EP0054025A1 - Nouveaux derives de l'alpha, alpha'-trehalose et medicaments les contenant - Google Patents

Nouveaux derives de l'alpha, alpha'-trehalose et medicaments les contenant

Info

Publication number
EP0054025A1
EP0054025A1 EP19810900515 EP81900515A EP0054025A1 EP 0054025 A1 EP0054025 A1 EP 0054025A1 EP 19810900515 EP19810900515 EP 19810900515 EP 81900515 A EP81900515 A EP 81900515A EP 0054025 A1 EP0054025 A1 EP 0054025A1
Authority
EP
European Patent Office
Prior art keywords
group
formula
residue
alanyl
carbons
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.)
Withdrawn
Application number
EP19810900515
Other languages
German (de)
English (en)
French (fr)
Inventor
Pierre Lefrancier
Michel Level
Françoise Audibert
Monique Parant
Jean Choay
Louis Chedid
Edgar Lederer
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.)
Bpifrance Financement SA
Original Assignee
Agence National de Valorisation de la Recherche ANVAR
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 Agence National de Valorisation de la Recherche ANVAR filed Critical Agence National de Valorisation de la Recherche ANVAR
Publication of EP0054025A1 publication Critical patent/EP0054025A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • C07H13/06—Fatty acids
    • 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

Definitions

  • the invention relates to new compounds endowed with biological and pharmacological properties of great value, and in particular among these products to those which have properties regulating the immune mechanisms.
  • the invention also relates to the applications of these new products, as well as the compositions specially suitable for their use.
  • the compounds according to the invention are derivatives of ⁇ -D-glucopyranosyl- ⁇ -D-glucopyranoside ( ⁇ , ⁇ '-trehalose), substituted asymmetrically on its two primary alcohol functions, in position C-6 of each of the monosaceharides constituents, according to the general formula
  • R 1 is a lipophilic group comprising at least 30 carbon atoms, preferably from 60 to 90 atoms, in particular a mycolic acid comprising from 80 to 90 carbon atoms;
  • R 2 is either OH, or an OR ester in which R is a radical comprising from 1 to 10 carbons, or NH 2 , the hydrogens of the amino group possibly being substituted by alkyl residues of 1 to 4 carbons, an aminoacyl residue substituted or not;
  • - X 1 is either a hydrogen or a muramyl or nor-muramyl or homo-muramyl residue which may or may not be substituted on the amino function at C-2 by acetyl or glycolyl groups, on the hydroxyl function at C-4 by an acyl group comprising at most -4 carbons and on the C-6 hydroxyl function by an acyl group comprising up to 90 carbons;
  • - X 2 is an aminoacyl residue from the group comprising: L-alanyl, L-arginyl, L-asparaginyl, L-aspartyle, L-cysteinyle, L-glutaminyle, L-glutamyle, glycyle, L-histidy L-hydroxyprolyle, L- isoleucyle, L-leucyle, L-lysyle, L-méthionyle, L-ornithyle, L-phenylalanyl, L-prolyl, L-seryle, L-threonyle, L-tryptophanyle, L-tyrosyle et L-valyle, atom d nitrogen of the characteristic chain element -NH -C0- of said aminoacyl residue being the case optionally N- substituted by a hydrocarbon group, in particular alkyl, comprising from 1 to 4 carbon atoms;
  • - X 3 may either not exist, or be an aminoacyl residue of the group indicated above or else a hydrocarbon residue comprising up to 10 carbons . in the formula of which there are two functions, such as for example alcohol, amino or carboxyl, able to be coupled, on the one hand with the ⁇ -carboxylic function of the D-glutamyl residue and, on the other hand, with the alcohol function in C-6 of the glucopyranosyl residue.
  • the group X 1 can more particularly be represented by the formula:
  • -R 3 is a hydrogen atom or a CH 2 OH or CH 3 group ;
  • R 6 is hydrogen or an acyl group comprising up to 90 carbon atoms
  • R 7 is a hydrogen atom or a methyl or ethyl radical.
  • the preferred compounds according to the invention are those in which X 2 is an L-alanyl, -N-methyl-L-alanyl or L-seryl residue.
  • the group R 3 is more particularly a methyl group.
  • the group R 7 is preferably a hydrogen atom or a methyl group. More preferably, and in the different classes of compounds envisaged above, R 2 . is an amino or ester group, in particular an n-butyl ester.
  • the invention also also relates, as preferred compounds, to those in which the groups R 4 and R 6 are both hydrogen.
  • X 3 is advantageously an L-alanyl group.
  • the products according to the invention are advantageously produced by reaction between a compound of formula
  • Ts is a tosyl group capable of reacting with the alkali salt, for example potassium salt of a carboxylic function, and a compound of formula
  • trehalose derivatives of formula III can be prepared according to the method described in POLONSKY et al.
  • the compounds according to the invention have non-specific stimulating properties, in particular adjuvants of immunity and anti-infectives. They also have anti-tumor properties with regard to certain types of tumors, in particular those which are capable of being treated by intra-lesional injections.
  • the adjuvant properties are found, more particularly in the compounds of the invention in which the group X .. is a derivative of the muramic type. They can be demonstrated in particular by the administration of these substances within a water-in-oil emulsion in the guinea pig vis-à-vis ovalbumin.
  • the results are shown in Table I by comparison with the adjuvant properties of N-acetyl-muramyl-L-alanyl- D-isoglutamine (MDP).
  • MDP N-acetyl-muramyl-L-alanyl- D-isoglutamine
  • the antitumor properties can be demonstrated by using the technique described by ELIYAHU YARKONI and collaborators; "International Journal of Cancer”: 22,564-569 (1978), by injection of an emulsion of compounds according to the invention in grafts of syngeneic murine fibro sarcoma in guinea pigs or mice.
  • any pharmaceutically acceptable oil can be used, in particular that known under the name of squalene or squalane.
  • the anti-tumor effect is manifested by a significant regression of the tumors.
  • the invention relates to bio.1oqic.ues reagents which can be constituted using the compounds according to the invention, in particular with a view to studying any standard adjuvant properties or, on the contrary, as eg ceptible of s' oppose certain effects linked to the administration of immunosuppressive substances.
  • the invention relates to medicaments? reifering as active principle at least one of the compounds according to the invention, this medicament being applicable as a regulator of the immune response of the subject to which it is administered.
  • drugs are especially applicable for the treatment of infectious diseases of bacterial or parasitic origin, or the inhibition of tumoral diseases.
  • the medicaments containing the compounds according to the invention can be used for the treatment of infants caused by agents resistant to antibiotics.
  • the application of these drugs is not only curative, it can also be done as a preventive measure.
  • the medicaments according to the invention can be administered to a host - animal or human being in any way suitable for obtaining the desired effect.
  • the invention naturally also relates to the various pharmaceutical compositions into which the compounds according to the invention can be incorporated, where appropriate in combination with other active substances.
  • compositions consist of injectable solutions or suspensions tables containing an effective dose of at least one product according to the invention.
  • these solutions or suspensions are produced in an isotonic sterilized aqueous phase, preferably saline or glucose.
  • the invention relates more particularly to such suspensions or solutions which are capable of being administered by intradermal, intramuscular or subcutaneous injections, or even by scarification.
  • compositions consist of the liposomal forms of the compounds according to the invention.
  • the liposomes due to the lipid (and in particular phospholipid) nature of the elements entering into their composition, constitute, for certain cases, a particularly suitable presentation.
  • the invention also relates to pharmaceutical compositions which can be administered by other routes, in particular by oral or rectal route, or also in forms intended to come into contact with mucous membranes, in particular the ocular, nasal, pulmonary or vaginal mucous membranes. Consequently, it relates to pharmaceutical compositions in which at least one of the compounds according to the invention is found associated with pharmaceutically acceptable excipients, solid or liquid, suitable for constituting forms of oral, ocular or nasal administration or with excipients suitable for constituting forms of rectal administration, or alternatively with excipients suitable for vaginal administration, for example gelatinous. Finally, it relates to compositions intended for the pulmonary route, in particular solutions prepared for administration by means of a conventional aerosol device.
  • the invention also consists of a method for strengthening the immune defenses of the host, comprising administering to it an effective dose of at least one of the products according to the invention, in one of the administration forms which has was mentioned above.
  • doses capable of inducing an action doses of 10 to 1000 ⁇ g per kg will be mentioned. of body for example 50 ⁇ g when the administration is carried out parenterally, or else a dose of 200 to 20,000 ug per kg. body, for example 1000 ⁇ q for other modes of administration, such as for example the oral route.
  • the invention also relates to the compositions containing at least one of the compounds according to the invention and being in the form of water-in-oil emulsions.
  • these emulsions contain from 1 to 10% by volume of oil, in particular squalene or squalane.
  • compositions can be used for performing intra-lesional injections in tumors of the mammary tumor, melanoma and other solid tumors type.
  • the invention finally relates to compositions of the above-mentioned type containing, in addition to the compounds according to the invention, in particular at the unit doses which have been indicated above, active principles of vaccine: the use of these compositions then being recommended when we want to take advantage of the adjuvant effect, immunologically non-specific of the compounds according to the invention in order to enhance the effect of the above vaccinating principles.
  • the invention therefore also relates to vaccine compositions containing at least one of the above compounds.
  • a vaccine antigen forming the active principle of such compositions mention may be made of that of influenza.
  • the invention is obviously not limited to the embodiments described above by way of example and the man of the art r> had to make modifications without departing from the scope of. claims below.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Engineering & Computer Science (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Biophysics (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP19810900515 1980-03-10 1981-03-09 Nouveaux derives de l'alpha, alpha'-trehalose et medicaments les contenant Withdrawn EP0054025A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR8005332 1980-03-10
FR8005332A FR2477551A1 (fr) 1980-03-10 1980-03-10 Nouveaux derives de l'a, a'-trehalose et medicaments les contenant

Publications (1)

Publication Number Publication Date
EP0054025A1 true EP0054025A1 (fr) 1982-06-23

Family

ID=9239492

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19810900515 Withdrawn EP0054025A1 (fr) 1980-03-10 1981-03-09 Nouveaux derives de l'alpha, alpha'-trehalose et medicaments les contenant

Country Status (3)

Country Link
EP (1) EP0054025A1 (enExample)
FR (1) FR2477551A1 (enExample)
WO (1) WO1981002576A1 (enExample)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU609914B2 (en) * 1987-12-16 1991-05-09 Kenneth Ronald Daff Method of and means for forming a hole in metal

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GR860379B (en) * 1985-02-22 1986-06-11 Akzo Nv Novel disaccharide and trisaccharide derivatives of the lipid a type
CN103665058B (zh) * 2013-11-29 2016-08-17 沈阳药科大学 毛樱桃中苯丙蔗糖酯苷类化合物及其制备方法和用途

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2319373A1 (fr) * 1975-07-29 1977-02-25 Anvar Nouveau procede d'esterification selective des fonctions alcool primaire de diholosides et produits ainsi obtenus
JPS54130516A (en) * 1978-03-31 1979-10-09 Yuuichi Yamamura Acyllnnacetylmuramylpeptide derivativeeantigen combination

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8102576A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU609914B2 (en) * 1987-12-16 1991-05-09 Kenneth Ronald Daff Method of and means for forming a hole in metal

Also Published As

Publication number Publication date
FR2477551B1 (enExample) 1983-02-25
FR2477551A1 (fr) 1981-09-11
WO1981002576A1 (fr) 1981-09-17

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Legal Events

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PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

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STAA Information on the status of an ep patent application or granted ep patent

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Effective date: 19820601

RIN1 Information on inventor provided before grant (corrected)

Inventor name: LEVEL, MICHEL

Inventor name: LEDERER, EDGAR

Inventor name: PARANT, MONIQUE

Inventor name: LEFRANCIER, PIERRE

Inventor name: AUDIBERT, FRANCOISE

Inventor name: CHOAY, JEAN

Inventor name: CHEDID, LOUIS