IE910684A1 - "New derivatives of pyridylsulfonylurea and of pyridylsulfonylthiourea process for preparing these and pharmaceutical compositions containing them" - Google Patents

"New derivatives of pyridylsulfonylurea and of pyridylsulfonylthiourea process for preparing these and pharmaceutical compositions containing them"

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Publication number
IE910684A1
IE910684A1 IE068491A IE68491A IE910684A1 IE 910684 A1 IE910684 A1 IE 910684A1 IE 068491 A IE068491 A IE 068491A IE 68491 A IE68491 A IE 68491A IE 910684 A1 IE910684 A1 IE 910684A1
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Ireland
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salts
formula
sulfonyl
pyrid
pharmaceutically acceptable
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IE068491A
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IE66021B1 (en
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Bernard Masereel
Bernard Pirotte
Marc Schynts
Jacques Delarge
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Adir
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Publication of IE66021B1 publication Critical patent/IE66021B1/en

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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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Derivatives of formula (I) <IMAGE> in which: - R denotes a cycloalkyl, bicycloalkyl or polycycloalkyl radical, - X denotes an oxygen or sulphur atom, - R1 denotes an alkyl, cycloalkyl, bicycloalkyl or polycycloalkyl radical. Medications.

Description

The present invention concerns new derivatives of pyridylsulfonylurea and of pyridylsulfonylthiourea, their preparation and pharmaceutical preparations containing them.
Numerous sulfonylureas and sulfonylthioureas are known in the literature, endowed in particular with diuretic or hypoglycemic properties. Pyridylsulfonylureas like Torasemide, which is a potent diuretic, are also known.
Other pyridylsulfonylureas have also been described on account of their diuretic and anti-inflammatory properties (French Patents No. 2 267 775 and No. 2 416 225).
Their diuretic effect is due to an inhibitory effect of Na+/K+/2C1 cotransport in the kidneys.
The applicant company has now discovered new pyridylsulfonylureas and pyridylsulphonylthioureas endowed not only with the ability to inhibit Na+/K+/2C1' cotransport and the passage of chlorides through the kidneys, but also with properties which block the cellular passage of potassium in the kidneys and the lungs.
These new derivatives differ from the derivatives of the prior art in also having the particularly valuable property of presenting an optimal partition coefficient and optimum pKa for passing through the blood-brain barrier.
The compounds of the invention are thus particularly valuable for the treatment of disorders such as arterial hypertension and edematous conditions of all origins, including cerebral edema.
More specifically the invention concerns derivatives of formula (I) (I) IE 91684 in which: R represents a cycloalkyl, bicycloalkyl or polycycloalkyl radical having 3 to 15 carbon atoms, optionally interrupted by one or more heteroatoms chosen from among nitrogen, oxygen and sulfur, X represents an oxygen or sulfur atom, Ri represents a straight- or branched-chain alkyl radical comprising 1 to 6 carbon atoms or a cycloalkyl, bicycloalkyl or polycycloalkyl radical containing 3 to 15 carbon atoms, optionally interrupted by one or more heteroatoms chosen from among nitrogen, oxygen and sulfur, with the proviso that, when X is an oxygen atom and at the same time R is a monocyclic or bicyclic alkyl radical, Rx cannot represent a linear or branched alkyl radical or a saturated heteromonocyclic group containing nitrogen and able to contain a second heteroatom, as well as their addition salts with a pharmaceutically acceptable inorganic or organic acid, and, when R or Rx represents a radical having one or more center(s) of asymmetry, their isomers, enantiomers and diastereoisomers.
The invention also encompasses a process for preparing derivatives of formula (I), which comprises: either condensing a derivative R NH έτ N in which R has the same meaning as of formula (II) /02—NH2 (II) in formula (I), with an isocyanate or isothiocyanate of formula (III) X = C = N - Rx (ill) in which X and Rx have the same meaning as in formula (I), in the presence of an alkaline agent such as a metal hydroxide or a tertiary amine in a polar solvent, to lead, after neutralization of the reaction medium preceded, if desired, by evaporating the solvent and taking up in water, to derivatives of formula (I), which are optionally converted into salts by adding a pharmaceutically acceptable inorganic or organic acid, or which are, if desired, separated into their isomers and then optionally converted into salts by adding a pharmaceutically acceptable inorganic or organic acid, - or condensing a derivative of formula (IV) R I NH I S02—NH—COOC2H5 (iv) N in which R has the same meaning as in formula (I), with an amine of formula (V) Ri - NH2 (V) in which Rx has the same meaning as in formula (I), by heating in an anhydrous solvent to obtain, if necessary after purification and neutralization, compounds of formula (I) in which X represents an oxygen atom, which are then be optionally converted into salts by 25 means of a pharmaceutically acceptable inorganic or organic acid, or which are, if desired, separated into their isomers and then optionally converted into salts by E 91684 - 4 adding a pharmaceutically acceptable inorganic or organic acid.
Among pharmaceutically acceptable inorganic or organic acids there may be mentioned, without this list being restrictive, hydrochloric, sulfuric, nitric, acetic, tartaric, malic, maleic, camphoric, methanesulfonic, ethanesulfonic and camphosulfonic acids, and the like.
The compounds of the invention possess very valuable 10 pharmacological properties.
They exhibit diuretic properties due to the inhibition of Na+/K+/2C1' cotransport and of the passage of chlorides, combined with potassium sparing properties because of inhibition of the membrane passage of potassium.
The compounds of the invention therefore find an application in the treatment of hypertension, being all the more valuable because the normalization of blood pressure is not accompanied by the leakage of potassium, which is known to have harmful effects, particularly for heart muscle.
The compounds of the invention also possess a lipophilic character, particularly well adapted to passing the blood-brain barrier, and consequently their inhibitory effect on Na+/K+/2C1 cotransport can exert itself directly on the astrocytes, thus preventing the swelling of the astrocytes which represents a very important part of cerebral edema.
The compounds of the invention therefore find an application in the treatment of edematous conditions and particularly cerebral edema.
Pharmaceutical compositions containing as active principle at least one compound of formula (I) or one of its addition salts with a pharmaceutically acceptable acid, alone or in combination with one or more inert nontoxic excipients or vehicles, are also the subject of the present invention.
Among pharmaceutical compositions according to the invention there may be mentioned more particularly IF 91684 those which are suitable for oral, parenteral, nasal, rectal or cutaneous administration, particularly simple or sugared tablets, capsules, pills and sachets, sublingual tablets, suppositories, skin creams and gels, aerosols, injectable solutions, nasal drops, and the like.
The effective dosage varies according to the age and weight of the patient, the severity of the affection, and also the route of administration. In general, unit dosages range between 0.1 and 500 mg in 1-3 doses daily.
The following examples illustrate the invention, without limiting it in any way.
Starting compounds of general formulae (II) and (IV) are described in the literature (Eur. J. Med. Chem. 15 (4), 299-304 (1980) and 16 (1), 65-68 (1981)) or can be prepared in a similar way.
Compounds of formula (II) can be obtained, in particular, by the action of an excess of an amine of formula RNH2, where R has the same meaning as in general formula (I), on a pyridine derivative of formula S02— NH2 in which Y represents a starting group such as a halogen or SO3H, by heating between 80 and 140‘C. If necessary after dilution and making the mixture alkaline and then, if desired, clarifying with charcoal, the compounds of formula (II) are precipitated at pH 7-8, spun down, dried and utilized as such in the following reactions.
In the examples that follow, the percentage analysis, and infra-red and :H NMR spectra agree with those of the expected structures.
IE 91684 EXAMPLE 1 : N- ((4( -cyclohexylamino) pyrid-3-yl) sulfonyl) -N' eye lohexylurea 0.01 mol of NaOH dissolved in a minimum of water is 5 added to a solution of 0.01 mol of (4-(cyclohexylamino)pyrid-3-yl) sulfonamide in 80 ml of a water/acetone mixture (1:1). The mixture is stirred with a magnetic rod, and 0.015 mol of cyclohexylisocyanate is added. Stirring is continued, while the reaction is followed by TLC (silica gel 60F254, mobile phase: ethyl acetate 9, methanol 1, triethylamine 0.2). Gentle heating can accelerate the reaction. The mixture is evaporated under reduced pressure, and the residue is taken up in 100 ml of 0.2 N NaOH. Any insoluble material is filtered out and the solution is corrected to pH 6.5-7 and left to crystallize for 1 hour in the refrigerator. The precipitate collected is suspended in 100 ml of a water/ acetone mixture (4:1) saturated with NaHCO3. The mixture is stirred for 1 hour and then filtered, and the filtrate is brought back to pH 6.5-7 and left to crystallize in the refrigerator. The crystals are collected, washed in cold water and dried under vacuum at normal temperature. Yield is around 50-60%. Melting point: 165-167’C.
EXAMPLE 2 : N-((4-(cycloheptylamino)pyrid-3-yl) sulfonyl)-N·eyelohexylurea ml of anhydrous toluene are added to 0.01 mol of ethyl N-(4-cycloheptylamino)pyrid-3-yl) sulfonyl carbamate, 0.0.5 mol of cyclohexyl amine and 3 g of 4λ molecular sieve, and subjected to reflux for several hours, with the reaction being followed by TLC (silica gel 60F254; mobile phase: ethyl acetate 9, methanol 1, acetic acid 0.2). The molecular sieve is separated out and the mixture is evaporated under reduced pressure. The residue is taken up in 100-150 ml of 0.2 N NaOH, and extracted twice with 50 ml of ether. The aqueous phase is corrected to pH 6.5-7 and left to crystallize for 1 hour in the refrigerator. The procedure is then continued as in Example 1. Yield is around 50-60%. Melting point : 165-169eC.
EXAMPLE 3 : N - ( ( 4-( eyelooctylamino )pyrid-3-yl)sulfony1-N · 5 cyclooctylurea nitrate The same operating conditions are used as in Example 2, but with ethyl N-(4-(cyclooctylamino)pyrid3-yl)sulfonyl carbamate and cyclooctylamine being used as the starting materials. After separating out the molecular sieve and evaporating under reduced pressure, the mixture is taken up in 75-100 ml of 0.2 N NaOH and extracted twice with 50 ml of ether, and 5-10 ml of nitric acid is added to the aqueous phase. It is then left overnight in the refrigerator.
The crystals are collected on filter paper, washed with a minimum of iced water and dried under vacuum at normal temperature. Yield is around 60-70%. Melting point: 144-146’C.
EXAMPLE 4 : N-((4-(cycloheptylamino)pyrid-3-yl) sulfonyl) -N' eye lohexylthiourea 0.01 mol of NaOH dissolved in a minimum of water is added to a solution of 0.01 mol of (4-(cycloheptylamino)pyrid-3-yl)sulfonamide in 80 ml of a water/acetone mixture (1:1). The mixture is stirred with a magnetic rod, and 0.015 mol of cyclohexylisothiocyanate is added. Stirring is continued, while the reaction is followed by TLC (silica gel 60F254; moblile phase: ethyl acetate 9, methanol 1, triethylamine 0.2). Gentle heating can accelerate the reaction. The mixture is evaporated under reduced pressure and the residue is taken up in 100 ml of 0.2 N NaOH. Any insoluble material is filtered out and the solution is corrected to pH 6.5-7 and left to crystallize for 1 hour in the refrigerator. The precipitate collected is suspended in 100 ml of a water/acetone mixture (4:1) saturated with NaHCO3. The mixture is stirred for 1 hour and then filtered, and the filtrate, brought back to pH 6.5-7, is left to crystallize in the refrigerator. The crystals are collected, washed in cold water and dried under vacuum at normal temperature. Yield is around 50-60%. Melting point: 195-197’C.
EXAMPLE 5 : N-(4-(bicyclo [2.2.1] heptanylamino) pyrid-3-yl) sulfonyl-N' isopropylthiourea g of (4-(bicyclo[2.2.5]heptanylamino)pyrid10 3-yl)sulfonamide are dissolved in 20 ml of acetone and ml of isopropylisothiocyanate and 5 ml triethylamine are added. The mixture is heated under reflux while the reaction is followed by TLC (silica gel 60F254; mobile phase: ethyl acetate 9, methanol 1, triethylamine 0.2).
It is evaporated to dryness, taken up in 120 ml of 0.2 N NaOH and filtered. The solution is extracted 3 times with 150 ml of ether, clarified with charcoal and corrected to pH 7.5. The product crystallizes out. Yield is around 50%. Melting point : 194-196°C.
EXAMPLE 6 : 11-( (4-( cyclooctylamino) pyrid-3-yl) sulfonyl) -N' ethylthiourea The procedure is identical to that of Example 5, using (4-(cyclooctylamino)pyrid-3-yl)sulfonamide and ethylisothiocyanate as the starting materials. Yield is similar. Melting point : 196-198’C.
By using the procedures described in the preceding examples, the derivatives of Examples 7 to 17 are obtained in the same way.
EXAMPLE 7 : N-((4-(cyclohexylamino)pyrid-3-yl)sulfonyl)-N'eyelooctylurea Melting point : 133-137’C EXAMPLE 8 : N-((4-( cyclooctylamino )pyrid-3-yl) sulfonyl) -N' eyeloheptylurea Melting point ί 156-160°C EXAMPLE 9 : N- ((4-(eyelohexylamino)pyrid-3-yl) sulfonyl) -N' cycloheptylurea Melting point : 145-150°C EXAMPLE 10 : N-((4-(cyclooctyl amino)pyrid-3-yl) sulfonyl)-N'eyelohexylurea Melting point : 144-148°C EXAMPLE 11 : N-((4-(eyeloheptylamino)pyrid-3-yl) sulfonyl)-N·15 cyclooctylurea Melting point : 140-145°C EXAMPLE 12 : N-( (4-(eyelododecylamino)pyrid-3-yl) sulfonyl)-N'ethylurea Melting point : 195-196 °C EXAMPLE 13 s N— ( (4-(cyclododecylamino)pyrid-3-yl) sulfonyl)-N'isopropylurea Melting point : 126-128"C EXAMPLE 14 : N—((4-(cycloheptylamino)pyrid-3-yl) sulfonyl)-N’isopropylthiourea Melting point : 196-198’C EXAMPLE 15 : N-( (4-(cyclooctylamino)pyrid-3-yl) sulfonyl)-N'isopropylthiourea Melting point : 194-195 °C EXAMPLE 16 : N-((4-(cyclohexylamino)pyrid-3-yl) sulfonyl)-N·ethylthiourea Melting point : 186-187 °C EXAMPLE 17 : N- ( (4-(2-(aza-2-bicyclo[3.3.0]octyl)amino)pyrid-3yl) sulfonyl)-N* -isopropylurea Melting point : 185-186*C EXAMPLE 18 : Determination of partition coefficients and pKa The coefficients of partition between n-octanol and water were determined at pH = 7.4 by conventional techniques and are expressed as logarithms to base 10 (Log P).
The pKa values represent the proton acidity These results indicate a lipophilic character at physiological pH which would favor passage through the blood-brain barrier.
EXAMPLE 19 : Inhibition of Na+/K+/2C1" cotransport and Cl" passage The 50% inhibitory concentration for Na+/K+/2C1 cotransport in vivo is decreased, in the case of the compound of Example 3, by about 60% relative to Torasemide (luminal membrane of the ascending branch of the loop of Ηβηΐέ in the nephron of perfused rabbits IE 91684 - 11 (Arzneim. Forsch. (1988) 38 (la), 151-152)), and by 85% relative to Torasemide in the case of the compound of Example 10 (erythrocyte membrane in normotensive rats).
The 50% inhibitory concentration for Cl' passage in 5 the kidneys in vivo is decreased, in the case of the compound of Example 8, by about 50% relative to Torasemide.
EXAMPLE 20 : Tablets containing 5 mg of N-((4-(eyelohexylamino)pyrid10 3-yl)sulfonyl)-N'-cyclohexylurea Formulation for 10,000 tablets N-((4-(cyclohexylamino)pyrid-3-yl) sulfonyl)- N'-cyclohexylurea 50 grams Lactose 150 grams Corn starch 750 grams Colloidal silica 2 grams Magnesium stearate 1 gram IE 91684

Claims (16)

1. A derivative of formula (I) R I * 1 H II I S02—NH—C—NH—Rl (I) in which: 5 R represents a cycloalkyl, bicycloalkyl or polycycloalkyl radical having 3 to 15 carbon atoms, optionally interrupted by one or more heteroatoms chosen from among nitrogen, oxygen and sulfur, X represents an oxygen or sulfur atom. 10 - R x represents a straight- or branched-chain alkyl radical comprising 1 to 6 carbon atoms or a cycloalkyl, bicycloalkyl or polycycloalkyl radical containing 3 to 15 carbon atoms, optionally interrupted by one or more heteroatoms chosen from among nitrogen, oxygen and 15 sulfur, with the proviso that, when X is an oxygen atom and at the same time R is a monocyclic or bicyclic alkyl radical, R x cannot represent a linear or branched alkyl radical or a saturated heteromonocyclic group containing 20 nitrogen and able to contain a second heteroatom, as well as its addition salts with a pharmaceutically acceptable inorganic or organic acid, and, when R or R x represents a radical comprising one or more centers of asymmetry, its isomers, enantiomers ind diastereoisomers.
2. A compound as claimed in claim 1, such that R and R x represent a cycloalkyl, bicycloalkyl or polycycloalkyl radical having
3. To 15 carbon atoms, optionally interrupted by one or more nitrogen atoms, as well as its salts, enantiomers and diastereoisomers. 5 3. N-( (4-(eye lohexyl amino )pyr id-3-yl) sulf onyl)-N'cyclohexylurea and its salts.
4. N- ((4-(cycloheptylamino)pyrid-3-yl) sulfonyl)-N'cyclohexylurea and its salts.
5. N-( (4-(cyclooctylamino)pyrid-3-yl)sulfonyl)-N'10 cyclooctylurea and its salts.
6. N-((4-(cycloheptylamino)pyrid-3-yl)sulfonyl)-N'cyclohexylthiourea and its salts.
7. N-((4-bicyclo[2.2.1]heptylamino )pyrid-3yl)sulfonyl)-N'-isopropylthiourea and its salts. 15
8. N-( (4-(cyclooctylamino)pyrid-3-yl)sulfonyl)-N'ethylthiourea and its salts.
9. N- ((4-(cyclododecylamino)pyrid-3-yl)sulfonyl)-N'ethylurea and its salts.
10. N- ((4-(2-(aza-2-bicyclo[3.3.0]octyl) amino)pyrid20 3-yl) sulfonyl)-N'-isopropylurea, its salts and its diastereoisomers.
11. A process for preparing derivatives of formula (I), which comprises: either condensing a derivative of formula (II) R NH S02—NH2 (II) in which R has the same meaning as in formula (I), with an isocyanate or isothiocyanate of formula (III) X = C = N - R x (Hi) in which X and R x have the same meaning as in formula (I), in the presence of an alkaline agent such as a metal hydroxide or a tertiary amine in a polar solvent, to lead, after neutralization of the reaction medium preceded, if desired, by evaporating the solvent and 5 taking up in water, to derivatives of formula (I), which are optionally converted into salts by adding a pharmaceutically acceptable inorganic or organic acid, or which are, if desired, separated into their isomers and then optionally converted into salts by adding a 10 pharmaceutically acceptable inorganic or organic acid, - or condensing a derivative of formula (IV) R I S02—MH— (gi COOC2H5 (IV) N in which R has the same meaning as in formula (I), with an amine of formula (V) 15 R x - NH 2 (V) in which R x has the same meaning as in formula (I), by heating in an anhydrous solvent to obtain, if necessary after purification and neutralization, compounds of formula (I) in which X represents an oxygen 20 atom, which are then optionally converted into salts by means of a pharmaceutically acceptable inorganic or organic acid, or which are, if desired, separated into their isomers and then optionally converted into salts by 25 adding a pharmaceutically acceptable inorganic or organic acid.
12. A pharmaceutical composition containing as active principle at least one compound as claimed in any one of claims 1 to 10, alone or in combination with one or more inert non-toxic excipents.
13. A pharmaceutical composition as claimed in claim 12 used in the treatment of arterial hypertension and edematous conditions. -1614.
14.A compound substantially as hereinbefore described with reference to the Examples.
15. A process substantially as hereinbefore described with reference to the Examples.
16. A composition substantially as hereinbefore described with reference to the Examples.
IE68491A 1990-03-02 1991-03-01 New derivatives of pyridylsulfonylurea and of pyridylsulfonylthiourea process for preparing these and pharmaceutical compostions containing them IE66021B1 (en)

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FR9002659A FR2659080B1 (en) 1990-03-02 1990-03-02 NOVEL PYRIDYLSULFONYLUREA AND PYRIDYLSULFONYLTHIOURAE DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.

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IE66021B1 IE66021B1 (en) 1995-11-29

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CA (1) CA2037189A1 (en)
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FR2685917A1 (en) * 1992-01-06 1993-07-09 Adir NOVEL PYRIDYLSULFONYLUREE DERIVATIVE OF PREPARATION METHODS AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
AU5542101A (en) 2000-04-14 2001-10-30 Univ Vanderbilt Purified and isolated potassium-chloride cotransporter nucleic acids and polypeptides and therapeutic and screening methods using same

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FR2659080B1 (en) 1994-07-08
AU632399B2 (en) 1992-12-24
FR2659080A1 (en) 1991-09-06
PT96926A (en) 1991-10-31
ES2057795T3 (en) 1994-10-16
AU7198191A (en) 1991-09-05
NZ237271A (en) 1993-04-28
EP0445039A1 (en) 1991-09-04
ZA911524B (en) 1991-12-24
IE66021B1 (en) 1995-11-29
DK0445039T3 (en) 1994-10-31
PT96926B (en) 1998-07-31
DE69102310T2 (en) 1994-11-03
JPH07119216B2 (en) 1995-12-20
ATE106873T1 (en) 1994-06-15
CA2037189A1 (en) 1991-09-03
OA09485A (en) 1992-11-15
DE69102310D1 (en) 1994-07-14
EP0445039B1 (en) 1994-06-08
JPH04211659A (en) 1992-08-03

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