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WO1992006080A1 - Agents antiarythmiques - Google Patents

Agents antiarythmiques Download PDF

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Publication number
WO1992006080A1
WO1992006080A1 PCT/EP1991/001654 EP9101654W WO9206080A1 WO 1992006080 A1 WO1992006080 A1 WO 1992006080A1 EP 9101654 W EP9101654 W EP 9101654W WO 9206080 A1 WO9206080 A1 WO 9206080A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
formula
compound
pharmaceutically acceptable
het
Prior art date
Application number
PCT/EP1991/001654
Other languages
English (en)
Inventor
Peter Edward Cross
Roger Peter Dickinson
Original Assignee
Pfizer Limited
Pfizer Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Limited, Pfizer Inc. filed Critical Pfizer Limited
Publication of WO1992006080A1 publication Critical patent/WO1992006080A1/fr

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Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C307/04—Diamides of sulfuric acids
    • C07C307/10—Diamides of sulfuric acids having nitrogen atoms of the sulfamide groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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
    • C07D233/88—Nitrogen atoms, e.g. allantoin

Definitions

  • This invention relates to antiarriiythmic agents useful in the treatment of cardiac arrhythmias.
  • the compounds of the invention prolong the duration of the action potential in cardiac muscle and conducting tissue, and thereby increase refractoriness to premature stimuli.
  • they are Class III antiarrhythmic agents according to the
  • Vaughan Williams Antiarrhythmic Action, E. M. Vaughan Williams, Academic Press, 1980. They are effective in atria, ventricles and conducting tissue both in vitro and in vivo and are therefore useful for the prevention and treatment of a wide variety of ventricular and supraventricular arrhythmias including atrial and ventricular fibrillation. Because they do not alter the speed at which impulses are conducted, they have less propensity than current drugs (mostly Class I) to precipitate or aggravate arrhythmias, and they also produce fewer neurological side effects. Some of the compounds also have positive inotropic activity and therefore are particularly beneficial in patients with impaired cardiac pump function.
  • the invention provides compounds of the formula:
  • R is C 1 -C 4 alkyl
  • R 1 is R 3 SO 2 NH or R 3 CONH
  • R 3 is C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl or NR 4 R , wherein R 4 and R 5 are each independently selected from H and C 1 -C 4 alkyl;
  • R 2 is H or OH
  • Het is either (a) 2-, 3- or 4-pyridyl optionally substituted by 1 or 2 substituents each independently selected from NH 2 and C 1 -C 4 alkyl, or (b) 2-imidazolyl optionally substituted by 1 or 2 C 1 -C 4 alkyl groups; and n is 1, 2 or 3;
  • C 3 and C 4 alkyl groups may be straight or branched chain.
  • the compounds of formula (I) may contain one or more asymmetric centres and thus they can exist as enanticaners or diastereoisomers.
  • the invention includes both mixtures and separate individual isomers.
  • the pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts formed from
  • hydrochloride hydrobromide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, maleate, fumarate, succinate, lactate, citrate, tartrate, gluconate, benzoate,
  • Some of the compounds may also form metal salts, particularly alkali metal and alkaline earth salts. Examples of the former include the sodium and potassium salts.
  • a preferred group of compounds of the formula (I) is that wherein R 1 is R 3 SO 2 NH; R 3 is C 1 -C 4 alkyl or NH(C 1 -C 4 alkyl); "Het” is either (a) 2- or 4-pyridyl optionally substituted by NH 2 , or (b) 1-(C 1 -C 4 alkyl)-2-imidazolyl optionally further substituted by a C 1 -C 4 alkyl group; and n is 1.
  • a particularly preferred group of compounds of the formula (I) is that wherein R is methyl; R is CH 3 SO 2 NH or CH 3 NHSO 2 NH; "Het” is either (a) 4-amino-2-pyridyl or 4-pyridyl, or (b) 1- methyl-2-imidazolyl or 1,5-dimethyl-2-imidazolyl; and n is 1.
  • the compounds of the formula (I) provided by the invention may be prepared by the following methods.
  • R 3 is C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl or NR 4 R 5 , wherein R 4 is H or C 1 -C 4 alkyl and R 5 is C 1 -C 4 alkyl, can be prepared by reacting a compound of the formula (II) with a sulphonyl halide of the formula (C 1 -C 4 alkyl or C 3 -C 7 cycloalkyl)SO 2 (Cl or Br), a sulph ⁇ nic anhydride of the formula [(C 1 -C 4 alkyl or C 3 -C 7 cycloalkyl)SO 2 ] 2 O or with a sulphamqyl chloride of the formula
  • R 4 R 5 NSO 2 Cl wherein R 4 is H or C 1 -C 4 alkyl and R 5 is C 1 -C 4 alkyl, in the presence of a suitable acid acceptor, e.g. triethylamine or pyridine.
  • a suitable acid acceptor e.g. triethylamine or pyridine.
  • the reaction is typically carried out at from 0°C to room temperature in a suitable organic solvent, e.g.
  • the reaction is carried out using pyridine as both the solvent and the acid acceptor;
  • H 2 NSO 2 NH can be prepared by reacting a compound of the formula (II) with sulphamide at up to, and preferably at, the reflux temperature in a suitable organic solvent, e.g. 1,4-dioxane;
  • R 3 CONH wherein R 3 is C 1 -C 4 alkyl or C 3 -C 7 cycloalkyl, can be prepared by acylating a compound of the formula (II) with either an acid halide of the formula (C 1 -C 4 alkyl or C 3 -C 7 cycloalkyl)CO(Cl or
  • an acid anhydride of the formula [(C 1 -C 4 alkyl or C 3 -C 7 cycloalkyl)CO] 2 O is typically carried out at from 0°C to room temperature in a suitable organic solvent, e.g. dichlorormethane, and in the presence of a suitable acid acceptor, e.g. triethylamine or pyridine. The reaction may also be carried out using pyridine as both the solvent and the acid acceptor.
  • a suitable organic solvent e.g. dichlorormethane
  • a suitable acid acceptor e.g. triethylamine or pyridine
  • the reaction may also be carried out using pyridine as both the solvent and the acid acceptor.
  • an acid anhydride is employed the reaction is typically carried out at up to the reflux temperature, preferably at 100°C, in a suitably compatible organic solvent, e.g.
  • a carboxylic acid of the formula (C 1 -C 4 alkyl or C 3 -C 7 cycloalkyl)COOH; d) H 2 NOONH- can be prepared by reacting a (compound of the formula (II) with sodium or potassium cyanate at up to, and preferably at, the reflux temperature in a suitable acidic solvent medium, e.g.
  • aqueous acetic acid e
  • (C 1 -C 4 alkyl)NHCONH can be prepared by reacting a compound of the formula (II) with a (C 1 -C 4 alkyl) isocyanate.
  • the reaction is preferably carried out at room temperature in a suitable organic solvent, e.g.
  • (C 1 -C 4 alkyl) 2 NOONH can be prepared by reacting a compound of the formula (U) with a carbamoyl chloride of the formula (C 1 -C 4 alkyl) 2 NCOCl.
  • the reaction is typically carried out at from 0°C to the reflux temperature in a suitable organic solvent, e.g. dichloromethane, and in the presence of a suitable acid acceptor, e.g.
  • R, R 1 , R 2 and n are as defined for formula (I) and R 6 is either H (IIIA)
  • X is 2- or 4- halo, preferably Cl or Br, and k is 0, 1 or 2.
  • the reaction is typically carried out at up to, and preferably at, the reflux temperature in a suitable organic solvent, e.g. n-butanol or amyl alcohol, and in the presence of a suitable acid acceptor, e.g. sodium carbonate or sodium bicarbonate; b) 2-, 3- or 4- pyridyl substituted by 1 NH 2 group and optionally further substituted by 1 NH 2 group or by 1 C 1 -C 4 alkyl group, can be prepared by reduction of a compound of the formula (IIIB) using conventional methods.
  • the reduction is carried out by catalytic hydrogenation using a suitable catalyst, e.g.
  • R 7 is H or C 1 -C 4 alkyl
  • R 8 is C 1 -C 4 alkyl
  • R 9 and R 10 are each independently H or C 1 -C 4 alkyl
  • each R 11 is C 1 -C 4 alkyl or the two groups R 11 are joined to form a C 2 -C 3 alkylene chain
  • Q is preferably halo (preferably iodo), (C 1 -C 4 alkyl) SO 3 -, -SO 3 - or CH 3 SO 3 -; with the proviso that not
  • R 7 , R 9 and R 10 in formula (IA) areC 1 -C 4 alkyl.
  • the thiourea (IV) is then S-alkylated, preferably using a C 1 -C 4 alkyl halide (preferably an iodide) or a compound of the formula
  • the S-alkyl derivative (V) can then be converted to an imidazole by two different methods.
  • the S-alkyl derivative (V) is reacted with the acetal or ketal (VI), e.g. by heating at from 60-130°C and preferably under reflux in a suitable organic solvent (such as pyridine), to form an intermediate guanidine.
  • a suitable organic solvent such as pyridine
  • the guanidine is then heated in aqueous acid, e.g. aqueous hydrochloric acid, and preferably under reflux, to cyclise it to the product (IA).
  • the S-alkyl derivative (V) is converted to the imidazole (IB) by reaction with propargylamine in a suitable organic solvent, e.g. pyridine, typically at a
  • Het and n are as defined for formula (I), may be prepared from intermediates of the formula:
  • borohydride is typically carried out in a suitable solvent, e.g. aqueous ethanol, at from 0°C to reflux temperature.
  • a suitable solvent e.g. aqueous ethanol
  • the intermediates of the formulae (II), (IIIA), (IIIB) and (VII), required for the preparation of the compounds of the invention of the formula (I), may be prepared by the following methods.
  • a carboxylic acid of formula (VIII) is coupled with an amine of formula (IX) to afford an amide of formula (X).
  • This may be effected by prior activation of (VIII), using a conventional peptide coupling reagent such as N,N'- dicyclohexylcarbodiimide, or by prior formation of the
  • acyl halide e.g. the acyl chloride
  • a conventional chlorinating reagent such as thionyl chloride.
  • the coupling is preferably carried out in the presence of an excess of a suitable acid acceptor, e.g.
  • Conversion of the amide (X) to amine (XI), in the second step, can be achieved by use of a typical amide reducing agent such as diborane whilst, in the third step, the nitro group of (XI) may be reduced, for example, by catalytic hydrogenation using a palladium catalyst, to provide the intermediate (II).
  • a typical amide reducing agent such as diborane
  • the nitro group of (XI) may be reduced, for example, by catalytic hydrogenation using a palladium catalyst, to provide the intermediate (II).
  • X is a halogen atom, preferably Cl or Br, and q, r and t are as previously defined for the formula (IIIB).
  • the reaction is typically carried out in the presence of an excess of a suitable acid acceptor, e.g. pyridine, which may also serve as an
  • the intermediate of formula (XVI), ⁇ vhich may be synthesised as described within Scheme 3, can be deprotected as described for the analogous deprotections of the compounds of formulae (XVII) and (XVIII), in Scheme 3, to provide the ⁇ -aminoketone of formula (XIX). Conversion of (XIX) to intermediates of formula (VII) may then be effected by the procedures described in Method 2, by analogy with the conversion of intermediates of formula (IIIA) to compounds of the formula (I).
  • the invention also includes any novel intermediates disclosed herein, such as those of the formulae (II), (III) and (VII).
  • salts are readily prepared by mixing solutions containing equimolar amounts of a free base of the formula (I) and the desired acid. The salt is isolated either after its precipitation from solution or after its recovery by evaporation of the solvent employed.
  • the biological activity of the compounds of the invention is assessed by measuring the effect of the compounds on atrial refractoriness.
  • guinea pig right hemiatria are mounted in a bath containing physiological salt solution, with one end connected to a force transducer.
  • the tissues are stimulated at 1 Hz using field electrodes.
  • Effective refractory period (ERP) is measured by introducing premature stimuli (S ) after every 8th basic stimulus (S 1 ).
  • S 1 S 2 coupling interval is gradually increased until S 2 reproducibly elicits a propagated response. This is defined as the ERP.
  • the test compound is then added to the bath and the concentration of compound required to increase ERP by 25% is determined (ED 25 ).
  • ERP is also measured in guinea pig right papillary muscles incufcated in physiological saline solution. Muscles are stimulated at one end using bipolar electrodes and the propagated ele ⁇ trogram is recorded at the opposite end via a unipolar surface electrode. ERP is determined as above using the extrastimulus technique. Condition time is obtained from a digital storage oscilloscope fcy measuring the interval between the stimulus artefact and the peak of the electrogram (i.e. the time required for the impulse to travel along the length of the muscle).
  • Atrial and ventricular ERPs are also measured in
  • the compounds of the formula (I) can be administered alone but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. They can be administered both to patients suffering from arrhythmias and also, prophylactically, to those likely to develop arrhythmias. For example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. They may be injected
  • parenterally for example, intravenously, intramuscularly or subcutaneously.
  • parenteral administration they are best used in the form of a sterile aqueous solution which may contain other solutes, for exairple, enough salts or glucose to make the solution isotonic with blood.
  • cardiac conditions such as ventricular and ventricular
  • supraventricular arrhythmias including atrial and ventricullr fibrillation
  • oral dosages of the compounds of the invention will be in the range from 1 to 75 mg daily, taken in up to 4 divided doses per day, for an average adult patient (70 kg).
  • individual tablets or capsules might contain 1 to 25 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier.
  • Dosages for intravenous administration would be expected to be within the range 0.5 to 10 mg per single dose as required.
  • a severe cardiac arrhythmia is preferably treated by the i.v. route in order to effect a rapid conversion to the normal rhythm. Variations on these dosages may occur depending on the weight and condition of the subject being treated and will be determined by the medical practitioner.
  • composition comprising a compound of the formula (I), as defined above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.
  • the invention also provides a method of preventing or reducing cardiac arrhythmias in a human being, which comprises administering to said human being an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition as defined above.
  • the invention yet further provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament, in particular as an antiarrhythmic agent.
  • the invention also provides the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or reduction of cardiac arrhythmias.
  • Methanesulphonyl chloride (0.126 g) was added to a stirred solution of the product of Preparation 1 (0.227 g) in pyridine (2.0 ml) at 0°C. The mixture was stirred for 18 hours, evaporated under vacuum and the residue dissolved in the minimum volume of water. The resulting solution was basified with saturated aqueous sodium bicarbonate solution and the resulting solid was filtered off, washed with water and dried. Purification by chromatography on silica gel, using a 9:1 mixture of dichloromethane and methanol as eluent, gave the product as a solid (0.18 g), m.p. 227-228°C (after crystallisation from ethyl acetate-methanol). Found:
  • Methylsulphamoyl chloride (0.155 g) was added to a stirred solution of 4-amino-N-methyl-N-(4-pyridyl)benzeneethanamine (the product of Preparation 1) (0.227 g) in pyridine (2 ml) and the mixture was stirred for 18 hours at room temperature and then evaporated under vacuum. The residue was treated with a few ml of dilute aqueous ammonia solution and the resulting mixture
  • N,N'-dicyclohexylcarbodiimide (10.3 g) was added to a stirred solution of 4-nitrobenzeneacetic acid (9.0 g) in tetrahydrofuran (200 ml) at -15°C and the resulting solution was stirred at this temperature for 10 minutes.
  • 4-Methylaminopyridine (6.8 g) was then added and the mixture was stirred at room temperature for 2 hours and then filtered. The filtrate was evaporated under vacuum and the residue dissolved in ethyl acetate. The solution was filtered, washed with saturated, aqueous sodium bicarbonate solution and then water, dried (Na 2 SO 4 ) and evaporated under vacuum.
  • the residual oil was chromatographed on silica gel using a methanol in ethyl acetate elution gradient (0-2%), and

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

Composés ayant la formule (I), dans laquelle R désigne alkyle C1-C4; R1 représente R3SO2NH ou R?3CONH; R2¿ désigne H ou OH; R3 désigne alkyle C¿1?-C4, cycloalkyle C3-C7 ou NR?4R5; R4 et R5¿ sont tous les deux sélectionnés indépendamment l'un de l'autre entre H et alkyle C¿1?-C4; 'Het' désigne soit (a) pyridyle 2, 3 ou 4 éventuellement substitué par un ou deux substituants sélectionnés indépendamment l'un de l'autre entre NH2 et alkyle C1-C4, soit (b) imidazolyl-2 éventuellement substitué par un ou deux groupes alkyles C1-C4; et n est égal à 1, 2 ou 3; ainsi que leurs sels pharmaceutiquement admissibles, constituant des agents antiarythmiques.
PCT/EP1991/001654 1990-09-27 1991-08-29 Agents antiarythmiques WO1992006080A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB909021056A GB9021056D0 (en) 1990-09-27 1990-09-27 Antiarrhythmic agents
GB9021056.8 1990-09-27

Publications (1)

Publication Number Publication Date
WO1992006080A1 true WO1992006080A1 (fr) 1992-04-16

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PCT/EP1991/001654 WO1992006080A1 (fr) 1990-09-27 1991-08-29 Agents antiarythmiques

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GB (1) GB9021056D0 (fr)
IE (1) IE913372A1 (fr)
PT (1) PT99040A (fr)
WO (1) WO1992006080A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6297375B1 (en) 1999-02-24 2001-10-02 Hoffmann-La Roche Inc. 4-phenyl-pyridine derivatives
US6552033B1 (en) 2000-05-16 2003-04-22 The Procter & Gamble Co. Imidazo-containing heterocyclic compounds, their compositions and uses
US7288658B2 (en) 2003-07-15 2007-10-30 Hoffmann-La Roche Inc. Process for preparation of pyridine derivatives
US8852634B2 (en) 2005-09-23 2014-10-07 Hoffmann-La Roche Inc. Dosage formulation

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0242173A1 (fr) * 1986-04-16 1987-10-21 Pfizer Limited Agents antiarhytmiques
EP0281254A1 (fr) * 1987-02-07 1988-09-07 Pfizer Limited Agents antiarythmiques
EP0291210A1 (fr) * 1987-05-02 1988-11-17 Pfizer Limited Agents antiarrhythmiques
EP0359389A1 (fr) * 1988-08-13 1990-03-21 Pfizer Limited Agents antiarythmiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0242173A1 (fr) * 1986-04-16 1987-10-21 Pfizer Limited Agents antiarhytmiques
EP0281254A1 (fr) * 1987-02-07 1988-09-07 Pfizer Limited Agents antiarythmiques
EP0291210A1 (fr) * 1987-05-02 1988-11-17 Pfizer Limited Agents antiarrhythmiques
EP0359389A1 (fr) * 1988-08-13 1990-03-21 Pfizer Limited Agents antiarythmiques

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6297375B1 (en) 1999-02-24 2001-10-02 Hoffmann-La Roche Inc. 4-phenyl-pyridine derivatives
US6479483B2 (en) 1999-02-24 2002-11-12 Hoffmann-La Roche Inc. 4-phenyl-pyridine derivatives
US6552033B1 (en) 2000-05-16 2003-04-22 The Procter & Gamble Co. Imidazo-containing heterocyclic compounds, their compositions and uses
US7288658B2 (en) 2003-07-15 2007-10-30 Hoffmann-La Roche Inc. Process for preparation of pyridine derivatives
US8852634B2 (en) 2005-09-23 2014-10-07 Hoffmann-La Roche Inc. Dosage formulation

Also Published As

Publication number Publication date
PT99040A (pt) 1992-08-31
GB9021056D0 (en) 1990-11-07
IE913372A1 (en) 1992-04-08

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