Apotex Inc.

Other

Wanren Li

Tim Fat Tam

Khashayar Karimian

Regis C Leung-Toung

Yingsheng Wang

Yanqing Zhao

Sue S Lee

Birenkumar Hasmukhbhai Shah

Denis Desilets

Tullio Cappelletto

Michael Spino

Jolanta Maria Wodzinska

Sandra Vittoria Agostino

Regis C S H Leung-Toung

Steve Patrick Bryson

The present invention provides an cycloalkyl derivative of 3-hydroxy-4-pyridinone which is useful for the chelation of metal ions such as iron. Its preparation and use is described. In particular, the invention concerns the removal of iron in chemical and biological systems including chelating agents having the formula I wherein Ris X with the proviso that Ris Y; or Ris T with the proviso that Ris W; or Ris X with the proviso that RRN when taken together form a heterocyclic ring selected from piperidinyl, morpholinyl, pyrrolidinyl or piperazinyl, wherein the group piperidinyl, morpholinyl, pyrrolidinyl or piperazinyl is either unsubstituted or substituted with one to three Cto Calkyl groups. X is C-Ccycloalkyl; Y is selected from the group consisting of Cto Ccycloalkyl; Cto Calkyl, and Cto Calkyl monosubstituted with a C-Ccycloalkyl; T is Cto Calkyl; W is C-Ccycloalkyl; Ris selected from the group consisting of hydrogen and Cto Calkyl; Ris selected from the group consisting of hydrogen and Cto Calkyl; Ris selected from the group consisting of hydrogen and Cto Calkyl; and its pharmaceutically acceptable salt thereof. Pharmaceutical compositions of such compounds are useful in the removal of excess body iron from patients with iron overload diseases.

Cycloalkyl derivatives of 3-hydroxy-4-pyridinones

The present invention relates to a novel process for the preparation of 1-alkyl or 1-cycloalkyl derivatives of 3-hydroxy-4-oxo-1,4-dihydropyridine-2-carboxamide of formula (I). The process includes reacting an amine RNHwith a compound of formula (II) in a solution of metal hydroxide in water to give a compound of formula (III). Subsequent reaction of the compound of formula (III) with an acid chloride formation reagent in an inert solvent gives compounds of formula (I). The acid chloride formation reagent is selected from oxalyl chloride and dimethylformamide, dimethylchloromethylene-ammonium chloride and thionyl chloride and dimethylformamide. If desired, a compound of formula (I) where Ris hydrogen may be formed when an intermediate substituent is used wherein Ris an alcohol protective group removable by catalytic hydrogenation. 

Process for the manufacture of 3-hydroxy-N-alkyl-1-cycloalky1-6-alkyl-4-oxo-1,4-dihydropyridine-2-carboxamide and its related analogues

The present invention provides an cycloalkyl derivative of 3-hydroxy-4-pyridinone which is useful for the chelation of metal ions such as iron. Its preparation and use is described. In particular, the invention concerns the removal of iron in chemical and biological systems including chelating agents having the formula (I); wherein Ris X with the proviso that Ris Y; or Ris T with the proviso that Ris W; or Ris X with the proviso that RRN when taken together form a heterocyclic ring selected from piperidinyl, morpholinyl, pyrrolidinyl or piperazinyl, wherein the group piperidinyl, morpholinyl, pyrrolidinyl or piperazinyl is either unsubstituted or substituted with one to three Cto Calkyl groups. X is C-Ccycloalkyl; Y is selected from the group consisting of Cto Ccycloalkyl; Cto Calkyl, and Cto Calkyl monosubstituted with a C-Ccycloalkyl; T is Cto Calkyl; W is C-Ccycloalkyl; Ris selected from the group consisting of hydrogen and Cto Calkyl; Ris selected from the group consisting of hydrogen and Cto Calkyl; Ris selected from the group consisting of hydrogen and Cto Calkyl; and its pharmaceutically acceptable salt thereof. Pharmaceutical compositions of such compounds are useful in the removal of excess body iron from patients with iron overload diseases. 

Processes for the manufacturing of 3-hydroxy-N,1,6-trialkyl-4-oxo-1,4-dihydropyridine-2-carboxamide

Processes for the manufacturing of 3-hydroxy-n,1,6-trialkyl-4-OXO-1,4-dihydropyridine-2-carboxamide

Thiadiazole compounds useful as inhibitors of cysteine activity dependent enzymes

Novel 1,2,4-thiadiazole compounds are provided, which are effective as inhibitors of cysteine activity-dependent enzymes and in particular of cysteine proteases. The compounds are useful in treating acne by inhibition of transglutaminase, common cold by inhibition of human rhinovirus 3C protease and inflammatory joint disease by inhibition of cathepsins. The compounds of the present invention are 3,5-disubstituted 1,2,4-thiadazole of the general formula (I): ##STR1## where Z is a nitrogen containing group with recognition sequence for the enzyme and Y is a substituent that tunes the reactivity of the inhibitor towards the thiol group of the cysteine activity-dependent enzyme. The Y group may also serve in recognition.

Thiadiazole compounds useful as inhibitors of cysteine activity

Thiols are trapped, and converted to disulfide compounds, by a process of reacting them with compounds containing a 1,2,4-thiadiazole ring structure carrying a substituent at position 3 of the thiadiazole ring, and being unsubstituted at position N-2. The process is useful pharmacologically, in inhibiting certain thiol-containing enzymes such as H.sup.+ /K.sup.+ -ATPase (the proton pump), and industrially, in selective removal of thiol compounds from gas or liquid mixtures.

Process for scavenging thiols

Novel thiadiazole compounds are provided, which are effective as proton pumps inhibitors, useful in treating peptic ulcers by inhibition of the proton pump enzyme H.sup.+ /K.sup.+ -ATPase. The compounds are 3-substituted 1,2,4-thiadiazolo [4,5-.alpha.]benzimidazole and 3-substituted imidazo[1,2-d]-1,2,4-thiadiazoles corresponding to the general formula: ##STR1## where X and Z either represent an optionally substituted benzene ring fused to the diazole nucleus, or represent a variety of independent chemical groupings (hydrogen, lower alkyl, halo, etc.) and Y is selected from a wide range, e.g. heterocyclics and carbonyl groups.

Proton pump inhibitors

Novel 3,5-disubstituted 1,2,4-thiadiazole compounds are provided, which are effective in treating peptic ulcers by the inhibition of H.sup.+ /K.sup.+ -ATPase. The compounds of the present invention are 3,5-disubstituted 1,2,4-thiadiazole corresponding to the general formula (I): ##STR1## where R.sup.1 is a group with cell penetration properties for the inhibition of the enzyme in-vitro and in-vivo, and Y is a substituent that tunes the reactivity of the inhibitor towards the cysteine residue of H.sup.+ /K.sup.+ -ATPase. The Y group may also serve in recognition.

Thiadiazole compounds useful as inhibitors of H.sup.+ /K.sup.+  atpase

Novel thiadiazole compounds are provided, which are effective as proton pumps inhibitors, useful in treating peptic ulcers by inhibition of the proton pump enzyme H.sup.+ /K.sup.+ -ATPase. The compounds are 3-substituted 1,2,4-thiadiazolo �4,5-.alpha.!benzimidazole and 3-substituted imidazo�1,2-d!-1,2,4-thiadiazoles corresponding to the general formula: ##STR1## where X and Z either represent an optionally substituted benzene ring fused to the diazole nucleus, or represent a variety of independent chemical groupings (hydrogen, lower alkyl, halo, etc.) and Y is an electronegative group.

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Etobicoke, Canada

Wanren Li