WO2003010157A1 - Derives de dioxane et un procede de preparation desdits derives - Google Patents

Derives de dioxane et un procede de preparation desdits derives Download PDF

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Publication number
WO2003010157A1
WO2003010157A1 PCT/IB2001/001314 IB0101314W WO03010157A1 WO 2003010157 A1 WO2003010157 A1 WO 2003010157A1 IB 0101314 W IB0101314 W IB 0101314W WO 03010157 A1 WO03010157 A1 WO 03010157A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
dioxane
dione
hydroxybenzyl
Prior art date
Application number
PCT/IB2001/001314
Other languages
English (en)
Inventor
Rajender Kumar Potlapally
Narasimha Murthy Kotra
Raju Sirisilla
Ramabhadra Sarma Mamillapalli
Om Reddy Gaddam
Venkateswarlu Akella
Original Assignee
Dr. Reddy's Research Foundation
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 Dr. Reddy's Research Foundation filed Critical Dr. Reddy's Research Foundation
Priority to PCT/IB2001/001314 priority Critical patent/WO2003010157A1/fr
Publication of WO2003010157A1 publication Critical patent/WO2003010157A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/12—1,4-Dioxanes; Hydrogenated 1,4-dioxanes not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/62—Halogen-containing esters
    • C07C69/63—Halogen-containing esters of saturated acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D321/00—Heterocyclic compounds containing rings having two oxygen atoms as the only ring hetero atoms, not provided for by groups C07D317/00 - C07D319/00
    • C07D321/02—Seven-membered rings

Definitions

  • the present invention relates to novel antidiabetic compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs and pharmaceutically acceptable compositions containing them. More particularly, the present invention relates to novel dioxane compounds of the general formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs and pharmaceutically acceptable compositions containing them.
  • R 1 represents hydrogen or ( -C ⁇ alkyl group; n is an integer ranging from 1 to 2.
  • the present invention also relates to a process for the preparation of compounds of formula (I).
  • the present invention also relates to novel intermediates of formula
  • the compounds of formula (I) are useful in lowering the plasma glucose, triglyceride, total cholesterol (TC); increase high density lipoprotein
  • HDL high density lipoprotein
  • LDL low density lipoprotein
  • the compounds of formula (I) are useful in reducing body weight, glucose intolerance and for the treatment and / or prophylaxis of diseases such as hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular diseases and related disorders.
  • the compound of formula (I) is also useful for the treatment and/or prophylaxis of insulin resistance (type II diabetes).
  • the compounds of formula (I) are also useful as intermediates for the preparation of many pharmaceutically active compounds. Few representative examples of such compounds are
  • Diabetes and insulin resistance is yet another disease which severely effects the quality of life of a large population in the world.
  • Insulin resistance is the diminished ability of insulin to exert its biological action across a broad range of concentrations.
  • the body secretes abnormally high amounts of insulin to compensate for this defect; failing which, the plasma glucose concentration inevitably raises and develops into diabetes.
  • diabetes mellitus is a common problem and is associated with a variety of abnormalities including obesity, hypertension, hyperlipidemia (J. Clin. Invest., (1985) 75 : 809 - 817; N. Engl. J. Med. (1987) 317 : 350 - 357 ; J. Clin. Endocrinol.
  • the main objective of the present invention is to provide novel compounds of the formula (I) for the treatment and / or prophylaxis of diabetes with high chiral purity, which can be used in the synthesis of pharmaceutically acceptable compounds, which will not have problems of racemization in subsequent steps, when used in the preparation of pharmaceutically acceptable compounds.
  • Another objective of the present invention is to provide a simple and robust process for the preparation of the compound of formula (I) .
  • the present invention provides novel dioxane compounds and their derivatives, their stereoisomers, their polymo ⁇ hs having the formula (I)
  • R 1 represents hydrogen or (C C ⁇ ⁇ lkyl group; n is an integer ranging from 1 to 2.
  • alkyl group represents methyl, ethyl, propyl, isopropyl, n- butyl, t-butyl and the like.
  • Particularly useful compounds according to the present invention include : ( ⁇ ) 3-(4-Hydroxybenzyl)-l,4-dioxane ⁇ 2,5-dione ; (+) 3-(4-Hydroxybenzyl)-l,4-dioxane-2,5-dione ; (-) 3-(4-Hydroxybenzyl)-l,4-dioxane-2,5-dione • ; ( ⁇ ) 3-(4-Hydroxybenzyl)-6-methyl-l,4-dioxane-2,5-dione ; (+) 3-(4-Hydroxybenzyl)-6-methyl-l,4-dioxane-2,5-dione ; (-) 3-(4-Hydroxybenzyl)-6-methyl-l,4-dioxane-2,5-dione ;
  • the reaction of compound of the formula (llf) using compound of formula (Ilg) to obtain a compound of formula (Lib.) may be carried out in the presence of dicyclohexyl carbodiimide (DCC) and a base such as sodium carbonate, potassium carbonate, N,N-dimethyl amino pyridine (DMAP) and the like or lewis acid such as boron trifluoro etherate and the like.
  • the reaction may be carried out in the presence of solvents such as toluene, benzene, DMF, DMSO, dichloromethane (DCM), dichloro ethane and the like.
  • the reaction may be carried out at a temperature in the range of 30 to 110 °C and the duration of the reaction may range from 2-40 h.
  • the cyclization of compound of formula (Ilh) to obtain compound of formula (Iii) may be carried out in the presence of acids such as sulfuric acid, p-TSA and the like or base such as sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium ethoxide, sodium methoxide, t- BuOK and the like.
  • the reaction may be carried out in the presence of solvents such as DMF, toluene and the like.
  • the reaction may be carried out at a temperature in the range of 0 to 110 °C and the duration of the reaction may range from 2-16 h.
  • the debenzylation of the compound of formula (Hi) to yield compound of formula (I) may be carried out using THF, aqueous acetic acid, ethyl acetate, aqueous (C C 6 ) alcohols such as aqueous methanol, ethanol, propanol, isopropanol and the like in the presence of metal catalysts such as Pd/C.
  • the cyclization of compound of formula (Llf) with compound of formula (I j) to obtain compound of formula (Hi) may be carried out in the presence of base such as triethyl amine, DMAP, N,N-diethylaniline, sodium carbonate, potassium carbonate, potassium sec.butoxide, sodium ethoxide, sodium methoxide, t-BuOK and the like.
  • the reaction may be carried out in the presence of solvents such as DMF, DCE, DCM, toluene and the like.
  • the reaction may be carried out at a temperature in the range of 0 to 11.0 °C and the duration of the reaction may range from 2-16 h.
  • the debenzylation of the compound of formula (Hi) to yield compound of formula (I) may be carried out using THF, aqueous acetic acid, ethyl acetate, aqueous (C ⁇ -C 6 ) alcohols such as aqueous methanol, ethanol, propanol, isopropanol and the like in the presence of metal catalysts such as Pd/C.
  • R represents benzyl
  • R represents hydrogen or alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl and the like
  • X represents halogen atom
  • n is an integer of 1 — 2.
  • R represents hydrogen or (CrC 6 )alkyl; R represents benzyl; n is an integer of 1 - 2.
  • the compounds of formula (I) are useful in the preparation of pharmaceutically important compounds such as
  • R represents hydrogen or alkyl group.
  • any reactive group in the substrate molecule may be protected according to conventional chemical practice.
  • Suitable protecting groups in any of the above mentioned reactions are tertiarybutyl dimethyl silylchloride, methoxymethyl chloride and the like. The methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.
  • the stereoisomers of the compounds forming part of this invention may be prepared by using compound of formula (I) in its single enantiomeric form in the process by resolving the mixture of stereoisomers by conventional methods.
  • Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with optically pure bases such as brucine, cinchona alkaloids and their derivatives, optically pure 2-alkyl phenethyl amine, phenyl glycinol and the like.
  • the diastereomeric salts may be obtained in pure form by fractional crystallization. Commonly used methods are compiled by Jaques et al in "Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981).
  • polymorphs of compound of general formula (I) forming part of this invention may be prepared by crystallization of compound of formula (I) under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X- ray diffraction or such other techniques.
  • Step (ii) Preparation of 2-(S)-(4-benzyloxybenzyl)-l,4-dioxan-2,5-dione.
  • the compounds of the present invention lower random blood sugar level. This can be demonstrated by in vitro as well as in vivo animal experiments.
  • mice C57 BL/KsJ-db/db mice developed by Jackson Laboratory, US, are obese, hyperglycemic, hyperinsulinemic and insulin resistant (J. Clin. Invest., (1990) 85 : 962-967), whereas heterozygous are lean and normoglycemic.
  • db/db model mouse progressively develops insulinopenia with age, a feature commonly observed in late stages of human type II diabetes when blood sugar levels are insufficiently controlled.
  • the state of pancreas and its course vary according to the models. Since this model resembles that of type ⁇ diabetes mellitus, the compounds of the present invention can be tested for blood sugar and triglycerides lowering activities.
  • mice of 8 to 14 weeks age having body weight range of 35 to 60 grams, bred at Dr. Reddy's Research Foundation (DRF) animal house, can be used in the experiment.
  • the mice are provided with standard feed (National Institute of Nutrition (NLN), India) and acidified water, ad libitum.
  • the animals having more than 350 mg / dl blood sugar can be used for testing.
  • the number of animals in each group is 4.
  • Test compounds will be suspended on 0.25 % carboxymethyl cellulose and administer to test group at a dose of 0.1 mg to 30 mg / kg through oral gavage daily for 6 days.
  • the control group receives vehicle (dose 10 ml / kg).
  • the blood samples can be collected one hour after administration of test compounds / vehicle for assessing the biological activity.
  • the random blood sugar and triglyceride levels can be measured by collecting blood (100 ⁇ l) through orbital sinus, using heparinised capillary in tubes containing EDTA which will be centrifuged to obtain plasma.
  • the plasma glucose and triglyceride levels can be measured spectrometrically, by glucose oxidase and glycerol-3-PO 4 oxidase/peroxidase enzyme (Dr. Reddy's Lab. Diagnostic Division Kits, India) methods respectively.
  • the blood sugar and triglycerides lowering activities of the test compound will be calculated according to the formula.
  • Percent reduction in Blood sugar can be calculated according to the formula :

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

Abstract

La présente invention concerne de nouveaux composés antidiabétiques, leurs dérivés, leurs analogues, leurs formes tautomères, leurs stéréoisomères, leurs polymorphes et des compositions pharmaceutiquement acceptables contenant ces composés. Cette invention concerne, plus particulièrement, de nouveaux composés de dioxane de formule générale (I), leurs dérivés, leurs analogues, leurs formes tautomères, leurs stéréoisomères, leurs polymorphes et des compositions pharmaceutiquement acceptables contenant ces composés, formule dans laquelle R1 représente hydrogène ou un groupe alkyle (en C1-C6) et n est un nombre entier de 1 à 2.
PCT/IB2001/001314 2001-07-23 2001-07-23 Derives de dioxane et un procede de preparation desdits derives WO2003010157A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IB2001/001314 WO2003010157A1 (fr) 2001-07-23 2001-07-23 Derives de dioxane et un procede de preparation desdits derives

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2001/001314 WO2003010157A1 (fr) 2001-07-23 2001-07-23 Derives de dioxane et un procede de preparation desdits derives

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WO2003010157A1 true WO2003010157A1 (fr) 2003-02-06

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9011832B2 (en) 2012-02-09 2015-04-21 Novus International, Inc. Heteroatom containing cyclic dimers
US9452143B2 (en) 2012-07-12 2016-09-27 Novus International, Inc. Matrix and layer compositions for protection of bioactives
US10584306B2 (en) 2017-08-11 2020-03-10 Board Of Regents Of The University Of Oklahoma Surfactant microemulsions

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5258391A (en) * 1987-05-15 1993-11-02 Scott Eugene J Van Phenyl alpha acyloxyalkanoic acids, derivatives and their therapeutic use
US5977374A (en) * 1991-11-20 1999-11-02 Sankyo Company, Limited 5-(4-hydroxy-OR 4-acetoxy-benzyl)-3- triphenylmethylthiazolidine-2,4-dione and method for producing same
WO2000059889A1 (fr) * 1999-04-06 2000-10-12 Sankyo Company, Limited DERIVES D'ACIDE CARBOXYLIQUE α-SUBSTITUES

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5258391A (en) * 1987-05-15 1993-11-02 Scott Eugene J Van Phenyl alpha acyloxyalkanoic acids, derivatives and their therapeutic use
US5977374A (en) * 1991-11-20 1999-11-02 Sankyo Company, Limited 5-(4-hydroxy-OR 4-acetoxy-benzyl)-3- triphenylmethylthiazolidine-2,4-dione and method for producing same
WO2000059889A1 (fr) * 1999-04-06 2000-10-12 Sankyo Company, Limited DERIVES D'ACIDE CARBOXYLIQUE α-SUBSTITUES
EP1167357A1 (fr) * 1999-04-06 2002-01-02 Sankyo Company, Limited Derives d'acide carboxylique alpha-substitues

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9011832B2 (en) 2012-02-09 2015-04-21 Novus International, Inc. Heteroatom containing cyclic dimers
US9284294B2 (en) 2012-02-09 2016-03-15 Novus International, Inc. Functionalized polymer compositions
US9447068B2 (en) 2012-02-09 2016-09-20 Novus International, Inc. Functionalized polymer compositions
US10457660B2 (en) 2012-02-09 2019-10-29 Novus International, Inc. Heteroatom containing cyclic dimers
US9452143B2 (en) 2012-07-12 2016-09-27 Novus International, Inc. Matrix and layer compositions for protection of bioactives
US9655863B2 (en) 2012-07-12 2017-05-23 Novus International, Inc. Matrix and layer compositions for protection of bioactives
US10584306B2 (en) 2017-08-11 2020-03-10 Board Of Regents Of The University Of Oklahoma Surfactant microemulsions

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