WO2002078707A1 - Sulfonamides pyrrolidines - Google Patents

Sulfonamides pyrrolidines Download PDF

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Publication number
WO2002078707A1
WO2002078707A1 PCT/US2002/009445 US0209445W WO02078707A1 WO 2002078707 A1 WO2002078707 A1 WO 2002078707A1 US 0209445 W US0209445 W US 0209445W WO 02078707 A1 WO02078707 A1 WO 02078707A1
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WO
WIPO (PCT)
Prior art keywords
methyl
piperazin
butyl
yloxy
thiophene
Prior art date
Application number
PCT/US2002/009445
Other languages
English (en)
Inventor
Dashyant Dhanak
Steven D. Knight
Jian Jin
Ralph A. Rivero
Anthony Sapienza
Original Assignee
Smithkline Beecham Corporation
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 Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to JP2002576973A priority Critical patent/JP2004524355A/ja
Priority to EP02757820A priority patent/EP1381365A4/fr
Priority to US10/472,976 priority patent/US20040138224A1/en
Publication of WO2002078707A1 publication Critical patent/WO2002078707A1/fr
Priority to US11/119,026 priority patent/US7019008B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to pyrrolidine sulfonamides, pharmaceutical compositions containing them and their use as urotensin II antagonists
  • cardiovascular homeostasis The integrated control of cardiovascular homeostasis is achieved through a combination of both direct neuronal control and systemic neurohormonal activation. Although the resultant release of both contractile and relaxant factors is normally under stringent regulation, an aberration in this status quo can result in cardiohemodynamic dysfunction with pathological consequences.
  • the principal mammalian vasoactive factors that comprise this neurohumoral axis namely angiotensin-II, endothelin-1, norepinephrine, all function via an interaction with specific G-protein coupled receptors (GPCR).
  • GPCR G-protein coupled receptors
  • this peptide has significant hemodynamic and endocrine actions in diverse end-organ systems and tissues:
  • osmoregulation effects which include the modulation of transepithelial ion (Na + , Cl " ) transport. Although a diuretic effect has been described, such an effect is postulated to be secondary to direct renovascular effects (elevated GFR)
  • Compounds that antagonize the Urotensin-II receptor may be useful in the treatment of congestive heart failure, stroke, ischemic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), COPD, fibrosis (e.g. pulmonary fibrosis), restenosis, atherosclerosis, dyslipidemia, asthma, (Hay DWP, Luttmann MA, Douglas SA: 2000, Br J Pharmacol: 131; 10-12) neurogenic inflammation and metabolic vasculopathies all of which are characterized by abnormal vasoconstriction and/or myocardial dysfunction. Since U-H and GPR14 are both expressed within the mammalian CNS (Ames et. al.
  • this invention provides for pyrrolidine sulfonamides and pharmaceutical compositions containing them.
  • this invention provides for the use of pyrrolidine sulfonamides as antagonists of urotensin II, and as inhibitors of urotensin II.
  • this invention provides for the use of pyrrolidine sulfonamides for treating conditions associated with urotensin II imbalance.
  • this invention provides for the use of pyrrolidine sulfonamides for the treatment of congestive heart failure, stroke, ischemic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), COPD, restenosis, asthma, neurogenic inflammation, migraine, metabolic vasculopathies, bone/cartilage/joint diseases, arthritis and other inflammatory diseases, fibrosis (e.g.
  • pulmonary fibrosis sepsis
  • atherosclerosis dyslipidemia
  • addiction schizophrenia, cognitive disorders/Alzheimers disease, impulsivity, anxiety, stress, depression, pain, neuromuscular function, diabetes, gastric reflux, gastric motility disorders, ulcers and genitourinary diseases.
  • the urotensin antagonist may be administered alone or in conjunction with one or more other therapeutic agents, said agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, A-II receptor antagonists, vasopeptidase inhibitors, diuretics, digoxin, and dual non-selective ⁇ - adrenoceptor and j -adrenoceptor antagonists.
  • ACE angiotensin converting enzyme
  • the present invention provides for compounds of Formula (I):
  • R2 is benzimidazolyl, quinolinyl, benzofuranyl, napthyl, indolyl, or benzothiophenyl, phenyl, furanyl, thienyl, or pyridyl substituted or unsubstituted by one, two or three halogen, C ⁇ _3 alkyl, Cj.3 alkoxy, or methylenedioxy groups;
  • R is C _6 alkyl, benzyl, or (CH2) n -C(0)NH2; wherein the benzyl may be unsubstituted or substituted by one or two C . alkyl, halogen, C j .g alkoxy, or methylenedioxy groups;
  • X j and X2 are independently hydrogen, halogen, C1.3 alkyl, Cj_3 alkoxy, nitro, CF3, or CN; n is 1, 2, or 3; m is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.
  • alkyl includes all straight chain and branched isomers.
  • Representative examples thereof include methyl, ethyl, n-propyl, w ⁇ -propyl, n-butyl, sec- butyl, iso-batyl, t-butyl, /z-pentyl and n-hexyl.
  • halogen' and halo' include fluorine, chlorine, bromine and iodine and fluoro, chloro, bromo and iodo, respectively.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active form. All of these compounds and their diastereoisomers are contemplated to be within the scope of the present invention.
  • R2 is benzothiopheneyl
  • X j is hydrogen, 3-Bromo, or 3-Chloro; and X2 is hydrogen or 5-Chloro.
  • Benzo[b]thiophene-2-carboxylic acid [(S)-l-(2- ⁇ 4-[3-bromo-4-((S)-pyrrolidin-3-yloxy)- benzenesulfonyl]-piperazin-l-yl ⁇ -ethylcarbamoyl)-3-methyl-butyl]-amide
  • Benzo[b]thiophene-2-carboxylic acid [(S)-3-methyl-l-(2- ⁇ 4-[4-(piperidin-4-yloxy) ⁇ benzenesulfonyl]-piperazin-l-yl ⁇ -ethylcarbamoyl)-butyl]-amide
  • resin-bound amine 3 was prepared by reductive animation of 2,6-dimethoxy-4-polystyrenebenzyloxy-benzaldehyde (DMHB resin) piperazinyl- ethylamine HCl salt 2 which was prepared from l-(2-aminoethyl)piperazine (1). Reactions of resin-bound amine 3 with various amino acids, followed by removal of the protecting group, resulted in the corresponding resin-bound amines 4. Amines 4 were then reacted with various acids to afford the corresponding resin-bound amides 5. Resin-bound amides 5 were subsequently treated with potassium carbonate and thiophenol to give secondary amines 6.
  • DMHB resin 2,6-dimethoxy-4-polystyrenebenzyloxy-benzaldehyde
  • Compounds of Formula (I) and their pharmaceutically acceptable salts may be administered in a standard manner for the treatment of the indicated diseases, for example orally, parenterally, sub-lingually, transdermally, rectally, via inhalation or via buccal administration.
  • Compounds of Formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as syrups, tablets, capsules and lozenges.
  • a syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavoring or coloring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used.
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils and are incorporated in a soft gelatin capsule shell.
  • Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil, or sesame oil.
  • a parenterally acceptable oil for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil, or sesame oil.
  • compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.
  • a typical suppository formulation comprises a compound of Formula (1) or a pharmaceutically acceptable salt thereof which is active when administered in this way, , with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa- ' > butter or other low melting vegetable waxes or fats or their synthetic analogues.
  • Typical transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to themselves a single dose.
  • Each dosage unit for oral administration contains suitably from 0.1 mg to 500 mg/Kg, and preferably from 1 mg to 100 mg/Kg, and each dosage unit for parenteral administration contains suitably from 0.1 mg to 100 mg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid.
  • Each dosage unit for intranasal administration contains suitably 1-400 mg and preferably 10 to 200 mg per person.
  • a topical formulation contains suitably 0.01 to 1.0% of a compound of Formula (I).
  • the daily dosage regimen for oral administration is suitably about 0.01 mg/Kg to 40 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid.
  • the daily dosage regimen for parenteral administration is suitably about 0.001 mg/Kg to 40 mg/Kg, of a compound of the Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid.
  • the daily dosage regimen for intranasal administration and oral inhalation is suitably about 10 to about 500 mg/person.
  • the active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity.
  • sulphonamide analogs may be used for the treatment of congestive heart failure, stroke, ischemic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), COPD, restenosis, asthma, neurogenic inflammation and metabolic vasculopathies, addiction, schizophrenia, impulsivity, anxiety, stress, depression, neuromuscular function, and diabetes.
  • the urotensin antagonist may be administered alone or in conjunction with one or more other therapeutic agents, said agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, vasopeptidase inhibitors, diuretics, digoxin, and dual non-selective ⁇ -adrenoceptor and oq- adrenoceptor antagonists.
  • agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, vasopeptidase inhibitors, diuretics, digoxin, and dual non-selective ⁇ -adrenoceptor and oq- adrenoceptor antagonists.
  • ACE angiotensin converting enzyme
  • Radioligand binding HEK-293 cell membranes containing stable cloned human and rat GPR-14 (20 ug/assay) were incubated with 200 pM [1251] h-U-II (200 Ci/mmol "1 in the presence of increasing concentrations of test compounds in DMSO (0.1 nM to 10 uM), in a final incubation volume of 200 ul (20 mM Tris-HCl, 5 mM MgC12). Incubation was done for 30 minutes at room temperature followed by filtration GF/B filters with Brandel cell harvester. 1 5 ⁇ l beled U-II binding was quantitated by gamma counting. Nonspecific binding was defined by 125j u_ ⁇ binding in the presence of 100 nM of unlabeled human U-II. Analysis of the data was performed by nonlinear least square fitting.
  • Ca 2+ -mobilization A microtitre plate based Ca 2+ -mobilization FLIPR assay (Molecular Devices,
  • HEK-293-GPR14 cells in T150 flask were prelabeled overnight with 1 uCi myo- H] inositol per ml of inositol free Dulbecco's modified Eagel's medium. After labeling, the cells were washed twice with Dulbecco's phosphate-buffered saline (DPBS) and then incubated in DPBS containing 10 mM LiCl for 10 min at 37°C.
  • DPBS Dulbecco's phosphate-buffered saline
  • the experiment was initiated by the addition of increasing concentrations of h-U-II (1 pM to l ⁇ M ) in the absence and presence of three different concentrations (0.3, 1 and 10 uM) of test compounds and the incubation continued for an additional 5 min at 37°C after which the reaction was terminated by the addition of 10% (final concentration) trichloroacetic acid and centrifugation.
  • the supematants were neutralized with lOOul of IM Trizma base and the inositol phosphates were separated on AG 1-X8 columns (0.8 ml packed, 100-200 mesh) in formate phase. Inositol monophosphate was eluted with 8 ml of 200 mM ammonium formate.
  • the resulting mixture was stirred at 0 °C for 1 h and warmed to rt and stirred at rt for 16 h.
  • the mixture was diluted with 1.5 L of CH 2 C1 2 and poured into 1 L of 1 M NaHC0 3 aqueous solution. After stirring for 15 min, the organic layer was separated and washed with 1 L of 1 M NaHC0 3 aqueous solution. The resulting organic layer was dried over K2CO3 and concentrated in vacuo. The residue was dissolved into 400 mL of 1,4-dioxane. The solution was concentrated in vacuo to remove the remaining triethylamine.
  • the above resin (7.914 mmol) was treated with 175 mL of 20% piperidine in anhydrous l-methyl-2-pyrrolidinone solution. After the mixture was shaken at rt for 15 min, the solution was drained and another 175 mL of 20% piperidine in anhydrous 1- methyl-2-pyrrolidinone solution was added. The mixture was shaken at rt for another 15 min. The solution was drained and the resin was washed with l-methyl-2-pyrrolidinone (3 x 175 mL), CH 2 Cl 2 /MeOH (1:1, 3 x 175 mL) and CH 2 C1 2 (3 x 175 mL).
  • the mixture was then allowed to warm to 0 °C over 1 h and shaken at rt for 19 h.
  • the resin was washed with tetrahydrofuran (3 x 10 mL), CH 2 Cl 2 /methanol (1:1, 10 x 10 mL).
  • the resulting resin was dried in vacuum oven at 35 °C for 24 h.
  • the dry resin was treated with
  • EXAMPLE 11 Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given below.
  • Step 1 Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitable mixer/blender.
  • Step 2 Add sufficient water portion-wise to the blend from Step 1 with careful mixing after each addition. Such additions of water and mixing until the mass is of a consistency to permit its conversion to wet granules.
  • Step 3 The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen.
  • Step 4 The wet granules are then dried in an oven at 140°F (60°C) until dry.
  • Step 5 The dry granules are lubricated with ingredient No. 5.
  • Step 6 The lubricated granules are compressed on a suitable tablet press.
  • a compound of Formula I (1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use.
  • a pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of a compound of formula I in polyethylene glycol with heating. This solution is then diluted with water for injections Ph Eur. (to 100 ml). The solution is then sterilized by filtration through a 0.22 micron membrane filter and sealed in sterile containers.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Psychiatry (AREA)
  • Diabetes (AREA)
  • Hospice & Palliative Care (AREA)
  • Pulmonology (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Emergency Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Addiction (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention porte sur des sulfonamides pyrrolidines, sur des compositions pharmaceutiques les contenant et sur leur utilisation en tant qu'antagonistes d'urotensine II.
PCT/US2002/009445 2001-03-29 2002-03-28 Sulfonamides pyrrolidines WO2002078707A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2002576973A JP2004524355A (ja) 2001-03-29 2002-03-28 ピロリジンスルホンアミド
EP02757820A EP1381365A4 (fr) 2001-03-29 2002-03-28 Sulfonamides pyrrolidines
US10/472,976 US20040138224A1 (en) 2002-03-28 2002-03-28 Pyrrolidine sulfonamides
US11/119,026 US7019008B2 (en) 2001-03-29 2005-04-29 Pyrrolidine sulfonamides

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US27961001P 2001-03-29 2001-03-29
US27959201P 2001-03-29 2001-03-29
US60/279,592 2001-03-29
US60/279,610 2001-03-29

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US10472976 A-371-Of-International 2002-03-28
US11/119,026 Continuation US7019008B2 (en) 2001-03-29 2005-04-29 Pyrrolidine sulfonamides

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Publication Number Publication Date
WO2002078707A1 true WO2002078707A1 (fr) 2002-10-10

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JP (1) JP2004524355A (fr)
WO (1) WO2002078707A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7375227B2 (en) 2001-12-04 2008-05-20 Actelion Pharmaceuticals Ltd. Quinoline derivatives
US7750161B2 (en) 2003-09-26 2010-07-06 Daniel Bur Pyridine derivatives
US8067601B2 (en) 2004-10-12 2011-11-29 Actelion Pharmaceticals Ltd. 1-[2-(4-benzyl-4-hydroxy-piperidin-1 -yl )-ethyl]-3-(2-methyl-quinolin- 4-yl)- urea as crystalline sulfate salt

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6265408B1 (en) * 1996-06-20 2001-07-24 Smithkline Beecham Plc Sulphonamide derivatives and their use in the treatment of CNS disorders

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6265408B1 (en) * 1996-06-20 2001-07-24 Smithkline Beecham Plc Sulphonamide derivatives and their use in the treatment of CNS disorders

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1381365A4 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7375227B2 (en) 2001-12-04 2008-05-20 Actelion Pharmaceuticals Ltd. Quinoline derivatives
US7750161B2 (en) 2003-09-26 2010-07-06 Daniel Bur Pyridine derivatives
US8067601B2 (en) 2004-10-12 2011-11-29 Actelion Pharmaceticals Ltd. 1-[2-(4-benzyl-4-hydroxy-piperidin-1 -yl )-ethyl]-3-(2-methyl-quinolin- 4-yl)- urea as crystalline sulfate salt

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Publication number Publication date
EP1381365A1 (fr) 2004-01-21
EP1381365A4 (fr) 2005-03-23
JP2004524355A (ja) 2004-08-12

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