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WO2005077368A2 - Nouveau traitement du reflux gastro-oesophagien pathologique iii - Google Patents

Nouveau traitement du reflux gastro-oesophagien pathologique iii Download PDF

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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
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WO
WIPO (PCT)
Prior art keywords
alkyl
oxadiazol
ylmethyl
benzonitrile
piperidin
Prior art date
Application number
PCT/US2005/000334
Other languages
English (en)
Other versions
WO2005077368A3 (fr
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/fr
Publication of WO2005077368A3 publication Critical patent/WO2005077368A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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.

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  • Veterinary Medicine (AREA)
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  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation d'un composé de formule (I) destiné à inhiber les relaxations transitoires du sphincter inférieur de l'oesophage. Un autre aspect de l'invention concerne l'utilisation des composés de formule (I) pour le traitement du reflux gastro-oesophagien pathologique.
PCT/US2005/000334 2004-02-03 2005-01-07 Nouveau traitement du reflux gastro-oesophagien pathologique iii WO2005077368A2 (fr)

Applications Claiming Priority (2)

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US54106004P 2004-02-03 2004-02-03
US60/541,060 2004-02-03

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WO2005077368A2 true WO2005077368A2 (fr) 2005-08-25
WO2005077368A3 WO2005077368A3 (fr) 2005-11-24

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WO2007040982A1 (fr) * 2005-09-29 2007-04-12 Astrazeneca Ab Composes pyridine a substitution 5-(phenlyisoxazolylethoxy)-triazol-3-yl pour le traitement de troubles neurologiques, psychiatriques ou douloureux
WO2007115077A3 (fr) * 2006-03-31 2007-12-27 Astrazeneca Ab Composés de benzimidazole bicyclique et leur utilisation comme potentialisateurs du récepteur métabotropique du glutamate
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
US8088771B2 (en) 2008-07-28 2012-01-03 Gilead Sciences, Inc. Cycloalkylidene and heterocycloalkylidene inhibitor compounds
US8088806B2 (en) 2005-05-09 2012-01-03 Achillion Pharmaceuticals, Inc. Thiazole compounds and methods of use
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
US8299111B2 (en) 2006-07-28 2012-10-30 Boehringer Ingelheim International Gmbh Compounds which modulate the CB2 receptor
US8299103B2 (en) 2009-06-15 2012-10-30 Boehringer Ingelheim International Gmbh Compounds which selectively 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
US8536169B2 (en) 2008-06-05 2013-09-17 Glaxo Group Limited Compounds
US8536182B2 (en) 2005-07-26 2013-09-17 Glaxo Group Limited Benzylpiperazine derivatives and their medical use
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
US12049466B2 (en) 2018-05-17 2024-07-30 Forma Therapeutics, Inc. Fused bicyclic compounds useful as ubiquitin-specific peptidase 30 inhibitors
US12291524B2 (en) 2022-05-19 2025-05-06 Astrazeneca Ab Amido heteroaromatic compounds

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

Family Cites Families (7)

* 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
NZ227841A (en) * 1988-02-12 1991-08-27 Merck Sharp & Dohme Heterocyclic compounds with at least two non-condensed five membered rings and pharmaceutical compositions
IL96891A0 (en) * 1990-01-17 1992-03-29 Merck Sharp & Dohme Indole-substituted five-membered heteroaromatic compounds,their preparation and pharmaceutical compositions containing them
US5492919A (en) * 1991-08-03 1996-02-20 Smithkline Beecham P.L.C. 5-HT4 receptor antagonists
WO1995032965A1 (fr) * 1994-06-01 1995-12-07 Yamanouchi Pharmaceutical Co. Ltd. Derive de l'oxadiazole et composition medicinale a base de ce dernier
SE0201943D0 (sv) * 2002-06-20 2002-06-20 Astrazeneca Ab New use
MXPA05001590A (es) * 2002-08-09 2005-05-23 Astrazeneca Ab Compuestos que tienen actividad en los receptores metabotropicos de glutamato.

Cited By (87)

* 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 (fr) * 2005-09-29 2007-04-12 Astrazeneca Ab Composes pyridine a substitution 5-(phenlyisoxazolylethoxy)-triazol-3-yl pour le traitement de troubles neurologiques, psychiatriques ou douloureux
WO2007115077A3 (fr) * 2006-03-31 2007-12-27 Astrazeneca Ab Composés de benzimidazole bicyclique et leur utilisation comme potentialisateurs du récepteur métabotropique du glutamate
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
US8536169B2 (en) 2008-06-05 2013-09-17 Glaxo Group Limited Compounds
US8658635B2 (en) 2008-06-05 2014-02-25 Glaxosmithkline Intellectual Property Development Limited Benzpyrazol derivatives as inhibitors of PI3 kinases
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
US10946025B2 (en) 2009-04-30 2021-03-16 Glaxo Group Limited Compounds
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
US10383879B2 (en) 2009-04-30 2019-08-20 Glaxo Group Limited Compounds
US10624898B2 (en) 2009-04-30 2020-04-21 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
US8299103B2 (en) 2009-06-15 2012-10-30 Boehringer Ingelheim International Gmbh Compounds which selectively modulate the CB2 receptor
US8735430B2 (en) 2009-06-15 2014-05-27 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
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
US9730886B2 (en) 2010-04-23 2017-08-15 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
US10351554B2 (en) 2011-10-11 2019-07-16 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
US10000478B2 (en) 2011-10-11 2018-06-19 Dana-Farber Cancer Institute, Inc. Pyrazol-3-ones that activate pro-apoptotic BAX
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
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
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
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
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
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
US10112934B2 (en) 2013-05-17 2018-10-30 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
US12344601B2 (en) 2013-05-17 2025-07-01 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
US10570125B2 (en) 2013-05-17 2020-02-25 Centrexion Therapeutics Corporation (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
US9650370B2 (en) 2013-05-17 2017-05-16 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
US12049466B2 (en) 2018-05-17 2024-07-30 Forma Therapeutics, Inc. Fused bicyclic compounds useful as ubiquitin-specific peptidase 30 inhibitors
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
US11718603B2 (en) 2019-01-31 2023-08-08 Pfizer Inc. CDK2 inhibitors
US11014911B2 (en) 2019-01-31 2021-05-25 Pfizer Inc. CDK2 inhibitors
US11773082B2 (en) 2019-01-31 2023-10-03 Pfizer Inc. CDK2 inhibitors
US12291524B2 (en) 2022-05-19 2025-05-06 Astrazeneca Ab Amido heteroaromatic compounds

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