MXPA02011160A

MXPA02011160A - Phosphate transport inhibitors.

Info

Publication number: MXPA02011160A
Application number: MXPA02011160A
Authority: MX
Inventors: Joseph Weinstock
Original assignee: Smithkline Beecham Corp
Priority date: 2000-05-12
Filing date: 2001-05-11
Publication date: 2003-03-10
Also published as: JP2003533477A; AU2001261471A1; CN1429108A; HUP0302234A2; IL152587A0; CZ20023701A3; NO20025399L; NO20025399D0; CA2408667A1; ZA200209106B; BR0110034A; PL359931A1; KR20020093983A; WO2001087294A1

Abstract

N Aryl 2 sulfonamidobenzamides, useful for treatment of chronic renal failure and uremic bone disease, are disclosed.

Description

INHIBITORS OF TRANSPORTATION OF PHOSPHATE FIELD OF THE INVENTION The present invention involves the treatment of chronic renal failure, bone uraemic disease and related diseases by inhibiting phosphate retention by certain N-aryl-2-sulfonamidobenzamides.

BACKGROUND PE THE INVENTION When the kidneys deteriorate, the adaptive mechanisms involved in restoring homeostasis can lead to further deterioration 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 United States. Although the use of dialysis and kidney transplantation have greatly improved the survival rate of patients with ESRD, several problems have arisen in these patients, which complicates their treatment of prolonged duration. The initial and main 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, it has been identified that phosphate retention (Pi) plays an important role in the progression of renal deficiency and the generation of secondary hyperparathyroidism (HPTH) and uraemic bone disease. The evidence implicating a role for the retention of Pi 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), demonstrated for the first time in a CRF model in rats that dietary restriction of Pi prevented renal functional impairment, as assessed by stabilization or improvement of creatinine levels. in serum, reduced proteinuria, improved histology and reduced mortality, similar findings were obtained in a nephrotic rat nephritis model with nephrotoxic serum (Karlinsky et al, Kidney Int. 17: 293-302 (1980)). However, these studies were criticized on the basis that the low diet in Pi is associated with ingestion of food flood and therefore the ingestion of protein that can reduce the progression of CRF. Therefore, Lumbertgul et al, Kidney Int. 29: 658-666, (1986) put 5/6 rats with the kidneys excised on a normal Pi diet, but gave a group a pi linker. All rats were fed in pairs and had similar intakes of calories, proteins, carbohydrates, vitamins and minerals. Both at 6 and 12 weeks, the rats that ingested the Pi linker exhibited a lower protein discretion, lower serum creatinine level, lower renal calcium content and less histological healing than rats that did not receive the Pi linker. . This study demonstrated unequivocally that the dietary restriction of Pi can have beneficial effects on the progression of CRF, regardless of the ingestion of calories and proteins in experimental animals. In addition to the beneficial effects of dietary restriction of Pi on the progression of CRF discussed above, we have also found evidence that dietary excess of Pi may accelerate the progression of CRF. Several studies in models with CRF rats (Kleinknecht et al, Kidney Int. 5: 534-541 (1979), Haut et al, Kidney Int. 17: 722-731, (1980), Giménez et al, Kidney Int. 22 : 36-41, (1982)) have shown that diets high in Pi lead to the faster deterioration of renal function, assessed by serum creatinine levels and the severity of histological lesions. Some evidence also suggests that the dietary restriction of Pi may also exhibit the progression of CRF in patients. Maschio et al, Kidney Int., 22: 371-376, (1982) and Maschio et al, Kidney Int., 24: S 277, (1983) put patients with mild and moderate renal insufficiency to protein and protein restricted diets. up to 76 months. They found that the rate of kidney function consumption was more prominent in the dietary restricted group 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. twenty-one:; 54-59, (1984) put patients with CRF either low protein or low protein diet and low in Pi, and found that the rate of kidney function decline decreased after the institution of dietary restrictions in both groups Importantly, they also observed a lower rate of wasting in patients with the low protein diet and low in Pi in comparison with the low protein diet only. In a study of 4 children with a low Pi diet, serum creatinine levels were reduced by half during the 6 months with the restricted diet compared to a similar period with a normal diet (McCrory et al, J. Pediatr 111: 410-412, (1987) .In addition, the growth rate in these children increased significantly with the diet low in Pi compared to the control period.Other studies with humans (Barrientos et al, Electrolyte Metab. 7: 127-133, (1982), Ciadrella et al, Nephron 42: 196-199, (1986), Gin et al, Metyabolism 36: 1080-1085, (1987)), mainly of short duration, have not been able to observe an effect of PI restriction in the course of CRF However, most of the animal studies discussed above together with studies with less well controlled humans suggest that dietary restriction of Pi is beneficial in slowing down the progression of the CRF, especially the insufficient Kidney disease between mild and moderate. The mechanism by which excess Pi leads to an increased rate of renal failure is unknown. However, almost all the evidence supports an interaction between the Pi and cellular Ca2 + accumulation. In the deficient kidney, an increase in the filtered load of Pi together with a reduction of the resolution of Pi secondary to high levels of parathyroid hormone (PTH) results in an increase in the concentration of tubular fluid Pi. This leads to an increased transepithelial flow of Ca2 + and high cellular Ca2 + levels, resulting in induced cellular deterioration by Ca2 + (Borle et al., Endocrinology 102: 1725-1732, (1978).) Alternatively or additionally, 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 renal hypermetabolism normally associated with the 5/6 kidneys model excised from CRF in rats may contribute to the progression of CRF in this model. Thus, the restriction of dietary Pi reduce renal oxygen consumption by 50% and reduce intracellular concentrations of Pi without altering the constant state concentration of ATP, as assessed by 31P-NRM in this model. Chronic kidney disease (CRF) affects more than 270,000 patients in the United States alone and costs an estimated 6.8 billion in annual health care costs. The initial and main contributors to the morbidity of patients with CRF are the abnormalities of electrolyte and bone metabolism induced by the progressive loss of renal excretory function. It has been identified that phosphate retention (Pi) plays an important role in the provision of CRF and the development of uraemic bone disease. Studies in the literature have shown that the dietary restriction of Pi slows down the progression of CRF in animal models and in small studies with patients; decreases elevated plasma PTH levels in patients and models of animals with CRF; and increases the circulating levels of 1, 25 (OH) 2 vitamin D and intestinal absorption of Ca2 +. Thus, the inhibition of transport of Pi by the intestine and the kidney to slow the progression of CRF and uraemic bone disease is considered beneficial. Thus, the inhibition of transport of Pi by the intestine and the kidney is beneficial to slow down the progression of the CRF and uraemic bone disease. Accordingly, there is a need to find an alternative means of reducing phosphate stress, in mammals, in addition to the dietary restriction of phosphate for the treatment of kidney diseases and uraemic bone disease.

BRIEF DESCRIPTION OF THE INVENTION The present invention involves novel methods of using N-aryl-2-sulfonamidobenzamides as phosphate transport inhibitors for the selective inhibition of transport of Pi in the kidney and / or intestine as a therapeutic treatment of chronic renal failure and uraemic bone disease. .

DETAILED DESCRIPTION OF THE INVENTION The present invention involves the use of phosphate transport inhibitors, for the treatment of chronic renal deficiency and uraemic bone disease, as well as other related diseases, as well as hyperphosphatemia, vitamin D metabolism, and secondary hyperparathyroidism, caused for the retention of phosphate. Preferably, the inhibitors for use herein are those that selectively inhibit Na + -dependent Pi transport in tissues, preferably kidney and intestinal tissue, of various species, including humans. The present invention relates to the use of compounds that are inhibitors of sodium-dependent phosphate transport, which are represented by the following formula (I): wherein: Ri and R2 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkyl, acyl, aroyl, haloalkyl, aryl, heteroaryl, halo, carboxy, carboalkoxy, carbamyl, alkylcarbamyl, arylcarbamyl, cyano, alkoxy, hydroxyl, phenylazo, amino, nitro, alkylamino, arylamino, arylalkylamino, acylamino, aroylamino, alkylthio, arylalkylthio, arylthio, alkylsulfinyl, arylsulfinyl, arylaminosilyfinyl, alkylsulfonyl, arylsulfonyl, arylalkysulfonyl, sulfamyl, arylsulfonamido, and alkylsulfonamido; or the Ri or R2 portion represents a fusion element that forms a benzothiophene, naphthalene, quinoline, or isoquinoline with the ring it replaces; or (R?) n and / or (R2) m and the ring it replaces represent a heterocycle selected from the group consisting of thiophene, furan, pyridine, pyrimidine and parazino, and benzoyl analogues; and R3 is independently selected from the group consisting of alkyl, haloalkyl, Ri-aryl and Ri-aralkyl, and heterocycles substituted by R f selected from the group consisting of thiophene, furan, pyridine, pyrazine, imidazole and thiazole, isoxasol, thiadiazole, oxadiazole, and benzo analogues thereof. As used herein, "alkyl" refers to an optionally substituted hydrocarbon group, attached by simple carbon-carbon bonds. Preferred alkyl substituents are those indicated herein. The alkylhydrocarbon group can be linear, branched or cyclic, saturated or unsaturated. As used herein, "aryl" refers to an optionally substituted aromatic group, at least one ring having a conjugated electron system of Pi, containing up to two conjugated or fused ring systems. "Aryl" includes arylcarbocyclic, aryl groups heterocyclic and biaryl, all of which may be optionally substituted. Preferred aryl substituents are those indicated herein. The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optionally active forms. It is contemplated that all of these compounds and diastereomers are within the scope of the present invention. Preferred compounds include, but are not limited to, the following: N-phenylthio-2- (3-trifluoromethylphenylsulfonamido) benzamide; 5-methoxy-N- (3-trifluoromethylphenyl) -2- (4-chlorophenylsulfonamido) benzamide; 5-bromo-N- (4-bromophen-I) -2- (5-chloro-2-thienylsulfonamido) benzamide; 5-bromo-N- (4-bromophenyl) -2- (3,3,3, -trifluoroethylsulfonamido) benzamide; 5-bromo-N- (4-bromophenyl) -2- (3-chloro-2-fluorophenylsulfonamido) benzamide; 5-bromo-N- (4-bromophenyl) -2- (3-chloropropylsulfonamido) benzamide; 5-bromo-N- (4-bromophenyl) -2- (4-methoxyphenylsulfonamido) benzamide; 5-bromo-N- (4-bromophenyl) -2- (2-fluorophenylisulfonamido) benzamide; N- (4-chlorophenyl) -2- (2-fluorophenylsulfonamido) benzamide; N- (4-bromophenyl) -2- (3,3,3-trifluoroethylsulfonamido) benzamide; N- (4-bromophenyl) -5-chloro-2- (3-chloro-2-fluorophenylsufonphonido) benzamide; N- (4-chlorophenyl) -2- (3,4-dichlorophenylsulfonamido) benzamide; N- (4-bromophenyl) -2- (2-thienylsulfonamido) benzamide; N- (4-bromophenyl) -2- (2-methoxycarbonyl-3-thienylsulfonamido) benzamide; N- (3,4-dichlorophenyl) -2- (2-fluorophenylsulfamido) benzamide; N- (4-chlorophenyl) -2- (3-trifluoromethyphenylsulfonamido) benzamide; 5-bromo-N- (4-chlorophenyl) -2- (3,4-dichlorophenylsulfonamido) benzamide; N- (4-chlorophenyl) -2- (3,4-dichlorophenesulfonamido) benzamide; N- (4-butoxyphenyl) -2- (3,4-dichlorophenylsulfonamido) benzamide; N- (4-chlorophenyl) -2- (3,5-dimethylisoxazole-4-sulfonamido) benzamide; N- (4-chlorophenyl) -2- (2, 1, 3-benzothiadiazole-4-sulfonylamino) benzamide; N- (3-trifluoromethoxyphenyl) -2- (5-bromothiophen-2-sulfonylamino) benzamide; N- (4-bromophenyl) -2- (phenylsulfonamido) benzamide and methoxy-N- (4-chlorophenyl) -2- (3-trifluoromethylphenylsulfonamiodobenzamide) The pharmaceutically acceptable salts, for use when basic groups are present, include acid salts of addition, such as those They contain sulfate, hydrochloride, maleate, phosphate, sulphamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluensultonate, cyclohexyl sulfamate and quinate. The 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, p-toluenesulfonic acid, ciciohexyl sulfamic acid, fumaric acid and quinic acid. The 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 present acid functional groups, such as carboxylic acid or phenol. The present invention provides compounds of formula (I) above that can be prepared using normal procedures. A general strategy for preparing the preferred compounds, described herein, can be carried out as described in this section. Using the protocols described herein as a model, one skilled in the art can readily produce other compounds of the present invention. With the appropriate manipulation and protection of any chemical functionality, the synthesis of the remaining compounds of the formula (I) is carried out by analogous methods to those described above and those described in the experimental section.

SCHEME 1 In order to use a compound of the formula (I) or a pharmaceutically acceptable salt thereof for treatments of humans and other mammals, it is usually formulated in accordance with common 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 its systemic administration, oral administration is preferred. For oral administration, the compounds can be formulated, for example, with conventional oral dosage forms, such as capsules, tablets and liquid preparations, such as syrups, elixirs and concentrated drops. Alternatively, injection (parenteral administration), for example intramuscular, intravenous, intraperitoneal and subcutaneous, can be used. For injection, the compounds of the invention are formulated in liquid solutions, preferably in pH regulators or physiologically combattable solutions, such as saline solution, Hank's solution or Ringer's solution. In addition, compounds can be formulated in solid form and be rescinded or suspended immediately before use. Freeze-dried forms can also be produced. Synthetic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrating agents suitable for the barrier to be rewarded are used in the formulation. Such penetrating agents are generally known in the art and include, for example, for transmucosal administration, viral salts and fucidic acid derivatives. In addition, detergents can be used to facilitate the awarding. The transglucose administration can be, for example by nasal sprays, rectal suppositories or vaginal suppositories. For topical administration, the compounds of the invention can be formulated as ointments, ointments, gels or creams, as is generally known in the art.

The amounts of various compounds to be administered can be determined by common procedures taking into account such factors as IC5o, EC50 of the compound, 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 that are to be considered with those known to those skilled in the art. The amounts administered also depend on the routes of administration and the degree of oral bioavailability. For exampleFor compounds with low oral bioavailability, relatively higher doses will have to be administered. Preferably, the composition is in unit dosage form. For example, for oral application a tablet or capsule can be administered, for its nasal application a regulated aerosol dose can be administered, for its transdermal application a topical formulation or a patch can be administered and for its transmucosal delivery it can be administered. administer an intra-oral patch. In each case, the dosage is such that the patient can administer a single dose. Each dosage unit for oral administration suitably contains from 0.01 to 500 mg / kg, and preferably from 0 to 50 mg / kg of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base. The daily dosage for the parenteral, nasal, inhalation, transmucosal or transdermal routes suitably contains 0.01 mg to 100 mg / kg of a compound of the formula (I).

A topical formulation suitably contains from 0.01 to 5.0% of a compound of the formula (I). The active ingredient can be administered from 1 to 6 times a 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, disease prevention, delays, and prophylaxis. The composition of the formula (I) and its pharmaceutically acceptable salts can be formulated, which are active when given orally, such as syrups, tablets, capsules and splints. A syrup formulation will generally consist of a suspension or solution of the liquid carrier compound or salt, for example ethanol, peanut oil, olive oil, glycerin or water with a flavoring or coloring agent. If the composition is in the form of a tablet, any pharmaceutical carrier commonly used to prepare solid formulations can be used.

Some examples of such vehicles include magnesium stearate, kaolin, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose. If the composition is in capsule form, any usual encapsulation is - suitable, using for example the vehicles mentioned above in a hard gelatinous capsule shell. If the composition is in the form of a soft gelatinous capsule shell, any pharmaceutical carrier commonly used to prepare dispersions or suspensions, for example aqueous gums, celluloses, silicates or oils, and incorporated into a soft gelatinous capsule shell. Typical parenteral compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous vehicle optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame oil. Typical compositions for inhalation are in the form of a solution, suspension or emulsion which can be administered as a dry powder or in an aerosol form using a conventional blowing agent such as dichlorodifluoromethane or trichlorofluoromethane. A typical suppository formulation comprises a compound of the formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this manner, with a binder and / or lubricant, 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, an ointment, a lotion or a paste or are in the form of medicated plaster, patch or membrane. Preferably, the composition is in unit dosage form, eg, tablet, capsule or regulated aerosol dosage, so that the patient can administer a single dose.

Unacceptable toxological effects are not expected when the compounds of the present invention are administered according to the present invention. Inhibition of sodium-dependent phosphate transport is determined by the ability of the test compound to inhibit the ingestion of radiolabeled inorganic phosphate by proximal tubule cells. Appropriate cells of human, rabbit or rat can be used.

Preparation of the cells and phosphate ingestion assay. Proximal rabbit tubule cells were isolated and cultured, according to a procedure of Sakhrani, L. M. et al. Am. J. Physiol. 246: F757-F764, (1984) whose disclosure is incorporated herein by reference in its entirety. Proximal human tubule cells were purchased from Clonetics (San Diego, CA) and cultured according to the supplier's instructions. On the day of the experiment, cells from the culture plants were harvested with 0.5 mM EDTA in pH regulated saline with phosphate. The cells were washed twice in pH buffer for ingestion (see below) and equilibrated at 37 ° C in the same pH regulator for 30 minutes. Aliquots of cells (100 μl, 0.5 to 1 million cells) were distributed in glass test tubes. They were added 50 μl of drug solution or pH regulator, followed by 50 μl of pH buffer for ingestion containing 100 μM [32 P] -K2HPO4 (0.5 to 1 μCi / tube). After varying periods of time (usually 4 minutes) a 37 ° C, the ingestions were stopped with 4 ml of cold stop solution (see below) and the cells were washed 3 times in this solution by centrifugation. The pelleted cells were dissolved in 0.5 ml of 1 N NaOH and 32 P was counted in a counter by liquid scintillation. S expresses the ingestion of phosphate as pmol of phosphate / mg of cellular protein.

Stop solution pH regulator for ingestion, pH 7.4 100 mM Mannitol 143 mM NaCl at 100 mM 15 mM Hepes 10 mM Na Arsenate 5.4 mM KCl 5 mM MgCl2 0.8 mM CaCI2 1.8 mM Glucose 0J% In the whole cell assay system indicated above for human proximal tubule cells, the cells are harvested by filtration and 32 P ingestion is measured. It is also possible to use 33P instead of 32P. Using human proximal tubule cells, the IC5o for 5-bromo-N- (4-bromophenyl) -2- (5-chloro-2-thienylsulfonamido) benzamide, 5-bromo-N- (4-bromophenyl) -2- ( 2-fluorophenylsulphonamido) benzamide, and 5-bromo-N- (4-bromophenyl) 2- (3-chloropropylsulfonamido) benzamide are 12, 15 and 14 μM, respectively.

The following examples illustrate the preparation of compounds and pharmaceutical compositions that can be used in this invention. The examples are not intended to limit the scope of this invention, which is defined hereinabove and is claimed below.

EXAMPLE 1 N- (4-bromophenHo) -2-amino-5-bromobenzamide An 11.6 ml portion of a 2.0 M solution of trimethylaluminum (23.2 mmole) was added to a solution of 4.0 g (23.25 mmole) of 4-bromoaniline at 0 ° C. The reaction mixture was kept at room temperature for 45 minutes and then cooled to 0 ° C. Methyl 2-amino-5-bromobenzoate (4.42 g, 23.25 mmol) was added in small portions and, after the vigorous evolution of gas ceased, the reaction mixture was maintained at room temperature for 18 hours. The reaction mixture was then poured into 250 ml of 10% HCl (more gas evolution occurred) and the solid formed was collected by filtration. The solid was washed with water and toluene at the same time and then dried at room temperature. TLC silica, CHCl3: MeOH 9: 1 with one drop of formic acid, R 0.80-0.90 and NMR identical to that of the authentic sample. This is a general procedure, which works with a wide variety of analogs of aniline and anthranyl aromatic and heteroaromatic acid. A mixture of 12.1 g (50 mmol) of 5-bromoisatoic anhydride 9.4 g (55 mmol) of 4-bromoaniline, and 0.2 g 85 mmol) of NaOH in 150 ml of dioxane was refluxed for 18 hours. The cooled reaction mixture was filtered and concentrated in vacuo. The residue was crystallized with the addition of ETOH at 95%. The solid was collected by filtration and washed with ethanol. A Purified sample by thick layer chromatography (silica, 15% EtOAC in hexane) yielded an NMR, MS, and expected elemental analysis. A similar procedure from 5-chloroisatoic anhydride and 4-bromoaniline gave N- (4-bromophenol) -2-amino-5-chlorobenzamide which gave the expected NMR, MS and elemental analysis.

EXAMPLE 2 5-Bromo-N- (4-bromophenyl) -2- (4-chlorophenylsulfonylamino) benzamide A solution of N- (4-bromophenyl) -2-amino-5-bromobenzamide (8.64 g, 23.3 mmol), 4-chlorobenzenesulfonyl chloride (4.98 g, 23.6 mmol), and 7.37 g (93.2 mmol) were allowed to stand. 30 ml of CH2Cl2 at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAC. The solution was washed twice with 10% HCl, water, 5% NaHCO3, water, and dried over MgSO. Concentration and recrystallization of EtOAc at 105 in hexane gave a product having NMR, MS in satisfactory elemental analysis.

EXAMPLE 3 5-Bromo-N- (4-bromophenol) -2- (4-bromophenylsulfonyl) amino) benzamide A solution of 31.5 mg (85 .mu.mol) of N- (4-bromophenyl) -2-amino-5-bromobenzamide, 32.5 mg (127.5 umol) of 4-bromobenzenesulfonyl chloride of, and 28 .mu.l (340 .mu.mol was stirred for 18 hours ) of pyridine in 1 ml of CH2Cl2. Then 84.5 mg (382 μmoles) of polyamine HL resin (Nova Biochem, 4.53 mmoles / g) were added, the mixture was stirred for 18 hours and the solids were removed by filtration. Concentration in vacuo and purification by preparative HPLC (C18, 20-acetonitrile at 95% - 0.1% aqueous TFA) gave a product that gave a satisfactory CLAR-MS analysis. Using similar to those of Examples 2 and 3 procedures, the reaction products of 5-bromo-N- (4-bromophenyl) -2- (4-chlorophenylsulfonylamino) benzamide with the following sulfonyl chlorides were obtained: 3- clorofenilo-, 4-chlorophenyl, 3,4-diclorofeniIo-, 3-chloro-4-fluoro-, 2-fluorofenilo-, 2,5-dimetoxifenilo-, 3,4-dimetoxifenilo-, 4-n-butoxifenilo-, 2 -trifluorometilfenilo-, 4-fenilazofenilo-, 4-trifluorometilfenilo-, 3,5-bis-trifluorometilfenilo-, 2-metilfenilo-, 2,4,6-trimetilfenilo-, 2-naphthyl-, methane, trifluorometano-, 2-tieniIo -, 5-chloro-2-thienyl-, 4-bifenilo-, 3-cloropropilo-, 4-cianofenilo-, 3,5-diclorofenilo-, estirilo-, 2-methoxycarbonyl-3-thienyl-, 4-yodofenilo-, 2,6-dichlorophenyl-, 4-t-butylphenyl, and 2,2,2-trifluoromethyl-. The products gave satisfactory results of the CLAR-MS analyzes.

Is incoforan herein all publications, including but not limited to, patents and patent applications, cited in this specification by reference as if specifically and individually indicated each individual publication are incorporated by reference present as if it were fully exposed. The foregoing description fully discloses the invention, including preferred embodiments thereof. The modifications and improvements of the modalities specifically set forth herein are within the scope of the following claims. Without further detail, it is believed that one skilled in the art can use, using the preceding description, the present invention to its fullest extent. Therefore, the examples herein are to be interpreted as merely illustrative and not as a limitation of the scope of the present invention in any way. The modalities of the invention in which a property or exclusive privilege is claimed are defined as follows.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - The use of a compound according to the formula (I) wherein: Ri and R2 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkyl, acyl, aroyl, haloalkyl, halo, carboxy, carboalkoxy, carbamyl, alkylcarbamyl, arylcarbamyl, cyano, alkoxy, hydroxyl, phenylazo, amino, nitro, alkylamino, arylamino, arylalkylamino, acylamino, aralylamino, alkylthio, arylalkylthio, arylthio, alkylsulfinyl, arylsulfinyl, arylalkylsulfinyl, alkylsulfonyl, arylsulfonyl, arylalkysulfonyl, sulfamyl, arylsulfonamido and alkylsulfonamido; or the Ri portion represents a molten element that forms a benzothiophene, naphthalene, quinoline, or isoquinoline with the ring it replaces; or (R?) n and the ring it replaces represent a heterocycle selected from the group consisting of thiophene, furan, pyridine, pyrimidine and parazino, and benzo analogs; and R3 is independently selected from the group consisting of alkyl, haloalkyl, Raryl and R-i-aralkyl, R-t-benzoaryl and R benzoaralkyl, and heterocycles substituted by Ri, selected from the group consisting of thiophene, furan, pyridine, pyrazine, imidazole, isoxasol, thiadiazole, oxadiazole and thiazole, and benzo analogs thereof, to prepare a medicament to inhibit transport of sodium-dependent phosphate in a subject.

2. The use as claimed in claim 1, wherein the compound of the group consisting of: N-phenyl-2- (3-trifluoromethylphenylsulfonamido) benzamide; 5-methoxy-N- (3-trifluoromethylphenyl) -2- (4-chlorophenylsulfonamido) benzamide; 5-bromo-N- (4-bromophenyl) -2- (5-chloro-2-thienylsulfonamido) benzamide; 5-bromo-N- (4-bromophenyl) -2- (3,3,3, -trifluoroethylsulfonamido) benzamide; 5-bromo-N- (4-bromophenyl) -2- (3-chloro-2-fluorophenylsufonomido) benzamide; 5-bromo-N- (4-bromophenyl) -2- (3-chloropropylsulfonamido) benzamide; 5-bromo-N- (4-bromophenyl) -2- (4-methoxyphenylsulfonamido) benzamide; 5-bromo-N- (4-bromophenyl) -2- (2-fiuorophenylsulfonamido) benzamide; N- (4-chlorophenyl) -2- (2-fluorophenylsulfonamido) benzamide; N- (4-bromophenyl) -2- (3,3,3-trifluoroethylsulfonamido) benzamide; N- (4-bromophenyl) -5-chloro-2- (3-chloro-2-fluorophenylsulfonamido) benzamide; N- (4-c [orophenyl) -2- (3,4-dichlorophenylsulfonamido) benzamide; N- (4-bromophenyl) -2- (2-thienylsulfonamido) benzamide; N- (4-bromophenyl) -2- (2-methoxycarbonyl-3-thienylsulfonamido) benzamide; N- (3,4-dichlorophenyl) -2- (2-fluorophenylsulfamido) benzamide; N- (4-chlorophenyl) -2- (3-trifluoromethylphenylsulfonamido) benzamide; 5-bromo-N- (4-chlorophenyl) -2- (3,4- dichlorophenylsulfonamido) benzamide; N- (4-chlorophenyl) -2- (3,4-dichlorophenylsulfonamido) benzamide; N- (4-butoxyphenyl) -2- (3,4-dichlorophenylsulfonamido) benzamide; N- (4-chlorophenyl) -2- (3,5-dimethylisoxazole-4-sulfonamido) benzamide; N- (4-chlorophenyl) -2- (2, 1, 3-benzothiadiazole-4-sulfonylamino) benzamide; N- (3-trifluoromethoxy-phenyl) -2- (5-bromothiophen-2-sulfonylamino) -benzamide; N- (4-bromophenyl) -2- (phenylsulfonamido) benzamide and 5-methoxy-N- (4-chlorophenyl) -2- (3-trifluoromethylphenylsulfonamidobenzamide) 3.- The use of a compound according to the formula ( I): wherein: Ri and R2 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkyl, acyl, aroyl, haloalkyl, halo, carboxy, carboalkoxy, carbamyl, alkylcarbamyl, arylcarbamyl, cyano, alkoxy, hydroxyl, phenylazo, amino, nitro, alkylamino, arylamino, arylalkylamino, acylamino, aralylamino, alkylthio, arylalkylthio, arylthio, alkylsulfinyl, arylsulfinyl, arylalkylsulfinyl, alkylsulfonyl, arylsulfonyl, arylalkysulfonyl, sulfamyl, arylsulfonamido and alkylsulfonamido; or the Ri portion represents a molten element that forms a benzothiophene, naphthalene, quinoline, or isoquinoline with the ring it replaces; or (R?) n and the ring it replaces represent a heterocycle selected from the group consisting of thiophene, furan, pyridine, pyrimidine and parazino, and benzo analogues; and R3 is independently selected from the group consisting of alkyl, haloalkyl, Ri-aryl and Ri-aralkyl, and heterocycles substituted by Ri, selected from the group consisting of thiophene, furan, pyridine, pyrazine, imidazole, soxasol, thiadiazole, oxadiazole and thiazole, and benzo analogs thereof, for preparing a medicament for causing phosphate excretion and / or inhibiting absorption in a subject. 4. A pharmaceutical composition characterized in that it comprises a compound as claimed in claim 1 and a pharmaceutically acceptable carrier. 5. The use of a compound according to the formula (I): wherein: Ri and R2 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkyl, acyl, aroyl, haloalkyl, halo, carboxy, carboalkoxy, carbamyl, alkylcarbamyl, arylcarbamyl, cyano, alkoxy, hydroxyl, phenylazo, amino, nitro, alkylamino, arylamino, arylalkylamino, acylamino, aralylamino, alkylthio, arylalkylthio, arylthio, alkylsulfinyl, arylsulfinyl, arylalkylsulfinyl, alkylsulfonyl, arylsulphonyl, arylalkysulfonyl, sulfamio, arylsulfonamido and alkylsulfonamido; or the Ri portion represents a molten element that forms a benzothiophene, naphthalene, quinoline, or isoquinoline with the replacement ring; or (R?) n and the ring it replaces represent a heterocycle selected from the group consisting of thiophene, furan, pyridine, pyrimidine and parazino, and benzo analogs; and R3 is independently selected from the group consisting of alkyl, haloalkyl, Ri-aryl and R-aralkyl, R-benzoaryl and Ri-benzoaralkyl, and heterocycles substituted by Ri, selected from the group consisting of thiophene, furan, pyridine, pyrazine, imidazole, isoxasol, thiadiazole, oxadiazole and thiazole, and benzo analogues thereof, to prepare a medicament for treating chronic renal failure, by inhibiting the phosphate transport system in a mammal. 6. The use as claimed in claim 5, in which uraemic bone disease is treated. 7. The use as claimed in claim 5, wherein the transport of phosphate in the kidney is inhibited. 8. The use as claimed in claim 5, wherein the transport of phosphate in the intestine is inhibited. 9. A pharmaceutical composition characterized in that it comprises a compound selected from the group consisting of: 5-bromo-N- (4-bromophenyl) -2- (2-fluorophenylisulfonamido) benzamide; 5-bromo-N- (4-bromophenyl) -2- (5-chloro-2-thienylsulfonamido) benzamide; 5-bromo-N- (4-bromophenyl) -2- (3,3,3-trifluoroethylsulfonamido) benzamide; 5-bromo-N- (4-bromophenyl) -2- (3-chloro-2-fluorophen-sulfonamido) benzamide; 5-bromo-N- (4-bromophenyl) -2- (3-chloropropylsulfonamido) benzamide; 5-bromo-N- (4-bromophenyl) -2- (2-methyl-phenylsulfonamido) benzamide; 5-bromo-N- (4-bromophenyl) -2- (2- thienylsulfonamido) benzamide; 5-bromo-N- (4-bromophenyl) -2- (2-methoxycarbonyl-3-thienylsulfonamido) benzamide; 5-bromo-N- (4-bromophenyl) -2- (4-cyanophenyl-sulfonamido) benzamide; 5-bromo-N- (4-bromophenyl) -2- (2-methylsulfonamido) benzamide; 5-bromo-N- (4-bromophenyl) -2- (3-trifluoromethylphenylsuifonamido) benzamide; 5-bromo-N- (4-bromophenyl) -2- (4-methoxyphenylsulfonamido) benzamide; 5-bromo-N- (4-bromophenyl) -2- (2-phenylsulfonamido) benzamide; and 5-bromo-N- (4-bromophenyl) -2 ~ (4-bromophen-sulfonamido) benzamide; and a pharmaceutically acceptable vehicle; N-phenyl-2- (3-trifluoromethylphenylsulfonamido) be4nzamide; 5-methoxy-N- (3-trifluoromethylphenyl) -2- (4-chlorophenylsulfonamido) benzamide; 5-methoxy-N- (4-bromophenyl) -2- (5-chloro-2-thienylsulfonamido) benzamide; 5-methoxy-N- (4-bromophenyl) -2- (3,3,3-trifluoroethylsulfonamido) benzamide; 5-methoxy-N- (4-bromophenyl) -2- (3,3-chloro-fluoro-phenylsulfonamido) -benzamide; 5-methoxy-N- (4-bromophenyl) -2- (3,3-chloropropylsulfonamido) benzamide; 5-methoxy-N- (4-bromophenyl) -2- (4-methoxyphenylisulfonamido) benzamide; 5-methoxy-N- (4-bromophenyl) -2- (2-fluorophenylsulfonamido) benzamide; N- (4-chlorophenyl-2- (2-fluorophenulphonamido) benzamide; N- (4-bromophenyl) -2- (3,3,3-trifluoroethylsulfonamido) benzamide; N- (4-bromophenyl) -5-chloro-2 - (3,3-chloro-2-fiuorophenylsufonamido) benzamide; N- (4-chlorophenyl) -2- (3,4-dichlorophenylsufonamido) benzamide; N- (4-bromophenyl) -2- (2-thieniisufonamido) benzamide; (4-bromophenyl) -2- (2-methoxy-3-thienylsufonamido) benzamide; N- (3,4-dichlorophenyl) -2- (2-phlorophenylsulfonamido) benzamide; N- (4-chlorophenyl) -2- (3 - trifluoromethylphenylsufonamido) benzamide; 5-bromo-N- (4-chlorophenyl) -2- (3,4-dichlorophenylsulfonamido) benzamide; N- (4-chlorophenyl) -2- (3,4-difluorophenylsufonamido) benzamide; N- (4-butoxyphenyl) -2- (3,4-difluorophenylsulfonamido) benzamide; N- (4-chlorophenyl) -2- (3,5-dimethylisoxazole-4-sulfonamido) benzamide; N- (4-chlorophenyl) -2- (2,1, 3-benzothiadiazole-4-sulfonylamino) benzamide; N- (3-trifluoromethoxyphenyl) -2- (5-bromo-thiophene-2-sulfonylamino) benzamide; N- (4-bromophenyl) -2- (phenylsulfonamido) benzamide and 5-methoxy-N- (4-chlorophenyl) -2- (3-trifluoromethylphenylsulfonamido) benzamide.