WO2002090353A1 - Sulfonamides - Google Patents

Sulfonamides Download PDF

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Publication number
WO2002090353A1
WO2002090353A1 PCT/US2002/014408 US0214408W WO02090353A1 WO 2002090353 A1 WO2002090353 A1 WO 2002090353A1 US 0214408 W US0214408 W US 0214408W WO 02090353 A1 WO02090353 A1 WO 02090353A1
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Prior art keywords
methyl
chloro
phenyl
alkyl
pyrrolidin
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PCT/US2002/014408
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English (en)
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Dashyant Dhanak
Timothy F. Gallagher
Steven D. Knight
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Smithkline Beecham Corporation
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Priority to JP2002587432A priority Critical patent/JP2004529170A/ja
Priority to US10/477,099 priority patent/US20040142948A1/en
Priority to EP02725952A priority patent/EP1385841A4/fr
Publication of WO2002090353A1 publication Critical patent/WO2002090353A1/fr

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Definitions

  • the present invention relates to sulfonamides, pharmaceutical compositions containing them and their use as urotensin II antagonists
  • 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)
  • 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.
  • Urotensin antagonists may provide end organ protection in hypersensitive cohorts in addition to lowering blood pressure. Since U-II and GPR14 are both expressed within the mammalian CNS (Ames et. al.
  • U-II receptors are expressed in rhabdomyosarcomas cell lines and therefore may have oncological indications.
  • Urotensin may also be implicated in various metabolic diseases such as diabetes (Ames et. al. Nature 1999, 401, 282, Nothacker et al., Nature Cell Biology 1 : 383-385, 1999) and in various gastrointestinal disorders, bone, cartilage, and joint disorders (e.g. arthritis and osteoporosis); and genito-urinary disorders. Therefore, these compounds may be useful for the prevention (treatment) of gastric reflux, gastric motility and ulcers, arthritis, osteoporosis and urinary incontinence.
  • this invention provides for sulfonamides and pharmaceutical compositions containing them.
  • this invention provides for the use of sulfonamides as antagonists of urotensin II, and as inhibitors of urotensin II.
  • this invention provides for the use of sulfonamides for treating conditions associated with urotensin II imbalance.
  • this invention provides for the use of sulfonamides for the treatment of congestive heart failure, stroke, ischemic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), renal disease (acute and chronic renal failure/end stage renal disease) along with peripheral vascular disease (male erectile dysfunction, diabetic retinopathy, intermittent claudication/ischemic limb disease) and ischemic/hemorrhagic stroke, 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, parkinsons, movement disorders, sleep-wake cycle, incentive motivation, 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 oq-adrenoceptor antagonists.
  • ACE angiotensin converting enzyme
  • the present invention provides for compounds of Formula (I):
  • Rl is naphthyl, quinolinyl, benzothiophenyl, benzthiadiazoyl, benzoaxdiazoyl, benzofuranyl, benzothiazoyl, benzoxazoyl, benzimidazoyl, benzodioxanyl, benzodioxoyl, benzodioxepinyl, naphthyridinyl, indoyl or quinazolinyl substituted or unsubstituted by one, two , three, four or five of any of the following: halogen, CF , OCF 3 , SCF 3 , N0 2 , CN, C ⁇ _ ⁇ alkyl, C ⁇ _ 6 alkoxy, NR 5 R 6 , CONR 7 R 8 , SC 1-6 alkyl, CO ⁇ C ⁇ alkyl), C . alkyl-COj C ] ,
  • R2 is hydrogen, halogen, CF3, CN or C 1.4 alkyl
  • R3, R4, R7, and R3 are independently hydrogen, . alkyl, or benzyl; R5, Rg, and R9, are independently hydrogen or C].g alkyl;
  • X is O, S or CH 2 ; n is 0, 1, or 2; or a pharmaceutically acceptable salt thereof.
  • alkyl includes all straight chain and branched isomers.
  • Representative examples thereof include methyl, ethyl, n-propyl, wo-propyl, n-butyl, sec- butyl, w ⁇ -butyl, t-butyl, n-pentyl and n-hexyl.
  • Tialogen' and nalo' 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.
  • Rl is naphthyl or benzodioxanyl, substituted or unsubstituted by halogen, or NR 5 R 6 .
  • R 2 is halogen
  • R3 is hydrogen
  • R4 is hydrogen
  • R5 is C . ⁇ alkyl.
  • Rg is C j .5 alkyl .
  • R9 is C 1.5 alkyl.
  • X is O.
  • n is i.
  • Preferred compounds are:
  • oxidation of aniline 8 gave nitrobenzene 9.
  • substitution of the aryl fluoride with various alcohols furnished the ethers 10.
  • Hydrogenation of the nitro group provided anilines 11, which were subsequently sulfonylated with variuos sulfonyl chlorides to furnish the target compounds 12.
  • 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.
  • 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.
  • a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavoring or coloring agent.
  • any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, agar, pectin, acacia, stearic acid, starch, lactose and sucrose.
  • composition is in the form of a capsule
  • any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • composition is in the form of a soft gelatin shell capsule
  • 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.
  • Typical 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.
  • 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.
  • 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
  • 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), renal disease (acute and chronic renal failure/end stage renal disease) along with peripheral vascular disease (male erectile dysfunction, diabetic retinopathy, intermittent claudication/ischemic limb disease) and ischemic/hemorrhagic stroke, 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
  • 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.
  • 125 ⁇ labeled U-II binding was quantitated by gamma counting. Nonspecific binding was defined by 125j j-II binding in the presence of 100 nM of unlabeled human U-II. Analysis of the data was performed by nonlinear least square fitting.
  • a microtitre plate based Ca 2+ -mobilization FLIPR assay (Molecular Devices, Sunnyvale, CA) was used for the functional identification of the ligand activating HEK-293 cells expressing (stable) recombinant GPR-14.
  • the day following transfection cells were plated in a poly-D-lysine coated 96 well black/clear plates. After 18-24 hours the media was aspirated and Fluo 3AM-loaded cells were exposed to various concentrations (10 nM to 30 uM) of test compounds followed by h-U-II. After initiation of the assay, fluorescence was read every second for one minute and then every 3 seconds for the following one minute. The inhibitory concentration at 50% (IC50)was calculated for various test compounds.
  • Inositol phosphates assays Molecular Devices, Sunnyvale, CA
  • HEK-293-GPR14 cells in T 150 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 supernatants were neutralized with lOOul of 1M 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.
  • 2-Chloro-5-nitroanisole (310 g, 1.7 mol) was taken up in a mixture of 48% aqueous hydrobromic acid (1.5 L) and acetic acid (1.2 L) and heated at reflux for 3 days. The dark solution was allowed to cool to room temperature, poured into ice water (10 L), and let stand for 3 h. The resultant dull yellow solid was filtered, washed with water, and dried in vacuo (230 g, 79%): mp 115-117 °C.
  • 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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Abstract

L'invention concerne des sulfonamides, des compositions pharmaceutiques les contenant, ainsi que leur utilisation en tant qu'antagonistes de l'urotensine II.
PCT/US2002/014408 2001-05-07 2002-05-07 Sulfonamides WO2002090353A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2002587432A JP2004529170A (ja) 2001-05-07 2002-05-07 スルホンアミド
US10/477,099 US20040142948A1 (en) 2002-05-07 2002-05-07 Sulfonamides
EP02725952A EP1385841A4 (fr) 2001-05-07 2002-05-07 Sulfonamides

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US28930601P 2001-05-07 2001-05-07
US60/289,306 2001-05-07

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005012275A2 (fr) * 2003-03-28 2005-02-10 Janssen Pharmaceutica, N.V. Composes benzo[1,2,5]thiadiazole
WO2006075808A1 (fr) * 2005-01-12 2006-07-20 Inje University Composition pharmaceutique comprenant un inhibiteur de p25/cdk5 permettant de prevenir ou de traiter une maladie neurodegenerative
US7265122B2 (en) 2003-02-28 2007-09-04 Encysive Pharmaceuticals, Inc. Pyridine, pyrimidine, quinoline, quinazoline, and naphthalene urotensin-II receptor antagonists
US7288538B2 (en) 2003-02-20 2007-10-30 Encysive Pharmaceuticals, Inc. Phenylenediamine urotensin-II receptor antagonists and CCR-9 antagonists
US7319111B2 (en) 2003-02-20 2008-01-15 Encysive Pharmaceuticals, Inc. Phenylenediamine Urotensin-II receptor antagonists and CCR-9 antagonists
US7320989B2 (en) 2003-02-28 2008-01-22 Encysive Pharmaceuticals, Inc. Pyridine, pyrimidine, quinoline, quinazoline, and naphthalene urotensin-II receptor antagonists
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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WO1998002708A2 (fr) * 1996-07-15 1998-01-22 Remington Arms Company, Inc. Ensemble culasse pour arme a feu electronique
WO1999038845A1 (fr) * 1998-01-29 1999-08-05 Tularik Inc. MODULATEURS DU RECEPTEUR ACTIVE DE LA PROLIFERATION DES PEROXYSOMES (PPARη)

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Publication number Priority date Publication date Assignee Title
WO1998002708A2 (fr) * 1996-07-15 1998-01-22 Remington Arms Company, Inc. Ensemble culasse pour arme a feu electronique
WO1999038845A1 (fr) * 1998-01-29 1999-08-05 Tularik Inc. MODULATEURS DU RECEPTEUR ACTIVE DE LA PROLIFERATION DES PEROXYSOMES (PPARη)

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7288538B2 (en) 2003-02-20 2007-10-30 Encysive Pharmaceuticals, Inc. Phenylenediamine urotensin-II receptor antagonists and CCR-9 antagonists
US7319111B2 (en) 2003-02-20 2008-01-15 Encysive Pharmaceuticals, Inc. Phenylenediamine Urotensin-II receptor antagonists and CCR-9 antagonists
US7265122B2 (en) 2003-02-28 2007-09-04 Encysive Pharmaceuticals, Inc. Pyridine, pyrimidine, quinoline, quinazoline, and naphthalene urotensin-II receptor antagonists
US7320989B2 (en) 2003-02-28 2008-01-22 Encysive Pharmaceuticals, Inc. Pyridine, pyrimidine, quinoline, quinazoline, and naphthalene urotensin-II receptor antagonists
WO2005012275A2 (fr) * 2003-03-28 2005-02-10 Janssen Pharmaceutica, N.V. Composes benzo[1,2,5]thiadiazole
WO2005012275A3 (fr) * 2003-03-28 2006-05-11 Janssen Pharmaceutica Nv Composes benzo[1,2,5]thiadiazole
US7241759B2 (en) 2003-03-28 2007-07-10 Janssen Pharmaceutica N.V. Benzo[1,2,5]thiadiazole compounds
US7550492B2 (en) 2003-03-28 2009-06-23 Janssen Pharmaceutica N.V. Benzo[1,2,5]thiadiazole compounds
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
WO2006075808A1 (fr) * 2005-01-12 2006-07-20 Inje University Composition pharmaceutique comprenant un inhibiteur de p25/cdk5 permettant de prevenir ou de traiter une maladie neurodegenerative

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