EP0687264A1 - Method for preparing n-methyl 2-(3-pyridyl) (1r,2r)-2-tetrahydrothiopyrancarbothioamide-1-oxide - Google Patents

Method for preparing n-methyl 2-(3-pyridyl) (1r,2r)-2-tetrahydrothiopyrancarbothioamide-1-oxide

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Publication number
EP0687264A1
EP0687264A1 EP94908384A EP94908384A EP0687264A1 EP 0687264 A1 EP0687264 A1 EP 0687264A1 EP 94908384 A EP94908384 A EP 94908384A EP 94908384 A EP94908384 A EP 94908384A EP 0687264 A1 EP0687264 A1 EP 0687264A1
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Prior art keywords
pyridyl
methyl
oxide
process according
salt
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EP94908384A
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German (de)
French (fr)
Inventor
Marie-Thérèse David-Comte
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Aventis Pharma SA
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Rhone Poulenc Rorer SA
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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
    • C07D409/04—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 directly linked by a ring-member-to-ring-member bond
    • 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

Definitions

  • PROCESS FOR THE PREPARATION OF N-METHYL PYRIDYL-3.-2 T ⁇ TRAHYDROTHIOPYRANNECARBOTHIOAMIDE-2-OXIDE- 1 -O R.2R
  • the present invention relates to a process for the preparation of N-methyl (3-pyridyl) -2 tetrahydrothiopyrannecarbothioamide-2-oxide-1- (1R, 2R) of formula:
  • R represents a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms
  • Het represents a heterocyclic radical of aromatic character
  • Y represents a valence bond or a methylene radical.
  • (1S.2S) UR, 2R) is useful as an antihypertensive agent (EP-0 097 584) and, particularly the isomer (1R, 2R), as a cardiac protector (EP-0 429 324) at doses for which the antihypertensive effect does not manifest itself .
  • N-methyl (pyridyl-3) -2 tetrahydrothiopyrannecarbothioamide-2-oxide-1- (1R . 2R) can be isolated from a mixture of the forms (1R.2R) and (1S.2S), in particular from the racemic mixture , by chiral phase chromatography (EP-0 097 584) or can be prepared by stereoselective methods (EP-0 426 557). These methods require the use of large quantities of solvents or else the carrying out of a large number of steps.
  • N-methyl (3-pyridyl) -2 tetrahydrothiopyrannecarbothioamide-2-oxide-1- (1R.2R) can be obtained at starting from a salt of the mixture of trans isomers (1R, 2R) and (1S.2S) and in particular of the racemic mixture with an optically active acid.
  • the method according to the invention consists in selectively precipitating in a suitable solvent a salt of the trans isomer (1R.2R) with an optically active acid and then in liberating the trans isomer (1R.2R) from its salt.
  • an optically active acid chosen from (-) - camphanic acid and (+) - 3-bromo-10 camphor-10 sulfonic acid.
  • the solvents which are particularly suitable for the selective crystallization of the salt of the trans isomer (1R.2R) with an optically active acid are preferably chosen from water, aliphatic alcohols containing 1 to 4 carbon atoms such as methanol , ethanol or isopropanol, and hydro-alcoholic mixtures.
  • (1R.2R) is released from its salt by means of an inorganic or organic base, operating in water or in a mixture consisting of water and an immiscible solvent in which the trans isomer (1R, 2R ) is soluble.
  • mineral base hydroxides or carbonates of alkali metals (sodium hydroxide, potassium hydroxide, sodium carbonate) are preferably used.
  • organic base tertiary aliphatic amines (triethylamine) or pyridine can be used, the basicity of which is strong enough to release the optically active acid from its salt.
  • potash is used in a hydroorganic medium such as a water-halogenated aliphatic hydrocarbon mixture such as a water-methylene chloride mixture: in this way, the isomer trans (1R, 2R) passes into solution in the organic solvent as it is formed, the salt of the optically active acid remaining in aqueous solution.
  • a hydroorganic medium such as a water-halogenated aliphatic hydrocarbon mixture such as a water-methylene chloride mixture
  • N-methyl (3-pyridyl) -2 tetrahydrothiopyrannecarbothioamide-2-oxide-1- (1R.2R) is separated from its solution according to the usual methods and it can be purified according to known techniques, for example by crystallization.
  • the mixture of trans isomers (1R.2R) and (1S.2S) of N-methyl (pyridyl-3) -2 tetrahydrothiopyrannecarbothioamide-2-oxide-1, and more particularly the racemic mixture, can be prepared under the conditions described in European patent EP-0 097 584.
  • the following examples illustrate the present invention.
  • the enantiomeric excess is close to 100%.
  • the yield is 33.4%.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Heart & Thoracic Surgery (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)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

A method for preparing N-methyl-2-(3-pyridyl) (1R,2R)-2-tetrahydrothiopyrancarbothioamide-1-oxide of formula (I) from a sel of a mixture of trans isomers (1S,2S) and (1R,2R) with an optically active acid.

Description

PROCEDE DE PREPARAΗON DE N-METHYL (PYRIDYL-3.-2 TΕTRAHYDROTHIOPYRANNECARBOTHIOAMIDE-2-OXYDE- 1 -O R.2R) PROCESS FOR THE PREPARATION OF N-METHYL (PYRIDYL-3.-2 TΕTRAHYDROTHIOPYRANNECARBOTHIOAMIDE-2-OXIDE- 1 -O R.2R)
La présente invention concerne un procédé de préparation du N-méthyl (pyridyl-3)-2 tétrahydrothiopyrannecarbothioamide-2-oxyde-l-(lR,2R) de formule :The present invention relates to a process for the preparation of N-methyl (3-pyridyl) -2 tetrahydrothiopyrannecarbothioamide-2-oxide-1- (1R, 2R) of formula:
qui est particulièrement utile comme anti-hypertenseur et comme protecteur cardiaque. which is particularly useful as an anti-hypertensive and as a cardiac protector.
Dans le brevet européen EP 0 097 584 ont été décrits des dérivés du thioamide de formule générale :In European patent EP 0 097 584, thioamide derivatives of general formula have been described:
dans laquelle R représente un atome d'hydrogène ou un radical alcoyle contenant 1 à 4 atomes de carbone, Het représente un radical hétérocyclique à caractère aromatique et Y représente une liaison de valence ou un radical méthylène. in which R represents a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, Het represents a heterocyclic radical of aromatic character and Y represents a valence bond or a methylene radical.
La présence de deux centres d'asymétrie conduit à 4 stéréoisomères pouvant être éventuellement séparés en deux couples racémiques cis et trans.The presence of two asymmetry centers leads to 4 stereoisomers which can be possibly separated into two cis and trans racemic couples.
Le produit de formule générale (II) pour lequel R représente un radical méthyle, Het représente un radical pyridyl-3 et Y représente un groupement méthylène sous forme du mélange racémique trans qui peut être représenté de la manière suivante :The product of general formula (II) for which R represents a methyl radical, Het represents a 3-pyridyl radical and Y represents a methylene group in the form of the trans racemic mixture which can be represented in the following way:
(1S.2S) UR,2R) est intéressant comme anti-hypertenseur (EP-0 097 584) et, particulièrement l'isomère (1R,2R), comme protecteur cardiaque (EP-0 429 324) à des doses pour lesquelles l'effet anti-hypertenseur ne se manifeste pas.(1S.2S) UR, 2R) is useful as an antihypertensive agent (EP-0 097 584) and, particularly the isomer (1R, 2R), as a cardiac protector (EP-0 429 324) at doses for which the antihypertensive effect does not manifest itself .
Le N-méthyl (pyridyl-3)-2 tétrahydrothiopyrannecarbothioamide-2-oxyde-l- (1R.2R) peut être isolé d'un mélange des formes (1R.2R) et (1S.2S), en particulier du mélange racémique, par chromatographie sur phase chirale (EP-0 097 584) ou peut être préparé par des méthodes stéréosélectives (EP-0 426 557). Ces procédés nécessitent la mise en oeuvre de quantités importantes de solvants ou bien la réalisation d'un nombre important d'étapes. II a maintenant été trouvé, et c'est ce qui fait l'objet de la présente invention, que le N-méthyl (pyridyl-3)-2 tétrahydrothiopyrannecarbothioamide-2-oxyde-l- (1R.2R) peut être obtenu à partir d'un sel du mélange des isomères trans (1R,2R) et (1S.2S) et en particulier du mélange racémique avec un acide optiquement actif.N-methyl (pyridyl-3) -2 tetrahydrothiopyrannecarbothioamide-2-oxide-1- (1R . 2R) can be isolated from a mixture of the forms (1R.2R) and (1S.2S), in particular from the racemic mixture , by chiral phase chromatography (EP-0 097 584) or can be prepared by stereoselective methods (EP-0 426 557). These methods require the use of large quantities of solvents or else the carrying out of a large number of steps. It has now been found, and this is the subject of the present invention, that N-methyl (3-pyridyl) -2 tetrahydrothiopyrannecarbothioamide-2-oxide-1- (1R.2R) can be obtained at starting from a salt of the mixture of trans isomers (1R, 2R) and (1S.2S) and in particular of the racemic mixture with an optically active acid.
Plus particulièrement, le procédé selon l'invention consiste à précipiter sélectivement dans un solvant approprié un sel de l'isomère trans (1R.2R) avec un acide optiquement actif puis à libérer l'isomère trans (1R.2R) de son sel.More particularly, the method according to the invention consists in selectively precipitating in a suitable solvent a salt of the trans isomer (1R.2R) with an optically active acid and then in liberating the trans isomer (1R.2R) from its salt.
Pour la mise en oeuvre du procédé selon l'invention, il est particulièrement avantageux d'utiliser un acide optiquement actif choisi parmi l'acide (-)-camphanique et l'acide (+)-bromo-3 camphor-10 sulfonique. Les solvants qui conviennent particulièrement bien pour la cristallisation sélective du sel de l'isomère trans (1R.2R) avec un acide optiquement actif sont choisis de préférence parmi l'eau, les alcools aliphatiques contenant 1 à 4 atomes de carbone tels que le méthanol, l'éthanol ou l'isopropanol, et les mélanges hydro¬ alcooliques. Le N-méthyl (pyridyl-3)-2 tétrahydrothiopyrannecarbothioamide-2-oxyde-l-For the implementation of the process according to the invention, it is particularly advantageous to use an optically active acid chosen from (-) - camphanic acid and (+) - 3-bromo-10 camphor-10 sulfonic acid. The solvents which are particularly suitable for the selective crystallization of the salt of the trans isomer (1R.2R) with an optically active acid are preferably chosen from water, aliphatic alcohols containing 1 to 4 carbon atoms such as methanol , ethanol or isopropanol, and hydro-alcoholic mixtures. N-methyl (3-pyridyl) -2 tetrahydrothiopyrannecarbothioamide-2-oxide-1-
(1R.2R) est libéré de son sel au moyen d'une base minérale ou organique en opérant dans l'eau ou dans un mélange constitué d'eau et d'un solvant non miscible dans lequel l'isomère trans (1R,2R) est soluble. Comme base minérale on utilise de préférence les hydroxydes ou les carbonates de métaux alcalins (soude, potasse, carbonate de sodium). Comme base organique peuvent être utilisés les aminés aliphatiques tertiaires (triéthylamine) ou la pyridine dont la basicité est suffisamment forte pour libérer l'acide optiquement actif de son sel. De préférence, on utilise la potasse en milieu hydroorganique tel qu'un mélange eau-hydrocarbure aliphatique halogène comme un mélange eau-chlorure de méthylène : de cette manière, l'isomère trans (1R,2R) passe en solution dans le solvant organique au fur et à mesure de sa formation, le sel de l'acide optiquement actif restant en solution aqueuse.(1R.2R) is released from its salt by means of an inorganic or organic base, operating in water or in a mixture consisting of water and an immiscible solvent in which the trans isomer (1R, 2R ) is soluble. As mineral base, hydroxides or carbonates of alkali metals (sodium hydroxide, potassium hydroxide, sodium carbonate) are preferably used. As organic base, tertiary aliphatic amines (triethylamine) or pyridine can be used, the basicity of which is strong enough to release the optically active acid from its salt. Preferably, potash is used in a hydroorganic medium such as a water-halogenated aliphatic hydrocarbon mixture such as a water-methylene chloride mixture: in this way, the isomer trans (1R, 2R) passes into solution in the organic solvent as it is formed, the salt of the optically active acid remaining in aqueous solution.
Le N-méthyl (pyridyl-3)-2 tétrahydrothiopyrannecarbothioamide-2-oxyde-l- (1R.2R) est séparé de sa solution selon les méthodes habituelles et il peut être purifié selon les techniques connues par exemple par cristallisation.N-methyl (3-pyridyl) -2 tetrahydrothiopyrannecarbothioamide-2-oxide-1- (1R.2R) is separated from its solution according to the usual methods and it can be purified according to known techniques, for example by crystallization.
Le mélange des isomères trans (1R.2R) et (1S.2S) du N-méthyl (pyridyl-3)-2 tétrahydrothiopyrannecarbothioamide-2-oxyde-l, et plus particulière¬ ment le mélange racémique, peut être préparé dans les conditions décrites dans le brevet européen EP-0 097 584. Les exemples suivants illustrent la présente invention.The mixture of trans isomers (1R.2R) and (1S.2S) of N-methyl (pyridyl-3) -2 tetrahydrothiopyrannecarbothioamide-2-oxide-1, and more particularly the racemic mixture, can be prepared under the conditions described in European patent EP-0 097 584. The following examples illustrate the present invention.
EXEMPLE 1EXAMPLE 1
Dans un réacteur de 2 litres, on introduit 1900 cm3 d'éthanol et 165 g du mélange racémique trans du N-méthyl (pyridyl-3)-2 tétrahydrothiopyrannecarbothio- amide-2-oxyde-l et 121,9 g d'acide (-)-camphanique. La suspension est chauffée à 65°C jusqu'à dissolution totale. Après refroidissement à 45°C, la cristallisation est amorcée avec 100 mg de sel de N-méthyl (pyridyl-3)-2 tétrahydrothiopyrannecarbo- thioamide-2-oxyde-l-(lR,2R) avec l'acide (-)-camphanique. La suspension est refroidie en 2 heures à une température voisine de 20°C puis agitée pendant 30 minutes à cette température. Les cristaux sont séparés par filtration puis lavés par 2 fois 150 cm3 d'éthanol et enfin séchés sous pression réduite à 40°C. On obtient ainsi 95,76 g d'un produit blanc contenant 57,7 % de N-méthyl (pyridyl-3)-2 tétrahydro- thiopyrannecarbothioamide-2-oxyde-l-(lR,2R).1900 cm3 of ethanol and 165 g of the trans racemic mixture of N-methyl (pyridyl-3) -2 tetrahydrothiopyrannecarbothioamide-2-oxide-1 and 121.9 g of acid are introduced into a 2-liter reactor. -) - camphanique. The suspension is heated to 65 ° C until complete dissolution. After cooling to 45 ° C, crystallization is initiated with 100 mg of N-methyl salt (3-pyridyl) -2 tetrahydrothiopyrannecarbo-thioamide-2-oxide-1- (1R, 2R) with acid (-) - camphanique. The suspension is cooled over 2 hours to a temperature in the region of 20 ° C. and then stirred for 30 minutes at this temperature. The crystals are separated by filtration then washed with 2 times 150 cm3 of ethanol and finally dried under reduced pressure at 40 ° C. 95.76 g of a white product are thus obtained containing 57.7% of N-methyl (3-pyridyl) -2 tetrahydro-thiopyrannecarbothioamide-2-oxide-1- (1R, 2R).
L'excès énantiomérique est voisin de 100 %.The enantiomeric excess is close to 100%.
Le rendement est de 33,4 %.The yield is 33.4%.
EXEMPLE 2EXAMPLE 2
Dans un réacteur de 2 litres, on introduit 940 cm3 de chlorure de méthylène, 188 g de sel de N-méthyl (pyridyl-3)-2 tétrahydrothiopyrannecarbothioamide-2- oxyde-l-(lR,2S) avec l'acide (-)-camphanique et 880 cm3 d'eau déminéralisée. A la suspension agitée, on ajoute 68,6 g d'une solution aqueuse de potasse à 30 % (p/p) en 10 minutes. On agite pendant 15 minutes. La phase organique séparée par décantation est lavée avec 188 cm3 d'eau distillée, puis séchée. Après évaporation du solvant, on obtient, avec un rendement de 83,7 %, 90,5 g de N-méthyl (pyridyl-3)-2 tétrahydro- thiopyrannecarbothioamide-2-oxyde- 1 - (1 R,2R) pur. L'excès énantiomérique est voisin de 100 %. 940 cm3 of methylene chloride, 188 g of N-methyl (pyridyl-3) -2 tetrahydrothiopyrannecarbothioamide-2-oxide-2- (1R, 2S) salt are added to a 2-liter reactor with acid (- ) -camphanique and 880 cm3 of demineralized water. To the stirred suspension, 68.6 g of a 30% (w / w) aqueous potassium hydroxide solution are added over 10 minutes. The mixture is stirred for 15 minutes. The organic phase separated by decantation is washed with 188 cm3 of distilled water, then dried. After evaporation of the solvent, 90.5 g of pure N-methyl (3-pyridyl) -2 tetrahydro-thiopyrannecarbothioamide-2-oxide-1 - (1 R, 2R) are obtained with a yield of 83.7%. The enantiomeric excess is close to 100%.

Claims

REVENDICATIONS
1 - Procédé de préparation du N-méthyl (pyridyl-3)-2 tétrahydrothio- pyrannecarbothioamide-2-oxyde-l-(lR,2R) de formule :1 - Process for the preparation of N-methyl (pyridyl-3) -2 tetrahydrothio-pyrannecarbothioamide-2-oxide-l- (1R, 2R) of formula:
caractérisé en ce que l'on précipite sélectivement dans un solvant approprié un sel du N-méthyl (pyridyl-3) -2 tétrahydrothiopyrannecarbothioamide-2-oxyde- 1 - ( 1R.2R) avec un acide optiquement actif choisi parmi l'acide (-)-camphanique et l'acide (+)- bromo-3 camphor-10 sulfonique. à partir du sel d'un mélange des isomères trans (1R.2R) et (1S.2S) du N-méthyl (pyridyl-3)-2 tétrahydrothiopyrannecarbothioamide- 2-oxyde-l avec l'acide optiquement actif, puis libère le N-méthyl (pyridyl-3)-2 tétrahydrothiopyrannecarbothiodiamine-2-oxyde-l-(lR,2R) de son sel. characterized in that a salt of N-methyl (pyridyl-3) -2 tetrahydrothiopyrannecarbothioamide-2-oxide- 1 - (1R.2R) is selectively precipitated in an appropriate solvent with an optically active acid chosen from acid ( -) - camphanic and (+) - bromo-3 camphor-10 sulfonic acid. from the salt of a mixture of the trans isomers (1R.2R) and (1S.2S) of N-methyl (pyridyl-3) -2 tetrahydrothiopyrannecarbothioamide-2-oxide-1 with the optically active acid, then releases the N-methyl (3-pyridyl) -2 tetrahydrothiopyrannecarbothiodiamine-2-oxide-1- (1R, 2R) of its salt.
2 - Procédé selon la revendication 1 caractérisé en ce que le solvant est choisi parmi l'eau, les alcools aliphatiques contenant 1 à 4 atomes de carbone et les mélanges hydro-alcooliques.2 - Process according to claim 1 characterized in that the solvent is chosen from water, aliphatic alcohols containing 1 to 4 carbon atoms and hydro-alcoholic mixtures.
3 - Procédé selon la revendication 2 caractérisé en ce que le solvant est choisi parmi le méthanol, l'éthanol et l'isopropanol.3 - Process according to claim 2 characterized in that the solvent is chosen from methanol, ethanol and isopropanol.
4 - Procédé selon la revendication 1 caractérisé en ce que la libération du N-méthyl (pyridyl-3)-2 tétrahydrothiopyrannecarbothioamide-2-oxyde-l-(lR,2R) de son sel avec l'acide optiquement actif est effectuée au moyen d'une base minérale ou organique.4 - Process according to claim 1 characterized in that the release of N-methyl (pyridyl-3) -2 tetrahydrothiopyrannecarbothioamide-2-oxide-l- (lR, 2R) from its salt with the optically active acid is carried out by means of a mineral or organic base.
5 - Procédé selon la revendication 4 caractérisé en ce que l'on opère dans l'eau ou dans un mélange d'eau et d'un solvant organique non miscible dans lequel le N-méthyl (pyridyl-3)-2 tétrahydrothiopyrannecarbothioamide-2-oxyde-l-(lR,2R) est soluble.5 - Process according to claim 4 characterized in that one operates in water or in a mixture of water and an immiscible organic solvent in which N-methyl (pyridyl-3) -2 tetrahydrothiopyrannecarbothioamide-2 -oxide-l- (1R, 2R) is soluble.
6 - Procédé selon la revendication 4 caractérisé en ce que la base minérale est choisie parmi les hydroxydes et les carbonates de métaux alcalins. 7 - Procédé selon la revendication 6 caractérisé en ce que la base minérale est la potasse.6 - Process according to claim 4 characterized in that the mineral base is chosen from hydroxides and carbonates of alkali metals. 7 - Method according to claim 6 characterized in that the mineral base is potash.
8 - Procédé selon la revendication 4 caractérisé en ce que la base organique est choisie parmi les aminés aliphatiques tertiaires et la pyridine.8 - Process according to claim 4 characterized in that the organic base is chosen from tertiary aliphatic amines and pyridine.
9 - Procédé selon la revendication 5 caractérisé en ce que l'on opère dans un mélange d'eau et d'un hydrocarbure aliphatique halogène. 9 - Process according to claim 5 characterized in that one operates in a mixture of water and a halogenated aliphatic hydrocarbon.
EP94908384A 1993-03-02 1994-02-28 Method for preparing n-methyl 2-(3-pyridyl) (1r,2r)-2-tetrahydrothiopyrancarbothioamide-1-oxide Withdrawn EP0687264A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9302369A FR2702213B1 (en) 1993-03-02 1993-03-02 Process for the preparation of N-methyl (pyridyl-3) -2 tetrahydrothiopyrannecarbothioamide-2-oxide-1- (1R, 2R).
FR9302369 1993-03-02
PCT/FR1994/000221 WO1994020493A1 (en) 1993-03-02 1994-02-28 Method for preparing n-methyl 2-(3-pyridyl) (1r,2r)-2-tetrahydrothiopyrancarbothioamide-1-oxide

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CA (1) CA2153577A1 (en)
CZ (1) CZ223895A3 (en)
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IE81170B1 (en) * 1988-10-21 2000-05-31 Zeneca Ltd Pyridine derivatives
FR2653770B1 (en) * 1989-10-31 1992-01-03 Rhone Poulenc Sante PROCESS FOR THE PREPARATION OF (PYRIDYL-3) -2 TETRAHYDROTHIOPYRANNECARBOTHIOAMIDE-2-OXYDES-1- (1R, 2R), LES (PYRIDYL-3) -2 TETRHYDROTHIOPYRANNECARBOTHIOAMIDE-2-OXYDES-2-OXYDES PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.

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HU9502571D0 (en) 1995-10-30
FR2702213A1 (en) 1994-09-09
FI954110A (en) 1995-09-01
IL108785A0 (en) 1994-06-24
SK107195A3 (en) 1995-12-06
CA2153577A1 (en) 1994-09-15
NO953386L (en) 1995-08-29
FR2702213B1 (en) 1995-04-07
US5688956A (en) 1997-11-18
PL310440A1 (en) 1995-12-11
WO1994020493A1 (en) 1994-09-15
HUT71923A (en) 1996-02-28
KR960701046A (en) 1996-02-24
ZA941367B (en) 1994-10-03
JPH08507304A (en) 1996-08-06
NO953386D0 (en) 1995-08-29
AU6144594A (en) 1994-09-26
CZ223895A3 (en) 1995-12-13

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