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WO2004043917A1 - Sulfonamides - Google Patents

Sulfonamides Download PDF

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Publication number
WO2004043917A1
WO2004043917A1 PCT/US2003/035351 US0335351W WO2004043917A1 WO 2004043917 A1 WO2004043917 A1 WO 2004043917A1 US 0335351 W US0335351 W US 0335351W WO 2004043917 A1 WO2004043917 A1 WO 2004043917A1
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WO
WIPO (PCT)
Prior art keywords
phenyl
oxy
trifluoromethyl
methyl
pyrrolidinyl
Prior art date
Application number
PCT/US2003/035351
Other languages
English (en)
Inventor
Linda S. Barton
Jason W. Dodson
Dimitri E. Gaitanopoulos
Gerald R. Girard
Bryan W. King
John Jeffrey Mcatee
Michael J. Neeb
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 AU2003291255A priority Critical patent/AU2003291255A1/en
Publication of WO2004043917A1 publication Critical patent/WO2004043917A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • 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
    • C07D409/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present mvention relates to 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)
  • Urotensin-II receptor 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.
  • Urotensin antagonists may provide end organ protection in hypersensitive cohorts in addition to lowering blood pressure.
  • U-II and GPR14 are both expressed within the mammalian CNS (Ames et. al. Nature 1999, 401, 282), they also may be useful in the treatment of addiction, schizophrenia, cognitive disorders/Alzheimers disease, (Gartlon J. Psychopharmacology (Berl) 2001 June; 155(4):426-33), impulsivity, anxiety, stress, depression, pain, migraine, neuromuscular function, parkinsons, movement disorders, sleep-wake cycle, and incentive motivation (Clark et al.Brain Research 923 (2001) 120-127. Functional 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.
  • diabetes Ames et. al. Nature 1999, 401, 282, Nothacker et al., Nature Cell Biology 1: 383-385, 1999
  • 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-IJ receptor antagonists, vasopeptidase inhibitors, diuretics, digoxin, and dual non-selective ⁇ -adrenoceptor and o -adrenoceptor antagonists.
  • ACE angiotensin converting enzyme
  • the present invention provides for compounds of Formula (I):
  • Ar is phenyl, pyridinyl, thienyl, furanyl, oxazoyl, pyrroyl, triazinyl, imidazoyl, pyrimidinyl, pyrazinyl, oxadiazoyl, pyrazoyl, triazoyl, thiazoyl, thiadiazoyl, naphthyl, quinolinyl, naphthyridinyl, benzodioxanyl, benzodioxoyl, benzodioxepinyl, azaspirononoyl, benothiophenyl, substituted or unsubstituted by one, two, three, or four of the following: halogen, CN, S(0) p (C 1 . 6 alkyl), CF 3 , OCF 3 , SCF3, C ⁇ _ 6 alkyl, Ph, OH, C j ⁇ alkoxy, CORi ⁇ ,
  • A is phenyl, pyridyl, thienyl, furanyl, , oxazoyl, pyrroyl, triazinyl, imidazoyl, pyrimidinyl, pyrazinyl, N-phenylpyrroyl, oxadiazoyl, pyrazoyl, triazoyl, thiazoyl, thiadiazoyl, naphthyl, indoyl, quinolinyl, quinazolinyl, naphthyridinyl, benzothiophenyl, benzofuranyl, benzodioxanyl, benzodioxoyl, benzodioxepinyl, benzothiazoyl, benzoxazoyl, benzothiadiazoyl, benzoxadiazoyl, or benzimidazoyl, all of which may be substituted or unsubstituted by one, two, three or four halogens,
  • Rl is hydrogen, C g alkyl, or -(CH 2 ) m R 1 ;
  • R 2 is hydrogen, halogen, CF3, CN, or C1.4 alkyl
  • R3 and R4 are independently hydrogen, C ⁇ . alkyl, benzyl, -C(Ri 3) 2 -ORn, -COOR ⁇ 2 ,
  • R5, Rg, R7, and Rg are independently hydrogen, Cj.g alkyl, or benzyl;
  • R is hydrogen or C j _g alkyl
  • R 12 is c 1-6 a]k y 1 '
  • Ri 3 is independently hydrogen or C ⁇ alkyl
  • X is O, S, or CH 2 ;
  • n is 0, 1 or 2;
  • m is 1 or 2;
  • p is 0, 1, or 2 provided that when R j4 is OH, m is 2; also provided that when A is thienyl, and Ar is phenyl, pyrazoyl, napthyl, quinolinyl, benzodioxoyl, or benzofuranyl, Y is not a bond; also provided that when A is phenyl and Y is a bond, Ar is attached ortho to S0 2 -; also provided that when Ar is phenyl, A is not pyridyl; 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, w ⁇ -butyl, t-butyl, n-pentyl and n-hexyl.
  • halogen' and halo' include fluorine, chlorine, bromine and iodine, and fluoro, chloro, bromo, and iodo, respectively.
  • Ar is preferably phenyl, pyridinyl, thienyl, furanyl, oxazoyl, pyrroyl, imidazoyl, pyrimidinyl, pyrazoyl, substituted or unsubstituted by one, two, or three of the following: Cl, Br, F, CN, S(0) p (C ⁇ _ 3 alkyl), CF 3 , C ⁇ _ 6 alkyl, OH, C ⁇ _ 3 alkoxy, CORi 1 , NR 5 R 6 ,
  • A is preferably phenyl, pyridyl, thienyl, furanyl, , oxazoyl, imadazolyl, pyrimidinyl, pyrazoyl, thiazoyl, all of which may be substituted or unsubstituted by one or two Cl, Br, F, C1-.3 alkyl, C _ alkoxy, CN, CF3 or N0 2 groups.
  • Y is preferably O, NH, -S(O p )-, CH 2 , or a bond.
  • Ri is preferably hydrogen or C j _ alkyl.
  • R is preferably hydrogen, Cl, Br, CF3, or C j _ 2 alkyl.
  • R3 and R4 are preferably hydrogen or C 1 -.3 alkyl.
  • R5, Rg, R 7 , and Rg are preferably hydrogen or C 1 .3 alkyl.
  • Ri 1 is preferably hydrogen or C 1.3 alkyl.
  • R ⁇ 3 is preferably hydrogen or C1 _3alkyl.
  • X is preferably O.
  • n is preferably 1.
  • p is preferably 0, 1 or 2.
  • Preferred compounds are : 4-(2-chlorophenoxy)-N-[3- ⁇ [(3R)-l-methylpyrrolidin-3-yl]oxy ⁇ -4-
  • More preferred compounds are: 4-[(3,5-dichlorophenyl)oxy]-N-[3- ⁇ [(3R)-l-methyl-3-pyrrolidinyl]oxy ⁇ -4-
  • 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.
  • Compounds of Formula (I) may be prepared as outlined in Schemes 1 - 9. Starting compounds 1 may be prepared as outlined in WO 289793, incorporated by reference herein.
  • Sulfonyl chlorides when not commercially available, can prepared by methods known in the art: Shahripour, A.B. et al. Bioorg. Med. Chem. 2002, 10, 31; Cross, P.E. et al. J. Med. Chem. 1978, 21, 845; Huntress et al J. Amer. Chem. Soc. 1941, 63, 3446; Hashimoto, H. et al J. Med. Chem. 2002, 45, 1511; O'Brien, P. M. et al. J.Med.Chem. 2000, 43, 156; Brandish, D. J.Med.Chem. 1999, 22, 4584.
  • a compound of the Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • 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.
  • 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), 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.
  • 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 i -adrenoceptor antagonists. No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention.
  • 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/mmor 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 j labeled U-II binding was quantitated by gamma counting.
  • Nonspecific binding was defined by 125j rj_ ⁇ 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+ -mobiIization 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.
  • 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 supernatants 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.
  • Example 1 The following examples were prepared according to the representative procedure in Example 1 using the appropriate sulfonyl chlorides as starting material, in some cases using acetonitrile rather than methylene chloride as the solvent, and in some cases also substituting Aniline B for Aniline A.
  • Toluene (0.5 mL) was added and stirred, and the suspension was heated to 100 °C and maintained at this temperature for 18 hours.
  • the solvent was removed via evaporation with a stream of nitrogen gas, and the residue was dissolved in 1 mL of DMSO, filtered through a 0.2 micron Acrodisk, and purified by preparative HPLC (YMC CombiPrep ODS-A, 50 x 20 mm, 20 mL/min, A: acetonitrile B: water, A: 5% to 95% during 20 min, UN detection at 214 nm) to give 11.2 mg (21%) of the title compound as a colorless film.
  • the aqueous suspension was extracted with ether (2 x 200 mL) and the combined organic layers were washed twice with water (400 mL), washed once with saturated NaCl (400 mL), dried over sodium sulfate, filtered, and concentrated to 1.9 g (93 %) of an orange oil which was used directly in the next step without further purification.
  • Aniline A (1.00 g, 3.84 mmol) was dissolved in 30 mL of acetonitrile and treated with 4-fluoro- 3-(trifluoromethyl)benzenesulfonyl chloride (1.9 g, 7.23 mmol) and pyridine (1.24 mL, 15.4 mmol) with vigorous stirring at room temperature. The reaction mixture was maintained for 18 hours, and then the solvent was removed under reduced pressure.
  • 3,5-Dichlorophenol (40.0 mg, 0.246 mmol) was dissolved in 1 mL of anhydrous DMF and treated with NaH (60 % dispersion in mineral oil, 13.2 mg, 0.328 mmol). After all bubbling had stopped, the reaction was stirred for an additional 30 minutes and treated with a solution of 4-fluoro-N-[3- ⁇ [(3R)-l-methyl-3-pyrrolidinyl]oxy ⁇ -4-(trifluoromethyl)phenyl]-3 (trifluoromethyl) benzene sulf onamide (80.0 mg, 0.164 mmol) in 0.5 mL of anhydrous DMF.
  • the reaction was heated at 70 °C for four hours, then at 105 °C for five hours, and then treated again with 3,5-dichlorophenol (133.7 mg, 0.82 mmol), NaH (60 % dispersion in mineral oil, 33.0 mg, 0.82 mmol) and calcium carbonate (82.1 mg, 0.82 mmol).
  • Examples 44-49 The following compounds were prepared by a method similar to the one described in Example 44 using the appropriate phenols or benzenethiols in place of 3,5-dichlorophenol.
  • Examples 50-105 The following compounds were prepared according to a procedure similar to the one described in Example 50, except substituting the appropriate phenol or benzenethiol for 2,3- dichlorothiophenol, and sometimes substituting the appropriate 4-fluorobenzenesulfonamide from the table above for 4-fluoro-N-[3- ⁇ [(3R)-l-methyl-3-pyrrolidinyl]oxy ⁇ -4-(trifluoromethyl) phenyl] benzenesulfonamide:
  • 3-fluoro-4-(trifluoromethyl)aniline (3.0 g, 16.8 mmol) was dissolved in 6 mL of acetonitrile, cooled to 0 °C, and treated with tetrafluoroboric acid (48% aqueous solution, 3.30 mL, 25.3 mmol) and tert-butyl nitrite (2.96 mL, 25.3 mmol). This reaction was maintained at 0 °C for one hour. In the meantime, a suspension of CuCl (2.50 g, 25.3 mmol) in 20 mL of acetonitrile at 0 °C was saturated with sulfur dioxide gas by bubbling the gas through the suspension with vigorous stirring for 30 minutes.
  • a microwave-safe vial, equipped with a magnetic stirring bar was charged with 12 mg (0.31mmol) of NaH (60% by weight) and 404 mg (1.24mmol) of Cs 2 C0 3 .
  • a solution consisting of 38 mg (0.31 mmol) 3-methoxyphenol and 0.36 mL of anhydrous NMP was prepared separately and added dropwise to the microwave vial.
  • Example 110-114 The following examples were prepared according to the representative procedure in Example 110 using the appropriate phenols and thiophenols in place of 3-methoxyphenol :
  • reaction mixture was heated to 95°C and maintained at that temperature for 4 h, after which time it was allowed to cool to room temperature and was quenched by pouring it into H 2 0 (375 mL) and brine (75 mL).
  • H 2 0 375 mL
  • brine 75 mL
  • the product was extracted from this aqueous mixture several times using ethyl acetate and the combined organic layers were dried over MgS0 , filtered, and concentrated to give 2.24 g (85%) of the title compound which was used directly in the next step without further purification.
  • a 10-mL round bottom flask equipped with an argon inlet and a magnetic stirring bar was charged with 393 mg (7.04 mmol) of iron powder suspended in 3.36 ml of glacial acetic acid. This mixture was heated to 60°C and maintained at that temperature for 15 min with vigorous stirring. The reaction mixture was removed from heating while a solution of 500 mg (1.76 mmol) of l,2-dichloro-3-(4-nitrophenoxy)benzene dissolved in 2 mL of glacial acetic acid was added and heating was then resumed at 80°C for 1 h. The reaction mixture was allowed to cool to room temperature and filtered through Celite.
  • a 10-mL round- bottom flask equipped with an argon inlet and magnetic stirring bar was charged with 200 mg (0.78 mmol) of 4-[(2,3-dichlorophenyl)oxy]aniline and 1 mL of anhydrous acetonitrile.
  • the contents of the flask were stirred at room temperature until all of the solids were dissolved and 0.15 mL (1.17 mmol) of HBF 4 (48% in H20) was added.
  • the flask was placed in an ice bath and cooled to 0°C for 30min before 0.14 mL (1.17 mmol) of t- Butyl nitrite was delivered to the flask and maintained at 0°C for 1 h.
  • a 5-mL round-bottom flask equipped with an argon inlet and a magnetic stirring bar was charged with 120 mg (0.46 mmol) of Aniline A and 4 mL of anhydrous methylene chloride.
  • the contents of the flask were stirred at room temperature until all of the solids were dissolved, and 42.7 uL of anhydrous pyridine was added.
  • the solution was stirred for 60 sec before 190 mg (0.56 mmol) of 4-[(2,3-dichlorophenyl)oxy]benzenesulfonyl chloride was added and the resulting mixture was stirred and maintained at room temperature for 18 hours.
  • Examples 116-121 The following examples were prepared according to the representive procedure in Example 117 using the appropriate phenols in place of 2,3-dichlorophenol and the appropriate nitrobenzenes in place of 4-fluoronitrobenzene.
  • Tribromoborane 25 g, 100 mmol was added dropwise to a solution of 2-bromo-5-nitroanisole (7.94 g, 34.2 mmol) in methylene chloride (100 mL) at 0 °C. The solution was allowed to warm to room temperature and react for 16 h. The reaction was then quenched by the addition of methanol (20 mL) and stirred for 3 h. The solvent was removed under reduced pressure and the remaining residue purified by column chromatography (400 g silica gel 60, 230-400 mesh, 5-20% ethyl acetate/hexanes as eluent) to give 2-bromo-5-nitrophenol (6.2 g, 83%). MS (ES) m/e 217.6 [M+H]+.
  • Diisopropyl azodicarboxylate (3.34 g, 16.5 mmol) was added dropwise to a solution of 2- bromo-5-nitrophenol (3.0 g, 13.8 mmol), (3S)-l-methyl-3-pyrrolidinol (1.4 g, 13.8 mmol), and triphenylphosphine (4.33 g, 16.5 mmol) in methylene chloride (100 mL). The reaction was maintained for 16 h at room temperature.
  • Examples 124-163 The following compounds were prepared according to a procedure similar to the one described in Example 123, except substituting the appropriate benzenethiol or alkanethiol for 3,5- dichlorothiophenol, and sometimes substituting the appropriate chloro-thiophene-sulfonamide from the table above for 4-Bromo-5-chloro-thiophene-2-sulfonic acid [3-((R)-l-methyl- pyrrolidin-3-yloxy)-4-trifluoromethyl-phenyl]-amide:
  • Example 164 The following examples were prepared according to the representative procedure in Example 164 using the appropriate phenols as starting material.
  • Example 173-225 The following compounds were prepared according to the procedure described in Example 172, using the appropriate boronic acid in place of (3-cyanophenyl)boronic acid:
  • EXAMPLE 226 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyrrole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des sulfonamides, des compositions pharmaceutiques les contenant ainsi que leur utilisation en tant qu'antagonistes de l'urotensine II.
PCT/US2003/035351 2002-11-06 2003-11-06 Sulfonamides WO2004043917A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003291255A AU2003291255A1 (en) 2002-11-06 2003-11-06 Sulfonamides

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US42414902P 2002-11-06 2002-11-06
US42416202P 2002-11-06 2002-11-06
US60/424,162 2002-11-06
US60/424,149 2002-11-06

Publications (1)

Publication Number Publication Date
WO2004043917A1 true WO2004043917A1 (fr) 2004-05-27

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AU (1) AU2003291255A1 (fr)
WO (1) WO2004043917A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7432258B2 (en) 2006-07-20 2008-10-07 Smithkline Beecham Corporation Morpholinyl and pyrrolidinyl analogs
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
JP2013531029A (ja) * 2010-07-09 2013-08-01 ファイザー・リミテッド 化合物
US8916553B2 (en) 2010-07-26 2014-12-23 Bristol-Myers Squibb Company Sulfonamide compounds useful as CYP17 inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6511989B2 (en) * 2000-11-03 2003-01-28 Aventis Pharma Deutschland Gmbh Acylaminoalkyl-substituted benzenesulfonamide derivatives, their preparation, their use and pharmaceutical preparations comprising them
US6686382B2 (en) * 1999-12-31 2004-02-03 Encysive Pharmaceuticals Inc. Sulfonamides and derivatives thereof that modulate the activity of endothelin
US6699884B2 (en) * 2001-04-20 2004-03-02 Pharmacia Corporation Fluoro-substituted benzenesulfonyl compounds for the treatment of inflammation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6686382B2 (en) * 1999-12-31 2004-02-03 Encysive Pharmaceuticals Inc. Sulfonamides and derivatives thereof that modulate the activity of endothelin
US6511989B2 (en) * 2000-11-03 2003-01-28 Aventis Pharma Deutschland Gmbh Acylaminoalkyl-substituted benzenesulfonamide derivatives, their preparation, their use and pharmaceutical preparations comprising them
US6699884B2 (en) * 2001-04-20 2004-03-02 Pharmacia Corporation Fluoro-substituted benzenesulfonyl compounds for the treatment of inflammation

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US7432258B2 (en) 2006-07-20 2008-10-07 Smithkline Beecham Corporation Morpholinyl and pyrrolidinyl analogs
US7749998B2 (en) 2006-07-20 2010-07-06 Glaxosmithkline Llc Morpholinyl and pyrrolidinyl analogs
JP2013531029A (ja) * 2010-07-09 2013-08-01 ファイザー・リミテッド 化合物
US9096558B2 (en) 2010-07-09 2015-08-04 Pfizer Limited N-sulfonylbenzamide compounds
US8916553B2 (en) 2010-07-26 2014-12-23 Bristol-Myers Squibb Company Sulfonamide compounds useful as CYP17 inhibitors

Also Published As

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