WO2002028353A2 - Phosphate transport inhibitors - Google Patents

Phosphate transport inhibitors Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
thiophene
carboxylic acid
amide
benzenesulfonylamino
phenyl
Prior art date
Application number
PCT/US2001/031318
Other languages
French (fr)
Other versions
WO2002028353A3 (en
Inventor
Joseph Weinstock
Robert G. Franz
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 AU2002213048A priority Critical patent/AU2002213048A1/en
Publication of WO2002028353A2 publication Critical patent/WO2002028353A2/en
Publication of WO2002028353A3 publication Critical patent/WO2002028353A3/en

Links

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

Abstract

Novel thiophene compounds, useful for treatment of chronic renal failure and uremic bone disease, are disclosed.

Description

PHOSPHATE TRANSPORT INHIBITORS FIELD OF THE INVENTION
The present invention involves the treatment of chronic renal failure, uremic bone disease and related diseases by inhibition of phosphate retention by certain thiophenes.
BACKGROUND OF THE INVENTION When kidneys are injured, the adaptive mechanisms involved in restoring homeostasis can lead to additional injury and an inexorable progression to end stage renal disease (ESRD) (Hostetter et al, Am. J. Physiol. 241.F85-F93 (1981)). ESRD affects more than 270,000 patients in the US. While the use of dialysis and kidney transplantation have dramatically improved the survival rate of patients with ESRD, a number of problems have appeared in these patients which complicates their long term management. Early and major contributors to the morbidity of patients with ESRD are abnormalities in mineral and bone metabolism induced by a progressive loss of renal excretory function. Among other factors, phosphate (Pi) retention has been identified as playing a major role in the progression of renal failure and in the generation of secondary hyperparathyroidism (HPTH) and uremic bone disease.
Evidence implicating a role for Pi retention in the progression of chronic renal failure (CRF) has come mainly from studies on experimental animals. Ibels et al, N. Engl. J. Med. 298:122-126, (1978), first demonstrated in a rat model of CRF that dietary Pi restriction prevented renal functional deterioration as assessed by stabilization or improvement of serum creatinine levels, reduced proteinuria, improved histology and reduced mortality. Similar findings were obtained in a rat model of nephrotoxic serum nephritis (Karlinsky et al, Kidney Int. 17:293-302 (1980)). However, these studies were criticized on the basis that a low Pi diet is associated with decreased food intake and thus protein intake which by itself can reduce the progression of CRF. Therefore, Lumlertgul et al, Kidney h t. 29:658-666, (1986) placed 5/6th nephrectomized rats on a normal Pi diet but gave one group a Pi binder. All rats were pair fed and had similar caloric, protein, carbohydrate, vitamin and mineral intakes. At both 6 and 12 weeks rats ingesting the Pi binder showed a lower protein excretion, lower serum creatinine level, lower renal calcium content and less histologic scarring than rats not receiving the Pi binder. This study demonstrated unequivocally that dietary Pi restriction can have beneficial effects on the progression of CRF independent of caloric and protein intake in experimental animals.
In addition to the beneficial effects of dietary Pi restriction on the progression of CRF discussed above, evidence has also been found that dietary Pi excess can accelerate the progression of CRF. A number of studies in rat models of CRF
(Kleinknecht et al, Kidney Int. 5:534-541, (1979); Haut et al, Kidney Int. 17:722-731, (1980); Gimenez et al, Kidney Int. 22:36-41, (1982)) have shown that diets high in Pi lead to a more rapid deterioration in renal function as assessed by serum creatinine levels and the severity of histologic lesions. Some evidence also suggests that dietary Pi restriction may slow the progression of CRF in patients. Maschio et al, Kidney Int., 22:371-376, (1982) and Maschio et al, Kidney Int., 24:S 273-S 277, (1983) placed patients with mild or moderate renal insufficiency on diets restricted in protein and Pi for up to 76 months. They found that the rate of decline in renal function was slower in the dietary restricted group than in the control group, especially in patients with mild CRF. Barsotti et al., Kidney Int. 24:S278-S284, (1983) and Barsotti et al., Clin. Nephrol. 21:54-59, (1984) placed CRF patients on either a low protein diet or on a low protein-low Pi diet and found that the rate of decline in renal function slowed after the institution of dietary restrictions in both groups. Importantly, they also observed a slower rate of decline in patients on the low protein-low Pi diet compared to the low protein diet alone. In a study of 4 children placed on a low Pi diet serum creatinine levels were halved during the 6 months on the restricted diet compared with a similar period on a normal diet (McCrory et al, J. Pediatr. 111:410-412, (1987). Furthermore, growth velocity in these children increased significantly on the low Pi diet compared with the control period. Other human studies (Barrientos et al, Electrolyte Metab. 7: 127-133, (1982); Ciadrella et al, Nephron 42:196-199, (1986); Gin et al, Metabolism 36:1080-1085, (1987)), mainly of short duration, have failed to observe an effect of Pi restriction on the course of CRF. Nevertheless, the bulk of the animal studies discussed above together with the less well controlled human studies suggest that dietary restriction of Pi is beneficial in slowing the progression of CRF, especially in mild to moderate renal insufficiency. The mechanism by which Pi excess leads to an increase in the rate of renal failure is unknown. However, most evidence supports an interaction between Pi and cellular Ca^+ accumulation. In the failing kidney a rise in the filtered load of Pi together with a reduction in Pi reabsorption secondary to elevated levels of parathyroid hormone (PTH) results in an increase in tubular fluid Pi concentration. This leads to an increased transepithelial flux of Ca^÷ and elevated cellular Ca^+ levels resulting in
Ca2+-induced cell injury (Borle et al., Endocrinology 102:1725-1732, (1978). Alternatively, or in addition, calcium-phosphate precipitation may occur resulting in renal calcification and nephrocalcinosis (Lau, K., Kidney Int. 36:918-937, (1989)). Finally, Shapiro et al., Am . J. Physiol. 258:F183-F188, (1990) suggested that the renal hypermetabolism normally associated with the 5/6th nephrectomized model of CRF in rats may contribute to the progression of CRF in this model. Thus, restriction of dietary Pi reduced renal oxygen consumption by 50 % and reduced intracelluar Pi concentrations without altering the steady state concentration of ATP as assessed by 3 lp-NMR in this model.
Chronic renal failure (CRF) affects more than 270,000 patients in the US alone and costs an estimated $6.8 billion in annual heath care costs. 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.
Studies in the literature have shown that dietary Pi restriction slows the progression of CRF in animal models and in small patient studies; decreases elevated plasma PTH levels in CRF animal models and patients; and increases the circulating levels of 1, 25 (OH)2 vitamin D and intestinal Ca2+ absorption.
Thus, inhibition of Pi transport by the gut and kidney is considered beneficial in slowing the progression of CRF and uremic bone disease. Thus, inhibition of Pi transport by the gut and kidney is beneficial in slowing the progression of CRF and uremic bone disease. Consequently, there exists a need to find an alternative means of reducing phosphate retention, in mammals, in addition to diet restriction of phosphate for the treatment of renal diseases, and uremic bone disease.
SUMMARY OF THE INVENTION 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.
DETAILED DESCRIPTION OF THE INVENTION 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. Preferably, 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:
Figure imgf000005_0001
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, isoxazole, thiazole, imidazole, pyrazole, thiadiazole, oxadiazole, and benzo analogs thereof; or Rl represents a fused ring selected from the group consisting of of thiophene, furan, pyridine, pyrimidine, pyrazine, isoxazole, thiazole, imidazole, pyrrazole, thiadiazole, oxadiazole, and benzo analogs thereof, and
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)-yl and
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-
(2, 1 ,3-benzothiadiazol)yl, 4-(3,5-dimethylisoxazol)-yl, 3-(2,5-dichlorothiophene)- yl, 5-chloro-2-thienyl, 2-(5-phenylsulfonylthiophene)-yl.
As used herein, "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;
As used herein, "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.
3-Benzenesulfonylamino-N-(3-chlorophenyl)-4-thiophenecarboxamide; 3-Benzenesulfonylamino-N-(3-chlorophenyl)-4-thiophenecarboxamide;
N-(4-Chlorophenyl)-3-[[[3-(trifluoromethyl)phenyl]sulfonyl]amino]-2- thiophenecarboxamide
N-(4-Chlorophenyl)-3-[[(2-fluorophenyl)sulfonyl]amino]-2- thiophenecarboxamide N-(4-Chlorophenyl)-3-[[(4-methoxyphenyl)sulfonyl]amino]-2- thiophenecarboxamide
3-[(Benzenesulfonyl)amino]-N-(4-chlorophenyl)-2-thiophenecarboxamide N-(4-Chlorophenyl)-3-[[(5-chloro-2-thienyl)sulfonyl]amino]-2- thiophenecarboxamide N-(4-Chlorophenyl)-3-[[(2,2,2-trifluoroethyl)sulfonyl]amino]-2- thiophenecarboxamide
3-[(Butylsulfonyl)amino]-N-(4-chlorophenyl)-2-thiophenecarboxamide 3-[(Butylsulfonyl)amino]-N-(3-chloro-4-methoxyphenyl)-2- thiophenecarboxamide N-[l , 1 -Biphenyl]-4-yl-3-[[[3-(trifluoromethyl)phenyl]sulfonyl]amino]-2- thiophenecarboxamide N-(3 ,4-Dichlorophenyl)-3 - [ [ [3-(trifluoromethyl)phenyl] sulf onyl] amino] -2- thiophenecarboxamide
N-[l,l'-Biphenyl]-4-yl-3-[[(2-fluorophenyl)sulfonyl]amino]-2- thiophenecarboxamide N-(3,4-Dichlorophenyl)-3-[[(2-fluorophenyl)sulfonyl]amino]-2- thiophenecarboxamide
N- [ 1 , 1 -Biphenyl] -4-yl-3 - [ [(4-methoxyphenyl)sulf onyl] amino] -2- thiophenecarboxamide
N-(3,4-Dichlorophenyl)-3-[[(4-methoxyphenyl)sulfonyl]amino]-2- thiophenecarboxamide
N- [ 1 , 1 -Biphenyl] -4-yl-3 - [(phenylsulfonyl) amino] -2-thiophenecarboxamide
N-(3,4-Dichlorophenyl)-3-[(phenylsulfonyl)amino]-2-thiophenecarboxamide
N-[l,l -Biphenyl]-4-yl-3-[[(5-chloro-2-thienyl)sulfonyl]amino]-2- thiophenecarboxamide 3-[[(5-Chloro-2-thienyl)sulfonyl]amino]-N-(3,4-dichloroρhenyl)-2- thiophenecarboxamide
N-[l,l'-Biphenyl]-4-yl-3-[[(2,2,2-trifluoroethyl)sulfonyl]amino]-2- thiophenecarboxamide
N-[l, -Biphenyl]-4-yl-3-[(butylsulfonyl)amino]-2-thiophenecarboxamide N-(3-Chloro-4-methoxyphenyl)-3-[[[3-
(trifluoromethyl)phenyl] sulf onyl] amino] -2-thiophenecarboxamide
N-(3 -Chloro-4-methoxyphenyl)-3 - [ [(2-fluorophenyl) sulf onyl] amino] -2- thiophenecarboxamide
N-(3 -Chloro-4-methoxyphenyl)-3 - [ [(4-methoxyphenyl)sulf onyl] amino] -2- thiophenecarboxamide
N-(3-Chloro-4-methoxyphenyl)-3-[(phenylsulfonyl)amino]-2- thiophenecarboxamide
N-(3-Chloro-4-methoxyphenyl)-3-[[(5-chloro-2-thienyl)sulfonyl]amino]-2- thiophenecarboxamide N-(3-Chloro-4-methoxyphenyl)-3-[[(2,2,2-trifluoroethyl)sulfonyl]amino]-2- thiophenecarboxamide N-[3-(Trifluoromethyl)phenyl]-3-[[[3- (trifluoromethyl)phenyl] sulf onyl] amino] -2-thiophenecarboxamid
3-(2-Fluoro-benzenesulfonylamino)-thiophene-2-carboxylic acid (3- trifluoromethyl-phenyl)-amide 3-(4-Methoxy-benzenesulfonylamino)-thiophene-2-carboxylic acid phenylamide
3-(4-Methoxy-benzenesulfonylamino)-thiophene-2-carboxylic acid (3- trifluoromethyl-phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3-trifluoromethyl- phenyl)-amide
3-(5-Chloro-thiophene-2-sulfonylamino)-thiophene-2-carboxylic acid (3- trifluoromethyl-phenyl)-amide
3-(2,2,2-Trifluoro-ethanesulfonylamino)-thiophene-2-carboxylic acid (3- trifluoromethyl-phenyl)-amide 3-(Butane-l-sulfonylamino)-thiophene-2-carboxylic acid phenylamide
3-(Butane-l-sulfonylamino)-thiophene-2-carboxylic acid (3-trifluoromethyl- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-butoxy-phenyl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-isopropyl-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-phenoxy-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-hexyloxy-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-methoxy-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2 -carboxylic acid (4-isopropoxy- phenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-acetyl-phenyl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-benzoyl-phenyl)- amide
{4-[(3-Benzenesulfonylamino-thiophene-2-carbonyl)-amino]-phenyl}-acetic acid ethyl ester 4-[(3-Benzenesulfonylamino-thiophene-2-carbonyl)-amino]-benzoic acid butyl ester
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-propionyl-phenyl)- amide
3-[(3-Benzenesulfonylamino-thiophene-2-carbonyl)-amino]-benzoic acid ethyl ester
3-Benzenesulfonylamino-thiophene-2-carboxylic acid [4-(2-hydroxy-ethyl)- phenyl] -amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid [4-(6-methyl- benzothiazol-2-yl)-phenyl]-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-diethylamino- phenyl)-amide
4-[(3-Benzenesulfonylamino-thiophene-2-carbonyl)-amino]-benzoic acid 2- diethylamino-ethyl ester
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2,4,6-trifluoro- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid [4-( lH-indazol-6- ylsulfamoyl)-phenyl]-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid [4-(thiazoI-2- ylsulfamoyl)-phenyl] -amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-hydroxymethyl- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-cyclohexyl- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-benzyloxy- phenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3-fluoro-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2-trifluoromethyl- phenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid phenylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid [4-(pyrimidin-2- ylsulfamoyl)-phenyl]-amide
2-[(3-Benzenesulfonylamino-thiophene-2-carbonyl)-amino]-benzoic acid ethyl ester 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-trifluoromethyl- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2,6-difluoro-phenyl)- amide
3-[(3-Benzenesulfonylamino-thiophene-2-carbonyl)-amino]-benzoic acid methyl ester
3-Benzenesulfonylamino-thiophene-2 -carboxylic acid (3-chloro-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid benzo[ 1 ,3] dioxol-5- ylamide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3,5-difluoro-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3 ,4-difluoro-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2-benzoyl-4-chloro- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid [2-( lH-indol-2-yl)- phenyl]-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid isoquinolin-5-ylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid naphthalen-2-ylamide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (9H-fluoren-2-yl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-phenylcarbamoyl- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-methyl-2-oxo-2H- chromen-7-yl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid biphenyl-2-ylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-fluoro-phenyl)- amide
4-[(3-Benzenesulfonylamino-thiophene-2-carbonyl)-amino]-benzoic acid ethyl ester 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2,6-dimethyl- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3,4-dimethoxy- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3,5-dichloro-pyridin- 4-yl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (5-oxo-5,6,7,8- tetrahydro-naphthalen-2-yl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3-acetyl-phenyl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3-benzoyl-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid quinolin-6-ylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid pyridin-4-ylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4,6-dimethyl- pyridin-2-yl)-amide
3-Benzenesulfonylamino-thiophene-2 -carboxylic acid (3-benzyloxy- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (5,6,7, 8-tetrahydro- naphthalen- 1 -yl)-amide 3-Benzenesulfonylamino-thiophene-2 -carboxylic acid (3,5-dimethoxy- phenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2-pyrrol-l-yl- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid ( 1 H-indazol-5-yl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid pyridin-2-ylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2-fluoro-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (thiophen-2- ylmethyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid benzylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid butylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (5-chloro-pyridin-2- yl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-ethyl-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2 -carboxylic acid (2,3-dichloro-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2,3-dimethyl- phenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2,3-dimethoxy- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid phenethyl-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3- dimethylsulfamoyl-4-methyl-phenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (lH-benzotriazol-5- yl)-amide
5-[(3-Benzenesulfonylamino-thiophene-2-carbonyl)-amino]-2-methoxy- benzoic acid methyl ester
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2-methyl- benzothiazol-6-yl)-amide 3-Benzenesulfonylamino-thiophene-2 -carboxylic acid (1,3-dihydro- isobenzofuran-5-yl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid [3-(l-methyl-lH- pyrazol-3-yl)-phenyl]-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid [3-(2-methyl- pyrimidin-4-yl)-phenyl]-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3-oxazol-5-yl- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid quinolin-5-ylamide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid cyclohexylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2-chloro-phenyl)- amide
3-[(3-Benzenesulfonylamino-thiophene-2-carbonyl)-amino]-propionic acid ethyl ester 4-[(3-Benzenesulfonylamino-thiophene-2-carbonyl)-amino]-butyric acid ethyl ester
3-[(3-Benzenesulfonylamino-thiophene-2-carbonyl)-amino]-4-methoxy- benzoic acid methyl ester
3-[(3-Benzenesulfonylamino-thiophene-2-carbonyl)-amino]-4-methyl- benzoic acid methyl ester
3 -B enzenesulf onylamino-thiophene-2-carboxylic acid (2-phenylamino- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid quinolin-8-ylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid isoquinolin- 1 -ylamide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2,4,6-trimethoxy- phenyl) -amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (5 ,6-dimethyl- 1 H- benzoimidazol-2-yl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid indan-5-ylamide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2,3-dihydro- benzo[ 1 ,4] dioxin-6-yl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (lH-indol-5-yl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-dimethylamino- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2-methoxy-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid #o!-tolylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (lH-benzoimidazol-2- yl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid benzothiazol-2- ylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4- trifluoromethanesulfonyl-phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3-trifluoromethoxy- phenyl) -amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (5-#tert!-butyl- isoxazol-3-yl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-methyl-pyridin-2- yl)-amide
3-[(3-Benzenesulfonylamino-thiophene-2-carbonyl)-amino]-thiophene-2- carboxylic acid methyl ester
3-Benzenesulfonylamino-thiophene-2-carboxylic acid benzo[l ,2,5]thiadiazol-4-ylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3 ,5-dichloro-phenyl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (1,3,5-trimethyl-lH- pyrazol-4-yl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4,5-dimethyl-thiazol- 2-yl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (furan-2-ylmethyl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (1,1-dimethyl- propyl)-amide
[(3-Benzenesulfonylamino-thiophene-2-carbonyl)-amino]-acetic acid ethyl ester 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (5-methyl-isoxazol-3- yl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2-methoxy-ethyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid thiazol-2-ylamide 3-Benzenesulfonylamino-thiophene-2 -carboxylic acid [l,3,4]thiadiazol-2- ylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2-benzyl-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid biphenyl-3-ylamide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid [4-(4-chloro- phenoxy)-phenyl]-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2-methylsulfanyl- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid ( 1 H-tetrazol-5-yl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (thiophen-3- ylmethyl)-amide
3-Benzenesulfonylamino-thiophene-2 -carboxylic acid naphthalen- 1 -ylamide
3-[(2-Fluorobenzenesulfonyl)amino]-N-(3,4-difluorophenyl)-2- thiophenecarboxamide
3 - [(Butanesulf onyl) amino] -N-(3 -trifluoromethylphenyl)-2- thiophenecarboxamide
3-Benzenesulfonyl)amino]-N-(3-chlorophenyl)-4-methyl-2- thiophenecarboxamide More preferred compounds include, but are not limited to:
3-[(Benzenesulfonyl)amino]-N-(3-chlorophenyl)-2-thiophenecarboxamide
3-[(Benzenesulfonyl)amino]-N-(2,3-dichlorophenyl)-2- thiophenecarboxamide
3-[(Benzenesulfonyl)amino]-N-(3,5~difluorophenyl)~2- thiophenecarboxamide
3-[(Benzenesulfonyl)amino]-N-(4-trifluoromethylphenyl)-2- thiophenecarboxamide
3-[(Benzenesulfonyl)amino]-N-(3,4-difluorophenyl)-2- thiophenecarboxamide
3-[(Benzenesulfonyl)amino]-N-(2-fluorenyl)-2-thiophenecarboxamide 3-[(Benzenesulfonyl)amino]-N-(3-chloro-2-pyridyl)-2- thiophenecarboxamide
3-[(Benzenesulfonyl)amino]-N-(3-methoxycarbonylphenyl)-2- thiophenecarboxamide
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
3-Benzenesulfonylamino-thiophene-2 -carboxylic acid 4-cyclohexylphenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid chlorophenyl amide 3-Benzenesulfonylamino-thiophene-2 -carboxylic acid 3,4-dichloro phenyl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid 2,3-dichloro phenyl)- amide 3-Benzenesulfonylamino-thiophene-2 -carboxylic acid 4-chlorophenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid 3,4-dichloro phenyl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid 2-chloro-3-methylphenyl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid 3 ,5-difluorophenyl)-amide 3-Benzenesulfonylamino-thiophene-2 -carboxylic acid 3 ,4-difluorophenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxy rlic acid ( 4' -fluorophenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxy lie acid ( 3-fluorophenyl)-amide 3 -B enzenesulf onylamino-thiophene-2-carboxy "lie acid ( 2-fluorophenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxy iic acid ( 3-trifluoromethylphenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxy riic acid ( 4' -trifluoromethylphenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxy rlic acid ( 3 -trifluoromethoxyphenyl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxy die acid ( 4-hexyloxyphenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxy lie acid ( 4-butoxyphenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxy lie acid ( 3 ,4-methylenedioxyphenyl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxy lie acid ( 3 ,5-dimethoxyphenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxy lie acid ( 3-benzyloxyphenyl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxy lie acid ( 2-methylthiophenyl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxy lie acid (' 4-methoxyphenyl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxy lie acid (' 4-isopropyloxyphenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxy lie acid ( 3-ethoxycarbonylphenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxy lie acid ( 4' -butoxycarbonylphenyl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxy lie acid ( 4' -propionylphenyl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxy lie acid 4-benzoylphenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxy lie acid 4-(l-keto-l,2,3,4- tetrahydronaphth-7-yl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxy lie acid ( 4< -acetylphenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxy lie acid ( 3-acetylphenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2-benzoyl-4-chlorophenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3-methoxycarbonyl-6- methylphenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4- ethoxycarbonylmethylphenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-(6-methylbenzothiazol-2- yl)phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3-(2-methylpyrimidin-4-yl)- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2 -carboxylic acid (3-(oxazol-5-yl)-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid isoquinolin-5-yl-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3,5-dichloropyridin-4-yl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3-(oxazol-5-yl)-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3-chloropyridin-6-yl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid quinolin-6-yl-amide 3-Benzene sulfonylamino-thiophene-2-carboxylic acid 1-naphthyl-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid 2-thiazolyl amide
3-(3-Trifluoromethylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(2-Chlorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(3-Chlorobenzenesulfonylamino)-thiophene-2-carboxylic acid 4-chlorophenyl amide
3-(3-Fluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide 3-(4-Fluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide 3-(2-Fluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(2-Trifluoromethylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide 3-(3-Trifluoromethylbenzenesulfonylamino)-thiophene-2-carboxylic acid 4- chlorophenyl amide
3-(4-Trifluoromethoxybenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(3,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(4-Chloro-3,5-dimethylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(4-Bromobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide 3-(4-Trifluoromethylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(3,5-Bistrifluoromethylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(3-Chloro-4-fluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(3-Fluoro-6-methylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(3.5-Dichlorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide 3-(3-Chloro-2-methylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(3,4^Dichlorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(3,5-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide 3-(2-Chloro-4-fluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(2-Bromobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide 3-(2,6-Dichlorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(4-Iodobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(2,4-Dichlorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide 3-(4-Nitrobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(4-Acetylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(4-Cyano-2-chlorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(4-Cyanobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(4-Methoxybenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide 3-(3,5-Dichloro-4-hydroxybenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(2,5-Dimethoxybenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(3-Methoxybenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(2-Methoxy-5-methylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(3,5-Difluoro-4-methoxybenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide 3-(2-Methylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide 3-(2,5-Dimethylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(4-Isopropylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide 3-(4-Methylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(4-Ethylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(2,4,6-Trimethylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(2-Naphthylsulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(l-Naphthylsulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(5-Dimethylamino-l-naphthylsulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide 3-(3,5-Dimethyl-4-isoxazolylsulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(2, 1 ,3-Benzothiadiazol-4-sulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(5-Bromothiophene-2-sulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(4-Chloro-2,l,3-benzo-oxadiazol-7-sulfonylamino)-sulfonylamino)-thiophene-2- carboxylic acid 3-chlorophenyl amide
3-( 1 ,3-Dimethyl-5-chloropyrazole-4-sulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide 3-(2,5-Dichlorothiophene-3-sulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(2-Methoxycarbonylthiophene-3-sulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(5-Isoxazol-3-yl-thiophene-2-sulfonylamino)-thiophene-2-carboxylic acid (3- chloro-phenyl)-amide 3-(5-Chloro-2,l,3-benzo-oxadiazol-4-sulfonylamino)-sulfonylamino)-thiophene-2- carboxylic acid 3-chlorophenyl amide
3-(2-Thienylsulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(5-Pyridin-2-yl-thiophene-2-sulfonylamino)-thiophene-2-carboxylic acid (3- chloro-phenyl)-amide
3-(Butylsulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(2-Phenylethenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(n-Propylsulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide 3-(i-Propylsulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(n-Octylsulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(2,2,2-Trifluoroethylsulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(3,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3 -(3 ,4-Difluorobenzenesulf onylamino)-thiophene-2-carboxylic acid 4-fluorophenyl amide
3 -(3 ,4-Difluorobenzenesulf onylamino)-thiophene-2-carboxylic acid 3 -fluorophenyl amide 3-(3,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3- trifluoromethoxyphenyl amide
3-(3,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 4- trifluoromethylphenyl amide
3-(3 ,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3,5- difluorophenyl amide
3-(3,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 4-n- hexyloxyphenyl amide
3-(3 ,4-Difluorobenzenesulf onylamino)-thiophene-2-carboxylic acid 4-n- butyloxyphenyl amide 3-(3,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 4-chlorophenyl amide 3-(3,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3,4- dichlorophenyl amide
3-(3 ,4-Difluorobenzenesulf onylamino)-thiophene-2-carboxylic acid 2- methylthiophenyl amide 3-(3,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 4- benzyloxyphenyl amide
3-(3,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3- benzoylphenyl amide
3-(3,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid phenyl amide 3-(3,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 2,3- dichlorophenyl amide
3-(3,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 4- trifluoromethoxyphenyl amide
3-(3,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid thiazol-2-yl- amide
3-(3,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 4,5-dichloro-2- thienyl amide
3-(3 ,4-Difluorobenzenesulf onylamino)-thiophene-2-carboxylic acid 5-chloro-2- thienyl amide 3-(3,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 5- phenylsulfonyl-2-thienyl amide
5-(4-Fluorophenyl)-3-(2-methylbenzenesulfonylamino)-thiophene-2-carboxylic acid
3-chlorophenyl amide
5-(2-Thienyl)-3-(2-methylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
4-Methyl-3-(4-chlorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
4-Benzenesulfonylamino-thiophene-3-carboxylic acid 4-chlorophenylamide
4-Benzenesulfonyϊamino-thiophene-3-carboxylic acid 3,5-difluorophenylamide 4-Benzenesulfonylamino-thiophene-3-carboxylic acid 3-chlorophenylamide
4-Benzenesulfonylamino-thiophene-3-carboxylic acid 2,3-dichlorophenylamide 4-Benzenesulfonylamino-thiophene-3-carboxylic acid 4-fluorophenylamide 4-Benzenesulfonylamino-thiophene-3-carboxylic acid 3-fluorophenylamide 4-(3 ,4-Difluorobenzenesulfonylamino)-thiophene-3-carboxylic acid 4- fluorophenylamide 2-Benzenesulfonylamino-thiophene-3-carboxylic acid 4-chlorophenylamide 3-Benzenesulfonylaminofuran-2-carboxylic acid 4-isopropylphenylamide 3-Benzenesulfonylaminofuran-2-carboxylic acid 3-chlorophenylamide 3-(3,4-Difluorobenzenesulfonylamino)-furan-2-carboxylic acid 4- fluorophenylamide
Pharmaceutically acceptable 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. 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.
Scheme 1
Figure imgf000026_0001
NH2 R3S02CI NH
R1 f pyridine R1
~- COOCH, l COOCH,
Figure imgf000026_0002
Scheme 2
Figure imgf000027_0001
R3S02CI pyridine
R3 O = S = 0
Figure imgf000027_0002
Scheme 3
Figure imgf000027_0003
In order to use 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. For systemic administration, oral administration is preferred. For oral administration, for example, the compounds can be formulated into conventional oral dosage forms such as capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops. Alternatively, injection (parenteral administration) may be used, e.g., intramuscular, intravenous, intraperitoneal, and subcutaneous. For injection, 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. In addition, 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. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives. In addition, detergents may be used to facilitate permeation. Transmucosal administration, for example, may be through nasal sprays, rectal suppositories, or vaginal suppositories.
For topical administration, 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.
Preferably the composition is in unit dosage form. For oral application, for example, 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. In each case, 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.
As used herein, "treatment" of a disease includes, but is not limited to prevention, retardation and prophylaxis of the disease. 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. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose. Where the 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. Where the 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 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.
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 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.
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. Preferably 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.
No unacceptable toxological effects are expected when compounds of the present invention are administered in accordance with the present invention.
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.
Phosphate Uptake Assay Human intestinal cells (1-407, American Type Culture Collection, Manassas, NA, USA) were cultured and harvested according to the supplier's instructions. Rat small intestine epithelial cells were isolated from male Sprague-Dawley rats according to Tepperman et al (Am J Physiol 265:G214-G218, 1993). On the day of the experiment, human intestinal cells were harvested or rat intestinal cells were isolated and washed in uptake buffer at pH 7.4 consisiting of (in mM) ΝaCl 143; KC1 5.4, MgCl2 0.8, CaCl2 1.8, glucose 5 and Hepes 15. Fifty Dl aliquots of the cells (0.5 to 1 million) were distributed in 96- well plates followed by 25 Dl of the compound to be tested and 25 Dl of 100 DM 32p. χne c_ι\s were incubated at room temperature for 15 minutes and then isolated by filtration and washed with stop solution which consisted of (in mM) mannitol 100, NaCl 100, Na arsenate 10 and Hepes 5. The cellular uptake of 32p was measured by liquid scintillation counting and expressed either as a per cent of control uptake in the absence of added compounds or as pmol phosphate/ mg cell protein.
In the above noted whole cell assay system for rabbit and human proximal tubule cells the cells are harvested by filtration and 32p uptake is measured. It is also possible to use 33p rather than 32p. Using human proximal tubule cells 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 μM respectively.
The following examples illustrate preparation of compounds and pharmaceutical compositions that may be used in this invention. The examples are not intended to limit the scope of this invention as defined hereinabove and as claimed below.
Example 1 Preparation of N-(4-FluorophenyI)-3-(phenyIsulfonyIamino)-thiophene-2- carboxamide
a) Methyl 3-(PhenylsulfonyIamino) thiophene-2-carboxyIate •
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. The reaction mixture was added to a dilute HCl-ice mixture and the resulting crystals collected by filtration and washed with water to give tan crystals, which after recrystallization from CH2Cl2-hexane had mp 109-110°C. b) 3-Phenylsulfonylaminothiophene-2-carboxylic Acid
5 A suspension of 18.8 g (63 mmol) of methyl 3-(phenylsulfonylamino)- thiophene-2-carboxylate in 100 ml of 10% aqueous NaOH was refluxed for two hours and allowed to stand at ambient temperature for 18 hours. The reaction mixture was washed with ethyl acetate and acidified with 10% HC1 to give crystals which were collected by filtration and washed with water to give tan crystals, mp 10 167-169°C. c) 3-(PhenylsuIfonylamino)-2-chIorocarbonylthiophene
A suspension of 3-phenylsulfonylaminothiophene-2-carboxylic acid (3.8 g, 13.5 mmol) and 1.79 g (14.15 mmol) of oxalyl chloride in 35 ml of CH2C12 was treated with one drop of DMF and stirred for two hours to give a clear solution. The 15 solution was concentrated in an argon stream and used without further purification in the next reaction.
1R: COCI peak at 1660 cm"1, COOH peak at 1653"1 absent, d) N-(4-FIuorophenyl)-3-(phenylsulfonylamino) thiophene-2-carboxamide
20 A solution of 4-fluoroaniline (0.25 g, 2.25 mmol) and triethylamine (1.52 g,
15 mmol) in 2.5 ml toluene was treated with a toluene - CH2C12 solution containing 0.53 g (1.77 mmol) of 3-phenylsulfonylamino-2-chlorocarbonylthiophene. After one hour the mixture was filtered and the filtrate dried over MgS04. Concentration under vacuum gave a gum which was dissolved in DMSO for purification by
25 preparative HPLC: column, OD5-A 30 x 75 mm; gradient 90% H2O/10% CH3CN to 10% H2O/90% CH3CN (all 0.16 TFA) in 2.7 min. The product, mp 158-160°C, was 100% pure by LC-MS.
A similar procedure using ethyl p-aminobenzoate gave crystals, mp 144- 146°C, of N-(4-ethoxycarbonyIphenyl)-3-phenylsulfonylaminothiophene -2-
30 carboxamide. Example 2 Preparation of N-(4-Chlorophenyl)-3-(phenylsulfonyIamino)thiophene-2- carboxamide
5 a) 3-Amino-N-(4-chlorophenyI) thiophene-2-carboxamide
A solution of 4-chloroaniline (6.38 g, 0.05 mmol) was dissolved in 50 ml of toluene, chilled to °C, and treated with 25 ml (0.05 mmol) of 2 M trimethylaluminum in toluene. After 0.5 hour the temperature was allowed to rise to 25°C and held for an additional 0.5 hour at which time no further gas evolution
10 occurred. The 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
15 vacuum. This was used without further purification in the next step.
b) N-(4-Chlorophenyl)-3-(phenylsulfonylamino)thiophene-2-carboxamide
A solution of 1.24 g (4.91 mmol) of 3-amino-N-(4-chlorophenyl)-thiophene- 2-carboxamide and 1.55 g (19.6 mmol) of pyridine in 50 ml of methylene chloride
20 was treated with 0.9 g (5.15 mmol) of benzenesulfonylchloride and stirred at 25° for 18 hours. The mixture was concentrated under vacuum, and the residue dissolved in ethyl acetate which was then washed in turn with water, 10% aqueous HC1, water, 5% NaHCO , and then dried over Mg504. The solution was concentrated under vacuum and the residue dissolved in a minimum of hot ethyl acetate which was then
25 diluted 3-fold with hexane. After standing for 18 hours the crystals which formed were collected, washed with 25% ethyl acetate-hexane, and dried.
Anal. Calcd for C17H13CIN2O3S2: C, 51.97; H, 3.34; N, 7.13. Found: C, 51.91; H, 3.23; N, 7.06. Example 3 Preparation of N-(4-chlorophenyl)-4-methyl-3-(phenylsulfonamido)-thiophene- 2-carboxamide Reaction of methyl 3-amino-4-methylthiophene-2-carboxylate with the complex prepared by reaction of 4-chloroaniline with trimethyl aluminum by the procedure of Example 2 gave 3-amino-N-(4-chlorophenyl)-4-methylthiophene-2-carboxamide as a tan solid. MS: M+l Calcd, 267; Found, 267. Reaction of this with benzenesulfonyl chloride by the method of Example 2 gave the desired product which after recrystallization from methanol was obtained as colorless crystals. MS: M+l Calcd 407; Found, 407.
Example 4 Preparation of N-(4-chlorophenyl)-4-(phenylsulfonamido)-thiophene-3- carboxamide
Reaction of methyl 4-aminothiophene-3-carboxylate with the complex prepared by reaction of 4-chloroaniline with trimethyl aluminum by the procedure of Example 2 gave 4-amino-N-(4-chlorophenyl)-3-carboxamide as a tan solid. MS: M+l Calcd, 267; Found, 267. Reaction of this with benzenesulfonyl chloride by the method of Example 2 gave the desired product which after preparative LC (C-18 ODS, 5 uM particle size, 20 x 50 mm column, 10% acetonitrile-water to 98% acetonitrile (all with 0.1% TFA) 6 min gradient) was obtained as an off-white solid. MS: M+l Calcd 393; Found, 393. Anal. Calcd for C17H13CIN2O3S2: C, 51.97, H, 3.34, N, 7.13. Found: C.51.63, H, 3.30, N/7.24.
Example 5 Parallel Synthesis of N-Substituted-(3-phenyIsulfonylamino)-thiophene-2- carboxamides
A 0.53 mmol sample of each amine or amine hydrochloride suspended in 20 ml of toluene containing 0.217 g (2.14 mmol) triethylamine and 0.5 ml of a methylene chloride solution containing 0.064 g (0.20 mmol) of 3- (phenylsulfonylamino)-2-chlorocarbonylthiophene was added and the mixture stirred 66 hr at amibient temperature. Each reaction vessel was then treated with 3 ml of 10% aqueous HCl, stirred, and filtered. If appreciable crystalline material was collected it was saved for purification. For most sample 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.
Example 6 3-(3,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 4- fluorophenyl Amide
Methyl N-(3 ,4-difluorophenylsulfonyl)-3-aminothiophene-2-carboxylate A solution of 1.73 g (11.03 mmol) of methyl 3-aminothiophene-2- carboxylate in 50 ml of pyridine at 0° C was treated with 4.69g (22.06 mmol) of 3,4-difluorobenzenesulfonylchloride in several portions. After stirring for 18 hr at ambient temperature the reacation mixture was poured into 250 ml of 10% HCl and extracted with ethyl acetate. The organic layer was separated, washed wisth brine, and dried over MgSO Concentration under vacuum gave an oil. TLC (silica,
CHCI3) product Rf 0.57, starting material, 0.35.
N-(3,4-Difluorophenylsulfonyl)-3-aminothiophene-2-carboxylic Acid A suspension of about 3.7 g (11 mmol) of methyl N-(3,4-
, difluorophenylsulfonyl)-3-aminothiophene-2-carboxylate in a mixture of 30 ml of 10% aqueous NaOH, 5 ml of ethanol, and 5 ml of water was refluxed for 4 hr to give a clear amber solution. This was poured into 100 ml of 10% HCl to give a gum which was extracted with ethyl acetate which was washed with brine, dried over MgSO4 and concentrated under vacuum to give a solid. Recrystallization from an ethanol-water mixture gave tan needles, MP 177-178° C. C,H, and N elemental analysis was satisfactory.
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.
3-(3,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 4-fluorophenyl Amide
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. The mixture was then stirred with 2 successive portions of a chloroform-methanol (9: 1) solution for 3 hours each. The combined extracts were concentrated under vacuum, and the residue dissolved in about 7 ml of a chloroform-methanol (9:1) solution and then filtered through a 0.45 um frit. After concentration the residue was dissolved in 125 ul of DMSO and a 20 ul portion analyzed by LCMS which indicated the presence of the desired product. The remaining solution was purified by preparative HPLC (C18, 20-95% aqueous acetonitrile, 0.1% TFA in all eluents). The fractions containing product were concentrated under vacuum and analyzed by LCMS. The product was essentially one substance, and had the correct molecular weight. Example 7 3-(3,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 4-n- butyloxyphenyl amide
A solution of 3-(3,4-difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid (63.8 mg, 0.20 mmol) in 1 ml of methylene chloride was treated in turn with diisopropylethylamine (105 ul, 0.6 mmol) and PyBOP (benzotriazol-1- yloxytris(pyrrolidino)phosphonium hexafluorophosphate, 127 mg, 0.24 mmol) and was stirred under argon for 30 min to give a clear solution. Then 36.3 mg (0.22 mmol) of 4-butoxyaniline dissolved in 1 ml of methylenechloride was added. After stirring at ambient temperature for 18 hours the solvent was removed by evaporation under a stream of argon and a sample taken for LCMS. This showed that the expected product was present. The residue was purified by preparative HPLC as in Example 1. LCMS was satisfactory for the purified sample.
Example 8
3-(3-Trifluoromethylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-Aminothiophene-2-carboxylic acid 3-chlorphenyl amide
A solution of 10.0 g (78.4 mmol) of 3-chloroaniline in 100 ml of toluene under argon was treated with trimethyl aluminum (39.2 ml, 78.4 mmol of a 2.0 M solution in toluene) in small portions over 30 min. The reaction mixture was stirred for 2.5 hr at ambient temperature and then 12.3 g (78.4 mmol) of methyl 3- aminothiophene-2-carboxylate added in small portions over 5 min. The reaction mixture was stirred at ambient for 18 hr and poured into vigorously stirred 500 ml of 10% HCl. The toluene layer on partial evaporation gave crystals, mp 201-212° C whose NMR spectrum was consistent with the expected structure. 3-(3-Trifluoromethylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
A mixture of 3-aminothiophene-2-carboxylic acid 3-chlorphenyl amide (1.06 g, 4.2 mmol), 3-trifluoromethylbenzenesulfonyl chloride, and 0.9 ml of pyridine in 30 ml of methylenechloride was stirred at ambient temperature for 3 hr. The reaction mixture was poured into 10% HCl, the organic phase collected and concentrated under vacuum to give a gum which on trituration with hexane, and then hexane-methylenechloride 2:1 gave crystals, mp 164-165° C, TLC (silica, CHCl3) Rf 0.15-0.25.
Example 9 3-BenzenesuIfonylaminofuran-2-carboxylic acid 4-isopropylphenylamide
3-Azidofuran-2-carboxylic acid 4-isopropyphenylamide 3-Azidofuran-2-carboxylic acid was prepared by the method of S.
Gronowitz, C. Westerlund and A.-B. Hornfeldt, Acta Chemica Scandinavia B, 29 224-232 (1975. 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 4-isopropyphenylamide Hydrochloride
The azide was dissolved in 5.5 ml of acetonitrile and sodium iodide (0.206 g, 1.38 mmol) was added. Then a solution of 0.129 ml of trimethylsilylchloride dissolved in 1.1 ml of acetonitrile was added and the mixture stirred for 18 hr at ambient temperature. A solution of 10% sodium thiosulfate was then added and the mixture extracted twice with ether. The organic layer was washed in turn with water, brine and then dried over magnesium sulfate. Concentration under vacuum gave a syrup which was dissolved in ether and acidified with ethereal hydrogen chloride to give a solid which was collected and washed with ether, mp 160° C dec.with the correct LCMS and NMR spectrum.
3-Aminofuran-2-carboxylic acid 3-chlorophenylamide hydrochloride prepared in a similar manner had mp 155° C.
3-Benzenesulfonylaminofuran-2-carboxylic acid 4-isopropylphenylamide Benzenesulfonyl chloride (0.040 ml, 0.31 mmol) was added to a stirred solution of 3-aminofuran-2-carboxylic acid 4-isopropyphenylamide hydrochloride in 0.5 ml of pyridine. After 62 hr the mixture was treated with 2 ml of 10% HCl and the mixture extracted with ethyl acetate. The organic layer was washed in turn with 10% HCl, water, saturated sodium bicarbonate, and brine, and dried over magnesium sulfate. Concentration gave a gum which was purified by preparative HPLC (C18, 20-95% aqueous acetonitrile, 0.1% TFA in all eluents). TLC (silica, hexane-ethyl acetate 6:4) Rf 0.45.
3-Benzenesulfonylaminofuran-2-carboxylic acid 3-chlorophenylamide prepared in a similar manner had Rf 0.29.
Example 10 4-Benzenesulfonylamino-thiophene-3-carboxylic acid 3,5-Difluorphenylamide
Methyl 4-Benzenesulfonylamino-thiophene-3-carboxylate
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
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
0.31.
Methyl 4-Benzenesulfonylamino-thiophene-3-carboxylate
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.
4-Benzenesulfonylamino-thiophene-3-carboxylic acid 3,5-Difluorphenylamide
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. Then 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. The toluene solution was collected, and the residue extracted twice with a methylene chloride-methanol mixture. The combined solutions were concentrated under vacuum, the residue dissolved in 0.5 ml of DMSO, and purified by preparative HPLC (C18, 20-95% aqueous acetonitrile, 0.1% TFA in all eluents). The product showed the correct molecular weight by LCMS.
Example 11
2-Benzenesulfonylaminothiophene-3-carboxylic acid 4-ChIorophenylamide
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. This in turn was converted by the method of Example 2 to 2-benzenesulfonylaminothiophene-3- carboxylic acid 4-chlorophenylamide and was purified by preparative HPLC (C18, 20-95% aqueous acetonitrile, 0.1% TFA in all eluents). The product showed the correct molecular weight by LCMS and gave the expected NMR spectrum.
Other compounds useful in the present invention can readily be synthesized using the following amines to prepare carboxamides:
2,6-dimethylaniline 3,4-dimethoxyaniline
4-amino-3 ,5-dichloropyridine
6-amino- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -one
3 -aminoacetophenone
3 -aminobenzophenone 6-aminoquinoline
4-aminopyridine
2-amino-4,6-dimethylpyridine
3 -benzyloxy aniline l-amino-5,6,7,8-tetrahydronaphthalene 3,5-dimethoxyaniline
1 -(2-aminophenyl)pyrrole
5-aminoindazole
2-aminopyridine
2-fluoroaniline 2-thiophenemethylamine benzylamine butylamine
2-amino-5-chloropyridine
2-amino-2-thiazoline 3,4-dimethoxyaniline
4-ethylaniline 2,3-dichloroanilline
2,3-dimethylaniline
2,3-dimefhoxyaniline phenethylamine 3-amino-6-methyl-n,n-dimethylbenzenesulfonamide
5-aminobenzotriazole methyl 5-amino-2-methoxybenzoate
6-amino-2-methylbenzothiazole l,3-dihydro-isobenzofuran-5-ylamine 3-(3-aminophenyl)-l-methyl-lh-pyrazole
4-(3-aminophenyl)-2-methylpyrimidine
3-(l,3-oxazol-5-yl)aniline
5-aminoquinoline cyclohexylamine hydrochloride 2-chloroaniline beta-alanine ethyl ester hydrochloride ethyl 4-aminobutyrate hydrochloride methyl 3-amino-4-methoxybenzoate methyl 3-amino-4-methylbenzoate 4-n-butylaniline4-butoxyaniline
4-isopropylaniline
4-phenoxyaniline
4-aminobiphenyl p-hexyloxyaniline p-anisidine
4-isopropoxyaniline
4-aminoacetophenone
4-aminobenzophenone ethyl 4-aminophenylacetate butyl 4-aminobenzoate p-aminopropiophenone ethyl 3-aminobenzoate
4-aminophenethyl alcohol
2-(4-aminophenyl)-6-methylbenzothiazole n,n-diethylphenylenediamine procaine hcl
2 ,4, 6-trifluoroaniline n 1 -(6-indazolyl)sulf anilamide sulfathiazole
4-morpholinoaniline 4-aminobenzyl alcohol
4-cyclohexylaniline
4-benzyloxyaniline hydrochloride
3-fluoroaniline
3 -aminobenzotrifluoride 2-aminobenzotrifluoride aniline sulfadiazine
3 ,4-dichloroaniline
4-chloroaniline ethyl anthranilate
4-aminobenzotrifluoride
2,6-difluoroaniline methyl 3-aminobenzoate
3-chloroaniline 2,3-dimethylaniline
3 ,4-methylenedioxy aniline
2-aminodiphenylamine
3 ,5-difluoroaniline
3 ,4-difluoroaniline 2-amino-5-chlorobenzophenone
2-(2-aminophenyl)indole 5-aminoisoquinoline
2-naphthylamine
2-aminofluorene p-aminobenzanilide 7-amino-4-methylcoumarin
2-aminobiphenyl
4-fluoroaniline; and benzocaine.
The following sulfonyl chlorides can be used to prepare sulfonamides useful in the present invention: benzenesulfonyl chloride
3 -trifluoromethylbenzenesulf onyl chloride
2-trifluoromethylbenzenesulfonyl chloride
4-trifluoromethylbenzenesulfonyl chloride 3,5-ditrifluoromethylbenzenesulfonyl chloride
2-chlorobenzenesulfonyl chloride
3-chlorobenzenesulfonyl chloride
2-fluoromethylbenzenesulfonyl chloride
3-fluorobenzenesulfonyl chloride 4-fluorobenzenesulfonyl chloride
3 ,4-difluorobenzenesulfonyl chloride
3 ,5-difluorobenzenesulfonyl chloride
4-trifluoromethoxybenzenesulfonyl chloride
4-chloro-3 ,5-dimethylbenzenesulfonyl chloride 4-bromobenzenesulfonyl chloride
4-bromo-2,5-difluorobenzenesulfonyl chloride
3 -chloro-4-fluorobenzenesulf onyl chloride
4-acetylbenzenesulfonyl chloride
2-chloro-4-cyanobenzenesulfonyl chloride 4-cyanobenzenesulfonyl chloride
4-nitrobenzenesulfonyl chloride -methoxybenzenesulfonyl chloride ,4-dimethoxybenzenesulf onyl chloride ,5-dichloro-4-hydroxybenzenesulfonyl chloride ,5-dimethoxybenzenesulfonyl chloride -methoxybenzenesulfonyl chloride -methoxy-5-methylbenzenesulfonyl chloride -methylbenzenesulfonyl chloride ,5-dimethylbenzenesulfonyl chloride -isopropylbenzenesulfonyl chloride -methylbenzenesulfonyl chloride -ethylbenzenesulfonyl chloride ,4,6-trimethylbenzenesulfonyl chloride -naphthylsulfonyl chloride -dimethylamino- 1-naphthylsulfonyl chloride ,5-dimethyl-4-isoxazolylsulfonyl chloride , 1 ,3-benzthiadiazol-4-ylsulfonyl chloride -bromo-2-thienylsulfonyl chloride , 1 ,3-benzoxadiazol-7-chloro-4-ylsulfonyl chloride -chloro- 1 ,3-dimethyl-4-pyrazolylsulfonyl chloride ,5-dichloro-3-thienylsulfonyl chloride -ethoxycarbonyl-3-thienylsulfonyl chloride -(3-oxazolyl)-2-thienylsulfonyl chloride -thienylsulfonyl chloride -butylsulfonyl chloride -propylsulfonyl chloride -propylsulfonyl chloride -octylsulfonyl chloride ,2,2-trifluoroethylsulfonyl chloride -phenylvinylsulfonyl chloride All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth. The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the area can, using the preceding description, utilize the present invention to its fullest extent. Therefore the Examples herein are to be construed as merely illustrative and not a limitation of the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.

Claims

What is claimed is:
A compound according to Formula I, Formula II or Formula III:
Figure imgf000047_0001
II III wherein
X is sulfur or oxygen;
R. 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 (Rι)n represents a (R^n substituted aryl or a heterocycle selected from the group consisting of thiophene, furan, pyridine, pyrimidine, pyrazine, isoxazole, thiazole, imidazole, pyrazole, thiadiazole, oxadiazole, and benzo analogs thereof; or Ri represents a fused ring selected from the group consisting of thiophene, furan, pyridine, pyrimidine, pyrazine, isoxazole, thiazole, imidazole, pyrrazole, thiadiazole, oxadiazole, and benzo analogs thereof, and
R2 and R3 are not hydrogen, but are independently selected from a group consisting of -(CHR4)n-(CHR5)m-(CHR6)p-(R1 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, Ri substituted aryl or heteroaryl,
2. A compound according to Claim 1 wherein RΪ is selected from the group consisting of hydrogen, bromide, chloride, methyl, 4-fluorophenyl, and 2-thienyl, and R2 is selected from the group consisting of 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-methylbenzofhiazol)- yl, and 3-(l,2,4-methylpyrazol)-yl and
R3 is selected from the group consisting of phenyl, benzyl, 2-naphthyl, 5- dimethylamin-1-naphthyl, 2-methylphenyl, 3,4-difluorophenyl, 2- or 3- fluorophenyl, 4-chlorophenyl, 3-trifluoromethylphenyl, 2,5-dimethylphenyl, 4- chloro-3,5-dimethylphenyl, 4-nitrophenyl, 4-methoxyphenyl, butyl, octyl, 2,2,2- trifluoroethyl, 2-thiazolyl, 4-(2,l,3-benzothiadiazol)yl, 4-(3,5-dimethylisoxazol)-yl, 3-(2,5-dichlorothiophene)-yl, 5-chloro-2-thienyl, and 2-(5- phenylsulfonylthiophene)-yl.
3. A compound according to Claim 1 wherein the compound is selected from the group of:
3-Benzenesulfonylarnino-N-(3-chlorophenyl)-4-thiophenecarboxamide; 3-Benzenesulfonylamino-N-(3-chlorophenyl)-4-thiophenecarboxamide;
N-(4-Chlorophenyl)-3-[[[3-(trifluoromethyl)phenyl]sulfonyl]amino]-2- thiophenecarboxamide
N-(4-Chlorophenyl)-3- [[(2-fluorophenyl)sulfonyl] amino] -2- thiophenecarboxamide
N-(4-Chlorophenyl)-3-[[(4-methoxyphenyl)sulfonyl]amino]-2- thiophenecarboxamide 3-[(Benzenesulfonyl)amino]-N-(4-chlorophenyl)-2-thiophenecarboxamide N-(4-Chlorophenyl)-3-[[(5-chloro-2-thienyl)sulfonyl]amino]-2- thiophenecarboxamide
N-(4-Chlorophenyl)-3-[[(2,2,2-trifluoroethyl)sulfonyl]amino]-2- thiophenecarboxamide 3-[(Butylsulfonyl)amino]-N-(4-chlorophenyl)-2-thiophenecarboxamide
3-[(Butylsulfonyl)amino]-N-(3-chloro-4-methoxyphenyl)-2- thiophenecarboxamide
N-[l,l'-Biphenyl]-4-yl-3-[[[3-(trifluoromethyl)phenyl]sulfonyl]amino]-2- thiophenecarboxamide N-(3 ,4-Dichlorophenyl)-3 - [ [ [3 -(trifluoromethyl)phenyl] sulfonyl] amino] -2- thiophenecarboxamide
N-[l,r-Biphenyl]-4-yl-3-[[(2-fluorophenyl)sulfonyl]amino]-2- thiophenecarboxamide
N-(3,4-Dichlorophenyl)-3-[[(2-fluorophenyl)sulfonyl]amino]-2- thiophenecarboxamide
N-[l,l'-Biphenyl]-4-yl-3-[[(4-methoxyphenyl)sulfonyl]amino]-2- thiophenecarboxamide
N-(3,4-Dichlorophenyl)-3-[[(4-methoxyphenyl)sulfonyl]amino]-2- thiophenecarboxamide N-[l,r-Biphenyl]-4-yl-3-[(phenylsulfonyl)amino]-2-thiophenecarboxamide
N-(3,4-Dichlorophenyl)-3-[(phenylsulfonyl)amino]-2-thiophenecarboxamide
N-[l,l'-Biphenyl]-4-yl-3-[[(5-chloro-2-thienyl)sulfonyl]amino]-2- thiophenecarboxamide
3-[[(5-Chloro-2-thienyl)sulfonyl]amino]-N-(3,4-dichlorophenyl)-2- thiophenecarboxamide
N-[l,l'-Biphenyl]-4-yl-3-[[(2,2,2-trifluoroethyl)sulfonyl]amino]-2- thiophenecarboxamide
N-[l,r-Biphenyl]-4-yl-3-[(butylsulfonyl)amino]-2-thiophenecarboxamide
N-(3-Chloro-4-methoxyphenyl)-3-[[[3- (trifluoromethyl)phenyl]sulfonyl]amino]-2-thiophenecarboxamide N-(3-Chloro-4-methoxyphenyl)-3-[[(2-fluorophenyl)sulfonyl]amino]-2- thiophenecarboxamide
N-(3-Chloro-4-methoxyphenyl)-3-[[(4-methoxyphenyl)sulfonyl]amino]-2- thiophenecarboxamide N-(3-Chloro-4-methoxyphenyl)-3-[(phenylsulfonyl)amino]-2- thiophenecarboxamide
N-(3-Chloro-4-methoxyphenyl)-3-[[(5-chloro-2-thienyl)sulfonyl]amino]-2- thiophenecarboxamide
N-(3-Chloro-4-methoxyphenyl)-3-[[(2,2,2-trifluoroethyl)sulfonyl]amino]-2- thiophenecarboxamide
N-[3-(Trifluoromethyl)phenyl]-3-[[[3- (trifluoromethyl)phenyl] sulfonyl] amino] -2-thiophenecarboxamid
3-(2-Fluoro-benzenesulfonylamino)-thiophene-2-carboxylic acid (3- trifluoromethyl-phenyl)-amide 3-(4-Methoxy-benzenesulfonylamino)-thiophene-2-carboxylic acid phenylamide
3-(4-Methoxy-benzenesulfonylamino)-thiophene-2-carboxylic acid (3- trifluoromethyl-phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3-trifluoromethyl- phenyl)-amide
3-(5-Chloro-thiophene-2-sulfonylamino)-thiophene-2-carboxylic acid (3- trifluoromethyl-phenyl)-amide
3-(2,2,2-Trifluoro-ethanesulfonylamino)-thiophene-2-carboxylic acid (3- trifluoromethyl-phenyl)-amide 3-(Butane-l-sulfonylamino)-thiophene-2-carboxylic acid phenylamide
3-(Butane-l-sulfonylamino)-thiophene-2-carboxylic acid (3-trifluoromethyl- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-butoxy-phenyl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-isopropyl-phenyl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-phenoxy-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-hexyloxy-phenyl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-methoxy-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-isopropoxy- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-acetyl-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-benzoyl-phenyl)- amide
{4-[(3-Benzenesulfonylamino-thiophene-2-carbonyl)-amino]-phenyl}-acetic acid ethyl ester 4-[(3-Benzenesulfonylamino-thiophene-2-carbonyl)-amino]-benzoic acid butyl ester
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-propionyl-phenyl)- amide
3-[(3-Benzenesulfonylamino-thiophene-2-carbonyl)-amino]-benzoic acid ethyl ester
3-Benzenesulfonylamino-thiophene-2-carboxylic acid [4-(2-hydroxy-ethyl)- phenyl] -amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid [4-(6-methyl- benzothiazol-2-yl)-phenyl]-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-diethylamino- phenyl)-amide
4-[(3-Benzenesulfonylamino-thiophene-2-carbonyl)-amino]-benzoic acid 2- diethylamino-ethyl ester
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2,4,6-trifluoro- phenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid [4-(lH-indazol-6- ylsulfamoyl)-phenyl]-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid [4-(thiazol-2- ylsulfamoyl)-phenyl]-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-hydroxymethyl- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-cyclohexyl- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-benzyloxy- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2 -carboxylic acid (3-fluoro-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2-trifluoromethyl- phenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid phenylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid [4-(pyrimidin-2- ylsulfamoyl)-phenyl]-amide
2-[(3-Benzenesulfonylamino-thiophene-2-carbonyl)-amino]-benzoic acid ethyl ester 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-trifluoromethyl- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2,6-difluoro-phenyl)- amide
3-[(3-Benzenesulfonylamino-thiophene-2-carbonyl)-amino]-benzoic acid methyl ester
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3-chloro-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid benzo[l,3]dioxol-5- ylamide ( 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3,5-difluoro-phenyl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3 ,4-difluoro-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2-benzoyl-4-chloro- phenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid [2-(lH-indol-2-yl)- phenyl]-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid isoquinolin-5-ylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid naphthalen-2-ylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (9H-fluoren-2-yl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-phenylcarbamoyl- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-methyl-2-oxo-2H- chromen-7-yl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid biphenyl-2-ylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-fluoro-phenyl)- amide
4-[(3-Benzenesulfonylamino-thiophene-2-carbonyl)-amino]-benzoic acid ethyl ester 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2,6-dimethyl- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3,4-dimethoxy- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3 ,5-dichloro-pyridin- 4-yl) -amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (5-oxo-5,6,7,8- tetrahydro-naphthalen-2-yl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3-acetyl-phenyl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3-benzoyl-phenyl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid quinolin-6-ylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid pyridin-4-ylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4,6-dimethyl- pyridin-2-yl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3-benzyloxy- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (5,6,7,8-tetrahydro- naphthalen- 1 -yl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3,5-dimethoxy- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2-pyrrol- 1 -yl- phenyl) -amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (lH-indazol-5-yl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid pyridin-2-ylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2-fluoro-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (thiophen-2- ylmethyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid benzylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid butylamide
3-Benzenesulfonylamino-thioρhene-2-carboxylic acid (5-chloro-pyridin-2- yl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-ethyl-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2,3-dichloro-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2,3-dimethyl- phenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2,3-dimethoxy- phenyl) -amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid phenethyl-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3- dimethylsulfamoyl-4-methyl-phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid ( lH-benzotriazol-5- yl)-amide
5-[(3-Benzenesulfonylamino-thiophene-2-carbonyl)-amino]-2-methoxy- benzoic acid methyl ester
3-Benzenesulfonylan ino-thiophene-2-carboxylic acid (2-methyl- benzothiazol-6-yl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (1,3-dihydro- isobenzofuran-5-yl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid [3-(l-methyl-lH- pyrazol-3-yl)-phenyl]-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid [3-(2-methyl- pyrimidin-4-yl)-phenyl] -amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3-oxazol-5-yl- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid quinolin-5-ylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid cyclohexylamide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2-chloro-phenyl)- amide
3-[(3-Benzenesulfonylamino-thiophene-2-carbonyl)-amino]-propionic acid ethyl ester
4-[(3-Benzenesulfonylamino-thiophene-2-carbonyl)-amino]-butyric acid ethyl ester
3-[(3-Benzenesulfonylamino-thiophene-2-carbonyl)-amino]-4-methoxy- benzoic acid methyl ester
3-[(3-Benzenesulfonylamino-thiophene-2-carbonyl)-amino]-4-methyl- benzoic acid methyl ester 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2-phenylamino- phenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid quinolin-8-ylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid isoquinolin- 1 -ylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2,4,6-trimethoxy- phenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (5,6-dimethyl-lH- benzoimidazol-2-yl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid indan-5-ylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2,3-dihydro- benzo [ 1 ,4]dioxin-6-yl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (lH-indol-5-yl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-dimethylamino- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2-methoxy-phenyl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid #o l-tolylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid ( 1 H-benzoimidazol-2- yl)-amide
3-Benzenesulfonylamino-thiophene-2 -carboxylic acid benzothiazol-2- ylamide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4- trifluoromethanesulfonyl-phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3-trifluoromethoxy- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (5-#tert!-butyl- isoxazol-3-yl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4-methyl-pyridin-2- yl)-amide
3-[(3-Benzenesulfonylamino-thiophene-2-carbonyl)-amino]-thiophene-2- carboxylic acid methyl ester 3-Benzenesulfonylamino-thiophene-2-carboxylic acid benzo[ 1 ,2,5]thiadiazol-4-ylamide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3,5-dichloro-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2 -carboxylic acid ( 1 ,3 ,5-trimethyl- 1 H- pyrazol-4-yl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (4,5-dimethyl-thiazol-
2-yl)-amide
3-Benzenesulfonylamino-thiophene-2 -carboxylic acid (furan-2-ylmethyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (1,1-dimethyl- propyl)-amide
[(3-Benzenesulfonylamino-thiophene-2-carbonyl)-amino]-acetic acid ethyl ester
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (5-methyl-isoxazol-3- yl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2-methoxy-ethyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid thiazol-2-ylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid [ 1 ,3 ,4]thiadiazol-2- ylamide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2-benzyl-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxyIic acid biphenyl-3-ylamide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid [4-(4-chloro- phenoxy)-phenyl] -amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (2-methylsulfanyl- phenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (lH-tetrazol-5-yl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (thiophen-3- ylmethyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid naphthalen- 1 -ylamide 3-[(2-Fluorobenzenesulfonyl)amino]-N-(3,4-difluorophenyl)-2- thiophenecarboxamide
3-[(Butanesulfonyl)amino]-N-(3-trifluoromethylphenyl)-2- thiophenecarboxamide
3-Benzenesulfonyl)amino]-N-(3-chlorophenyl)-4-methyl-2- thiophenecarboxamide 4. A compound according to claim 1 selected from the group consisting of:
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 3-Benzenesulfonylamino-thiophene-2-carboxylic acid 4-cyclohexylphenyl)-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid 3,4-dichloro phenyl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid 2,3-dichloro phenyl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid 4-chlorophenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid 3,4-dichloro phenyl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid 2-chloro-3-methylphenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid 3,5-difluorophenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid 3 ,4-difluorophenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid 4-fluorophenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid 3-fluorophenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid 2-fluorophenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid 3-trifluoromethylphenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid 4-trifluoromethylphenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid 3 -trifluoromethoxyphenyl)- amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid 4-hexyloxyphenyl)-amide 3-Benzenesulfonylamino-thiophene-2 ■carboxylic acid 4-butoxyphenyl)-amide 3-Benzenesulfonylamino-thiophene-2 •carboxylic acid 3 ,4-methylenedioxyphenyl)- amide
3-Benzenesulfonylamino-thiophene-2 -carboxylic acid 3 ,5-dimethoxyphenyl)- amide
3-Benzenesulfonylamino-thiophene-2 •carboxylic acid 3-benzyloxyphenyl)- amide 3-Benzenesulfonylamino-thiophene-2 ■carboxylic acid 2-methylthiophenyl)- amide 3-Benzenesulfonylamino-thiophene-2 ■carboxylic acid 4-methoxyphenyl)- amide 3-Benzenesulfonylamino-thiophene-2 •carboxylic acid 4-isopropyloxyphenyl)- amide
3-Benzenesulfonylamino-thiophene-2 ■carboxylic acid 3-ethoxycarbonylphenyl)- amide
3-Benzenesulfonylamino-thiophene-2 -carboxylic acid 4-butoxycarbonylphenyl)- amide 3-Benzenesulfonylamino-thiophene-2 ■carboxylic acid 4-propionylphenyl)- amide 3-Benzenesulfonylamino-thiophene-2 carboxylic acid 4-benzoylphenyl)-amide 3-Benzenesulfonylamino-thiophene-2 ■carboxylic acid 4-(l-keto-l,2,3,4- tetrahydronaphth-7-yl)-amide 3-Benzenesulfonylamino-thiophene-2 •carboxylic acid 4-acetylphenyl)-amide 3-Benzenesulfonylamino-thiophene-2 carboxylic acid 3-acetylphenyl)-amide 3-Benzenesulfonylamino-thiophene-2 ■carboxylic acid 2-benzoyl-4-chlorophenyl)- amide
3-Benzenesulfonylamino-thiophene-2 -carboxylic acid 3 -methoxycarbonyl-6- methylphenyl)-amide 3-Benzenesulfonylamino-thiophene-2 -carboxylic acid ethoxycarbonylmethylphenyl)-amide 3-Benzenesulfonylamino-thiophene-2 carboxylic acid (4-(6-methylbenzothiazol-2- yl)phenyl)-amide 3-Benzenesulfonylamino-thiophene-2 •carboxylic acid (3-(2-methylpyrimidin-4-yl)- phenyl)-amide 3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3-(oxazol-5-yl)-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid isoquinolin-5-yl-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3,5-dichloropyridin-4-yl)- 5 amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3-(oxazol-5-yl)-phenyl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid (3-chloropyridin-6-yl)- amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid quinolin-6-yl-amide 10. 3-Benzene sulfonylamino-thiophene-2-carboxylic acid 1-naphthyl-amide
3-Benzenesulfonylamino-thiophene-2-carboxylic acid 2-thiazolyl amide
3-(3-Trifluoromethylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(2-Chlorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl 15 amide
3-(3-Chlorobenzenesulfonylamino)-thiophene-2-carboxylic acid 4-chlorophenyl amide
3-(3-Fluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide 20 3-(4-Fluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(2-Fluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(2-Trifluoromethylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3- 25 chlorophenyl amide
3-(3-Trifluoromethylbenzenesulfonylamino)-thiophene-2-carboxylic acid 4- chlorophenyl amide
3-(4-Trifluoromethoxybenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide 30 3-(3,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide 3-(4-Chloro-3 ,5-dimethylbenzenesulf onylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(4-Bromobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide 3-(4-Trifluoromethylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(3 ,5-Bistrifluoromethylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(3-Chloro-4-fluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(3-Fluoro-6-methylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(3 -5-Dichlorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide 3-(3-Chloro-2-methylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(3,4-Dichlorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(3 ,5-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(2-Chloro-4-fluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3 - chlorophenyl amide
3-(2-Bromobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide 3-(2,6-Dichlorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(4-Iodobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(2,4-Dichlorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide 3-(4-Nitrobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide 3-(4-Acetylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3 -chlorophenyl amide
3-(4-Cyano-2-chlorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide 3-(4-Cyanobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(4-Methoxybenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(3,5-Dichloro-4-hydroxybenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(2,5-Dimethoxybenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(3-Methoxybenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide 3-(2-Methoxy-5-methylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(3 ,5-Difluoro-4-methoxybenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(2-Methylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(2,5-Dimethylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(4-Isopropylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide 3-(4-Methylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(4-Ethylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(2,4,6-Trimethylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(2-Naphthylsulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide 3-(l-Naphthylsulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(5-Dimethylamino- l-naphthylsulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(3 ,5-Dimethyl-4-isoxazolylsulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(2, 1 ,3-Benzothiadiazol-4-sulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(5-Bromothiophene-2-sulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide 3-(4-Chloro-2, 1 ,3-benzo-oxadiazol-7-sulfonylamino)-sulfonylamino)-thiophene-2- carboxylic acid 3-chlorophenyl amide
3-( 1 ,3-Dimethyl-5-chloropyrazole-4-sulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(2,5-Dichlorothiophene-3-sulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
3-(2-Methoxycarbonylthiophene-3-sulfonylamino)-thiophene-2 -carboxylic acid 3- chlorophenyl amide
3-(5-Isoxazol-3-yl-thiophene-2-sulfonylamino)-thiophene-2-carboxylic acid (3- chloro-phenyl)-amide 3-(5-Chloro-2, 1 ,3-benzo-oxadiazol-4-sulfonylamino)-sulfonylamino)-thiophene-2- carboxylic acid 3-chlorophenyl amide
3-(2-Thienylsulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(5-Pyridin-2-yl-thiophene-2-sulfonylamino)-thiophene-2-carboxylic acid (3- chloro-phenyl)-amide 3-(Butylsulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(2-Phenylethenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(n-Propylsulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide
3-(i-Propylsulfonylamino)-thiophene-2 -carboxylic acid 3-chlorophenyl amide 3-(n-Octylsulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide 3-(2,2,2-Trifluoroethylsulfonylamino)-thiophene-2-carboxylic acid- 3-chlorophenyl amide
3-(3,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-chlorophenyl amide 3-(3,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 4-fluorophenyl amide
3-(3 ,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3-fluorophenyl amide
3-(3 ,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3- trifluoromethoxyphenyl amide
3-(3 ,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 4- trifluoromethylphenyl amide
3-(3 ,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3 ,5- difluorophenyl amide 3-(3,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 4-n- hexyloxyphenyl amide
3-(3 ,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 4-n- butyloxyphenyl amide
3-(3 ,4-Difluorobenzenesulf onylamino)-thiophene-2-carboxylic acid 4-chlorophenyl amide
3-(3,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3,4- dichlorophenyl amide
3-(3,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 2- methylthiophenyl amide 3-(3,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 4- benzyloxyphenyl amide
3-(3 ,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3- benzoylphenyl amide
3-(3,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid phenyl amide 3-(3,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 2,3- dichlorophenyl amide 3-(3 ,4-Difluorobenzenesulf onylamino)-thiophene-2-carboxylic acid 4- trifluoromethoxyphenyl amide
3-(3 ,4-Difluorobenzenesulf onylamino)-thiophene-2-carboxylic acid thiazol-2-yl- a ide 3-(3,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 4,5-dichloro-2- thienyl amide
3 -(3 ,4-Difluorobenzenesulf onylamino)-thiophene-2-carboxylic acid 5-chloro-2- thienyl amide
3-(3 ,4-Difluorobenzenesulfonylamino)-thiophene-2-carboxylic acid 5- phenylsulfonyl-2-thienyl amide
5-(4-Fluorophenyl)-3-(2-methylbenzenesulfonylamino)-thiophene-2-carboxylic acid
3-chlorophenyl amide
5-(2-Thienyl)-3-(2-methylbenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide 4-Methyl-3-(4-chlorobenzenesulfonylamino)-thiophene-2-carboxylic acid 3- chlorophenyl amide
4-Benzenesulfonylamino-thiophene-3-carboxylic acid 4-chlorophenylamide
4-Benzenesulfonylamino-thiophene-3-carboxylic acid 3,5-difluorophenylamide
4-Benzenesulfonylamino-thiophene-3-carboxylic acid 3-chlorophenylamide 4-Benzenesulfonylamino-thiophene-3-carboxylic acid 2,3-dichlorophenylamide
4-Benzenesulfonylamino-thiophene-3-carboxylic acid 4-fluorophenylamide
4-Benzenesulfonylamino-thiophene-3-carboxylic acid 3-fluorophenylamide
4-(3 ,4-Difluorobenzenesulfonylamino)-thiophene-3-carboxylic acid 4- fluorophenylamide 2-Benzenesulfonylamino-thiophene-3-carboxylic acid 4-chlorophenylamide
3-Benzenesulfonylaminofuran-2-carboxylic acid 4-isopropylphenylamide
3-Benzenesulfonylaminofuran-2-carboxylic acid 3-chlorophenylamide
3-(3,4-Difluorobenzenesulfonylamino)-furan-2-carboxylic acid 4- fluorophenylamide
5. A method of causing phosphate excretion and/or inhibiting phosphate absorption by administering to a subject in need thereof a safe and effective amount of a compound according to claim 1.
6. A method of treating chronic renal failure by inhibiting the phosphate transport system in a mammal in need thereof, by administering to a subject in need thereof a safe and effective amount of a compound a compound according to claim 1.
7. A method according to claim 6 wherein uremic bone disease is treated.
8. A method according to claim 6 wherein the phosphate transport is inhibited in the kidney.
9. A method according to claim 6 wherein the phosphate transport is inhibited in the intestine.
10. A method of inhibiting sodium dependent phosphate transport by administering to a subject in need thereof a safe and effective amount of a compound according to claim 1.
11. A method of inhibiting oxidative phosphorylation in a subject in need thereof comprising administering a safe and effective amount of a compound according to claim 1.
12. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
PCT/US2001/031318 2000-10-05 2001-10-05 Phosphate transport inhibitors WO2002028353A2 (en)

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

Publications (2)

Publication Number Publication Date
WO2002028353A2 true WO2002028353A2 (en) 2002-04-11
WO2002028353A3 WO2002028353A3 (en) 2002-07-11

Family

ID=22896359

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2001/031318 WO2002028353A2 (en) 2000-10-05 2001-10-05 Phosphate transport inhibitors

Country Status (2)

Country Link
AU (1) AU2002213048A1 (en)
WO (1) WO2002028353A2 (en)

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2378179A (en) * 2001-08-03 2003-02-05 Pantherix Ltd Aromatic sulfonamides and their use in treating bacterial diseases
WO2003044009A1 (en) * 2001-11-22 2003-05-30 Biovitrum Ab Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
US6881741B2 (en) 2001-06-11 2005-04-19 Virochem Pharma Inc. Compounds and methods for the treatment or prevention of Flavivirus infections
EP1534259A2 (en) * 2002-08-15 2005-06-01 Icagen, Inc. Sulfonamides as potassium channel blockers
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 (en) * 2001-12-26 2007-11-21 Genzyme Corporation Phosphate transport inhibitors
US7319111B2 (en) * 2003-02-20 2008-01-15 Encysive Pharmaceuticals, Inc. Phenylenediamine Urotensin-II receptor antagonists and CCR-9 antagonists
WO2008026687A1 (en) 2006-09-01 2008-03-06 Kyorin Pharmaceutical Co., Ltd. Pyrazolopyridine carboxamide derivative and phosphodiesterase (pde) inhibitor comprising the derivative
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 (en) * 2007-10-05 2009-04-09 Encysive Pharmaceuticals Inc. Thiophene-2-carboxamide derivatives as modulators of ccr9 receptor
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 (en) * 2009-04-30 2010-11-04 住友化学株式会社 Thiophene derivative
WO2013062065A1 (en) * 2011-10-27 2013-05-02 アステラス製薬株式会社 Aminoalkyl-substituted n-thienyl benzamide derivative
WO2014029983A1 (en) 2012-08-21 2014-02-27 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
US9663483B2 (en) 2010-06-07 2017-05-30 Novomedix, Llc Furanyl compounds and the use thereof
WO2018129556A1 (en) 2017-01-09 2018-07-12 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
WO2018129552A1 (en) 2017-01-09 2018-07-12 Ardelyx, Inc. Compounds useful for treating gastrointestinal tract disorders
WO2018129557A1 (en) 2017-01-09 2018-07-12 Ardelyx, Inc. Inhibitors of nhe-mediated antiport
EP3351248A1 (en) 2008-12-31 2018-07-25 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
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 (en) 2018-02-27 2019-09-06 日本曹達株式会社 Heteroaryl sulfonamide compound and pest control agent
WO2022193187A1 (en) * 2021-03-17 2022-09-22 Biofront Ltd. (Cayman) Modulators of fpr1 and methods of using same

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0421365A2 (en) * 1989-10-03 1991-04-10 Wakamoto Pharmaceutical Co., Ltd. Tetrazoleacetic acid derivatives having aldose reductase inhibitory activity
WO2000002851A1 (en) * 1998-07-08 2000-01-20 Aventis Pharma Deutschland Gmbh Sulfur substituted sulfonylaminocarboxylic acid n-arylamides, their preparation, their use and pharmaceutical preparations comprising them

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0421365A2 (en) * 1989-10-03 1991-04-10 Wakamoto Pharmaceutical Co., Ltd. Tetrazoleacetic acid derivatives having aldose reductase inhibitory activity
WO2000002851A1 (en) * 1998-07-08 2000-01-20 Aventis Pharma Deutschland Gmbh Sulfur substituted sulfonylaminocarboxylic acid n-arylamides, their preparation, their use and pharmaceutical preparations comprising them

Cited By (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7351703B2 (en) * 1998-07-08 2008-04-01 Sanofi-Aventis Deutschland Gmbh Sulfonylamino carboxylic acid N-arylamides as guanylate cyclase activators
US7132436B2 (en) 2000-05-22 2006-11-07 Biovitrum Ab Inhibitors of 11-β-hydroxy steroid dehydrogenase type 1
US7618961B2 (en) 2000-05-22 2009-11-17 Biovitrum Ab Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
US7030135B2 (en) 2000-05-22 2006-04-18 Biovitrum Ab Inhibitors of 11-β-hydroxy steroid dehydrogenase type 1
US6881741B2 (en) 2001-06-11 2005-04-19 Virochem Pharma Inc. Compounds and methods for the treatment or prevention of Flavivirus infections
GB2378179A (en) * 2001-08-03 2003-02-05 Pantherix Ltd Aromatic sulfonamides and their use in treating bacterial diseases
US7094792B2 (en) 2001-11-22 2006-08-22 Biovitrum Ab Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
WO2003044009A1 (en) * 2001-11-22 2003-05-30 Biovitrum Ab Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
US7671051B2 (en) 2001-11-22 2010-03-02 Biovitrum Ab Inhibitors of 11-β-hydroxy steroid dehydrogenase type 1
EP1815860A3 (en) * 2001-12-26 2007-11-21 Genzyme Corporation Phosphate transport inhibitors
EP1534259A4 (en) * 2002-08-15 2006-10-04 Icagen Inc Sulfonamides as potassium channel blockers
JP4936666B2 (en) * 2002-08-15 2012-05-23 アイカジェン， インコーポレイテッド Sulfonamides as potassium channel blockers
EP1534259A2 (en) * 2002-08-15 2005-06-01 Icagen, Inc. Sulfonamides as potassium channel blockers
JP2006502141A (en) * 2002-08-15 2006-01-19 アイカジェン， インコーポレイテッド Sulfonamides as potassium channel blockers
US7402608B2 (en) 2002-12-10 2008-07-22 Virochem Pharma Inc. Compounds and methods for the treatment or prevention of Flavivirus infections
US7579340B2 (en) 2003-02-20 2009-08-25 Pfizer 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
AU2004212985B2 (en) * 2003-02-20 2010-10-14 Encysive Pharmaceuticals Inc. Phenylenediamine urotensin-II receptor antagonists and CCR-9 antagonists
US7288538B2 (en) 2003-02-20 2007-10-30 Encysive Pharmaceuticals, Inc. Phenylenediamine urotensin-II receptor antagonists and CCR-9 antagonists
US7569600B2 (en) 2005-05-13 2009-08-04 Virochem Pharma Inc. Compounds and methods for the treatment of prevention of Flavivirus infections
US8158675B2 (en) 2005-05-13 2012-04-17 Vertex Pharmaceuticals (Canada) Incorporated Compounds and methods for the treatment or prevention of Flavivirus infections
US8674118B2 (en) 2005-05-13 2014-03-18 Vertex Pharmaceuticals Incorporated Compounds and methods for the treatment or prevention of flavivirus infections
US7759390B2 (en) 2005-12-22 2010-07-20 Novartis Ag Inhibitors of CCR9 activity
WO2008026687A1 (en) 2006-09-01 2008-03-06 Kyorin Pharmaceutical Co., Ltd. Pyrazolopyridine carboxamide derivative and phosphodiesterase (pde) inhibitor comprising the derivative
WO2009044311A1 (en) * 2007-10-05 2009-04-09 Encysive Pharmaceuticals Inc. Thiophene-2-carboxamide derivatives as modulators of ccr9 receptor
EP3939964A1 (en) 2008-12-31 2022-01-19 Ardelyx, Inc. Combinations for inhibiting nhe-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders
EP3351248A1 (en) 2008-12-31 2018-07-25 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
WO2010126167A1 (en) * 2009-04-30 2010-11-04 住友化学株式会社 Thiophene derivative
US9663483B2 (en) 2010-06-07 2017-05-30 Novomedix, Llc Furanyl compounds and the use thereof
CN103906741A (en) * 2011-10-27 2014-07-02 安斯泰来制药株式会社 Aminoalkyl-substituted n-thienyl benzamide derivative
US9062032B2 (en) 2011-10-27 2015-06-23 Astellas Pharma Inc. Aminoalkyl-substituted N-thienylbenzamide derivative
CN103906741B (en) * 2011-10-27 2016-01-20 安斯泰来制药株式会社 The N-thienyl benzamide derivatives that aminoalkyl replaces
EA023955B1 (en) * 2011-10-27 2016-07-29 Астеллас Фарма Инк. Aminoalkyl-substituted n-thienyl benzamide derivative
WO2013062065A1 (en) * 2011-10-27 2013-05-02 アステラス製薬株式会社 Aminoalkyl-substituted n-thienyl benzamide derivative
WO2014029983A1 (en) 2012-08-21 2014-02-27 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
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
US10272079B2 (en) 2013-04-12 2019-04-30 Ardelyx, Inc. NHE3-binding compounds and methods for inhibiting phosphate transport
US10940146B2 (en) 2013-04-12 2021-03-09 Ardelyx, Inc. NHE3-binding compounds and methods for inhibiting phosphate transport
WO2018129557A1 (en) 2017-01-09 2018-07-12 Ardelyx, Inc. Inhibitors of nhe-mediated antiport
WO2018129552A1 (en) 2017-01-09 2018-07-12 Ardelyx, Inc. Compounds useful for treating gastrointestinal tract disorders
US11147884B2 (en) 2017-01-09 2021-10-19 Ardelyx, Inc. Inhibitors of NHE-mediated antiport
WO2018129556A1 (en) 2017-01-09 2018-07-12 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
US11242337B2 (en) 2017-01-09 2022-02-08 Ardelyx, Inc. Compounds useful for treating gastrointestinal tract disorders
WO2019167863A1 (en) 2018-02-27 2019-09-06 日本曹達株式会社 Heteroaryl sulfonamide compound and pest control agent
WO2022193187A1 (en) * 2021-03-17 2022-09-22 Biofront Ltd. (Cayman) Modulators of fpr1 and methods of using same
WO2022194240A1 (en) * 2021-03-17 2022-09-22 Biofront Ltd. (Cayman) Modulators of fpr1 and methods of using the same

Also Published As

Publication number Publication date
AU2002213048A1 (en) 2002-04-15
WO2002028353A3 (en) 2002-07-11

Similar Documents

Publication Publication Date Title
WO2002028353A2 (en) Phosphate transport inhibitors
AU2006212761B2 (en) Combination therapy
TWI277615B (en) Substituted oxazolidinones and their use
US6515002B2 (en) Compounds and compositions for treating C1s-mediated diseases and conditions
JP5085659B2 (en) Indazole derivatives useful as L-CPT1 inhibitors
KR101240809B1 (en) Biaryl sulfonamide derivatives
KR101721025B1 (en) Tetrahydrobenzothiophene compound
CA2750339A1 (en) Bumetanide, furosemide, piretanide, azosemide, and torsemide analogs, compositions and methods of use
CN104718205B (en) Sodium channel inhibitor, its preparation method and its purposes
CN102548965A (en) Substituted amide compound
TW200900397A (en) Tricyclic compounds as matrix metalloproteinase inhibitors
CA2641880A1 (en) Treatment of duchenne muscular dystrophy
KR20000049197A (en) The preparation and use of ortho-sulfonamido heteroaryl hydroxamic acids as matrix metalloproteinase and TACE inhibitors
ZA200200464B (en) Phosphate transport inhibitors.
KR20020002501A (en) Preventive or therapeutic drugs for diabetes
AU2014207408A1 (en) Pharmaceutical compositions comprising nitroxyl donors
WO2001082924A1 (en) Phosphate transport inhibitors
CA2408667A1 (en) Phosphate transport inhibitors
WO2001049289A1 (en) Pharmaceutical and veterinary uses of endothelin antagonists
WO2006062247A1 (en) Substituted heterocyclic compound and thrombopoietin receptor activator
US9603834B2 (en) 1,2- bis-sulfonamide derivatives as chemokine receptor modulators
US20030216449A1 (en) Phosphate transport inhibitors
TW200400026A (en) Use of substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones for producing medicaments with an inhibitory effect on pancreatic lipase
WO2004043368A2 (en) Sulfonamides

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PH PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

AK Designated states

Kind code of ref document: A3

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PH PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase in:

Ref country code: JP