WO2001005398A1 - Inhibiteurs de transport de phosphate - Google Patents
Inhibiteurs de transport de phosphate Download PDFInfo
- Publication number
- WO2001005398A1 WO2001005398A1 PCT/US2000/019616 US0019616W WO0105398A1 WO 2001005398 A1 WO2001005398 A1 WO 2001005398A1 US 0019616 W US0019616 W US 0019616W WO 0105398 A1 WO0105398 A1 WO 0105398A1
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- WIPO (PCT)
- Prior art keywords
- benzamide
- bromophenyl
- bromo
- group
- fluorophenylsulfonamido
- Prior art date
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- 0 C*1C=CC(NC(C(C=CC(CN=C)C2)=C2N)=O)=CC=C1 Chemical compound C*1C=CC(NC(C(C=CC(CN=C)C2)=C2N)=O)=CC=C1 0.000 description 2
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having 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
- C07D241/24—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
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/08—Bridged systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/08—Bridged systems
Definitions
- the present invention involves the treatment of chronic renal failure, uremic bone disease and related diseases by inhibition of phosphate retention by certain N- aryl-2-sulfonamidobenzamides.
- ESRD end stage renal disease
- calcium-phosphate precipitation may occur resulting in renal calcification and nephrocalcinosis (Lau, K., Kidney Int. 36:918-937, (1989)).
- 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.
- 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 Ca 2 + absorption.
- inhibition of Pi transport by the gut and kidney is considered beneficial in slowing the progression of CRF and uremic bone disease.
- inhibition of Pi transport by the gut and kidney is beneficial in slowing the progression of CRF and uremic bone disease.
- the present invention involves novel methods of using of N-aryl-2- sulfonamidobenzamides 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 present invention relates to the use of compounds that are inhibitors of sodium-dependent phosphate transport, which are represented by the following Formula (I):
- R ⁇ 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, alkysulfinyl, arylsulfinyl, arylalkylsulfinyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfamyl, arylsulfonamido, and al
- R3 is independently selected from the group consisting of alkyl, haloalkyl, R ⁇ aryl and R ⁇ aralkyl, and Ri substituted heterocycles selected from the group consisting of thiophene, furan, pyridine, pyrimidine, pyrazine, imidazole, and thiazole, and benzo analogs thereof.
- 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.
- 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.
- Preferred compounds include, but are not limited to:
- 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 Formula (I) 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 Formula (I) is accomplished by methods analogous to those above and to those described in the Experimental section.
- a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
- 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.
- treatment of a disease includes, but is not limited to prevention, retardation and prophylaxis of the disease.
- Composition of Formula (I) 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. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose.
- composition is in the form of a capsule
- any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
- composition is in the form of a soft gelatin shell capsule
- any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell.
- Typical parenteral compositions consist of a solution or suspension of 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 compound of Formula (I) 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.
- 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.
- Rabbit proximal tubule cells were isolated and cultured according to the procedure of Sakhrani, L. M. et al., Am. J. Physiol. 246:F757-F764, (1984) whose disclosure is incorporated herein by reference in its entirety.
- Human proximal tubule cells were purchased from Clonetics (San Diego, CA) and grown according to the suppliers' instructions. On the day of the experiment, cells were harvested from culture plates with 0.5 mM EDTA in phosphate buffered saline. The cells were washed twice in uptake buffer (see below) and equilibrated at 37 C in the same buffer for 30 minutes. Aliquots of cells (100 ul, 0.5 to 1 million cells) were distributed into glass test tubes.
- uptake buffer containing 100 uM [ 32 P]-K2HPO4 ( 0.5 to 1 uCi/tube). After varying periods of time (usually 4 minutes) at 37 C, uptakes 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 IN NaOH and 32 P was counted in a liquid scintillation counter. Phosphate uptake is expressed as pmol phosphate/mg cell protein.
- the cells are harvested by filtration and 3 p uptake is measured. It is also possible to use 33p rather than 3 p_ Using human proximal tubule cells the IC50 for 5-bromo-N-(4-bromophenyl)-2-(5-chloro-2- fhienylsulfonamido)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.
- 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.
Abstract
Priority Applications (12)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU0202938A HUP0202938A3 (en) | 1999-07-20 | 2000-07-19 | N-aryl-2-sulfonamidobenzamides as phosphate transport inhibitors and pharmaceutical compositions containing them |
NZ516619A NZ516619A (en) | 1999-07-20 | 2000-07-19 | Phosphate transport inhibitors |
BR0012568-7A BR0012568A (pt) | 1999-07-20 | 2000-07-19 | Inibidores do transporte de fosfato |
JP2001510455A JP2003504403A (ja) | 1999-07-20 | 2000-07-19 | リン酸輸送阻害物質 |
AU63543/00A AU6354300A (en) | 1999-07-20 | 2000-07-19 | Phosphate transport inhibitors |
EP00950437A EP1202729A1 (fr) | 1999-07-20 | 2000-07-19 | Inhibiteurs de transport de phosphate |
MXPA02000753A MXPA02000753A (es) | 1999-07-20 | 2000-07-19 | Inhibidores de transporte de fosfato. |
CA002379657A CA2379657A1 (fr) | 1999-07-20 | 2000-07-19 | Inhibiteurs de transport de phosphate |
IL14769700A IL147697A0 (en) | 1999-07-20 | 2000-07-19 | Phosphate transport inhibitors |
KR1020027000801A KR20020015382A (ko) | 1999-07-20 | 2000-07-19 | 포스페이트 수송 억제제 |
PL00353741A PL353741A1 (en) | 1999-07-20 | 2000-07-19 | Phosphate transport inhibitors |
NO20020278A NO20020278D0 (no) | 1999-07-20 | 2002-01-18 | Fosfattransportinhibitorer |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14464699P | 1999-07-20 | 1999-07-20 | |
US60/144,646 | 1999-07-20 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2001005398A1 true WO2001005398A1 (fr) | 2001-01-25 |
Family
ID=22509500
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2000/019616 WO2001005398A1 (fr) | 1999-07-20 | 2000-07-19 | Inhibiteurs de transport de phosphate |
Country Status (19)
Country | Link |
---|---|
EP (1) | EP1202729A1 (fr) |
JP (1) | JP2003504403A (fr) |
KR (1) | KR20020015382A (fr) |
CN (1) | CN1361687A (fr) |
AR (1) | AR030911A1 (fr) |
AU (1) | AU6354300A (fr) |
BR (1) | BR0012568A (fr) |
CA (1) | CA2379657A1 (fr) |
CO (1) | CO5190714A1 (fr) |
CZ (1) | CZ2002204A3 (fr) |
HU (1) | HUP0202938A3 (fr) |
IL (1) | IL147697A0 (fr) |
MX (1) | MXPA02000753A (fr) |
NO (1) | NO20020278D0 (fr) |
NZ (1) | NZ516619A (fr) |
PL (1) | PL353741A1 (fr) |
TR (1) | TR200200112T2 (fr) |
WO (1) | WO2001005398A1 (fr) |
ZA (1) | ZA200200464B (fr) |
Cited By (21)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2001087294A1 (fr) * | 2000-05-12 | 2001-11-22 | Smithkline Beecham Corporation | Inhibiteurs du transport de phosphate |
GB2378179A (en) * | 2001-08-03 | 2003-02-05 | Pantherix Ltd | Aromatic sulfonamides and their use in treating bacterial diseases |
WO2003018536A1 (fr) * | 2001-08-30 | 2003-03-06 | Starpharma Limited | Agents chimiotherapeutiques |
WO2003057225A2 (fr) * | 2001-12-26 | 2003-07-17 | Genzyme Corporation | Inhibiteurs de transport du phosphate |
WO2006077901A1 (fr) * | 2005-01-20 | 2006-07-27 | Shionogi & Co., Ltd. | Inhibiteur de l’expression du ctgf |
US7582673B2 (en) | 2004-10-21 | 2009-09-01 | High Point Pharmaceuticals, Llc | Bissulfonamide compounds as agonists of GalR1, compositions, and methods of use |
WO2009146875A1 (fr) * | 2008-06-03 | 2009-12-10 | Fresenius Medical Care Deutschland Gmbh | Compositions pharmaceutiques renfermant des modulateurs de la gamma sécrétase |
WO2011097145A3 (fr) * | 2010-02-02 | 2011-12-22 | Honeywell International Inc. | Composés fluorescents bleu-vert |
EP2590655A1 (fr) * | 2010-07-07 | 2013-05-15 | Ardelyx, Inc. | Composés et procédés pour l'inhibition du transport de phosphate |
WO2014029983A1 (fr) | 2012-08-21 | 2014-02-27 | Ardelyx, Inc. | Composés et procédés d'inhibition d'un antiport à médiation par nhe dans le traitement de troubles associés à une rétention de fluide ou à une surcharge de sel et de troubles du tractus gastro-intestinal |
US8809339B2 (en) | 2010-07-07 | 2014-08-19 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
US8815908B2 (en) | 2010-07-07 | 2014-08-26 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
US8916569B2 (en) | 2010-07-07 | 2014-12-23 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
US9382239B2 (en) | 2011-11-17 | 2016-07-05 | Dana-Farber Cancer Institute, Inc. | Inhibitors of c-Jun-N-terminal kinase (JNK) |
WO2018043400A1 (fr) * | 2016-08-30 | 2018-03-08 | 日本曹達株式会社 | Composé benzamide de sulfonylamino et agent de lutte antiparasitaire |
WO2018129552A1 (fr) | 2017-01-09 | 2018-07-12 | Ardelyx, Inc. | Composés utiles pour le traitement de troubles du tractus digestif |
WO2018129556A1 (fr) | 2017-01-09 | 2018-07-12 | Ardelyx, Inc. | Composés et procédés pour l'inhibition d'un antiport à médiation par échangeur sodium/proton (nhe) dans le traitement de troubles associés à une rétention d'eau ou à une surcharge en sel et de troubles du tractus gastro-intestinal |
WO2018129557A1 (fr) | 2017-01-09 | 2018-07-12 | Ardelyx, Inc. | Inhibiteurs d'antiport à médiation par nhe |
EP3351248A1 (fr) | 2008-12-31 | 2018-07-25 | Ardelyx, Inc. | Composés et procédés d'inhibition d'un antiport à médiation par nhe dans le traitement de troubles associés à une rétention de fluide ou à une surcharge de sel et de troubles du tractus gastro-intestinal |
US10272079B2 (en) | 2013-04-12 | 2019-04-30 | Ardelyx, Inc. | NHE3-binding compounds and methods for inhibiting phosphate transport |
US10376481B2 (en) | 2012-08-21 | 2019-08-13 | Ardelyx, Inc. | Compounds and methods for inhibiting NHE-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders |
Families Citing this family (2)
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CN103183623A (zh) * | 2013-03-12 | 2013-07-03 | 中国医学科学院医药生物技术研究所 | 一组苯磺酰胺基苯甲酰胺类衍生物及制备和应用 |
CN105395532B (zh) * | 2015-11-25 | 2017-11-14 | 中国医学科学院医药生物技术研究所 | 2‑苯磺酰胺基苯甲酰胺类化合物在肝损伤保护和肝纤维化防治中的应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5034417A (en) * | 1987-05-29 | 1991-07-23 | Fujisawa Pharmaceutical Co., Ltd. | New alkanesulfonanilide derivatives, processes for preparation thereof and pharmaceutical composition comprising the same |
US5210079A (en) * | 1988-01-07 | 1993-05-11 | E. I. Du Pont De Nemours And Company | Treatment of chronic renal failure with imidazole angiotensin-II receptor antagonists |
-
2000
- 2000-07-18 CO CO00053928A patent/CO5190714A1/es not_active Application Discontinuation
- 2000-07-18 AR ARP000103686A patent/AR030911A1/es not_active Application Discontinuation
- 2000-07-19 IL IL14769700A patent/IL147697A0/xx unknown
- 2000-07-19 HU HU0202938A patent/HUP0202938A3/hu unknown
- 2000-07-19 NZ NZ516619A patent/NZ516619A/xx unknown
- 2000-07-19 MX MXPA02000753A patent/MXPA02000753A/es unknown
- 2000-07-19 KR KR1020027000801A patent/KR20020015382A/ko not_active Application Discontinuation
- 2000-07-19 BR BR0012568-7A patent/BR0012568A/pt not_active Application Discontinuation
- 2000-07-19 JP JP2001510455A patent/JP2003504403A/ja not_active Withdrawn
- 2000-07-19 EP EP00950437A patent/EP1202729A1/fr not_active Withdrawn
- 2000-07-19 TR TR2002/00112T patent/TR200200112T2/xx unknown
- 2000-07-19 CN CN00810644A patent/CN1361687A/zh active Pending
- 2000-07-19 CZ CZ2002204A patent/CZ2002204A3/cs unknown
- 2000-07-19 AU AU63543/00A patent/AU6354300A/en not_active Abandoned
- 2000-07-19 CA CA002379657A patent/CA2379657A1/fr not_active Abandoned
- 2000-07-19 PL PL00353741A patent/PL353741A1/xx not_active Application Discontinuation
- 2000-07-19 WO PCT/US2000/019616 patent/WO2001005398A1/fr active IP Right Grant
-
2002
- 2002-01-18 NO NO20020278A patent/NO20020278D0/no not_active Application Discontinuation
- 2002-01-18 ZA ZA200200464A patent/ZA200200464B/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5034417A (en) * | 1987-05-29 | 1991-07-23 | Fujisawa Pharmaceutical Co., Ltd. | New alkanesulfonanilide derivatives, processes for preparation thereof and pharmaceutical composition comprising the same |
US5210079A (en) * | 1988-01-07 | 1993-05-11 | E. I. Du Pont De Nemours And Company | Treatment of chronic renal failure with imidazole angiotensin-II receptor antagonists |
Cited By (38)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001087294A1 (fr) * | 2000-05-12 | 2001-11-22 | Smithkline Beecham Corporation | Inhibiteurs du transport de phosphate |
GB2378179A (en) * | 2001-08-03 | 2003-02-05 | Pantherix Ltd | Aromatic sulfonamides and their use in treating bacterial diseases |
WO2003018536A1 (fr) * | 2001-08-30 | 2003-03-06 | Starpharma Limited | Agents chimiotherapeutiques |
EP1815860A2 (fr) | 2001-12-26 | 2007-08-08 | Genzyme Corporation | Inhibiteurs de transport du phosphate |
WO2003057225A3 (fr) * | 2001-12-26 | 2004-04-08 | Genzyme Corp | Inhibiteurs de transport du phosphate |
JP2005514413A (ja) * | 2001-12-26 | 2005-05-19 | ジェンザイム コーポレーション | リン酸塩輸送インヒビター |
US7119120B2 (en) | 2001-12-26 | 2006-10-10 | Genzyme Corporation | Phosphate transport inhibitors |
EP1815860A3 (fr) * | 2001-12-26 | 2007-11-21 | Genzyme Corporation | Inhibiteurs de transport du phosphate |
WO2003057225A2 (fr) * | 2001-12-26 | 2003-07-17 | Genzyme Corporation | Inhibiteurs de transport du phosphate |
US7582673B2 (en) | 2004-10-21 | 2009-09-01 | High Point Pharmaceuticals, Llc | Bissulfonamide compounds as agonists of GalR1, compositions, and methods of use |
WO2006077901A1 (fr) * | 2005-01-20 | 2006-07-27 | Shionogi & Co., Ltd. | Inhibiteur de l’expression du ctgf |
WO2009146875A1 (fr) * | 2008-06-03 | 2009-12-10 | Fresenius Medical Care Deutschland Gmbh | Compositions pharmaceutiques renfermant des modulateurs de la gamma sécrétase |
EP3939964A1 (fr) | 2008-12-31 | 2022-01-19 | Ardelyx, Inc. | Combinaisons d'inhibition d'un antiport a mediation par nhe dans le traitement de troubles associes a une retention de fluide ou a une surcharge de sel et de troubles du tractus gastro-intestinal |
EP3351248A1 (fr) | 2008-12-31 | 2018-07-25 | Ardelyx, Inc. | Composés et procédés d'inhibition d'un antiport à médiation par nhe dans le traitement de troubles associés à une rétention de fluide ou à une surcharge de sel et de troubles du tractus gastro-intestinal |
US8664425B2 (en) | 2010-02-02 | 2014-03-04 | Honeywell International Inc. | Bluegreen fluorescent compounds |
WO2011097145A3 (fr) * | 2010-02-02 | 2011-12-22 | Honeywell International Inc. | Composés fluorescents bleu-vert |
US8815908B2 (en) | 2010-07-07 | 2014-08-26 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
EP2590655A4 (fr) * | 2010-07-07 | 2013-12-18 | Ardelyx Inc | Composés et procédés pour l'inhibition du transport de phosphate |
EP2590655A1 (fr) * | 2010-07-07 | 2013-05-15 | Ardelyx, Inc. | Composés et procédés pour l'inhibition du transport de phosphate |
US8815910B2 (en) | 2010-07-07 | 2014-08-26 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
US8916569B2 (en) | 2010-07-07 | 2014-12-23 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
US9278102B2 (en) | 2010-07-07 | 2016-03-08 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
US9289430B2 (en) | 2010-07-07 | 2016-03-22 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
US9289429B2 (en) | 2010-07-07 | 2016-03-22 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
US9301951B2 (en) | 2010-07-07 | 2016-04-05 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
US8809339B2 (en) | 2010-07-07 | 2014-08-19 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
US9382239B2 (en) | 2011-11-17 | 2016-07-05 | Dana-Farber Cancer Institute, Inc. | Inhibitors of c-Jun-N-terminal kinase (JNK) |
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 |
WO2014029983A1 (fr) | 2012-08-21 | 2014-02-27 | Ardelyx, Inc. | Composés et procédés d'inhibition d'un antiport à médiation par nhe dans le traitement de troubles associés à une rétention de fluide ou à une surcharge de sel et de troubles du tractus gastro-intestinal |
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 |
WO2018043400A1 (fr) * | 2016-08-30 | 2018-03-08 | 日本曹達株式会社 | Composé benzamide de sulfonylamino et agent de lutte antiparasitaire |
US10793520B2 (en) | 2016-08-30 | 2020-10-06 | Nippon Soda Co., Ltd. | Sulfonylaminobenzamide compound and pest control agent |
WO2018129556A1 (fr) | 2017-01-09 | 2018-07-12 | Ardelyx, Inc. | Composés et procédés pour l'inhibition d'un antiport à médiation par échangeur sodium/proton (nhe) dans le traitement de troubles associés à une rétention d'eau ou à une surcharge en sel et de troubles du tractus gastro-intestinal |
WO2018129557A1 (fr) | 2017-01-09 | 2018-07-12 | Ardelyx, Inc. | Inhibiteurs d'antiport à médiation par nhe |
WO2018129552A1 (fr) | 2017-01-09 | 2018-07-12 | Ardelyx, Inc. | Composés utiles pour le traitement de troubles du tractus digestif |
US11147884B2 (en) | 2017-01-09 | 2021-10-19 | Ardelyx, Inc. | Inhibitors of NHE-mediated antiport |
US11242337B2 (en) | 2017-01-09 | 2022-02-08 | Ardelyx, Inc. | Compounds useful for treating gastrointestinal tract disorders |
Also Published As
Publication number | Publication date |
---|---|
BR0012568A (pt) | 2002-04-30 |
CO5190714A1 (es) | 2002-08-29 |
TR200200112T2 (tr) | 2002-05-21 |
KR20020015382A (ko) | 2002-02-27 |
CA2379657A1 (fr) | 2001-01-25 |
IL147697A0 (en) | 2002-08-14 |
NO20020278L (no) | 2002-01-18 |
JP2003504403A (ja) | 2003-02-04 |
HUP0202938A3 (en) | 2006-07-28 |
NZ516619A (en) | 2004-02-27 |
HUP0202938A2 (hu) | 2003-01-28 |
NO20020278D0 (no) | 2002-01-18 |
AU6354300A (en) | 2001-02-05 |
CN1361687A (zh) | 2002-07-31 |
EP1202729A1 (fr) | 2002-05-08 |
AR030911A1 (es) | 2003-09-03 |
CZ2002204A3 (cs) | 2002-11-13 |
PL353741A1 (en) | 2003-12-01 |
MXPA02000753A (es) | 2002-07-22 |
ZA200200464B (en) | 2003-04-30 |
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