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WO2004043368A2 - Sulfonamides - Google Patents

Sulfonamides Download PDF

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Publication number
WO2004043368A2
WO2004043368A2 PCT/US2003/035357 US0335357W WO2004043368A2 WO 2004043368 A2 WO2004043368 A2 WO 2004043368A2 US 0335357 W US0335357 W US 0335357W WO 2004043368 A2 WO2004043368 A2 WO 2004043368A2
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
chloro
methyl
oxy
pyrrolidinyl
Prior art date
Application number
PCT/US2003/035357
Other languages
English (en)
Other versions
WO2004043368A3 (fr
Inventor
Linda S. Barton
Christopher T. Louer
John Jeffrey Mcatee
Michael J. Neeb
Ning Wang
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 AU2003295408A priority Critical patent/AU2003295408A1/en
Publication of WO2004043368A2 publication Critical patent/WO2004043368A2/fr
Publication of WO2004043368A3 publication Critical patent/WO2004043368A3/fr

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Classifications

    • 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
    • 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

Definitions

  • the present invention 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 c -adrenoceptor antagonists.
  • ACE angiotensin converting enzyme
  • the present invention provides for compounds of Formula (I):
  • R j is hydrogen, halogen, or C . alkyl
  • Ar is phenyl, pyrazolyl, thiazolyl, dibenzofuranyl, benzodioxolyl, quinolinyl, or naphthalenyl, all of which may be substituted or unsubstituted by one or two of the following: halogen, CN, SCC j .6 alkyl), CF 3 , OCF 3 , SCF3, C . alkyl, Ph, OPh, C g alkoxy, C0 2 (C 1 . 6 alkyl), NR 5 R 6 , NR 5 COR 6 , CONR 5 R 6 , COR5, N0 2 , ⁇ .3 alkylenedioxy, CH 2 OH or CH 2 CN;
  • R 2 is hydrogen, halogen, or CF3.
  • R5 and Rg are independently hydrogen or C . alkyl
  • R9 is hydrogen or Cj.g alkyl; 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, wo-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 phenyl.
  • Preferred substituents for Ar are hydrogen, CN, halogen, CF3, C0 2 CH3, C ⁇ _ 2 alkoxy,
  • R 2 is preferably hydrogen, Cl, or CF3.
  • R j is preferably hydrogen, BR, or Cl.
  • R9 is preferably Cj_ 2 alkyl.
  • Preferred compounds are : 5-chloro-N-[3- ⁇ [(3R)-l-methyl-3-pyrrolidinyl]oxy ⁇ -4-(trifluoromethyl)phenyl]-3-[4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide;
  • 2-thiophenesulfonamide 4-(4-biphenylyl)-5-chloro-N-(4-chloro-3- ⁇ [(3R)-l-methyl-3-pyrrolidinyl]oxy ⁇ phenyl)-2- thiophenesulfonamide; 5-chloro-N-(4-chloro-3- ⁇ [(3R)-l-methyl-3-pyrrolidinyl]oxy ⁇ phenyl)-4-[4-(phenyloxy)phenyl]- 2-thiophenesulfonamide;
  • 2-thiophenesulf onamide N-[3- ⁇ [(3R)-l-methyl-3-pyrrolidinyl]oxy ⁇ -4-(trifluoromethyl)phenyl]-5-phenyl-2- thiophenesulfonamide; 5-[3-(methyloxy)phenyl]-N-[3- ⁇ [(3R)-l-methyl-3-pyrrolidinyl]oxy ⁇ -4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide;
  • More Preferred compounds are: 5-chloro-3-(4-cyanophenyl)-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 Scheme 1.
  • 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. /. 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.Me ⁇ Chem. 2000, 43, 156; Brandish, D. J.Med.Chem. 1999, 22, 4584.
  • 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.
  • compositions are 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.
  • 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, ische ic 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-D. receptor antagonists, vasopeptidase inhibitors, diuretics, digoxin, and dual non-selective D-adrenoceptor and o. ⁇ -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.
  • HEK-293-GPR14 cells in T150 flask were prelabeled overnight with 1 uCi myo-[ 3 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.
  • Example 565 Using the general procedure oultined in Example 565, the following compounds were prepared.
  • the reaction mixture was placed under argon atmosphere and heated to 120 °C in the microwave for 600 sec.
  • the solvent was removed by evaporation and the residue was purified by preparative HPLC (Xterra Prep RP, 75 x 30 mm, 25 mL/min, A: acetonitrile B: water, 0.1% TFA; A: 10 to 90% during 10 min, UN detection at 214 nm) to give 12 mg (9%) of the title compound as a free base.
  • the hydrochloride salt was formed from by dissolving the substrate in methanol, adding hydrochloric acid in ether (IM) and evaporating the volatile materials to give a solid.
  • Aniline CF3 (80 mg, 0.31 mmol) was dissolved in 2 mL of methylene chloride and treated with methyl 3-(chlorosulfonyl)-4-phenyl-5-(trifluoromethyl)-2-thiophenecarboxylate (118 mg, 0.307 mmol) and pyridine (0.025 mL, 0.31 mmol) with vigorous stirring at room temperature. The reaction mixture was maintained for 18 hours, and then the solvent was removed under reduced pressure.
  • Examples 210-214 The following examples were prepared according to the representative procedure in Example 209 using the appropriate sulfonyl chlorides as starting material, and in some cases using acetonitrile rather than methylene chloride as the solvent.
  • EXAMPLE 215 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 drag 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.
  • Ph Eur. to 100 ml
  • the above specification and Examples fully disclose how to make and use the compounds of the present invention.
  • the present invention is not limited to the particular embodiments described hereinabove, but includes all modifications thereof within the scope of the following claims.
  • the various references to journals, patents and other publications which are cited herein comprise the state of the art and are incorporated herein by reference as though fully set forth.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pyrrole Compounds (AREA)

Abstract

La présente invention concerne des sulfonamides, des compositions pharmaceutiques les contenant, ainsi que leur utilisation comme antagonistes de l'urotensine II.
PCT/US2003/035357 2002-11-06 2003-11-06 Sulfonamides WO2004043368A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003295408A AU2003295408A1 (en) 2002-11-06 2003-11-06 Sulfonamides

Applications Claiming Priority (4)

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US42416202P 2002-11-06 2002-11-06
US42412802P 2002-11-06 2002-11-06
US60/424,162 2002-11-06
US60/424,128 2002-11-06

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WO2004043368A2 true WO2004043368A2 (fr) 2004-05-27
WO2004043368A3 WO2004043368A3 (fr) 2004-07-22

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Cited By (4)

* 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
US9096558B2 (en) 2010-07-09 2015-08-04 Pfizer Limited N-sulfonylbenzamide compounds

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA103319C2 (en) 2008-05-06 2013-10-10 Глаксосмитклайн Ллк Thiazole- and oxazole-benzene sulfonamide compounds

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6423717B1 (en) * 1996-12-19 2002-07-23 Smithkline Beecham P.L.C. Sulphonamide derivatives, process for their preparation, and their use as medicaments

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6423717B1 (en) * 1996-12-19 2002-07-23 Smithkline Beecham P.L.C. Sulphonamide derivatives, process for their preparation, and their use as medicaments
US6599904B2 (en) * 1996-12-19 2003-07-29 Smithkline Beecham P.L.C. Sulphonamide derivatives, process for their preparation, and their use as medicaments

Cited By (5)

* 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
US9096558B2 (en) 2010-07-09 2015-08-04 Pfizer Limited N-sulfonylbenzamide compounds

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Publication number Publication date
AU2003295408A1 (en) 2004-06-03
AU2003295408A8 (en) 2004-06-03
WO2004043368A3 (fr) 2004-07-22

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