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WO2002028353A2 - Inhibiteur du transport de phosphate - Google Patents

Inhibiteur du transport de phosphate Download PDF

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Publication number
WO2002028353A2
WO2002028353A2 PCT/US2001/031318 US0131318W WO0228353A2 WO 2002028353 A2 WO2002028353 A2 WO 2002028353A2 US 0131318 W US0131318 W US 0131318W WO 0228353 A2 WO0228353 A2 WO 0228353A2
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WO
WIPO (PCT)
Prior art keywords
thiophene
carboxylic acid
amide
benzenesulfonylamino
phenyl
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US2001/031318
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English (en)
Other versions
WO2002028353A3 (fr
Inventor
Joseph Weinstock
Robert G. Franz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
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 Corp filed Critical SmithKline Beecham Corp
Priority to AU2002213048A priority Critical patent/AU2002213048A1/en
Publication of WO2002028353A2 publication Critical patent/WO2002028353A2/fr
Publication of WO2002028353A3 publication Critical patent/WO2002028353A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three 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
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen 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
    • 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 invention involves the treatment of chronic renal failure, uremic bone disease and related diseases by inhibition of phosphate retention by certain thiophenes.
  • ESRD end stage renal disease
  • Chronic renal failure affects more than 270,000 patients in the US alone and costs an estimated $6.8 billion in annual heath care costs.
  • CRF Chronic renal failure
  • Early and major contributors to the morbidity of CRF patients are abnormalities in electrolyte and bone metabolism induced by the progressive loss of renal excretory function.
  • Phosphate (Pi) retention has been identified as playing a major role in the progression of CRF and in the development of uremic bone disease.
  • the present invention involves novel methods of using of thiopenes as phosphate transport inhibitors for the selective inhibition of Pi transport in the kidney and/or the intestine as a therapeutic treatment in chronic renal failure and uremic bone disease.
  • the present invention involves the use of inhibitors of phosphate transport, for the treatment of chronic renal failure, and uremic bone disease, as well as other related diseases, such as hyperphosphatemia, vitamin D metabolism, and secondary hyperparathyroidism caused by the retention of phosphate.
  • inhibitors for use herein are those which selectively inhibit Na + -dependent Pi transport in tissues, preferably renal and intestinal tissue, from a number of species, including human.
  • the compounds of the present invention that inhibit phosphate transport are represented by Formulas I, II and III:
  • I II in X is sulfur or oxygen
  • Rl is independently selected from a group consisting of hydrogen, alkyl, aryl, haloalkyl, alkenyl, arylalkyl, arylalkenyl, halo, carboxy, carboalkoxy, carbamyl, alkyl or alkylcarbamyl, cyano, alkoxy, hydroxyl, amino or alkylamino, nitro, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamyl, aryl or alkylsulfonamido, or represents a fused ring forming a benzothiophene, or (Rl)n represents a (Rl)n substituted aryl or a heterocycle selected from the group consisting of thiophene, furan, pyridine, pyrimidine, pyrazine, isox
  • R2 and R3 are not hydrogen, but are independently selected from a group consisting of ⁇ (CHR4)n-(CHR5)m-(CHR6)p-(Rl substituted aryl or heteroaryl), alkyl, haloalkyl, or alkyl interrupted by one or more oxygen or sulfur atoms.
  • the carbon chain may also contain a double bond.
  • m,n, and p are independently 0-3.
  • R4,R5, and R6 are independently hydrogen, lower alkyl, Rl substituted aryl or heteroaryl,
  • Preferred compounds include those in which Rl is selected from the group hydrogen, bromide, chloride, methyl, 4-fluorophenyl, 2-thienyl, and R2 is selected from the group phenyl, 3,5-difluorophenyl, 3- trifluoromethoxyphenyl, 2-methylphenyl, 4-hexyloxyphenyl, 3- or 4- ethoxycarbonylphenyl, 4-benzoylphenyl, 3- or 4-chlorophenyl, 2,3- or 3,4- dichlorophenyl, 3-chloro-4-methoxyphenyl, 4-fluorophenyl, 4-bromophenyl, 4- hexyloxyphenyl, 4-(4-methoxybenzoylaminophenyl), l-(5- dimethylaminonaphthalene)-yl, 5-isoquinolyl, 6-quinolyl, 6-(2-methylbenzothiazol)- yl, 3-(l,2,4-methylpyrazol)
  • R3 is selected from the group phenyl, benzyl, 2-naphthyl, 5-dimethylamin-l- naphthyl, 2-methylphenyl, 3,4-difluorophenyl, 2- or 3-fluorophenyl, 4-chlorophenyl, 3-trifluoromethylphenyl, 2,5-dimefhylphenyl, 4-chloro-3,5-dimethylphenyl, 4- nitrophenyl, 4-methoxyphenyl, butyl, octyl, 2,2,2-trifluoroethyl, 2-thiazolyl, 4-
  • alkyl refers to an optionally substituted hydrocarbon group joined together by single carbon-carbon bonds. Preferred alkyl substituents are as indicated throughout.
  • the alkyl hydrocarbon group may be linear, branched or cyclic, saturated or unsaturated. All alkyl groups may be substituted with groups selected from R3 and the chains may be interrupted at one or more places with hetero atoms such as N, O, or S; the chains may be straight, branched or cyclic; they may be saturated or unsaturated;
  • aryl refers to an optionally substituted aromatic group with at least one ring having a conjugated pi-electron system, containing up to two conjugated or fused ring systems.
  • Aryl includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted. Preferred aryl substituents are as indicated throughout.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds and diastereomers are contemplated to be within the scope of the present invention.
  • Also preferred compounds include, but are not imited to 3-Benzenesulfonylamino-thiophene-2-carboxylic acid 4-chlorophenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid 4-ethylphenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid 1 ,3-dihydrobenzofuran-5- yl)-amide
  • salts for use when basic groups are present include acid addition salts such as those containing sulfate, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, /?-toluenesulfonate, cyclohexylsulfamate and quinate.
  • Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, -toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, -toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present.
  • the present invention provides compounds of Formulas (I) and II above, which can be prepared using standard techniques. An overall strategy for preparing preferred compounds described herein can be carried out as described in this section. Using the protocols described herein as a model, one of ordinary skill in the art can readily produce other compounds of the present invention. With appropriate manipulation and protection of any chemical functionality, synthesis of the remaining compounds of Formulas (I) and II is accomplished by methods analogous to those above and to those described in the Experimental section.
  • a present compound 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.
  • the present compounds can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical (transdermal), or transmucosal administration.
  • oral administration is preferred.
  • the compounds can be formulated into conventional oral dosage forms such as capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops.
  • injection parenteral administration
  • the compounds of the invention are formulated in liquid solutions, preferably, in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution.
  • the compounds may be formulated in solid form and re-dissolved or suspended immediately prior to use. Lyophilized forms can also be produced.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives.
  • detergents may be used to facilitate permeation.
  • Transmucosal administration for example, may be through nasal sprays, rectal suppositories, or vaginal suppositories.
  • the compounds of the invention can be formulated into ointments, salves, gels, or creams, as is generally known in the art.
  • the amounts of various compounds to be administered can be determined by standard procedures taking into account factors such as the compound IC50, EC50, the biological half -life of the compound, the age, size and weight of the patient, and the disease or disorder associated with the patient. The importance of these and other factors to be considered are known to those of ordinary skill in the art.
  • Amounts administered also depend on the routes of administration and the degree of oral bioavailability. For example, for compounds with low oral bioavailability, relatively higher doses will have to be administered.
  • the composition is in unit dosage form.
  • a tablet, or capsule may be administered, for nasal application, a metered aerosol dose may be administered, for transdermal application, a topical formulation or patch may be administered and for transmucosal delivery, a buccal patch may be administered.
  • dosing is such that the patient may administer a single dose.
  • Each dosage unit for oral administration contains suitably from 0.01 to 500 mg/Kg, and preferably from 0.1 to 50 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
  • the daily dosage for parenteral, nasal, oral inhalation, transmucosal or transdermal routes contains suitably from 0.01 mg to 100 mg/Kg, of a compound of Formula (I).
  • a topical formulation contains suitably 0.01 to 5.0% of a compound of Formula (I).
  • the active ingredient may be administered from 1 to 6 times per day, preferably once, sufficient to exhibit the desired activity, as is readily apparent to one skilled in the art.
  • compositions of present compounds 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.
  • 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.
  • any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • 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 a 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 present compound 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 analogs.
  • a binding and/or lubricating agent for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogs.
  • Typical dermal and 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 a single dose.
  • Sodium-dependent phosphate transport inhibition is determined by the ability of the test compound to inhibit the uptake of radio-labeled inorganic phosphate by proximal tubule cells. Appropriate cells from human, rabbit, or rat may be used.
  • the cells are harvested by filtration and 32p uptake is measured. It is also possible to use 33p rather than 32p.
  • the IC50 for 5-bromo-N-(4-bromophenyl)-2-(5-chloro-2- thienylsulfonamido)benzamide, 5-bromo-N-(4-bromophenyl)-2-(2- fluorophenylsulfonamido)benzamide, and 5-bromo-N-(4-bromophenyl)-2-(3- chloropropylsulfonamido)benzamide are 12, 15, and 14 ⁇ M respectively.
  • Methyl 3-aminothiophene-2-carboxylate (lOg, 68.6 mmol) was dissolved in 200 ml of pyridine, cooled to 0°, and then benzenesulfonyl chloride (13.8 g, 78.4 mmol) added and the mixture alllowed to warm to 25°C. After one hour a second portion of benzenesulfonyl chloride (13.8 g, 78.4 mmol) was added and the reaction mixture allowed to stand for 20 hours.
  • reaction mixture was cooled to 0°C and methyl 3-aminothiophene-2- carboxylate added in small portions to control gas evolution.
  • the reaction mixture was allowed to stand at ambient temperatures for 20 hours and then poured carefully to control gas evolution into 250 ml of 10% HC1.
  • the solid which formed was collected by filtration, washed with water and toluene and then dried at 60°C under
  • the toluene filtrate was filtered through several grams of silica gel 60, 230-400 mesh, and the silica gel washed with 5 ml of 10% methanol-chloroform.
  • the combined filtrates were concentrated under vacuum and the residue dissolved in 700 Dl of dimethylsulfoxide and purified by preparation HPLC (C18, 20-95% acetonitrile- 0.1% acqueous TFA). The products gave satisfactory HPLC-MS analyses.
  • N-(3,4-Difluorophenylsulfonyl)-3-aminothiophene-2-carboxylic Acid A suspension of about 3.7 g (11 mmol) of methyl N-(3,4-
  • N-(3 ,4-Difluorophenylsulfonyl)-3-aminothiophene-2-carboxylic Acid Chloride A suspension of N-(3,4-difluorophenylsulfonyl)-3-aminothiophene-2- carboxylic acid (1.71g, 5.36 mmol) in 14 ml of methylene chloride was treated with 0.71 g (5.63 mmol) of oxalyl chloride and 1 drop of DMF. After 1 hr this reaction mixture was used without further manipulation in the next reaction.
  • This compound was prepared as one member of a parallel synthesis array .
  • 4-Fluoroaniline (58.3 mg, 0.52 mmol) was dissolved in 2.5 ml of a solution prepared by dissolving 30 ml of triethylamine in 200 ml of toluene.
  • To this was added at ambient temperature 500 ul of the acid chloride solution and the mixture stirred for lhr, then an additional 100 ul of acid chloride solution added.
  • the reaction mixture was stirred for 18 hr under a nitrogen atmosphere, and then 725 mg of Combisorb S sulfonic acid scavenger (Agilent, silica gel support, 0.45 mmol per g) added and the mixture stirred for 4 hr.
  • Combisorb S sulfonic acid scavenger Alent, silica gel support, 0.45 mmol per g
  • Oxalyl chloride (71 ul, 0.82 mmol) was added to a suspension of 100 mg (0.65 mmol) of 3-azidofuran-2-carboxylic acid in 50 ml of dichloromethane and 5 ul of DMF. After 1 hr the solvents were removed under a stream of argon, the residue taken up in 50 ml of dichloromethane, and again the solvents removed under a stream of argon.
  • the acid chloride was dissolved in 1 ml of dichloromethane and added to a solution of 0.112 ml (0.816 mmol) of 4- isopropylaniline in 1 ml of pyridine. After 18 hr the solvents were evaporated under a stream of argon and the residue treated with 3 ml of 10% HCL. On stirring a solid was obtained which had the expected NMR spectrum and correct molecular weight by LCMS.
  • 3-Aminofuran-2-carboxylic acid 3-chlorophenylamide hydrochloride prepared in a similar manner had mp 155° C.
  • Example 1 The method of Example 1 was used to obtain crystals, after recrystallization from methylene chloride-hexane, mp 93-95° C, which had the expected values for C, H, and N elemental analysis. 4-Benzenesulfonylamino-thiophene-3-carboxylic Acid
  • Example 1 The method of Example 1 was used to obtain crystals, mp 213-215° C, which on TLC (silica, chloroform-methanol 9: 1 with a drop of formic acid) had Rf
  • Example 1 The method of Example 1 was used to obtain 4-benzenesulfonylamino- thiophene-3-carboxylic acid chloride, which was used without purification.
  • the acid chloride was dissolved in methylene chloride to give a solution containing 60 mg (0.2 mmol) in 0.5 ml.
  • 3,5-Difluoroaniline 25.8 mg, 0.20 mmol was added to a suspension of 320 mg of Combisorb S Tertiary Amine Scavenger Resin (silica gel based, 0.8 mmol base per gram) in 2 ml of toluene in tubes fitted with a frit at the bottom.
  • the acid chloride solution 0.5 ml was added and the mixture shaken under argon for 18 hr.
  • 225 mg of Combisorb S Sulfonic Acid Scavenger Resin (silica gel based, 0.45 mmol of acid per gram) was added, the volume adjusted with toluene to 4 ml, and the mixture shaken for 2.5 hr.
  • Methyl 2-benzenesulfonylaminothiophene-3-carboxylate was prepared by the method of Example 1 for the analogous compound starting from methyl 2- aminothiophene-3-carboxylate (K. Gewald,Chem.Ber. 98, 3571-3577 (1965)). This was converted by the method of Example 1 to 2-benzenesulfonylaminothiophene-3- carboxylic acid, which had the expected NMR spectrum.
  • sulfonyl chlorides can be used to prepare sulfonamides useful in the present invention: benzenesulfonyl chloride

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux composés de thiophène qui sont utiles pour traiter l'insuffisance rénale chronique et la maladie urémique osseuse.
PCT/US2001/031318 2000-10-05 2001-10-05 Inhibiteur du transport de phosphate Ceased WO2002028353A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002213048A AU2002213048A1 (en) 2000-10-05 2001-10-05 Phosphate transport inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US23806800P 2000-10-05 2000-10-05
US60/238,068 2000-10-05

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WO2002028353A2 true WO2002028353A2 (fr) 2002-04-11
WO2002028353A3 WO2002028353A3 (fr) 2002-07-11

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GB2378179A (en) * 2001-08-03 2003-02-05 Pantherix Ltd Aromatic sulfonamides and their use in treating bacterial diseases
WO2003044009A1 (fr) * 2001-11-22 2003-05-30 Biovitrum Ab Inhibiteurs de la 11-beta-hydroxysteroide-deshydrogenase de type 1
US6881741B2 (en) 2001-06-11 2005-04-19 Virochem Pharma Inc. Compounds and methods for the treatment or prevention of Flavivirus infections
JP2006502141A (ja) * 2002-08-15 2006-01-19 アイカジェン， インコーポレイテッド カリウムチャンネル遮断薬としてのスルホンアミド
US7030135B2 (en) 2000-05-22 2006-04-18 Biovitrum Ab Inhibitors of 11-β-hydroxy steroid dehydrogenase type 1
US7094792B2 (en) 2001-11-22 2006-08-22 Biovitrum Ab Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
US7288538B2 (en) 2003-02-20 2007-10-30 Encysive Pharmaceuticals, Inc. Phenylenediamine urotensin-II receptor antagonists and CCR-9 antagonists
EP1815860A3 (fr) * 2001-12-26 2007-11-21 Genzyme Corporation Inhibiteurs de transport du phosphate
US7319111B2 (en) * 2003-02-20 2008-01-15 Encysive Pharmaceuticals, Inc. Phenylenediamine Urotensin-II receptor antagonists and CCR-9 antagonists
WO2008026687A1 (fr) 2006-09-01 2008-03-06 Kyorin Pharmaceutical Co., Ltd. Dérivé de pyrazolopyridine carboxamide et inhibiteur de phosphodiestérase (pde) comprenant le dérivé
US7351703B2 (en) * 1998-07-08 2008-04-01 Sanofi-Aventis Deutschland Gmbh Sulfonylamino carboxylic acid N-arylamides as guanylate cyclase activators
US7402608B2 (en) 2002-12-10 2008-07-22 Virochem Pharma Inc. Compounds and methods for the treatment or prevention of Flavivirus infections
WO2009044311A1 (fr) * 2007-10-05 2009-04-09 Encysive Pharmaceuticals Inc. Modulateurs de récepteur ccr9 et leurs procédés d'utilisation
US7569600B2 (en) 2005-05-13 2009-08-04 Virochem Pharma Inc. Compounds and methods for the treatment of prevention of Flavivirus infections
US7759390B2 (en) 2005-12-22 2010-07-20 Novartis Ag Inhibitors of CCR9 activity
WO2010126167A1 (fr) * 2009-04-30 2010-11-04 住友化学株式会社 Dérivé de thiophène
WO2013062065A1 (fr) * 2011-10-27 2013-05-02 アステラス製薬株式会社 Dérivé de n-thiényl benzamide substitué avec un aminoalkyle
WO2014029983A1 (fr) 2012-08-21 2014-02-27 Ardelyx, Inc. Composés et procédés d'inhibition d'un antiport à médiation par nhe dans le traitement de troubles associés à une rétention de fluide ou à une surcharge de sel et de troubles du tractus gastro-intestinal
US9663483B2 (en) 2010-06-07 2017-05-30 Novomedix, Llc Furanyl compounds and the use thereof
WO2018129552A1 (fr) 2017-01-09 2018-07-12 Ardelyx, Inc. Composés utiles pour le traitement de troubles du tractus digestif
WO2018129556A1 (fr) 2017-01-09 2018-07-12 Ardelyx, Inc. Composés et procédés pour l'inhibition d'un antiport à médiation par échangeur sodium/proton (nhe) dans le traitement de troubles associés à une rétention d'eau ou à une surcharge en sel et de troubles du tractus gastro-intestinal
WO2018129557A1 (fr) 2017-01-09 2018-07-12 Ardelyx, Inc. Inhibiteurs d'antiport à médiation par nhe
EP3351248A1 (fr) 2008-12-31 2018-07-25 Ardelyx, Inc. Composés et procédés d'inhibition d'un antiport à médiation par nhe dans le traitement de troubles associés à une rétention de fluide ou à une surcharge de sel et de troubles du tractus gastro-intestinal
US10272079B2 (en) 2013-04-12 2019-04-30 Ardelyx, Inc. NHE3-binding compounds and methods for inhibiting phosphate transport
US10376481B2 (en) 2012-08-21 2019-08-13 Ardelyx, Inc. Compounds and methods for inhibiting NHE-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders
WO2019167863A1 (fr) 2018-02-27 2019-09-06 日本曹達株式会社 Composé de sulfonamide hétéroaryle et agent de lutte antiparasitaire
WO2022194240A1 (fr) * 2021-03-17 2022-09-22 Biofront Ltd. (Cayman) Modulateurs de fpr1 et leurs procédés d'utilisation

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