,2,4] oxadiazol-3 -yl} - benzonitrile;
3 - [3 -(3 -Chloro-phenyl)- [ 1,2,4] oxadiazol-5 -yl] -4-pyridin-2-ylmethyl-morpholine ;
3-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-4-thiazol-2-ylmethyl-morpholine; 2-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-piperidin-l-ylmethyl}-pyridine;
2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-l-thiazol-2-ylmethyl-piperidine; or a pharmaceutically acceptable salt or an optical isomer thereof. A. CLASSIFICATION OF SUBJECT MATTER IPC 7 C22C38/42
According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) IPC 7 C22C
Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
Electronic data base consulted during the international search (name of data base and, where practical, search terms used) EPO-Internal , PAJ , COMPENDEX , WPI Data
c. DOCUMENTS CONSIDERED TO BE RELEVANT Category ° Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No
WO 02/079534 A (CRS HOLDINGS, INC; MARTIN, 1-74 JAMES, W; K0SA, THEODORE) 10 October 2002 (2002-10-10) the whol e document US 5681 528 A (MARTIN ET AL) 1-74 28 October 1997 (1997-10-28) the whol e document PATENT ABSTRACTS OF JAPAN 1-74 vol. 015, no. 100 (C-0813), 11 March 1991 (1991-03-11) -& JP 02 310339 A (KAWASAKI STEEL CORP), 26 December 1990 (1990-12-26) abstract -/--
Further documents are listed in the continuation of box C Patent family members are listed in annex ° Special categories of cited documents later document published after the international filing date or pπoπty date and not in conflict with the application but "A- document defining the general state of the art which is not cited to understand the principle or theory underlying the considered to be of particular relevance invention 'E' earlier document but published on or after the international document of particular relevance, the claimed invention filing date cannot be considered novel or cannot be considered to "L" document which may throw doubts on pπoπty claιm(s) or involve an inventive step when the document Is taken alone which is cited to establish the publication date of another document of particular relevance, the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the O" document referring to an oral disclosure use, exhibition or document is combined with one or more other such docuother means ments, such combination being obvious to a person skilled ■P" document published prior to the international filing date but In the art later than the priority date claimed document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 21 July 2005 04/08/2005 Name and mailing address of the ISA Authorized officer European Patent Office, P B 5818 Patentlaan 2 NL - 2280 HV Ri|swi|k Tel (+31-70) 3 0-2040, Tx 31 651 epo nl, Fax (+31-70) 340-3016 Swi atek , R
Form PCT/ISA 210 (second sheet) (January 2004) e C.(Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT Category ° Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No
US 5035855 A (UTSUNOMIYA ET AL) 1-74 30 July 1991 (1991-07-30) the whole document FR 2086805 A (ARMC0 STEEL CORP) 1-74 31 December 1971 ( 1971-12-31) the whole document
Form PCT/ISA 210 (continuation of second sheet) (January 2004) a e 2 of 2 Patent document Publication Patent family Publication cited in search report date member(s) date WO 02079534 A 10-10-2002 AT 286991 T 15-01-2005 BR 0208714 A 20-07-2004 CA 2442068 Al 10-10-2002 DE 60202598 Dl 17-02-2005 EP 1373590 Al 02-01-2004 P 2004522859 T 29-07-2004 MX PA03008788 A 12-02-2004 O 02079534 Al 10-10-2002 US 2003049153 Al 13-03-2003 US 5681528 A 28-10-1997 AT 188512 T . 15-01-2000 BR 9611065 A 13-07-1999 CA 2232679 Al 03-04-1997 DE 69606061 Dl 10-02-2000 DE 69606061 T2 24-08-2000 EP 0859869 Al 26-08-1998 ES 2142087 T3 01-04-2000 IL 123755 A 13-08-2000 JP 2000502404 T 29-02-2000 JP 3227468 B2 12-11-2001 TW 428032 B 01-04-2001 O 9712073 Al 03-04-1997 US 5855844 A 05-01-1999 JP 02310339 A 26-12-1990 NONE US 5035855 A 30-07-1991 JP 60036649 A 25-02-1985 AT 392654 B 27-05-1991 AT 249984 A 15-10-1990 DE 3427602 Al 21-02-1985 FR 2550226 Al 08-02-1985 _ GB 2145734 A , B 03-04-1985 NL 8402402 A 01-03-1985 SE 461398 B 12-02-1990 SE 8403861 A 06-02-1985 FR 2086805 A 31-12-1971 FR 2086805 A5 31-12-1971
-
Form PCT/ISA/210 (patent family annex) (January 2004) Abstract
The present invention relates to the use of a compound of formula I for the inhibition of transient lower esophageal sphincter relaxations. A further aspect of the invention is directed to the use of compounds disease.
Figure imgf000034_0001
(I)
002.1316047.2
30
PCT/US2005/000334 2004-02-03 2005-01-07 Treatment of gastro-esophageal reflux disease (gerd) WO2005077368A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US54106004P 2004-02-03 2004-02-03
US60/541,060 2004-02-03

Publications (2)

Publication Number Publication Date
WO2005077368A2 true WO2005077368A2 (en) 2005-08-25
WO2005077368A3 WO2005077368A3 (en) 2005-11-24

Family

ID=34860189

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2005/000334 WO2005077368A2 (en) 2004-02-03 2005-01-07 Treatment of gastro-esophageal reflux disease (gerd)

Country Status (1)

Country Link
WO (1) WO2005077368A2 (en)

Cited By (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007040982A1 (en) * 2005-09-29 2007-04-12 Astrazeneca Ab 5- (phenylisoxazolylethoxy) -triazol- 3 -yl substituted pyridine compounds for the treatment of neurological, psychiatric or pain disorders
WO2007115077A2 (en) * 2006-03-31 2007-10-11 Astrazeneca Ab Bicyclic benzimidazole compounds and their use as metabotropic glutamate receptor potentiators
US7678796B2 (en) 2006-05-05 2010-03-16 Astrazeneca Ab MGluR5 modulators I
US8012981B2 (en) 2006-06-15 2011-09-06 Glaxo Group Limited Benzylpiperazine derivatives as motilin receptor agonists
US8048899B2 (en) 2008-09-25 2011-11-01 Boehringer Ingelheim International Gmbh Compounds which selectively modulate the CB2 receptor
US8088806B2 (en) 2005-05-09 2012-01-03 Achillion Pharmaceuticals, Inc. Thiazole compounds and methods of use
US8088771B2 (en) 2008-07-28 2012-01-03 Gilead Sciences, Inc. Cycloalkylidene and heterocycloalkylidene inhibitor compounds
US8106209B2 (en) 2008-06-06 2012-01-31 Achillion Pharmaceuticals, Inc. Substituted aminothiazole prodrugs of compounds with anti-HCV activity
US8124764B2 (en) 2008-07-14 2012-02-28 Gilead Sciences, Inc. Fused heterocyclyc inhibitor compounds
US8134000B2 (en) 2008-07-14 2012-03-13 Gilead Sciences, Inc. Imidazolyl pyrimidine inhibitor compounds
US8178568B2 (en) 2008-07-10 2012-05-15 Boehringer Ingelheim International Gmbh Sulfone compounds which modulate the CB2 receptor
US8183263B2 (en) 2007-05-22 2012-05-22 Achillion Pharmaceuticals, Inc. Heteroaryl substituted thiazoles
US8252829B2 (en) 2009-06-05 2012-08-28 Link Medicine Corporation Aminopyrrolidinone derivatives and uses thereof
US8258316B2 (en) 2009-06-08 2012-09-04 Gilead Sciences, Inc. Alkanoylamino benzamide aniline HDAC inhibitor compounds
US8283357B2 (en) 2009-06-08 2012-10-09 Gilead Sciences, Inc. Cycloalkylcarbamate benzamide aniline HDAC inhibitor compounds
US8299103B2 (en) 2009-06-15 2012-10-30 Boehringer Ingelheim International Gmbh Compounds which selectively modulate the CB2 receptor
US8299111B2 (en) 2006-07-28 2012-10-30 Boehringer Ingelheim International Gmbh Compounds which modulate the CB2 receptor
US8329735B2 (en) 2010-03-05 2012-12-11 Boehringer Ingelheim International Gmbh Tetrazole compounds which selectively modulate the CB2 receptor
US8344018B2 (en) 2008-07-14 2013-01-01 Gilead Sciences, Inc. Oxindolyl inhibitor compounds
US8383615B2 (en) 2009-06-16 2013-02-26 Boehringer Ingelheim International Gmbh Azetidine 2-carboxamide derivatives which modulate the CB2 receptor
US8383651B2 (en) 2009-09-22 2013-02-26 Boehringer Ingelheim International Gmbh Compounds which selectively modulate the CB2 receptor
US8524751B2 (en) 2009-03-09 2013-09-03 GlaxoSmithKline Intellecutual Property Development 4-oxadiazol-2-YL-indazoles as inhibitors of P13 kinases
US8536182B2 (en) 2005-07-26 2013-09-17 Glaxo Group Limited Benzylpiperazine derivatives and their medical use
US8536169B2 (en) 2008-06-05 2013-09-17 Glaxo Group Limited Compounds
US8546563B2 (en) 2007-11-07 2013-10-01 Boehringer Ingelheim International Gmbh Compounds which modulate the CB2 receptor
US8575162B2 (en) 2009-04-30 2013-11-05 Glaxosmithkline Intellectual Property Development Limited Compounds
US8658635B2 (en) 2008-06-05 2014-02-25 Glaxosmithkline Intellectual Property Development Limited Benzpyrazol derivatives as inhibitors of PI3 kinases
US8716317B2 (en) 2008-06-09 2014-05-06 Sanofi Sulfonamides with heterocycle and oxadiazolone headgroup, processes for their preparation and their use as pharmaceuticals
US8729263B2 (en) 2012-08-13 2014-05-20 Novartis Ag 1,4-disubstituted pyridazine analogs there of and methods for treating SMN-deficiency-related conditions
US8765743B2 (en) 2008-06-05 2014-07-01 Glaxosmithkline Intellectual Property Development Limited Compounds
US8796310B2 (en) 2011-05-04 2014-08-05 Merck Sharp & Dohme Corp. Amino-pyridine-containing spleen tyrosine kinase (SYK) inhibitors
US8846936B2 (en) 2010-07-22 2014-09-30 Boehringer Ingelheim International Gmbh Sulfonyl compounds which modulate the CB2 receptor
US8853218B2 (en) 2006-06-28 2014-10-07 Glaxo Group Limited Compounds
US8865744B1 (en) 2013-05-17 2014-10-21 Boehringer Ingelheim International Gmbh (Cyano-dimethyl-methyl)-isoxazoles and -[1,3,4]thiadiazoles
US8889670B2 (en) 2009-02-18 2014-11-18 Boehringer Ingelheim International Gmbh Heterocyclic compounds which modulate the CB2 receptor
US8993576B2 (en) 2010-10-27 2015-03-31 Glaxo Group Limited 6-(1H-indol-4-yl)-4-(5-{[4-1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazole hemi succinate salt, polymorphs and pharmaceutical compositions thereof
US9040712B2 (en) 2013-01-23 2015-05-26 Novartis Ag Thiadiazole analogs thereof and methods for treating SMN-deficiency-related-conditions
US9303024B2 (en) 2011-10-11 2016-04-05 Dana-Farber Cancer Institute, Inc. Pyrazol-3-ones that activate pro-apoptotic BAX
US9315454B2 (en) 2010-01-15 2016-04-19 Boehringer Ingelheim International Gmbh Compounds which modulate the CB2 receptor
US9604965B2 (en) 2010-04-23 2017-03-28 Cytokinetics, Inc. Substituted pyridazines as skeletal muscle modulators
US9730886B2 (en) 2010-04-23 2017-08-15 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US9771379B2 (en) 2015-09-24 2017-09-26 Pfizer Inc. N-(2-(2-amino-6-substituted-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]OXAZIN-8a(8H)-yl)-thiazol-4-yl) amides
US9994528B2 (en) 2010-04-23 2018-06-12 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
US10450269B1 (en) 2013-11-18 2019-10-22 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10973817B2 (en) 2014-02-10 2021-04-13 Sentinel Oncology Limited Pharmaceutical compounds
US11014911B2 (en) 2019-01-31 2021-05-25 Pfizer Inc. CDK2 inhibitors
US11053195B2 (en) 2013-03-15 2021-07-06 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11247987B2 (en) 2017-10-06 2022-02-15 Forma Therapeutics, Inc. Inhibiting ubiquitin specific peptidase 30
US11535618B2 (en) 2018-10-05 2022-12-27 Forma Therapeutics, Inc. Fused pyrrolines which act as ubiquitin-specific protease 30 (USP30) inhibitors
US11672799B2 (en) 2013-07-31 2023-06-13 Novartis Ag 1,4-disubstituted pyridazine quinolne analogs there of and methods for treating SMN-deficiency-related conditions

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8759380B2 (en) 2011-04-22 2014-06-24 Cytokinetics, Inc. Certain heterocycles, compositions thereof, and methods for their use

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
EP0438230A2 (en) * 1990-01-17 1991-07-24 MERCK SHARP &amp; DOHME LTD. Indole-substituted five-membered heteroaromatic compounds
WO1993002677A1 (en) * 1991-08-03 1993-02-18 Smithkline Beecham Plc 5-ht4 receptor antagonists
WO2004000316A1 (en) * 2002-06-20 2003-12-31 Astrazeneca Ab Use of mglur5 antagonists for the treatment of gerd
WO2004014902A2 (en) * 2002-08-09 2004-02-19 Astrazeneca Ab Compounds having an activity at metabotropic glutamate receptors

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995032965A1 (en) * 1994-06-01 1995-12-07 Yamanouchi Pharmaceutical Co. Ltd. Oxadiazole derivative and medicinal composition thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
EP0438230A2 (en) * 1990-01-17 1991-07-24 MERCK SHARP &amp; DOHME LTD. Indole-substituted five-membered heteroaromatic compounds
WO1993002677A1 (en) * 1991-08-03 1993-02-18 Smithkline Beecham Plc 5-ht4 receptor antagonists
WO2004000316A1 (en) * 2002-06-20 2003-12-31 Astrazeneca Ab Use of mglur5 antagonists for the treatment of gerd
WO2004014902A2 (en) * 2002-08-09 2004-02-19 Astrazeneca Ab Compounds having an activity at metabotropic glutamate receptors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch, Week 199603 Derwent Publications Ltd., London, GB; Class B03, AN 1996-030501 XP002326438 -& WO 95/32965 A1 (YAMANOUCHI PHARM CO LTD) 7 December 1995 (1995-12-07) *

Cited By (85)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8236953B2 (en) 2004-12-29 2012-08-07 Glaxo Group Limited Process for preparing piper azine derivatives
US8088806B2 (en) 2005-05-09 2012-01-03 Achillion Pharmaceuticals, Inc. Thiazole compounds and methods of use
US8536182B2 (en) 2005-07-26 2013-09-17 Glaxo Group Limited Benzylpiperazine derivatives and their medical use
US7476684B2 (en) 2005-09-29 2009-01-13 Astrazeneca Ab Compounds for the treatment of neurological, psychiatric or pain disorders
WO2007040982A1 (en) * 2005-09-29 2007-04-12 Astrazeneca Ab 5- (phenylisoxazolylethoxy) -triazol- 3 -yl substituted pyridine compounds for the treatment of neurological, psychiatric or pain disorders
WO2007115077A2 (en) * 2006-03-31 2007-10-11 Astrazeneca Ab Bicyclic benzimidazole compounds and their use as metabotropic glutamate receptor potentiators
WO2007115077A3 (en) * 2006-03-31 2007-12-27 Astrazeneca Ab Bicyclic benzimidazole compounds and their use as metabotropic glutamate receptor potentiators
US7678796B2 (en) 2006-05-05 2010-03-16 Astrazeneca Ab MGluR5 modulators I
US8012981B2 (en) 2006-06-15 2011-09-06 Glaxo Group Limited Benzylpiperazine derivatives as motilin receptor agonists
US8853218B2 (en) 2006-06-28 2014-10-07 Glaxo Group Limited Compounds
US8299111B2 (en) 2006-07-28 2012-10-30 Boehringer Ingelheim International Gmbh Compounds which modulate the CB2 receptor
US8183263B2 (en) 2007-05-22 2012-05-22 Achillion Pharmaceuticals, Inc. Heteroaryl substituted thiazoles
US8546563B2 (en) 2007-11-07 2013-10-01 Boehringer Ingelheim International Gmbh Compounds which modulate the CB2 receptor
US8765743B2 (en) 2008-06-05 2014-07-01 Glaxosmithkline Intellectual Property Development Limited Compounds
US8658635B2 (en) 2008-06-05 2014-02-25 Glaxosmithkline Intellectual Property Development Limited Benzpyrazol derivatives as inhibitors of PI3 kinases
US8536169B2 (en) 2008-06-05 2013-09-17 Glaxo Group Limited Compounds
US8106209B2 (en) 2008-06-06 2012-01-31 Achillion Pharmaceuticals, Inc. Substituted aminothiazole prodrugs of compounds with anti-HCV activity
US8716317B2 (en) 2008-06-09 2014-05-06 Sanofi Sulfonamides with heterocycle and oxadiazolone headgroup, processes for their preparation and their use as pharmaceuticals
US8178568B2 (en) 2008-07-10 2012-05-15 Boehringer Ingelheim International Gmbh Sulfone compounds which modulate the CB2 receptor
US8124764B2 (en) 2008-07-14 2012-02-28 Gilead Sciences, Inc. Fused heterocyclyc inhibitor compounds
US8134000B2 (en) 2008-07-14 2012-03-13 Gilead Sciences, Inc. Imidazolyl pyrimidine inhibitor compounds
US8344018B2 (en) 2008-07-14 2013-01-01 Gilead Sciences, Inc. Oxindolyl inhibitor compounds
US8088771B2 (en) 2008-07-28 2012-01-03 Gilead Sciences, Inc. Cycloalkylidene and heterocycloalkylidene inhibitor compounds
US8349871B2 (en) 2008-09-25 2013-01-08 Boehringer Ingelheim International Gmbh Therapeutic uses of compounds which selectively modulate the CB2 receptor
US8362039B2 (en) 2008-09-25 2013-01-29 Boehringer Ingelheim International Gmbh Therapeutic uses of compounds which selectively modulate the CB2 receptor
US8372874B2 (en) 2008-09-25 2013-02-12 Boehringer Ingelheim International Gmbh Compounds which selectively modulate the CB2 receptor
US8048899B2 (en) 2008-09-25 2011-11-01 Boehringer Ingelheim International Gmbh Compounds which selectively modulate the CB2 receptor
US8889670B2 (en) 2009-02-18 2014-11-18 Boehringer Ingelheim International Gmbh Heterocyclic compounds which modulate the CB2 receptor
US8524751B2 (en) 2009-03-09 2013-09-03 GlaxoSmithKline Intellecutual Property Development 4-oxadiazol-2-YL-indazoles as inhibitors of P13 kinases
US8609657B2 (en) 2009-04-30 2013-12-17 Glaxosmithkline Intellectual Property Development Limited Compounds
US8575162B2 (en) 2009-04-30 2013-11-05 Glaxosmithkline Intellectual Property Development Limited Compounds
US8580797B2 (en) 2009-04-30 2013-11-12 Glaxo Smith Kline Intellectual Property Development Limited Compounds
US8586583B2 (en) 2009-04-30 2013-11-19 Glaxosmithkline Intellectual Property Development Limited Compounds
US8586590B2 (en) 2009-04-30 2013-11-19 Glaxosmithkline Intellectual Property Development Limited Compounds
US10624898B2 (en) 2009-04-30 2020-04-21 Glaxo Group Limited Compounds
US10383879B2 (en) 2009-04-30 2019-08-20 Glaxo Group Limited Compounds
US10946025B2 (en) 2009-04-30 2021-03-16 Glaxo Group Limited Compounds
US8252829B2 (en) 2009-06-05 2012-08-28 Link Medicine Corporation Aminopyrrolidinone derivatives and uses thereof
US8258316B2 (en) 2009-06-08 2012-09-04 Gilead Sciences, Inc. Alkanoylamino benzamide aniline HDAC inhibitor compounds
US8283357B2 (en) 2009-06-08 2012-10-09 Gilead Sciences, Inc. Cycloalkylcarbamate benzamide aniline HDAC inhibitor compounds
US8735430B2 (en) 2009-06-15 2014-05-27 Boehringer Ingelheim International Gmbh Compounds which selectively modulate the CB2 receptor
US8299103B2 (en) 2009-06-15 2012-10-30 Boehringer Ingelheim International Gmbh Compounds which selectively modulate the CB2 receptor
US8383615B2 (en) 2009-06-16 2013-02-26 Boehringer Ingelheim International Gmbh Azetidine 2-carboxamide derivatives which modulate the CB2 receptor
US8383651B2 (en) 2009-09-22 2013-02-26 Boehringer Ingelheim International Gmbh Compounds which selectively modulate the CB2 receptor
US9315454B2 (en) 2010-01-15 2016-04-19 Boehringer Ingelheim International Gmbh Compounds which modulate the CB2 receptor
US8329735B2 (en) 2010-03-05 2012-12-11 Boehringer Ingelheim International Gmbh Tetrazole compounds which selectively modulate the CB2 receptor
US9730886B2 (en) 2010-04-23 2017-08-15 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US11369565B2 (en) 2010-04-23 2022-06-28 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US10765624B2 (en) 2010-04-23 2020-09-08 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US10272030B2 (en) 2010-04-23 2019-04-30 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US10076519B2 (en) 2010-04-23 2018-09-18 Cytokinetics, Inc. Substituted pyridazines as skeletal muscle modulators
US9604965B2 (en) 2010-04-23 2017-03-28 Cytokinetics, Inc. Substituted pyridazines as skeletal muscle modulators
US9994528B2 (en) 2010-04-23 2018-06-12 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
US8846936B2 (en) 2010-07-22 2014-09-30 Boehringer Ingelheim International Gmbh Sulfonyl compounds which modulate the CB2 receptor
US8993576B2 (en) 2010-10-27 2015-03-31 Glaxo Group Limited 6-(1H-indol-4-yl)-4-(5-{[4-1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazole hemi succinate salt, polymorphs and pharmaceutical compositions thereof
US8796310B2 (en) 2011-05-04 2014-08-05 Merck Sharp & Dohme Corp. Amino-pyridine-containing spleen tyrosine kinase (SYK) inhibitors
US10844053B2 (en) 2011-10-11 2020-11-24 Dana-Farber Cancer Institute, Inc. Pyrazol-3-ones that activate pro-apoptotic BAX
US9303024B2 (en) 2011-10-11 2016-04-05 Dana-Farber Cancer Institute, Inc. Pyrazol-3-ones that activate pro-apoptotic BAX
US11358960B2 (en) 2011-10-11 2022-06-14 Dana-Farber Cancer Institute, Inc. Pyrazol-3-ones that activate pro-apoptotic BAX
US10351554B2 (en) 2011-10-11 2019-07-16 Dana-Farber Cancer Institute, Inc. Pyrazol-3-ones that activate pro-apoptotic BAX
US10000478B2 (en) 2011-10-11 2018-06-19 Dana-Farber Cancer Institute, Inc. Pyrazol-3-ones that activate pro-apoptotic BAX
US8729263B2 (en) 2012-08-13 2014-05-20 Novartis Ag 1,4-disubstituted pyridazine analogs there of and methods for treating SMN-deficiency-related conditions
US10195196B2 (en) 2012-08-13 2019-02-05 Novartis Ag 1,4-disubstituted pyridazine analogs there of and methods for treating SMN-deficiency-related conditions
US11229648B2 (en) 2012-08-13 2022-01-25 Novartis Ag 1,4-disubstituted pyridazine analogs thereof and methods for treating SMN-deficiency-related conditions
US9545404B2 (en) 2012-08-13 2017-01-17 Novartis Ag 1,4-disubstituted pyridazine analogs there of and methods for treating SMN-deficiency-related conditions
US10758533B2 (en) 2012-08-13 2020-09-01 Novartis Ag 1,4-disubstituted pyridazine analogs there of and methods for treating SMN-deficiency-related conditions
US9040712B2 (en) 2013-01-23 2015-05-26 Novartis Ag Thiadiazole analogs thereof and methods for treating SMN-deficiency-related-conditions
US11053195B2 (en) 2013-03-15 2021-07-06 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10570125B2 (en) 2013-05-17 2020-02-25 Centrexion Therapeutics Corporation (Cyano-dimethyl-methyl)-isoxazoles and -[1,3,4]thiadiazoles
US11725004B2 (en) 2013-05-17 2023-08-15 Centrexion Therapeutics Corporation (Cyano-dimethyl-methyl)-isoxazoles and -[1,3,4]thiadiazoles
US10112934B2 (en) 2013-05-17 2018-10-30 Centrexion Therapeutics Corporation (Cyano-dimethyl-methyl)-isoxazoles and -[1,3,4]thiadiazoles
US9650370B2 (en) 2013-05-17 2017-05-16 Centrexion Therapeutics Corporation (Cyano-dimethyl-methyl)-isoxazoles and -[1,3,4]thiadiazoles
US8865744B1 (en) 2013-05-17 2014-10-21 Boehringer Ingelheim International Gmbh (Cyano-dimethyl-methyl)-isoxazoles and -[1,3,4]thiadiazoles
US11084810B2 (en) 2013-05-17 2021-08-10 Centrexion Therapeutics Corporation (Cyano-dimethyl-methyl)-isoxazoles and -[1,3,4]thiadiazoles
US11672799B2 (en) 2013-07-31 2023-06-13 Novartis Ag 1,4-disubstituted pyridazine quinolne analogs there of and methods for treating SMN-deficiency-related conditions
US10450269B1 (en) 2013-11-18 2019-10-22 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10973817B2 (en) 2014-02-10 2021-04-13 Sentinel Oncology Limited Pharmaceutical compounds
US11786524B2 (en) 2014-02-10 2023-10-17 Sentinel Oncology Limited Pharmaceutical compounds
US9771379B2 (en) 2015-09-24 2017-09-26 Pfizer Inc. N-(2-(2-amino-6-substituted-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]OXAZIN-8a(8H)-yl)-thiazol-4-yl) amides
US11247987B2 (en) 2017-10-06 2022-02-15 Forma Therapeutics, Inc. Inhibiting ubiquitin specific peptidase 30
US11535618B2 (en) 2018-10-05 2022-12-27 Forma Therapeutics, Inc. Fused pyrrolines which act as ubiquitin-specific protease 30 (USP30) inhibitors
US11814386B2 (en) 2018-10-05 2023-11-14 Forma Therapeutics, Inc. Fused pyrrolines which act as ubiquitin-specific protease 30 (USP30) inhibitors
US11014911B2 (en) 2019-01-31 2021-05-25 Pfizer Inc. CDK2 inhibitors
US11718603B2 (en) 2019-01-31 2023-08-08 Pfizer Inc. CDK2 inhibitors
US11773082B2 (en) 2019-01-31 2023-10-03 Pfizer Inc. CDK2 inhibitors

Also Published As

Publication number Publication date
WO2005077368A3 (en) 2005-11-24

Similar Documents

Publication Publication Date Title
WO2005077368A2 (en) Treatment of gastro-esophageal reflux disease (gerd)
WO2005077345A1 (en) Compounds for the treatment of gastro-esophageal reflux disease
WO2005077373A2 (en) Treatment of gastro-esophageal reflux disease (gerd)
TWI358409B (en) Heteroaryl substituted piperidine derivatives
US9776997B2 (en) 3-aryl-substituted imidazo[1,2-A]pyridines and their use
JP5511379B2 (en) CGRP receptor antagonist
EP2906553B1 (en) Orexin receptor antagonists which are [ortho bi (hetero )aryl]-[2-(meta bi (hetero)aryl)-pyrrolidin-1-yl]-methanone derivatives
EP2544679B1 (en) Pde10 inhibitors and related compositions and methods
US8354398B2 (en) Substituted isoxazole compounds
JP5552430B2 (en) P2X3 receptor antagonist for the treatment of pain
JP7098214B2 (en) Use of sGC stimulants for the treatment of non-alcoholic steatohepatitis (NASH)
AU2018282747A1 (en) Compounds for modulating S1P1 activity and methods of using the same
CA2728161C (en) Therapeutic agent for inflammatory bowel disease
EP1697333A1 (en) (3,4-disubstituted)propanoic carboxylates as s1p (edg) receptor agonists
EP2370431A1 (en) 1, 2, 4 -oxadiazole derivatives and their therapeutic use
TW200538113A (en) Compounds
KR20130004316A (en) Bisaryl-bonded aryltriazolones and use thereof
AU2003241585B2 (en) Use of mGluR5 antagonists for the treatment of GERD
KR20080000622A (en) Novel oxadiazole derivatives and their medical use
JP2009298786A (en) Inhibitor of akt activity
TW200901995A (en) Pharmaceutical compositions and their methods of use
TW201130821A (en) Benzimidazole inhibitors of leukotriene production
TW201536777A (en) 2,3-dihydrobenzofuran-5-yl compounds as DYRK kinase inhibitors
JP2002121153A (en) Combined therapy for depression and anxiety
TW200815428A (en) Oxazolidone derivatives as PR modulators

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase in:

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

122 Ep: pct application non-entry in european phase