WO1991007420A1 - Nouveaux derives n-glycosidiques d'acide aminobenzoique et procede de preparation - Google Patents

Nouveaux derives n-glycosidiques d'acide aminobenzoique et procede de preparation Download PDF

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Publication number
WO1991007420A1
WO1991007420A1 PCT/HU1990/000074 HU9000074W WO9107420A1 WO 1991007420 A1 WO1991007420 A1 WO 1991007420A1 HU 9000074 W HU9000074 W HU 9000074W WO 9107420 A1 WO9107420 A1 WO 9107420A1
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WO
WIPO (PCT)
Prior art keywords
acetamido
deoxy
benzoic acid
salts
gluco
Prior art date
Application number
PCT/HU1990/000074
Other languages
English (en)
Inventor
Antal Kovács
Zoltán SZURMAI
Lóránt Jánossy
István CSERNUS
András LIPTÁK
Pál NÁNÁSI
János ERDEI
Sándor Jancsó
Katalin née Hadady KOVÁCS
Katalin Marossy
Erzsébet Takács
János HARANGI
János KERÉKGYÁRTÓ
Original Assignee
BIOGAL Gyógyszergyár Rt.
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 BIOGAL Gyógyszergyár Rt. filed Critical BIOGAL Gyógyszergyár Rt.
Publication of WO1991007420A1 publication Critical patent/WO1991007420A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems

Definitions

  • the present invention relates to novel aminobenzoic acid N-glycoside derivatives of formula I
  • R stands for 2-acetamido-2-deoxv-D- glucopyranosyl group, to the pharmaceutically acceptable esters and salts thereof, to pharmaceutical compositions comprising the same and a process for the preparation of the novel compounds.
  • the novel compounds are suitable for the prevention or treatment of diseases caused by pathological free radical reactions.
  • SUBSTITUTE SHEET residual group formed by the removal of -OH from the 1(alpha) or 1(beta) -position of arabinose, xylose, rhamnose, glucose, galactose, mannose or fructose and to the pharmaceutically active salts thereof.
  • the compounds are suitable for the treatment of cerebral ischemia and inhibit thro bocite aggregation.
  • antioxidants may influence the different stages of lipidperoxidation, but one specific anti- oxidant may exhibit more activities.
  • Such antioxidants include e.g. vitamin A, C and E, D-penicillamine, lipoic acid, lobenzarit disodium, 5,6-methylene-bis(2,2,3-tri- methyl)-1,2-dihydroquinoline.
  • the present invention is based on the recognition that compounds of formula I, their pharmaceutically acceptable esters and salts are suitable for the preven ⁇ tion or treatment of diseases caused by pathological free radical reactions.
  • the invention is based on the further recognition that the compounds of formula I can be prepared by reacting a ino benzoic acid with N-acetyl glucosamine. Hitherto the glycosilation of amino benzoic acids with N-acetyl glucosamine could have not been carried out with the known techniques.
  • the present invention relates to novel aminobenzoic acid N-glycoside derivatives of formula I
  • HEET wherein R stands for 2-acetamido-2-deoxy-D-gluco- pyranosyl group, to the pharmaceutically acceptable esters and salts thereof.
  • the pharmaceutically acceptable esters include the C ⁇ _ 4 alkyl esters, i.e. methyl, ethyl, propyl, i-propyl, butyl, i-butyl, sec-butyl esters.
  • the pharmaceutically acceptable salts include the metal salts, preferably the alkaline metal salts, such as sodium or potassium salts.
  • the present invention also covers the steric isomers of the compounds of formula I.
  • the present invention covers
  • Preferred compounds are the 2-, 3- or 4-(2- acetamido-2-deoxy-D-glucopyranosyl) benzoic acid C ⁇ __ 4 alkyl esters, more preferred compounds are 2-, 3- or 4- -(2-acetamido-2-deoxy-D-glucopyranosyl) benzoic acid methyl ester and 2-, 3- or 4-(2-acetamido-2-deoxy-D- glucopyranosyl) benzoic acid ethyl ester.
  • Other preferred group of compounds is the 2-, 3- or 4-(2-acetamido-2-deoxy-D-glucopyranosyl) benzoic acid alkaline metal salts from which 2-, 3- or 4-(2- acetamido-2-deoxy-D-glucopyranosyl) benzoic acid sodium salt is the most preferred.
  • the compounds of formula I are prepared by reacting a compound of formula II COOR 1
  • R is the same as defined hereinabove, R 1 is hydrogen or alkyl group, with N-acetyl glucosamine and if desired, transforming the compound thus obtained into pharmaceutically active ester or salt in a manner known per se.
  • the compounds of formula I can be prepared by glycosilating the corresponding amino benzoic acid derivative with N-acetyl glucosamine in water.
  • the amino benzoic acid N-glycoside derivatives thus prepared can be recovered in the form of pure anomers with good yield.
  • o-, m- or p-amino-benzoic acid and N-acetyl glucosamine are suspended in water,' the reaction mixture is heated to a temperature of 60 to 95 °C, kept at the same temperature for some minutes, then cooled to room temperature and the free acid is recovered.
  • the metal salt of the carbonic acid can be prepared in a manner known per se.
  • the reaction mixture is slightly acidified by the addition of a mineral acid, preferably hydrochloric acid and then heated.
  • the target compound crystallizes from the mixture after cooling and if desired it can be recrystallized from ethanol.
  • the acute toxicity of compounds according to Example 1 to 4 was measured by using the conventional test method on CFLP mice by oral administration.
  • the LD5 0 value of all of the compounds was higher than 10 g/kg
  • antioxidant and free radical scavenger activity of the compounds of the invention was examined on the basis of the in vitro test worked out by Stocks at al. (Stocks, I. et_al, Clin. Sci. Mol. Med. 215-22, 223- -33, 1974) . The following compounds were used in the test:
  • the C50 value (that concentration which is necessary to reduce the initial autooxidation with 50 %) of the compounds was measured.
  • the C50 value is characteristic for the antioxidant properties of the compound; the less is C50 the better radical scavenger the compound is.
  • 4-(2-acetamido-2-deoxy-D- glucopyranosyl) benzoic acid methyl ester exhibits surprisingly high antioxidant activity and inhibits lipid peroxidation depending on the dose. Its C50 value is 0.66 mM.
  • the comparative compounds did not influence the lipidperoxidation. At a concentration of 0.66 mM they reduced the initial auto ⁇ oxidation in an extent of less than 25 %.
  • the C50 value of vitamine E which is generally used in therapy against pathological free radical reactions, is 0 . 45 mM.
  • the advantage of the compounds of the invention over vitamin E is that they are water and lipid soluble, while vitamin E is only lipid soluble.
  • Dosage forms suitable for internal administration contain from about 1 milligram to about 500 milligrams of active ingredient per unit. The dosage administered vary depending upon known factors such as the mode and route of administration, age, health and weight of the recipient; nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired.
  • the active ingredient will ordinarily be present in an amount of about 0.5 to 95 % by weight based on the total weight of the compositon.
  • compositions comprising the compounds of the invention as active ingredient can be administered via any of the accepted modes of administration for therapeutic agents. These methods include oral, parenteral, transdermal, rectal, subcutaneous and other systemic modes.
  • the pharma ⁇ ceutical composition should, of course, be in a sterile form.
  • the compositions may be in the form of solid dosage forms such as capsules, tablets, coated tablets, powders, suppositories or liquid dosage forms such as syrups, emulsions, injections, elixirs, suspensions, emulsions, etc.
  • non-toxic solids include, for example, pharmaceutical grades of manitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like may be used.
  • the active compound may be formulated as suppositories using, for example, polyalkylene glycols, such as propylene glycol, as carrier.
  • Liquid dosage forms can, for example, be prepared by dissolving, dispersing, suspending, emulsifying, etc. an active compound and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like.
  • an excipient such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like.
  • the pharmaceutical composition may also contain minor amounts of nontoxic auxiliary substances such as wetting agents, pH buffering agents, preservatives, flavouring agents, etc., for example, sodium acetate, sodium lauryl sulphate, sorbitan mono- laurate, triethanolamine sodium acetate, triethanolamine oleate, etc.
  • nontoxic auxiliary substances such as wetting agents, pH buffering agents, preservatives, flavouring agents, etc., for example, sodium acetate, sodium lauryl sulphate, sorbitan mono- laurate, triethanolamine sodium acetate, triethanolamine oleate, etc.
  • the following mixture was prepared by homogenizing the ingredients then the mixture was filled into hard gelatine capsules.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Saccharide Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On décrit des nouveaux composés dont la formule est (I), où R représente un groupe 2-acétamido-2-désoxy-D-glucopyranosyle, les esters et sels pharmaceutiquement actifs de ceux-ci, des compositions pharmaceutiques qui les contiennent, et leur procédé de préparation. Les nouveaux composés sont utiles à la prévention ou au traitement des maladies provoquées par des réactions de radicaux libres pathologiques.
PCT/HU1990/000074 1989-11-14 1990-11-14 Nouveaux derives n-glycosidiques d'acide aminobenzoique et procede de preparation WO1991007420A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU5889/89 1989-11-14
HU588989A HU208146B (en) 1989-11-14 1989-11-14 Process for producing aminobenzoic acid-n-glycoside derivatives

Publications (1)

Publication Number Publication Date
WO1991007420A1 true WO1991007420A1 (fr) 1991-05-30

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/HU1990/000074 WO1991007420A1 (fr) 1989-11-14 1990-11-14 Nouveaux derives n-glycosidiques d'acide aminobenzoique et procede de preparation

Country Status (3)

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HU (1) HU208146B (fr)
PL (1) PL287761A1 (fr)
WO (1) WO1991007420A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0604641A1 (fr) * 1992-06-30 1994-07-06 SHAPIRO, Howard, K. Composition contenant des derives amines ou apparentes aux amines d'acide benzoique et utilisations, y compris dans le traitement de maladies inflammatoires
JP2005526813A (ja) * 2002-03-28 2005-09-08 アルケミア リミティッド 単糖のアノマー誘導体

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2708667A1 (de) * 1977-02-28 1978-08-31 Inst Pour La Rech Et La Produc N-decanoyl-d-glucosamin, arzneimittel mit strahlenschutzwirkung und adjuvanseigenschaften
DE3046796A1 (de) * 1979-12-14 1981-09-24 Kureha Kagaku Kogyo K.K., Tokyo "aminobenzoesaeurederivate und deren verwendung"

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2708667A1 (de) * 1977-02-28 1978-08-31 Inst Pour La Rech Et La Produc N-decanoyl-d-glucosamin, arzneimittel mit strahlenschutzwirkung und adjuvanseigenschaften
DE3046796A1 (de) * 1979-12-14 1981-09-24 Kureha Kagaku Kogyo K.K., Tokyo "aminobenzoesaeurederivate und deren verwendung"

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0604641A1 (fr) * 1992-06-30 1994-07-06 SHAPIRO, Howard, K. Composition contenant des derives amines ou apparentes aux amines d'acide benzoique et utilisations, y compris dans le traitement de maladies inflammatoires
EP0604641A4 (fr) * 1992-06-30 1995-08-02 Howard K Shapiro Composition contenant des derives amines ou apparentes aux amines d'acide benzoique et utilisations, y compris dans le traitement de maladies inflammatoires.
JP2005526813A (ja) * 2002-03-28 2005-09-08 アルケミア リミティッド 単糖のアノマー誘導体

Also Published As

Publication number Publication date
HU208146B (en) 1993-08-30
HUT55405A (en) 1991-05-28
HU895889D0 (en) 1990-02-28
PL287761A1 (en) 1991-08-12

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