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WO2004089945A1 - Derives de rosiglitazone utiles comme agents antidiabetiques - Google Patents

Derives de rosiglitazone utiles comme agents antidiabetiques

Info

Publication number
WO2004089945A1
WO2004089945A1 PCT/IB2004/001108 IB2004001108W WO2004089945A1 WO 2004089945 A1 WO2004089945 A1 WO 2004089945A1 IB 2004001108 W IB2004001108 W IB 2004001108W WO 2004089945 A1 WO2004089945 A1 WO 2004089945A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
pharmaceutically acceptable
mammal
organic solvent
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IB2004/001108
Other languages
English (en)
Inventor
Yatendra Kumar
Radhakrishnan Gowrishankar
Ram Chander Aryan
Kumar Hari Bhushan
Manoj Kumar Mishra
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy Laboratories Ltd
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 Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of WO2004089945A1 publication Critical patent/WO2004089945A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the field of the invention relates to rosiglitazone derivatives of Formula VI and their pharmaceutically acceptable salts.
  • the invention concerns methods for the preparation of such derivatives, pharmaceutical compositions comprising the same and methods of treatment comprising administration of such compositions. These derivatives are putative metabolites of rosiglitazone.
  • Diabetes is a seminal cause of several chronic and progressive diseases, which adversely affect a number of organs, including the nervous and vascular systems. More than 90% of diabetic patients are non-insulin dependent i.e., type II diabetes (non-insulin dependent diabetes mellitus NIDDM).
  • type II diabetes is a metabolic disorder characterized by hyperglycemia and insulin resistance and lead to several secondary complications such as neuropathy, nephropathy, retinopathy, atherosclerosis and other coronary artery diseases.
  • type II diabetes although the pancreatic B cells are capable of producing insulin, insulin is unable to act in all the target tissues due to a metabolic disorder. This abnormality, which leads to hyperinsulinemia, is referred to insulin resistance.
  • thiazolidinedione derivatives have been developed which act as insulin sensitizers.
  • a specific advantage of thiazolidinedione derivatives as insulin sensitizers is that they may be able to prevent the progression of diabetes and related complications without the risk of hypoglycemia.
  • Over the past decades and after the discovery of ciglitazones by a group of scientists by Takeda several thiazolidinedione derivatives of diverse structures have been developed. Encouraging clinical reports on troglitazone have generated interest among the people to develop newer thiazolidinedione analogues.
  • the US FDA has approved one of the thiazolidinedione derivatives, commonly termed as rosiglitazone.
  • rosiglitazone is ( ⁇ )-5- [[4(methypyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione and has structural Formula VII.
  • rosiglitazone The antidiabetic activity of rosiglitazone has been demonstrated in animal models of type II diabetes in which hyperglycemia and/or impaired glucose tolerance is a consequence of insulin resistance in target tissues. Rosiglitazone reduces blood glucose concentrations and reduces hyperinsulinemia. Rosiglitazone also prevents the development of overt diabetes.
  • the metabolic changes produced by rosiglitazone result in increased responsiveness of insulin-dependent tissues, and so the metabolites of rosiglitazone are more effective in the treatment of diabetes and as insulin sensitizing agents.
  • Xenobioteca, 26 (6), (1996) describes various derivatives shown in Figure 1, which are metabolites of rosiglitazone such as phenoxyacetic acid derivatives, N-desmethyl- glucuronide derivatives, 5-0-glucoronide derivatives, N-desmethyl-3-0-sul ⁇ hate derivatives, 3-0-glucuronide derivatives, N-desmethyl-3 -sulphate derivatives, N- desmethyl-3-hydroxy derivatives, 5-0 sulphate derivatives, N-desmethyl-5-hydroxy derivatives, 3-0-sulphate, 5-hydroxy derivatives, N-desmethyl, 3-hydroxy derivatives.
  • rosiglitazone such as phenoxyacetic acid derivatives, N-desmethyl- glucuronide derivatives, 5-0-glucoronide derivatives, N-desmethyl-3-0-sul ⁇ hate derivatives, 3-0-glucuronide derivatives, N-desmethyl-3 -sulphate derivatives, N- desmethyl-3-hydroxy derivatives, 5-0 sulph
  • phase I metabolites N-desmethyl rosiglitazone (M 12) and unconjugated para hydroxy rosiglitazone (M 13) were 20-fold less potent than and equipotent with rosiglitazone, respectively.
  • novel derivatives of rosiglitazone of Formula VI and pharmaceutically acceptable salts thereof are putative metabolites of rosiglitazone and belong to the class of phenoxy acetic acid derivatives.
  • FORMULA VI The term compounds of Formula VI or pharmaceutically acceptable salts thereof, wherein R is hydrogen or a lower alkyl group having from one to four carbon atoms includes solvates, hydrates and polymorphic forms of compounds of Formula VI .
  • compositions that include a therapeutically effective amount of compounds of Formula VI or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable carriers, excipients or diluents.
  • the inventors have developed processes for the preparation of compounds of Formula VI and salts thereof, wherein R is hydrogen or a lower alkyl group, which are putative metabolites of rosiglitazone.
  • the process involves a) treating 4-hydroxybenzaldehyde of Formula I
  • 4-Hydroxybenzaldehyde of Formula I is reacted with bromoacetic acid in the presence of an organic solvent and abase. After the completion of reaction, water is added to the reaction mass and extracted with ethyl acetate to obtain 4-formylphenoxyacetic acid of Formula II.
  • the organic solvent may be one or more of ketones and mixtures thereof.
  • the ketone may include one or more of acetone, ethyl methyl ketone, methyl isobutyl ketone.
  • the base may be one or more of hydroxides, or carbonates of an alkali metal. Potassium carbonate in anhydrous form is a particular example.
  • step b) the compound of Formula II is reacted with 2-amino pyridine derivatives of Formula III, wherein R is same as above, in an organic solvent in the presence of a condensing agent to get a compound of Formula IV.
  • the condensing agent may be one or more of N'-ethylcarbodiimide, N-(3- dimethylaminopropyl)-! -hydroxy-7-azabenzotriazole, chlorodimethoxytriazine, benzotriazole-l-yloxy-tris(dimethyl amino)phosphonium hexaflourophosphate (BOP reagent), triethylamine, and N-methyl morpholine.
  • the organic solvent may be one or more of chlorinated hydrocarbons and mixtures thereof.
  • the chlorinated hydrocarbon may include one or more of chloroform, dichloromethane, and 1,2-dichloroethane.
  • the compound of Formula IV is further condensed with 2,4-thiazolidinedione, to obtain compound of Formula V.
  • the reaction can be carried out in the presence of an organic solvent.
  • the organic solvent may be one or more of lower alkanols and mixtures thereof.
  • the lower alkanol may include one or more of a primary, secondary and tertiary alcohol having from one to six carbon atoms.
  • lower alkanol may include one or more of a primary, secondary and tertiary alcohol having from one to four carbon atoms. Examples include methanol, ethanol, n-propyl alcohol, isopropyl alcohol, isobutanol, n- butanol, and t-butanol.
  • the compound of Formula V is reduced with a reducing agent, in the presence of cobalt chloride hexahydrate and dimethyl glyoxime, to form the compound of Formula VI, which can then be converted into its pharmaceutically acceptable salt by any conventional method.
  • the reducing agent may include one or more of conventional reducing agents such as sodium borohydride, potassium borohydride, tetralkyl ammonium borohydride, and zinc borohydride.
  • conventional reducing agents such as sodium borohydride, potassium borohydride, tetralkyl ammonium borohydride, and zinc borohydride.
  • Sodium borohydride is a particular example.
  • the resulting compounds of Formula VI or pharmaceutically acceptable salts thereof may be formulated into ordinary dosage forms such as, for example, tablets, capsules, pills, solutions, etc.
  • the medicaments can be prepared by conventional methods with conventional pharmaceutically acceptable excipients, diluents and carriers.
  • compositions include dosage forms suitable for oral, buccal, rectal, and parenteral including subcutaneous, intramuscular, and ophthalmic administration.
  • the oral dosage forms may include solid dosage forms, like powder, tablets, capsules, suppositories, sachets, troches and lozenges as well as liquid suspensions and elixirs.
  • Parenteral dosage forms may include intravenous infusions, sterile solutions for intramuscular, subcutaneous or intravenous administration, dry powders to be reconstituted with sterile water for parenteral administration, and the like.
  • the present invention is further illustrated by the following examples which are provided merely to be exemplary and are not intended to limit the scope of the invention.
  • 4-hydroxybenzaldehyde (10 g, 0.082 moles) in acetone (150 ml)
  • anhydrous potassium carbonate 24.92 g, 0.18 moles
  • bromoacetic acid 11.96 g, 0.86 moles
  • the reaction mixture was refluxed overnight, and was cooled to room temperature, followed by the addition of water (300 ml) to dissolve the solid.
  • the resulting solution was washed with ethyl acetate (200ml x 2) and pH of the aqueous layer was adjusted to about 2.0 with 6N hydrochloric acid.
  • Dicyclohexyl carbodiimide (DCC) 5.072 g, 0.0246 moles
  • 4- formylphenoxy)-acetic acid 4.024 g, 0.0224 moles
  • dichloromethane 25 ml
  • 2- aminopyridine 2.0 g, 0.0213 moles

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Emergency Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Endocrinology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention se rapporte à des dérivés de rosiglitazone de la formule VI et à leurs sels pharmaceutiquement acceptables. L'invention se rapporte à des procédés de préparation de ce type de dérivés, à des compositions pharmaceutiques les comprenant et à des procédés de traitement consistant à administrer de telles compositions. Ces dérivés sont des métabolites présumés de la rosiglitazone.
PCT/IB2004/001108 2003-04-09 2004-04-08 Derives de rosiglitazone utiles comme agents antidiabetiques Ceased WO2004089945A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN590DE2003 2003-04-09
IN590/DEL/2003 2003-04-09

Publications (1)

Publication Number Publication Date
WO2004089945A1 true WO2004089945A1 (fr) 2004-10-21

Family

ID=33156198

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2004/001108 Ceased WO2004089945A1 (fr) 2003-04-09 2004-04-08 Derives de rosiglitazone utiles comme agents antidiabetiques

Country Status (1)

Country Link
WO (1) WO2004089945A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0306228A1 (fr) * 1987-09-04 1989-03-08 Beecham Group Plc Thiazolidinediones substituées

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0306228A1 (fr) * 1987-09-04 1989-03-08 Beecham Group Plc Thiazolidinediones substituées

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BOLTON G C ET AL: "The fate of a thiazolidinedione antidiabetic agent in Rat and dog", XENOBIOTICA, TAYLOR AND FRANCIS, LONDON,, GB, vol. 26, no. 6, 1996, pages 627 - 636, XP000926113, ISSN: 0049-8254 *

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