EP1575587A1 - Iminozucker-derivate als glucosidase-inhibitoren - Google Patents

Iminozucker-derivate als glucosidase-inhibitoren

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Publication number
EP1575587A1
EP1575587A1 EP02808072A EP02808072A EP1575587A1 EP 1575587 A1 EP1575587 A1 EP 1575587A1 EP 02808072 A EP02808072 A EP 02808072A EP 02808072 A EP02808072 A EP 02808072A EP 1575587 A1 EP1575587 A1 EP 1575587A1
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EP
European Patent Office
Prior art keywords
formula
compound
group
divalent
bis
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.)
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EP02808072A
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English (en)
French (fr)
Inventor
Jasbir Singh Arora
Nidhi Gupta
Mohammad Salman
Geeta Sharma
Jang Bahadur Gupta
Upendra Kumar Pandit
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Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories Ltd
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Publication of EP1575587A1 publication Critical patent/EP1575587A1/de
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
    • 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 present disclosure relates to iminosugar derivatives and processes for the preparation thereof.
  • the disclosed compounds have c-glucosidase inhibiting properties, and are useful in the treatinent of diabetes.
  • the present disclosure also relates to pharmaceutical compositions containing the disclosed compounds and to their use as anti- diabetic agents.
  • Carbohydrates mainly in the form of poly- or di-saccharides are major dietary constituents. Enzymatic degradation of these complex carbohydrates to monosaccharides is an essential prerequisite for their absorption and is mediated by a class of enzymes known as glucosidases. Other than intestinal digestion, glucosidases are involved in a wide range of important biological processes such as post-translational processing of glycoproteins and the lysosomal catabolism of glycoconjugates.
  • ⁇ -Glucosidase is one such member of this class responsible for the breakdown of sucrose, maltose, trehalose and starch into simple sugars for absorption.
  • This enzyme is present at the brush border membrane of enterocytes in the small intestine. Modulation of carbohydrate absorption via inhibition of the luminal ⁇ -glucosidase enzyme effectively reduces postprandial hyperglycaemia and thus, improves glycaemic control in patients with Non-Insulin
  • NIDDM Dependent Diabetes Mellitus
  • Type-II diabetes Other than its therapeutic role in NIDDM, ⁇ -glucosidase inhibitors may be useful in inhibition of tumour metastasis and viral replication.
  • 1-Azasugars are a very potent class of glucosidase inhibitors. Pyranoses and furanoses with the ring oxygen replaced by an imino group are useful as potent glucosidase inhibitors.
  • DNJ Deoxynojirimycin
  • DNJ Deoxynojirimycin
  • Several of its derivatives have been described in United States Patent Nos 5,273,981 to German et al, 5,451,679 to Barta et al, 5,595,981 to Bart et al., 5,663,342 to Barta et al., and WO 00/39140.
  • AGI's ⁇ -glucosidase inhibitors
  • Acarbose which is an oligosaccharide slows down the breakdown of disaccharides and polysaccharides and other complex carbohydrates into monosaccharides. The enzymatic generation and subsequent absorption of glucose is delayed and the postprandial blood glucose values, which are characteristically high in patients with type II diabetes, are reduced with acarbose.
  • AGIs do not prevent the absorption of carbohydrates and complex sugars, but they do delay their absorption.
  • other AGI's include miglitol and voglibose.
  • Miglitol which is a pseudomonosaccharide (hydroxyethyl derivative of deoxynojirimycin) and acarbose appear to be equally effective, but miglitol is generally preferred. Acarbose has occasionally been associated with liver toxicity and requires liver monitoring, whereas miglitol does not. Neither appears to have any significant drug interactions.
  • Voglibose (3,4-dideoxy-4-[[2-hydroxy-l-(hydroxymethyl) ethyl] amino] -2-C-(hydroxymethyl)-D-epi-inositol), disclosed for example in United States Patent No. 4,701,559 to Horii et al., is a potent ⁇ -glucosidase inhibitor, the therapeutic dosage being 0.1 and 0.2 mg as compared to 50 mg and 100 mg for acarbose and miglitol.
  • Glucosidase inhibitors have the potential to produce several beneficial therapeutic effects including reduction of rise in postprandial blood glucose levels (See United States Patent No. 4,634,765), inhibition of tumour metastasis (See Dennis J.W Be Cancer Research, 46, 5131 (1986)), and inhibition of viral replication (see Tyms et al., EEES Eett., 237, 128 (1988)).
  • the present invention results from the recognition that particular bis- and tris- azasugars can be useful as glucosidase inhibitors.
  • bis- and tris-azasugars coupled with urea, thiourea or other linkage at C-6 are useful glucosidase inhibitors.
  • the present invention also results from the recognition that these azasugar compounds can be used to treat diabetes in mammals, and can be used to selectively antagonize - glucosidase receptors in mammals.
  • compositions containing these azasugar compounds which are useful in the treatment of diabetes.
  • the present invention also includes within its scope prodrugs of these azasugar compounds.
  • prodrugs will be functionalized derivatives of these azasugar compounds, which are readily converted in vivo into these azasugar compounds.
  • carboxylic acid esters can be formed from free hydroxyl groups on the azasugar compounds described herein, by reaction with carboxylic acids.
  • carboxylic acid esters can be formed from carboxylic acid groups on the azasugar compounds described herein, by reaction with alcohols.
  • amide linkages can be formed between either amino groups on the azasugar compounds and carboxylic acids, or between carboxylic acid groups on the azasugars and amines. These ester and amide linkages can be hydrolyzed by particular esterases and amidases known to those of ordinary skill in the art.
  • the invention also includes the enantiomers, diastereomers, N-oxides, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates of these azasugar compounds as well as metabolites having the same type of - glucosidase inhibiting activity as these azasugar compounds.
  • the invention further includes pharmaceutical compositions comprising these azasugar compounds, their prodrugs, metabolites, enantiomers, diastereomers, N-oxides, polymorphs, solvates or pharmaceutically acceptable salts thereof, in combination with pharmaceutically acceptable carriers and optionally included excipients.
  • FORMULA I and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs, metabolites, wherein; A represents hydrogen, lower (CrC ) alkyl, lower (C 2 -C 4 ) alkenyl, lower (C 2 -C ) alkynyl; X-G represents C O or CH 2 ;
  • R represents hydrogen, alkyl (d-C 6 ), acyl, aryl, aralkyl such as benzyl; Y represents O or NH;
  • NH— C is selected from the group consisting (CH 2 ) m , where m is an integer ranging from 1-6; di- or trivalent cycloalkylene (C -C 6 ) group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, which may be substituted; di- or trivalent arylene such as phenylene, naphthylene and the like, which may be substituted; di- or trivalent 5-7 membered heterocyclyl group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen suphur and oxygen, including aziridinyl, pyrrolidinyl, mo ⁇ holinyl, piperidinyl, piperazinyl and the like, which may be substituted; di- or trivalent 5-7 membered heteroaryl group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen suphur and oxygen, including aziridinyl, pyrrolidinyl
  • group Ar includes substituted or unsubstituted di- or trivalent phenylene, naphthylene, pyridyl, quinolinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, benzopyranyl, pyrazolyl and the like; o o
  • R 2 is selected from the group consisting of the di- and trivalent 5-7- 1 membered heterocyclyl group containing 2 or more hetero atoms selected from the group consisting of nitrogen, sulphur and oxygen, including aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl and the like; and o o
  • R 3 is selected from the group selected from (CH 2 ) m where m is an integer ranging from 1 to 6; di- or trivalent cycloalkylene (C 3 -C 6 ) group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; and di- or trivalent arylene such as phenylene, naphthylene and the like, which may be substituted.
  • Z can also represent R 3 directly.
  • derivatives of the particular iminosugars for example, derivatives of bis-[2,3,4-tri-O-benzyl-N-propyl-D-gluco- ⁇ - lactam], bis-[2,3,4-trihydroxy-N-propyl-D-gluco- ⁇ -lactam], bis-[N-allyl-2,3,4-tri-O- benzyl-l,5-dideoxy-l,5-imino-D-glucitol], tris-[2,3,4-tri-O-benzyl-N-propyl-D-gluco- ⁇ - lactam], and tris [2,3,4-trihydroxy-N-propyl-D-gluco- ⁇ -lactam].
  • polyhydroxylated piperidines polyhydroxylated pyrrolidines, polyhydroxylated indolizidines, polyhydroxylated pyrrolizidines, and other derivatives with substituents at the anomeric position, such as aldonolactams of L-fucose, D-galactose, D-glucose, D- glucouronic acid, D- and L-mannose, N-acetyl-D-galactosamine, N-acetyl-D- glucosamine, and D- and L-rhamnose, to name a few examples.
  • the compounds of the present invention may be prepared, for example, according llowing reaction sequences (Schemes I-NII) to yield the compounds of Formula I.
  • B B wherein B and R ⁇ are the same as defined earlier
  • B and R ⁇ are the same as defined earlier
  • a compound of Formula II available according to procedures disclosed in Tetrahedron, 50 (14), 4215-4224 (1994), and Tet. Lett, 37 (4), 547-50 (1996)
  • ⁇ -toluene sulphonyl chloride in an organic solvent for a period varying between 2-24 hours to give the compound of Formula III.
  • This reaction is carried out in the presence of a base such as triethylamine or diisopropylamine.
  • the organic solvent can be, for example, a chlorinated solvent, such as dichloromethane, dichloroethane or chloroform.
  • the compound of Formula III on reaction with sodium azide in a polar aprotic solvent (such as, for example, dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), or dimethylacetamide) at a temperature ranging from 10-100°C for a period ranging from one to several hours, gives the compound of Formula IV.
  • a polar aprotic solvent such as, for example, dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), or dimethylacetamide
  • This compound on catalytic reduction in a polar solvent, yields the corresponding amine of Formula V.
  • the catalyst preferably used in the reduction of azide of Formula TV is Palladium/carbon, the reduction being suitably carried out in, for example, polar protic solvents such as methanol or ethanol.
  • Compounds of Formula II are reduced in organic solvents such as tetrahydrofuran or diethylether to give compounds of Formula IX.
  • the reaction is carried out at about 20-70°C for a time period of 2-20 hours.
  • the preferable temperature range is 30-50°C.
  • the reducing agent preferably used in the reaction is lithium aluminium hydride.
  • cyanuric chloride also known as chlorotriazine, trichlorocyanidine, tricyanogen chloride, cyanuric acid trichloride, or 2,4,6-trichloro-s-triazine
  • abase in a suitable solvent (such as, for example, acetone and acetonitrile) at a temperature ranging from 0° to 80°C to yield the compound of Formula XII.
  • the base can be an inorganic or organic base, such as potassium carbonate, sodium carbonate, triethylamine and diisopropylamine.
  • XN can also be prepared by methods illustrated in Scheme IN.
  • the methods include condensation of Formula N with a compound of Formula XIII in presence of an organic base (for example, triethylamine or diisopropylamine) in a suitable solvent (such as an organic solvent, for example chlorinated solvents such as dichloromefhane, dichloroethane or chloroform) at a temperature ranging from 0° to 50°C preferably at 10-
  • an organic base for example, triethylamine or diisopropylamine
  • a suitable solvent such as an organic solvent, for example chlorinated solvents such as dichloromefhane, dichloroethane or chloroform
  • the debenzylation of compounds of Formula XIV can be carried out in polar protic solvents, such as methanol or ethanol.
  • Scheme N compounds of Formula N are reacted with bromoacetyl bromide in presence of an organic base (for example, triethylamine or diisopropylamine) in a solvent (for example, an organic solvent such as chlorinated solvents like dichloromethane, dichloroethane and chloroform) at a temperature ranging from 0° to 60°C, preferably at
  • an organic base for example, triethylamine or diisopropylamine
  • a solvent for example, an organic solvent such as chlorinated solvents like dichloromethane, dichloroethane and chloroform
  • XNI which is further condensed with piperazine in the presence of a base (for example, potassium carbonate or sodium carbonate) and a phase transfer catalyst (such as, for example, tetrabutylammonium bromide or potassium iodide) in a solvent (for example, in an aprotic solvent such as acetone or acetonitrile) for a period ranging from 10 to 45 hours to give a compound of Formula XNII (Formula I, when A is CH CH CH 3 , X-G is
  • Scheme VII illustrates exemplary synthesis of compounds of Formula XXIN (Formula I, where A is CH 2 CH 2 CH 3 , X-G is CO, R is Bn, Y is ⁇ H, and Z is C— ⁇ H— 4 — ⁇ H — C
  • Formula XXIII in the presence of a base (for example, organic base, for example, triethylamine or diisopropylamine) and a solvent (such as chlorinated solvents, for example, dichloromethane, dichloroethane or chloroform) at temperatures ranging from about 20-60°C for a period varying between 1-24 hours to produce the corresponding compound of Formula XXIN (Formula I, A is CH 2 CH 2 CH 3 , X-G is CO, R is Bn, Y is
  • Each of the compounds disclosed herein can be created with other azasugars, such as N-containing fructo-, glucofurano-, arabinofurano-, mannofurano-, furano-, arabino-, or manno- ⁇ -lactams, as would be understood by those of ordinary skill in the art upon inspection of the present disclosure.
  • Bis-azasugars can contain identical or different sugar groups. Further the compounds disclosed herein can involve trivalent central bridging moieties, and can thus contain three azasugar groups (tris-azasugar compounds), the sugar groups of which can be all the same or not all the same.
  • compositions including a therapeutically effective amount of a compound of Formula I, or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, as described herein, along with a pharmaceutically acceptable carrier, and optionally but desirably, pharmaceutically acceptable excipients.
  • the invention also provides for methods of selectively antagonizing ⁇ -glucosidase receptors in a mammal.
  • the methods include administering to a mammal a therapeutically effective amount of a compound having the structure of Formula I, or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, as described herein.
  • the invention also provides for methods of treating diabetes in a mammal.
  • the methods include administering to a mammal a therapeutically effective amount of a compound having the structure of Formula I, or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, as described herein.
  • compositions can be by injection or by gradual infusion over time.
  • the compositions can be administered intravenously, intraperitoneally, intramuscularly, subcutaneously, intracavity, or transdermally.
  • Preferred methods for delivery of the compositions include orally, by encapsulation in microspheres or proteinoids, by aerosol delivery to the lungs, or transdermally by iontophoresis or transdermal electroporation. Other methods of administration will be known to those skilled in the art.
  • Preparations for parenteral administration of the pharmaceutical compositions described herein include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.
  • Formulation of the pharmaceutical compositions may be carried out in conventional manner using one or more physiologically and/or pharmaceutically acceptable carriers or excipients.
  • the compounds and their pharmaceutically acceptable salts and solvates may be formulated for administration by inhalation or insufflation (either through the mouth or the nose) or oral, buccal, parenteral, or rectal administration.
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (for example, pregelatinized maize starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (for example, lactose, macrocrystalline cellulose or calcium hydrogen phosphate); lubricants (for example, magnesium stearate, talc or silica); disintegrants (for example, potato starch or sodium starch glycolate); or wetting agents (for example, sodium lauryl sulphate).
  • binding agents for example, pregelatinized maize starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose
  • fillers for example, lactose, macrocrystalline cellulose or calcium hydrogen phosphate
  • lubricants for example, magnesium stearate, talc or silica
  • disintegrants for example, potato starch or sodium starch glycolate
  • wetting agents for example, sodium lauryl s
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a sdry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventionsl means with pharmaceutically acceptable additives such as suspending agents (for example, sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (for example, lecithin or acacia); non-aqueous vehchles (for example, almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (for example, methyl or propyl-p-hdroxybenzoates or sorbic acid).
  • the preparations may also contain buffer salts, flavoring, coloring and sweetening agents as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • the compounds mahy be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspension, solutions or emulsions in oily or aqueous vehicles, and may contain formuatory agents such as suspending, stailizing and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen- free water, before use.
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formuated as a depot preparation.
  • Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchance resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the therapeutic compositions of the invention also contain a carrier or excipient, many of which are known to skilled artisans. Excipients which can be used include buffers (for example, citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, proteins (for example, serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, and glycerol. Methods for making such formulations are well-known and can be found in, for example, "Remington's Pharmaceutical Sciences.”
  • terapéuticaally effective amount is meant the quantity of a compound or composition according to the invention necessary to prevent, cure or at least partially arrest the symptoms of the disorder and its complications. Amounts effective to achieve this goal will, of course, depend on the severity of the disease and the weight and general state of the patient. Typically, dosages used in vitro may provide useful guidance in the amounts useful for in situ administration of the pharmaceutical composition, and animal models maybe used to determine effective dosages for treatment of particular disorders.
  • Step 1 Preparation of N-Allyl-6-O-(p-toluenesulfonyI)-2,3,4-tri-O-benzyl-D- gluco- ⁇ -lactam
  • N-allyl-2,3,4-tri-O-benzyl-D-gluco- ⁇ -lactam (0.487 gm) (prepared by the method reported in Tetrahedron, 50 (14), 4215-4224 (1994), Eet. Eett., 37 (4), 547-50 (1996)) was dissolved in dichloromethane (10 ml). To this was added triethylamine (1.01 gm) and cooled to 0°C. p-Toluenesulphonyl chloride (1.143 gm) was added to the reaction mixture, which was then concentrated at room temperature and stirred for additional 2 hours. The contents of the reaction mixture were poured into ice cold water (50 ml). The compound was extracted with dichloromethane.
  • the oganic layer was dried over anhydrous sodium sulphate (Na 2 SO 4 ) and the solvent was evaporated under vacuum.
  • the crude material was purified by column chromatography using ethylacetate - hexane (2:8) mixture as eluent.
  • Step 2 Preparation of 6-Azido-N-allyl-2,3,4-tri-O-benzyl-D-gluco- ⁇ -Iactam.
  • the product obtained from Step 1 (0.641 gm) was dissolved in N,N- dimethylformamide (DMF) (10 ml).
  • DMF N,N- dimethylformamide
  • NaN 3 sodium azide
  • NH 4 C1 ammonium chloride
  • the reaction mixture was stirred at 40°C for 5 hours.
  • the reaction mixture was poured into cold water (50 ml).
  • the product was extracted with ethyl acetate (2 times 25 ml) and the organic layer was washed with brine (50 ml).
  • the product from the preceding step (0.512 gm) was dissolved in 10 ml ethanol and Pd/C (Palladium/carbon) (10%, 0.102 gm) was added and the system was placed under a hydrogen atmosphere using hydrogen balloon. The reaction was stirred at room temperature for 5 hours. The reaction mixture was then filtered through celite, washed with methanol (50 ml) and the solvent removed under vacuum. The compound obtained was used as such for the next step without further purification.
  • Step 4 Preparation of 6,6'-[l,3-benzene- ⁇ diyl-bis(iminocarbonylimino)-4- methyl ⁇ ]-bis-[2,3,4-tri-O-benzyl-N-propyl-D-gluco- ⁇ -lactam]
  • Example 1A Preparation of 6.6'ri,4-cvclohexane-diyl-bis(iminocarbonylimino ]-bis- r2,3,4-tri-O-benzyl-N-propyl-D-gluco- ⁇ -lactam] (Compound No.2)
  • Example IB Preparation of 6,6'-rL3-benzene- ⁇ diyl-bis(iminocarbonylimino -4-chloro- 6-methyl) 1-bis ⁇ r2,3 ,4-tri-O-benzyl-N-propyl-D-gluco- ⁇ -lactam] (Compound No.3)
  • the title compound was prepared by using 4-chloro-6-methyl-l,3-phenylene diisocyanate in place of 4-methyl- 1,3 -phenylene diisocyanate in Step 4 to get the title compound in semi solid state, with the following spectral information: IR (CH 2 C1 2 ) : v 1670, 1645 cm "1 ; NMR (CDC1 3 ): ⁇ 0.82-0.87 (m, 6H,2xCH 3 ), 1.60 (m, 4H, 2xCH 2 ), 1.94 (s, 3H, CH 3 ), 2.95-3.00 (m, 2H, 2xCH), 3.34 (m, 2H,
  • Example 1C Preparation of 6,6'-[4,4'- ⁇ bisphenyllmethyl-diyl-bis- (iminocarbonylimino)]-bis-[2,3,4-tri-O-benyl-N-propyl-D-gluco- ⁇ -lactam] (Compound No.4
  • Example ID Preparation of 6,6'-
  • Example IE Preparation of 6,6' -[1, 4-benzene-diyl-bis(iminothiocarbonylimino ⁇ ]-bis- [2,3,4-tri-O-benzyl-N-propyl-D-gluco- ⁇ -lactam] (Compound No. 6)
  • the title compound was. obtained by using 1,4-butane diisothiocyanate in place of 4-methyl-l,3-phenylene diisocyanate in Step4 to get the title compound in semisolid state, with the following spectral information: IR (CH 2 C1 2 ) : v 1654 cm ⁇ NMR (CDC1 3 ): ⁇ 0.82-0.87 (m, 6H,2xCH 3 ), 1.38 (m, 4H, 2xCH 2 ), 1.52-1.59 (m, 4H, 2xCH 2 ) 2.04-2.06..
  • Example 2A Preparation of 6,6'-[l,4-cvclohexanediyl-bis(iminocarbonylimino)]-bis- [2,3,4-teihvdroxy-N-propyl-D-gluco- ⁇ -lactaml (Compound No.9) The title compound had m.p.
  • Example 2B Preparation of 6,6'-[l,3-benzene-(diyl-bis(iminocarbonylimino -2- methyl>1-bis-[2,3,4-trihydroxy-N-propyl-D-gluco- ⁇ -lactam] (Compound No .10)
  • Example 2C Preparation of 6,6'-[ " 4,4'- ⁇ bisphenyl)methyldiyl-bis- (iminocarbonylimino ]-bis- 2,3,4-trihydroxy-N-propyl-D-gluco- ⁇ -lactam (Compound No.11)
  • Step 1 Preparation of N-AUyl-2,3,4-tri-O-benzyl-l,5-dideoxy-l,5- iminoglucitol
  • N-allyl-2,3,4-tri-O-benzyl-D-gluco- ⁇ -lactam (prepared by the method reported in Tetrahedron, 50 (14), 4215-4224 (1994), Eet. Eett., 37 (4), 547-50 (1996)) (0.486 gm) was dissolved in tetrahydrofuran (THF) (15 ml).
  • LAH (0.114gm) was added to the above solution and the reaction mixture was heated to 40°C. Once the addition was complete, the reaction was stirred at 40°C for 2 hours.
  • the reaction mixture was cooled to O°C and ethyl acetate (10 ml) and water (2 ml) were added. The reaction mixture was then stirred for another 1 hour at room temperature.
  • Step 2 Preparation of 6,6'-[l,3-xylenediyI-bis-(oxo)]-bis- ⁇ N-alIyl-2,3,4-tri-O- benzyl-l,5-dideoxy-l,5-imino-D-glucitoI]
  • Example 3 A Preparation of 6,6'-[l,4-xylenediyl-bis-(oxo 1-bis-rN-allyl-2, 3,4-tri-O- benzyl-L5-dideoxy-l,5-imino-D-glucitol] (Compound No.13)
  • Example 5A Preparation of 6,6'.6"-ri.3,6-benzeneniyl-tris-(iminocarbonv ]tris-(2,3,4- tri-O-benzyl-N-propyl-D-gluco- ⁇ -lactaml (Compound No.16)
  • Example 6 Preparation of 6,6 ⁇ 6"-[l,3,6-benzene-triyl-tris-(iminocarbony ]-tris- 2,3,4- trihydroxy-N-propyl-D-gluco- ⁇ -lactam] (Compound No.17)
  • the ester obtained in Example 5 was debenzylated as described in Example 2 to give the desired product having a m.p.: 211°C.
  • Step 1 Preparation of 6-N- ⁇ 2-(bromo)-acetyl ⁇ -N-propyl-2,3,4-tri-O-benzyl- D-gluco- ⁇ -lactam
  • DCM dichloromethane
  • TAA Triethylamine
  • Step 2 Preparation of 6,6'- [l,4-piperazinediyl-bis-(acetylimmo)] -bis- [2,3,4- tri-O-benzyl-N-propyl-D-gluco- ⁇ -lactam]
  • Step 1 Preparation of 2,3,4-Tri-O-benzyl-6-N-(p-nitrophenyl carbamate)-N- propyl-D-gluco- ⁇ -lactam
  • DCM dichloromethane
  • TEA triethyalmine
  • p-nitrophenyl chloroformate 0.53gm
  • the product was extracted with dichloromethane (2 times 25 ml) and washed with water, dried over anhydrous Na 2 SO 4 and the solvent was removed under vacuum.
  • the product was purified by column chromatography and eluted with ethylacetate-hexane mixture (6:4).
  • Step 2 Preparation of 6,6'-Bis(imino)carbonyl-bis (2,3,4-tri-O-benzyl-N- propyl-D-gluco- ⁇ -lactam)
  • Example 11A Preparation of 6,6'-[l,4-benzenediylbis(iminocarbonylimino ]-bis-r2,3,4- tri-O-benzyl-N-propyl-D-gluco- ⁇ -lactaml (Compound No. 23)
  • Example 11B Preparation of 6,6'-
  • Example 12 Pharmacolo ical Testing Results: ⁇ -glucosidase inhibition activity The ⁇ -glucosidase inhibition activity was determined by modifing an assay procedure described by Evans et. al. Phytochemistry, 22, 768-770 (1983). The activity of yeast ⁇ -glucosidase was measured at pH 7.4 in N-2-hydroxyethyl ⁇ iperazine-N-ethane sulfonic acid (HEPES) buffer in a 96-well microtiter plate. The release of -nitrophenol from the the substrate -nitrophenylglycoside by yeast ⁇ -glucosidase was measured spectrophotometrically in the presence and absence of the test compound at different concentrations. Each assay included inhibitor of the enzyme as a standard. Results are expressed as IC 50 value of the test compound. The specific methodology was as follows: to 100ml of 50 mM HEPES buffer, pH 8.
  • test compound in DMSO (DMSO alone in control) and 40 ⁇ l (0.03 units) yeast ⁇ -glucosidase (Sigma) in HEPES buffer were added and preincubated at room temperature for 15 minutes.
  • Acarbose is an alphaglucosidase inhibitor which is already in the market and being used in patients of type II diabetes. Our stategy was to identify compounds that were equal to or more potent than acarbose in an in vitro enzyme assay using yeast alpha glucosidase. It may be noted that a Kj of 77.9 ⁇ m (ICso ⁇ 127 ⁇ M) has been reported for acarbose using yeast alpha glucosidase in an in vitro enzyme inhibition assay (Archives of Biochemistry and Biophysics, 371, No. 8, (1999), pp. 277-283). For table entries given with an asterisk, the percent inhibition at the given concentration was more than 30%, and could not be quantitatively checked beyond this concentration because of precipitation.
  • the disclosed compounds are predicted to have the characteristic of speifically inhibiting the activity of ⁇ -glucosidase (an enzyme which breaks down disaccharides, etc.) at intestinal levels. Accordingly, these compounds can effectively inhibit the production of monosaccharides, which cause high blood sugar levels.
  • ⁇ -glucosidase an enzyme which breaks down disaccharides, etc.

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EP02808072A 2002-10-29 2002-10-29 Iminozucker-derivate als glucosidase-inhibitoren Withdrawn EP1575587A1 (de)

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