WO1995006653A1 - Glycosylamides de 6-amino-6-desoxy-saccharoses - Google Patents

Glycosylamides de 6-amino-6-desoxy-saccharoses Download PDF

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Publication number
WO1995006653A1
WO1995006653A1 PCT/EP1994/002733 EP9402733W WO9506653A1 WO 1995006653 A1 WO1995006653 A1 WO 1995006653A1 EP 9402733 W EP9402733 W EP 9402733W WO 9506653 A1 WO9506653 A1 WO 9506653A1
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WO
WIPO (PCT)
Prior art keywords
amino
deoxy
methyl
compounds
formula
Prior art date
Application number
PCT/EP1994/002733
Other languages
German (de)
English (en)
Inventor
Oswald Lockhoff
Yutaka Hayauchi
Burkhard Mielke
Helmut Brunner
Klaus STÜNKEL
Michael Sperzel
Klaus Schaller
Original Assignee
Bayer Aktiengesellschaft
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
Priority claimed from DE4404370A external-priority patent/DE4404370A1/de
Application filed by Bayer Aktiengesellschaft filed Critical Bayer Aktiengesellschaft
Priority to AU76136/94A priority Critical patent/AU7613694A/en
Publication of WO1995006653A1 publication Critical patent/WO1995006653A1/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
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/12—Acyclic radicals, not substituted by cyclic structures attached to a nitrogen atom of the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
    • C07K9/001—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence having less than 12 amino acids and not being part of a ring structure
    • C07K9/005—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence having less than 12 amino acids and not being part of a ring structure containing within the molecule the substructure with m, n > 0 and m+n > 0, A, B, D, E being heteroatoms; X being a bond or a chain, e.g. muramylpeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to substituted (6-amino-6-deoxy-glycosyl) amides, processes for their preparation and their use in medicaments.
  • glycosylamides from aldopyranoses or from amino sugars can increase the body's immune response (DE-OS 3 213 650). It is also known that amino acids substituted (2-amino-2-deoxy-glycosyl) amides can cause both an increase in the specific and non-specific immune response (DE-OS 3 521 994).
  • the present invention now relates to substituted (6-amino-6-deoxy-glycosyl) amides of the general formula (I),
  • R 1 represents straight-chain or branched, saturated or unsaturated alkyl having up to 25 carbon atoms
  • R 2 represents straight-chain or branched, saturated or unsaturated alkyl having up to 25 carbon atoms
  • R 3 represents hydroxy or acetylamino
  • R 4 for a radical of the formula
  • R 3 for hydrogen, C j - to C 7 - alkyl, hydroxymethyl, 1-hydroxyethyl,
  • R 6 represents hydrogen or a radical of the formula
  • R 7 has the meaning of R 5 given above and is the same or different with it
  • R 8 stands for hydrogen or a protective group customary in peptide chemistry (cf. A. Hubbuch, contacts (Darmstadt) 1979. 14; EE Bullesbach, contacts (Darmstadt) 1980. 23),
  • n a number 0, 1 or 2
  • the compounds according to the invention have several asymmetric carbon atoms. They can therefore exist in various stereochemical forms.
  • the invention relates both to the individual isomers and to their mixtures.
  • R 1 represents a straight-chain, saturated or monounsaturated alkyl radical having 10 to 20 carbon atoms
  • R 2 represents a straight-chain, saturated or monounsaturated alkyl radical having 10 to 20 carbon atoms
  • R 3 represents hydroxy or acetylamino
  • R 4 for a radical of the formula
  • R 5 for hydrogen, C r to C 7 alkyl, hydroxymethyl, 1-hydroxyethyl, mercapto-methyl, 2-methylthio-ethyl, 3-aminopropyl, 3-ureido-propyl, 3-
  • R 6 represents hydrogen or a radical of the formula
  • R 7 has the meaning of R 5 given above and is the same or different with it
  • R 8 represents hydrogen, acetyl, benzoyl, trichloroacetyl, trifluoroacetyl, methoxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl or fluorenylmethyoxycarbonyl,
  • R 1 represents a straight-chain, saturated or monounsaturated alkyl radical having 10 to 20 carbon atoms
  • R 2 represents a straight-chain, saturated or monounsaturated alkyl radical having 10 to 20 carbon atoms
  • R 3 represents hydroxy or acetylamino
  • R 4 for a radical of the formula
  • R 3 represents hydrogen, C j - to C 7 -alkyl, hydroxymethyl, 1-hydroxyethyl,
  • R 6 represents hydrogen or a radical of the formula
  • R 7 has the meaning of R 5 given above and is the same or different with it
  • R 8 represents hydrogen, benzyloxycarbonyl or tert-butyloxycarbonyl
  • n a number 0, 1 or 2
  • R 1 , R 2 and R 3 have the meaning given above
  • R 5 , R 7 and n have the meaning given above,
  • R 9 represents a protective group for the nitrogen atom of amino acids which is customary in peptide chemistry and which can be split off again selectively while maintaining the peptide bond
  • R 10 represents a hydroxyl group or an escape group customary in peptide chemistry for the activation of amino acids
  • the 6-hydroxy function can be selectively introduced into a sulfonic acid ester of the general formula (IV)
  • R 11 represents, for example, methyl, triflourmethyl or p-tolyl
  • nucleophilic substitution of the 6-O-sulfonate groups in the compounds of formula (IV) with nitrogen nucleophiles an optionally blocked amino function can be introduced into the sugar residues.
  • Preferred nitrogen nucleophiles are azide anions which are used to form the 6-azido-6-deoxy-hexopyranosyl-amides of the formula (V)
  • Azido functions are blocked amino groups and can be converted into the amino groups under reducing conditions.
  • the 6-O-sulfonates (IV) are converted into the 6-azido-6-deoxy compounds (V) in an inert solvent, preferably N, N-dimethylformamide, with alkali azides, for example lithium azide or sodium azide, if appropriate elevated temperature.
  • the 6-O-methanesulfonates or the 6-O-toluenesulfonates are reacted with azide ions at temperatures of 50-150 °, preferably at 80-120 °.
  • the corresponding more reactive 6-O-trifluoromethanesulfonates are preferably reacted with azide ions at 40-80 °.
  • the conversion of the azido function into the amino function can take place under reductive conditions (see S.
  • Patai (ed.): The Chemistry of the Azido Group, Interscience Publishers, 1971). Preferred methods of the present application are the use of hydrogen in the presence of transition metals, preferably palladium / carbon.
  • This process is preferably used to prepare the compounds of the general formula (II) with saturated alkyl radicals R 1 and R 2 .
  • unsaturated alkyl radicals R 1 and / or R 2 in compounds of the general formula (II) the azido group is reduced by using reducing agents in which the unsaturated alkyl radicals are not reduced to the saturated alkyl radicals, for example by using the Staudinger Reaction.
  • the azido group is reduced by using phosphines, preferably triphenylphosphine, in the presence of organic nitrogen bases (cf. H. Paulsen et al., Chem. Ber. 114 (1981) 3242).
  • phosphines preferably triphenylphosphine
  • Suitable protective groups R 9 for the amino function in compounds of the formula (III) are, for example, acyl groups such as trifluoroacetyl or trichloroacetyl, o-nitrophenylsulfenyl, 2,4-dinitrophenylsulfenyl or optionally substituted lower alkoxycarbonyl such as methoxycarbonyl, tert.-butyloxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, fluorenylmethoxycarbonyl or 2,2,2-trichloroethoxycarbonyl.
  • acyl groups such as trifluoroacetyl or trichloroacetyl, o-nitrophenylsulfenyl, 2,4-dinitrophenylsulfenyl or optionally substituted lower alkoxycarbonyl such as methoxycarbonyl, tert.-butyloxycarbonyl, benzyl
  • Preferred amino protective groups R 9 are the tert-butyloxycarbonyl group or the benzyloxycarbonyl group.
  • 6-amino-6-deoxy-glycosylamides of the general formula (II) can be linked to the amino acids or the di- or oligopeptides of the general formula (III) by conventional methods of peptide chemistry (E. Wünsch et al .: synthesis von Peptiden, in: Methods of Organic Chemistry (Houben-Weyl) (E. Müller, ed.) Volume XV / I and XV / II, 4th edition, Thieme Verlag Stuttgart (1974)).
  • the condensation of the compounds of formula (II) with the compounds of formula (III) can also be carried out when the carboxy group is activated.
  • An activated carboxy group can be, for example, a carboxylic anhydride, preferably a mixed anhydride with alkyl carbonates, acetic acid or another carboxylic acid, or an amide of the acid, such as an imidazolide, or an activated ester such as, for example, cyanomethyl ester, pentachlorophenyl ester or N-hydroxyphthalimide ester.
  • Activated esters can also be obtained from the amino acid derivatives of the formula (III) in which R 10 is OH and N-hydroxysuccinimide or 1-hydroxybenzotriazole in the presence of a dehydrating agent such as carbodiimide.
  • the protective groups R 8 used with preference in the compounds of the general formula (I), the N-carbobenzoxy group and the N-tert-butyloxycarbonyl group, can be eliminated to give the amidic groups present in the compounds. Such methods are known in principle.
  • the carbobenzoxy group can be selected by hydrogenolysis in the presence of transition metals, such as palladium on carbon, in a suitable solvent such as methanol, ethanol, glacial acetic acid or tetrahydrofuran, either in pure form or in a combination of the solvents with one another, or also water split off, which can be carried out both at normal pressure and at elevated pressure.
  • transition metals such as palladium on carbon
  • a suitable solvent such as methanol, ethanol, glacial acetic acid or tetrahydrofuran
  • Suitable conditions include the use of hydrogen chloride or trifluoroacetic acid, either in pure form or diluted in suitable solvents such as glacial acetic acid, dichloromethane, diethyl ether, dioxane or ethyl acetate.
  • mice Female mice (CFW j ) weighing approx. 18 g were randomly divided into groups. The animals then became intraperitoneal, subcutaneous. or treated intravenously with a dose of 10 mg / kg body weight of the compounds of the formula (I) according to the invention, or received physiological saline solution. Twenty-four hours later, the animals were infected intraperitoneally with the 10-fold lethal dose (LD 50 ) of Escherichia coli C14. The following table shows that the survival rates seven days after infection in mice which had been treated with the compounds of the formula (I) according to the invention were significantly higher than that of mice which had received physiological saline solution.
  • glycosylamides of 6-amino-6-deoxy sugars have good activity as immunomodulator stimulators, in particular also as adjuvants for TNF formation.
  • RES retico-endothelial system
  • TNF- ⁇ is triggered, for example, by stimuli such as bacterial endotoxins / lipopolysaccharides (LPS) (B. Beutler et al. 1985 Nature 316: 562).
  • LPS lipopolysaccharides
  • TNF can play a critical role, ie overproduction or chronic production of TNF leads to Pathological changes in symptoms such as malaria or other diseases of mycobacterial origin
  • TNF-dependent, pathological changes under the conditions of bacterial sepsis with transition to lethal shock is well documented - at least in experimental animal models.
  • the stem cell number in the bone marrow of C57BL / 6 mice was reduced by fluorouracil (FU) and its regeneration was then examined under the influence of the GLAs (30 mg / kg sc). As shown in Fig. 1, the reconstitution of the damaged bone marrow is accelerated by the GLAs, the hematopoietic activity is increased.
  • FU fluorouracil
  • TNF is an important mediator of septic shock. It could be shown that glycolipids significantly reduce the E. coli-mediated TNF activity in the serum of mice (preventive). Glycolipids thus inhibit an important mediator of septic shock. NMRI mice were pretreated once with 30 mg / kg glycolipid subcutaneously, one hour later with a lethal dose (10 x LD 50 ) E. coli. TNF activity was determined 1.5 hours after infection.
  • mice are treated with 0.2 ml of a lethal germ suspension i.v. infected in the tail vein.
  • mice are observed until 4 h after treatment for possible
  • mice From 1 day to 14 days after infection, the mice are assessed once a day in the morning. The state of health is recorded in 5 levels. (- good - slightly ill - sick - seriously ill - dead -) The critically ill mice are killed after the assessment, they should not suffer.
  • mice are fixed in the hand.
  • the mice are fixed on the cage lid.
  • the mice are at the i.v. -Application and i.v. -Infection fixed in a mouse cage.
  • the mice are placed under red light for approximately 10 minutes before IV treatment and infection in order to dilate the tail veins.
  • Endocan is water soluble.
  • Animal husbandry The animals are kept in Type II Makrolon cages. All animals receive food and water ad libitum.
  • the N-carbobenzoxy-protected compound of the general formula (VI) (1.0 mmol) is dissolved in tetrahydrofuran (10 ml), methanol (5 ml) and 1N hydrochloric acid (1 ml) and mixed with 10% palladium-carbon ( 0.2 g) added.
  • the mixture is hydrogenated for 16 h at normal pressure in a hydrogen atmosphere. It is then suctioned off through a Celite filter layer and the residue is concentrated under reduced pressure.
  • the residue is purified by column chromatography on silica gel (mobile phase dichloromethane-methanol-concentrated ammonia 10: 1: 0.1).
  • the residue is dissolved in tetrahydrofuran (5 ml), water (30 ml) and 1N hydrochloric acid (1.5 ml) and freeze-dried.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Biophysics (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne des (6-amino-6-desoxy-glycosyl)-amides substitués de formule générale (I). L'invention concerne leurs procédés de préparation et leur utilisation dans des médicaments.
PCT/EP1994/002733 1993-08-30 1994-08-17 Glycosylamides de 6-amino-6-desoxy-saccharoses WO1995006653A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU76136/94A AU7613694A (en) 1993-08-30 1994-08-17 Glycosyl amides of 6-amino-6-deoxy sugars

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE4329092 1993-08-30
DEP4329092.2 1993-08-30
DE4404370A DE4404370A1 (de) 1993-08-30 1994-02-11 Glycosylamide von 6-Amino-6-desoxy-zuckern
DEP4404370.8 1994-02-11

Publications (1)

Publication Number Publication Date
WO1995006653A1 true WO1995006653A1 (fr) 1995-03-09

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ID=25929035

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1994/002733 WO1995006653A1 (fr) 1993-08-30 1994-08-17 Glycosylamides de 6-amino-6-desoxy-saccharoses

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AU (1) AU7613694A (fr)
WO (1) WO1995006653A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0091645A1 (fr) * 1982-04-14 1983-10-19 Bayer Ag Dérivés N-glycosylés d'amides d'acides carboniques, leur méthode de préparation et leur emploi pour influencer le système immunogène
EP0338308A2 (fr) * 1988-04-16 1989-10-25 Bayer Ag N-glycosylamides substitués, leur procédé de préparation et leur utilisation comme médicaments

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0091645A1 (fr) * 1982-04-14 1983-10-19 Bayer Ag Dérivés N-glycosylés d'amides d'acides carboniques, leur méthode de préparation et leur emploi pour influencer le système immunogène
DE3213650A1 (de) * 1982-04-14 1983-10-27 Bayer Ag, 5090 Leverkusen N-glycosylierte carbonsaeureamid-derivate, verfahren zu ihrer herstellung sowie ihre verwendung zur beeinflussung der koerpereigenen abwehr
EP0338308A2 (fr) * 1988-04-16 1989-10-25 Bayer Ag N-glycosylamides substitués, leur procédé de préparation et leur utilisation comme médicaments

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LOCKHOFF O.: "Glycolipids as Immunomodulators: Syntheses and properties", ANGEWANDTE CHEMIE. INTERNATIONAL EDITION, vol. 30, no. 12, 1991, WEINHEIM DE, pages 1611 - 1620 *

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Publication number Publication date
AU7613694A (en) 1995-03-22

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