NZ204379A - N-acetylglucosamine derivatives and pharmaceutical compositions - Google Patents
N-acetylglucosamine derivatives and pharmaceutical compositionsInfo
- Publication number
- NZ204379A NZ204379A NZ204379A NZ20437983A NZ204379A NZ 204379 A NZ204379 A NZ 204379A NZ 204379 A NZ204379 A NZ 204379A NZ 20437983 A NZ20437983 A NZ 20437983A NZ 204379 A NZ204379 A NZ 204379A
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- benzyl
- spacer
- formula
- hydrogen
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-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/002—Protozoa antigens
- A61K39/015—Hemosporidia antigens, e.g. Plasmodium antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
- C07H3/06—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Tropical Medicine & Parasitology (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Animal Behavior & Ethology (AREA)
- Genetics & Genomics (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Epidemiology (AREA)
- Saccharide Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
New Zealand Paient Spedficaiion for Paient Number £04379
I
2043 79
M DRAWINGS
Pili
.... -S--3Q.
Complete- Specification Filed:1-?!"?. !5~ Class: .
Publication Date: ... ?.P. AUG 1985 P.O. Journal, ilo: ... t P-.7. ?K.
N.Z.No.
NEW ZEALAND
Patents Act 1953
COMPLETE SPECIFICATION
"N-acetylglucosamine derivatives, a process for their preparation and their use for combating malaria."
We, BEHRINGWERKE AKTIENGESELLSCHAFT of D-3 550 Marburg 1, Federal Republic of Germany, a corporation organized under the laws of the Federal Republic of Germany do hereby declare the invention, for which we pray that a Patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement : -
204379
1. A composition for combating malaria containing a chemical compound of the general formula I
HC0CH3
wherein, in formula I:
1.1. R^ is hydrogen or
1.2. R1 is C-j to Cg-alkanyl, -alkenyl or -alkinyl,
in each case branched or straight-chain, or a sub t
stituted or unsubstituted, alicyclic or aromatic hydrocarbon radical, or
1.3. a spacer, which is suitable for linking to"pro-teins or aminated matrices, or
1.4. a spacer bound to a natural or synthetic carrier, and
1.5. R^, R^ and R* are hydrogen or -L-fucopy-
ranosyl, but at most one radical is «C-L-fuco-pyranosyl, and a pharmaceutically acceptable carrier.
2. If R^ is a spacer, it has the general formula
-R-COR^, is 0.3 nm to 3 nm long and can contain the atoms C, H, 0, N, S and P, possibility of reaction with the remaining groups contained in the compound of the formula I being excluded.
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3. As a spacer, is preferably
3.1. -<CH2)nNHC0(CH2>mC0R5 or
3.2. -(CH2)nC0NH(CH2)mC0R5 or
3.3. -(CH2)xC0R^,inwhich
3.A. n = 1 to 10, m = 1 to 10,
3.5. x = 3 to 17 and
3.6.1. R^ is -H or -OH, or
3.6.2. R^ is C-j-Cg-alkanoxy, -alkenoxy or -alkin-
oxy, in each case branched or straight-chain, 0-10 phenyl, preferably substituted by inductive atoms or groups, such as N02, or substituted or un-substituted 0-benzyl, or
3.6.3. -NH, -NHNH2 or -N3.
4. R1 is preferably -(CH2>nNHCO(CH2>mCOR5,
in which R = alkoxy, n = 2 and m = 4 or 7.
. R^ is furthermore preferably -(CH2) xC0R**,
in which R^ = alkoxy and x = 3 to 10, particularly preferably in which x = 8.
6. If R^ denotes a spacer and carrier, R^ is a
soluble or insoluble, natural or synthetic carrier,
preferably a protein or a synthetic or natural polymer containing amino groups, preferably human albumin, collagen or aminated silica gel.
7. The glycosidic bond to the spacer is preferably a 25 -bond.
8. The invention relates to the use of a chemical compound of the formula I
8.1. for the chemotherapy and chemoprophylaxis of malaria and
2 043 7 9
8.2. for the preparation of a vaccine for malaria. 9. The invention furthermore relates to a chemical compound of the formula I,
9.1. in which is hydrogen 5 9.2. and R2, R^ and R^ have the meaning given unde r 1.5,
9.3. but the compound in which R^ is °C-L-fucopyra-nosyl and R^, R2 and R^ are hydrogen being excluded,
10. and to a process for its preparation.
11. The invention furthermore relates to a compound of the formula I,
11.1. in which R has the meaning given under 1.2.
TP /
11.2. and R , R and R have the meaning given 15 under 1 .5 .,
12. and to a process for its preparation.
13. The invention moreover relates to a compound of the formula I,
13.1. in which is as in 1.2.,
13.2.1 R^ is 2,3,4-tri-0-benzy I- ^ -L-fucopyranosy I and 2 3
R and R together are alkylidene, preferably isop ropy I idene,
13.2.2. or R is 2,3,4-tri-0-benzy l-°<-L-fucopyra nosy I and R^ and R^ together are alkylidene, prefe-
rably benzy Iidene,
13.2.3. or R^ is 2,3,4-tri-0-benzy I- ^—L-fucopyranosy I,
2
R is benzyl, benzy loxymethy I, methoxymethyI or allyl and R^ is benzyl, benzy loxymethyI or acyl, preferably acetyl,
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13.2.A. but, for a compound according to 13.2.3., the compound in which R2 is a I ly I or benzyl and R^
is benzyl being excluded if is ^-benzyl,
14. and to a process for its preparation.
15. The invention furthermore relates to a compound of the formula I,
A
.1.1. in which R is a spacer according to 1.3. and 2.,
.1.2. preferably a spacer, according to 3.1. to 3.6.2.,
.2. and R2, R^ and R^,
15.2.1. have the meaning given under 1.5.,
.2.2. or under 13.2.1.,
.2.3. or under 13.2.2.,
.2.4. or under 13.2.3.,
.3.1. but the compound in which the spacer is as in 3.3.,
15.3.2. in which is as in 3.6.1. or 3.6.2., being excluded,
.3.3. if the glycosidic bond to the spacer is a -bond,
16. and to a process for its preparation.
17. The invention moreover relates to a compound of
the formula I,
A
17.1. in which R - according to 1.4. - is a spacer bonded to a natural or synthetic carrier,
p 7 /
17.2. and R, R and R have the meaning given under 1.5.,
17.3.1. but the compound containing a spacer according to 3.3. being excluded
17.3.2. if the glycosidic bond to the spacer is a /3-bond,
18. and to a process for its preparation.
An isolated, purified, non-toxic, soluble parasitic
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antigen which is stable, preservabte and immunogenic per se, i.e. requires no adjuvant when administered, is nowadays considered the ideal vaccine for malaria (R.S.Desowitz and L.H.Miller, Bull. WHO (1980) 5£, 897-908). No such 5 vaccine exists.
There was therefore the object of isolating, purifying and characterizing antigens of the ma larial parasite P.falciparum and testing their possible suitability as a malaria vaccine.
It is known that the isolation of proteins from a protein mixture can be greatly simplified by affinity chromatography. Analogously, antigens can be isolated by immunoadsorbents to which corresponding antibodies or lectins are bound, and antibodies can be isolated by i m-15 munoadsorbents to which corresponding antigens are bound. In this respect, access to monoclonal antibodies, for example by cell fusion (G.Kohler and C. Milstein, Nature (1975), 256, 495-497), and access to synthetic carbohydrate antigenic determinants vhich can be covalently attached 20 to a carrier protein or a solid matrix by means of a suitable spacer.(R.U. Lemieux, D. R. Bundle and D.A. Baker,
U.S. Patent No. 4,238 ,473) ; and R«U» Lemieux,
Chem. Soc. Rev. (1978) ^23-^52), have recently been of particular interest.
Surprisingly, it has now been found that compounds of the formula I are suitable for selective isolation of ceptors of the malarial parasite Plasmodium falciparum, specially when covalently attached to a solid matrix by eans of a spacer.
It has furthermore been found that compounds of
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the formula I can be used for the chemotherapy and chemo-prophylaxis of malaria.
Vanderberg et al. (M.M. Weiss, J.D. Oppenheim and J.P. Vanderberg, Exp. Parasitol. (1981) 5_1_, 400-407) have 5 found that the invasion of human erythrocytes by P. falciparum merozoites in synchronized in vitro culture is inhibited by addition of N-acetyl-D-glucosamine (DGlcNAc), D-glucosamine hydrochloride (DGlcNHjCl) and L-fucose.
They have furthermore found that intraerythrocytic growth 10 of the ma lari al parasites is inhibited by DGlcNH^Cl or L-fucose but not, however, by N-acetyl-D-glucosamine.
From this, they concluded that DGlcNH^Cl and L-fucose are toxic to malarial parasites.
The authors have assumed that D-GlcNAc acts as a 15 specific penetration inhibitor by blocking a receptor essential for the invasion process.
They have furthermore assumed that DGlcNAc is an important component of the glycoprotein receptor, which mediates the recognition or penetration of P-falciparum 20 merozoitesinto human erythrocytes,whereas D-ClcNHjCl and L-fucose are toxic.
Surprisingly, it has now been found that - in contrast to the findings of Vanderberg et al. - D-GlcNAc is toxic to intraerythrocytic parasite development, whereas L-fu-25 cose - again in contrast to the findings of Vanderberg et al. - is not toxic.
It has furthermore been found that the methyl'K-or (^-glycoside corresponding to DGlcNAc, i.e. methyl-2-acetamido-S-deoxy-^-or -(^-D-glucopyranoside (<y - or
204379
-DGLcNAcOMe), is not toxic to intraerythrocytic growth of P. fa Iciparum, but, in comparison with other methyl glycosides, such as, for example, methyl - or /3-D-glu-copyranoside, methyl ^ - or @-D-ga lactopyranoside, methyl 5 cv - or -L-fucopyranoside or methyl -D-mannopyranoside, has a greatly increased inhibitory potency on the invasion process,
It has furthermore been found, surprisingly, that with a compound of formula I, in which L-fucose is bl-glycosidi-
cally bound to N-acetyl-D-glucosamine, the inhibiting 10 action of DGlcNAc on the invasion of human erythrocytes by P. falciparum raerozoites in synchronized in vitro culture is increased.
19.1. The invention thus relates to the use of a com-
1 A
pound of the general formula I in which R to R 15 have the meaning given under 1.1. to 6.,
19.1.1. for the chemotherapy and chemoprophylaxis of malaria and
19.1.2. for the preparation of a vaccine for malaria.
19.2.1. The invention furthermore relates to a compound
of the general formula I in which R^ to R^
19.2.1. have the meaning given under 9.1. and 9.2., with the restriction made under 9.3., or
19.2.2. have the meaning given under 11.1. and 11.2.
19.3. The invention moreover relates to a compound of 25 the general formula I in which R*' to R^ have the meaning given under 11.1. and 11.2.
19.4. The invention furthermore relates to a compound of the general formula I
19.4.1. in which R^ is as in 1.2.
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p /
19.4.2. and Rc to R H have the meaning given in 13.2.1. or 13.2.2. or 13.2.3.,
19.4.3. but the restriction made in 13.2.4. applies to a compound according to 13.2.3.
19.5. The invention moreover relates to a compound of the general formula I
A
19.5.1.1. in which R is a spacer according to 15.1.1.,
19.5.1.2. preferably a spacer according to 15.1.2.,
p /
19.5.2. and R to R have the meaning given under 1.5. 10 or 13.2.1. or 13.2.2. or 13.2.3.,
19.5.3. but the compound
^ A
19.5.3.1. in which R to R are as in 1.5. being excluded
19.5.3.2.1. if the spacer is as in 3.3.,
\
19.5.3.2.2. in which R^ is as in 3.6.1. or 3.6.2.,
19.5.3.2.3. and if the glycosidic bond to the spacer is a -bond.
19.6. The invention furthermore relates to a compound of the general formula I 20 19.6.1 in which R^ - according to 1.4. - is a spacer bound to a natural or synthetic carrier 19.6.2. and R2, R^ and R^ have the meaning given under 1 .5 . ,
19.6.3.1. but the compound in which the spacer is as in 25 3.3.
19.6.3.2. in which R5 is as in 6., being excluded
19.6.3.3. if the glycosidic bond to the spacer is a ft -bond.
. The invention moreover relates to a process for
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the preparation of a compound, of the general formula I, mentioned under point 19.2., 19.3., 19.4., 19.5. or 19.6.
Process for the preparation of a compound of the formula I 5 21. The process according to the invention for the preparation of a chemical compound of the formula I comprises
21.1. synthesizing a compound of the general formula II
H0(CH2>nNHC0(CH2)mC0R5,
in which n and m have the meaning given under 3.4.
and R"5 has the meaning given under 3.6.2., by reacting an aminoa Icoho I, for example 2-aminoetha-nol, with a dicarboxylic acid monoester, for example monomethyl adipate, in the presence of di-15 cyclohexy1carbodiimide in dry dimethy Iformamide,
or
21.2. synthesizing a compound of the general formula III
H0(CH2)nC0NHCCH2>mC0R5,
in which n, m and R"* have the meaning given un-20 der 21.1., for example analogously to 21.1. by reacting an O-hydroxycarboxy lic acid, for example glycolic acid, with an ^-aminocarboxyIic acid ester, for example ethyl 4-aminobutyrate, or
21.3. synthesizing a compound,of the general formula IV 25 HO(CH2)xCOR5,
in which x and R*5 have the meaning given under 3.5. and respectively, 3.6.2., in a manner which is known per se (R.U.Lemieux, D.R.Bundle and D.A.Baker, J. Am. Chem. Soc. 97, (1975), 4076-
204379
4083) and
22.1. reacting a compound of the formula II, III or IV with 2-acetamido-3,4,6-tri-0-acyl-(preferably acetyl or benzoyI)-2-deoxy- \ -D-glucopyranosyl 5 bromide or chloride in a manner which is known per se (R.U.Lemieux, D.R.Bundle and D.A.Baker, J. Am. Chem. Soc. 97_ (1975), 4076-4083) to give a compound of the formula I in which
22.1.1. R2, R^ and R^ are acyl, preferably acetyl 10 or benzoyl,
22.1.2. and R has the meaning given under 3. to 3.5., in which R is as in 3.6.2. and
22.1.3. the glycosidic bond to the spacer is a ^3-bond,
22.1.4. the restriction made under 15.3.1. and 15.3.2. 15 applying to the reaction of a compound of the formula IV, or
23. reacting a compound of the formula II, III or IV
with 3,4,6-1ri-0-acy I - (preferab ly acetyl or benzoy l)-2-az ido-2-deoxy-^5 -D-glucopyranosyl chloride 20 in a manner which is known per se (European Patent
Application No. 0,044,188) to give a compound of the formula V
4
23.1.1. in which R has the meaning given under 3. to 25 3.5., in which R5 has the meaning given under
204379
3.6.2.,
23.1.2. R2, R^ and R^ are as under 22.1.1. and
23.1.3. the glycosidic bond to the spacer is an V -bond,
and
23.2.1. reducing the 2-azido group to the amino group in a manner which is known per se, preferably by catalytic hydrogenation or by reduction with hydrogen sulfide in pyridine/triethylamine, and 23.2.2. acetylating the product in a manner which is 10 known per se, preferably by means of acetic anhy dride in dry methanol,
23.3. a compound of the formula I in which 1 5
23.3.1. R to R have the meanings given under 23.1.1. and 23 .1 .2. and
23.3.2. the glycosidic bond to the spacer is an ^-bond, being formed, or 24. reacting the halogeno-sugar mentioned under 22.1.
A
with an alcohol of the general formula HOR , in which R has the meaning given in 1.2., in a i
manner which is known per se
.1. to give a compound of the formula I in which
.2. R2, R^ and R^ are as under 22.1.1.,
.3. R has the meaning given in 1.2. and
.4. the glycosidic bond is a - bond, or
26.1 . reacting the ha logeno-sugar mentioned under 23.
4
with an alcohol of the general formula HOR1 in which R^ has the meaning given under 1.2., in a manner which is known per se, whereupon a compound of the general formula V in which
. V •
2 043 79
26.2. R2, R3 and R^ are as under 22.1.1.,
26.3. R^ has the meaning given in 1.2. and
26.4. the glycosidic bond is an CV*-bond is obtained,
and
27.1. converting this compound, analogously to 23.2.1.
and 23.2.2., into a compound of the general formula I
27.1.1. in which R1 is as in 1.2., R2, R3 and R^" have the meaning given in 22.1.1. and
27.1.2. the glycosidic bond to the spacer is an ^-bond,
and
28. converting the compound of the formula I obtained according to 22.1., 23.3., 25.1.-4. and 27.1.
28.1. into a compound of the formula I in which
07 /
28.1.1. R , R and R are hydrogen and
28.1.2. R^ has the meaning given under 1.2., 1.3. and 3. to 3.5., in which R-5 is as under 3.6.2., in a manner which is known per se, preferably by means of sodium methylate in dry methanol,
29. and converting this compound, in a manner which is known per se, into a compound of the formula Iinwhich
1
29.1. R has the meaning given under 28.1.2.,
29.2. R^ is hydrogen and
29.3. R and R , together with the bridge carbon atom, are alkylidene, preferably isop ropy I idene,
or
. into a compound of the formula I in which
.1. R^ is as under 28.1.2.,
2.043 7 9
.2. Rc is hydrogen and
.3. R3 and R^, together with the bridge carbon atom, are benzylidene or alkylidene, or
31. into a compound according to 30., and converting 5 this compound
32. via a compound of the formula I
32.1. in which R^ has the meaning given under 28.1.2.,
32.2. R3 and R^, together with the bridge carbon atom, have the meaning given in 30.3. and
2
32.3. R is benzyl, benzy loxymethy I, methoxymethy I or a I ly I, and
33. via a compound of the formula I
33.1. in which R has the meaning given under 28.1.2.,
2
33.2. R has the meaning given under 32.3. and 15 33.3. R3 and R^ are hydrogen,
34. into a compound of the formula I
34.1. in which R^ has the meaning given under 28.1.2.,
34.2. R has the meaning given in 32.3.,
34.3. R3 is hydrogen and
34.4. R^ is benzyl, benzy loxymethy I or acyl, preferably acetyl, and
. reacting the compound obtained in 29., 30. or 34. 35.1. with 2,3,4-tri-0-benzy I- -L-fucopyranosy I bromide or
35.2. with 1-0-(N-methyl)-acetimidyl-2,3,4-tri-0-benzyl-(i -L-fucopyranose in a manner which is known per se
36. to give a compound of the formula I 36.1. in which R^ is as in 28.1.2. and
-«- ■ 2043 7 9
36.2. R2, R3 and R^ are as in 13.2.1. or 13.2.2. or 13.2.3., and then, in a manner which is known per se,
37. splitting off the protective groups of a compound
of the formula I in which R^ is as in 28.1.2.
and R2 to R^ are as in 13.2.1. in any desired sequence by hydrolysis, preferably by dilute tri-fluoroacetic acid, and hydrogenolysis, preferably by means of pa Iladium-on-charcoa I, or
38. splitting off the protective groups of a compound of the formula I in which R is as in 28.1.2. and R2 to R^ are as in 13.2.2.
38.1. either hydrogeno lyticaI ly, if R3 and R^ together are benzylidene,
38.2. or hydrolytica I ly and hydrogenolyticaIly, if R3 and R ^ together are alkylidene, or
39. splitting off the protective groups of a compound of the formula I in which R1 is as in 28.1.2.
and R2 to R^ are as in 13.2.3.
39.1. either hydro lytica I ly, if R2 and R^ are benzyl or benzyloxymethy I,
39.2. or by means of titanium tetrachloride and hydro-geno lyticaI ly, if R is methoxymethyI and R is benzyl or benzyloxymethyl,
39.3. or by means of tris-CtriphenyIphosphine)-rhodium-(I) chloride and a mixture of mercury bromide and oxide and hydrogeno lytica I ly, if R is allyl and R^ is benzyl or benzy loxymethy I,
39.4. or by means of sodium methylate in dry methanol
204379
and hydrogenolytically, if is acyl, preferably acetyl, and R is benzyl or benzyloxymethy I,
39.5. or in a combination of the reactions according to 39.4. and 39.2., if is acyl, preferably acetyl,
2
and R is methoxymethy I,
39.6. or in a combination of the reactions according to 39.4. and 39.3., if R^ is acyl, preferably acetyl,
2
andRisallyl,
40. a compound of the formula I in which p 7 /
40.1. R , R and R are hydrogen or °C -L-fucopyra-nosyl,
40.2. but at most one radical is ^ -L-fucopyra-nosy I,
40.3. and R has the meaning given under 28.1.2.,
40.4.1. but in the case where R^ was benzyl before split-ting off of protective groups, R is now hydrogen, 40.4.2. but the compound in which R3 is -L-fucopyra-
4 p /
nosyl and R , R and R are hydrogen being excluded, being obtained,
41 . and converting a compound according to point 40.,
A
for which the restriction that R does not have the meaning given under 1.2. applies,
42. into a compound of the general formula I
p 7 /
42.1. in which R, R and R have the meaning given 25 under 40.1. and are subject to the restriction mentioned in 40.2.
1 1
42.2. and R is a spacer mentioned under point 2.
42.3. preferably a spacer classified according to point 3. to 3.5.
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42.4. in which R is -OH, -NHNH2 or-Nj, in a manner which is known per se,
43. and, finally, coupling or attaching a compound accor ding to point 42. to a soluble or insoluble carrier with free amino groups in a manner which is known per se (R .U.Lemieux, D.R.Bundle and D.A.
Baker, U.S. Patent No. 4,238,473) .
* «
Examples of suitable carriers are peptides or proteins, preferably bovine serum albumin or human albumin,
red or white blood cells, aminated silica gel, plas tics carrying amino groups or oIigo- or poly-saccharides carrying amino groups.
A compound obtained in this manner may, depending on its structure, serve as a macromolecule tolerated by' humans, or may be used as an antigen or immunoadsorbent.
Use of a compound of the formula I for the chemotherapy and chemoprophy laxis of malaria
For the chemotherapy and chemoprophylaxis of malaria, a compound of* the formula I, tolerated by humans, in which the 1 k 5
radicals R to R or R have the meaning given under 1.1. to 6. is administered orally or pa renteraIly, once or several times, in an effective amount of, for example, 0.1 jjg to 100 mg of active compound per kg of body weight, if appropriate in combination with an auxiliary and/or additive tolerated by humans.
Use of a compound of the formula I for the preparation of a malaria vaccine
2 8 MAR I985m/i To prepare a vaccine for malaria, intact merozoites or a merozoite lysate are incubated with a compound of
2043 7 9
the formula I in which R^ is a spacer bound to a solid carrier, preferably an aminated matrix, and R2 to R^ have the meaning given in 1.5. The incubated intact merozoites are lysed under buffered physiological conditions (A.Kile-jian, Proc. Natl. Acad. Sci. USA (1980), 7_7, 3695-3699).
The carrier thus treated is washed and subsequently eluted, preferably over a column, by chaotropic change or at a pH between 2.5 and 5 or between 8 and 11 or by addition of N-acety Ig lucosamine or -DG IcNAcOMe.
The product obtained in this manner, which can be purified in a manner which is known per se, is administered as a vaccine for active immunization against malaria.
204379
Claims (2)
1. A composition for combating malaria containing a chemical compound of the general formula I kxoch3 wherein, in formula I: 1.1. 1s hydrogen or 1.2. R1 is C-j to Cg-alkanyl, -alkenyl or -alkinyl, in each case branched or straight-chain, or a sub stituted or unsubst1tuted, alicyclic or aromatic hydrocarbon radical, or 1.3. a spacer, which is suitable for linking to proteins or aminated matrices, or 1.4. a spacer bound to a natural or synthetic carrier, and 1.5. R2, R3 and R^ are hydrogen or ^ -L-f ucopy- ranosyl, but at most one radical is ■C-L-fuco-pyranosyl, and a pharmaceutical^ acceptable carrier.
2. A composition as claimed in claim 1 in which R"'" is benzyl or substituted benzyl.
3. A composition as claimed in claim 1 in £04-379 - 20 - which the spacer 1s -CCH2>nNHC0<CH2>mC0R5, 1n which n e 1 to 10, m * 1 to 10 and R^ 1s -H, -OH, C-j-Cg-alkanoxy, -alkenoxy, or -alkinoxy, 1n each case branched or straight-chain, 0-phenyl, optionally substituted by inductive atoms or groups.
4. A composition as claimed 1n claim 1, 1n which the spacer is -(CH2)nC0NH(CH2>mC0R5, in which n = 1 to 10, m = 1 to 10 and is -H, -OH, C-j-Cg-a Ikanoxy, -alkenoxy, or -alkinoxy, in each case branched or straight-chain, 0-phenyI,optionally substituted by inductive atoms or groups substituted or unsubst 1 tuted 0-benzyl, -NH2, -NHNH2 or -Nj.
5. A composition as claimed in claim 1, in which the spacer is -<CH2)xC0R^ in which x = 3 to 17 and R^ is -H, -OH, C-j-Cg-alkanoxy, -alkenoxy or -alkinoxy, in each case branched or straight-chain, 0-phenyl, optionally' substituted by inductive atoms or groups 2 substituted or unsubstituted 0-benzyl, -NH2, -NHNH2 or -N3. ■6. composition as claimed in claim 1, in which the spacer is -(CH2>pNHC0(CH2)mC0R5 or -<CH2>n-C0NH(CH2)mC0R^, in which n = 2, m = 4 or 7 and R^ is -H, -OH, branched or straight-chain C-j-Cg-a Ikoxy, 0-phenyl, optionally substituted by inductive atoms or groups.
7. A composition as claimed in claim 1, in which the spacer is -<CH2)xC0R^ in which x - 3 to 10 and R^ ^ f *" ... is -H, -OH, branched or straight-chain C.,-Cg-a Ikoxy, " v ■ n 4 J Ui;i 1985 204379 - 21 - O-phenyl, optionally substituted by inductive atoms or groups^ 8- A -composition as claimed in claim 1, in. which the spacer is -(CH2>xC0r5, in which x = 8 and is -H, -OH, branched or straight-ch,ain C-j-Cg-a Ikoxy, 0-phenyl, optionally substituted by inductive atoms or groups* A composition as c laimed in claim 1, in which, if denotes a spacer and carrier, R ^ is spacer coupled to a soluble natural carrier.
10. A composition as claimed in claim 1, in which, if denotes a spacer and carrier, R 1 is a spacer coupled to human albumin, collagen or bovine serum albumin. 1 1. A composition as claimed in claim 1, in to which, if R^ denotes a spacer and carrier, R^ is a spacer coupled/ an insoluble natural or synthetic carrier, .carrying amino ^groups; ^2 -A' composition as claimed in claim 1 , in which, if R^ denotes a spacer and carrier, R^ is a spacer coupledrto an aminated silica gel. 1 3. A composition as claimed in claim 1, in ,1 which the glycosidic bond to R' is a ^-bond. .j ^ A "composition as claimed in claim 1, in which the glycosidic bond to R^ is an Of--bond. .j j. A composition as claimed in any of claims 1 to 9 or 12 or 1 \ for the chemotherapy and chemoprophy- 204379 - 22 - taxis of malaria.
16. The use of a compound as describeain any of claims 10 to 1S in a process for the preparation of a vaccine for malaria, which comprises bringing .such a compound together with merozoltes in suspension, lysing the merozoites bound to the compound, separating off and washing the undissolved phase, detaching the merozolte constituents bound to the compound by chaotropic change or a change in pH or by addition of N-acetylglucosamine or -DGlcNAcOMe and working up the product to a vaccine. 17- The use as claimed in claim 16, wherein the merozoites are lysed. as ^described
18. A compound of the formula I^iri claim 1, in which is hydrogen and R2, R3 and R^ are hydrogen or -L-fucopyranosyI, but at most one radical 1s -L-fucopyranosy I and the compound in which R3 is<\--L-fucopyranosyI and R^, R2 and R^ are hydrogen 1s excluded.
19. a compound of the formula ^^in^^claim 1, in which R^ 1s C-j to Cg-alkanyl, -alkenyl or -alkinyl, in each case branched or straight-chain, or a substituted or unsubstituted, alicyclic or aromatic hydrocarbon radical, and R2, R3 and R^ are hydrogen or -L-f ucopyranosy I, but at moat one radical is -L-fucopyranosyI. as described nv 20. A compound of the formula lyin claim 1, in which "A ' . ' « 1 R is to Cg-alkanyl, -alkenyl, or -alkinyl, in 204379 - 23 - each case branched or stra18ht-cha1n, or a substituted or unsubstltuted, all cyclic"or aromatic hydrocarbon radical, 2 and R4 Is 2,3,4- tri-0-benzyI-V-L-fucopyranosyl and R and R3 together are alkylidene, or R2 is 2,3,4- tri-0-benzyl- -L-fucopyranosyl and R3 and R4 together are alkylidene, or R3 is 2,3,4- tri-0-benzyl-0*-L-fucopyranosyI, R2 is benzyl, benzyl- oxymethyl, methoxymethyl or allyl and R4 is benzyl, benzyloxymethyl or acyl, but the compound in which R2 is allyl or benzyl and R4 is benzyl being excluded if R1 is c^-benzy l- as described 21- A compound of the formula IMn claim 1, in which R1 is -(CH2)nNHC0CCH2)mC0R5, -(CH2>nC0NHCCH2)m-COR5 or -CCH2)xC0R5, in which n = 1 to 10, m = 1 to 10, x = 3 to 17 and R5 is -H, -OH, C1-C8-aIkanoxy, -al- kenoxy or -alkinoxy, in each case branched or straight-chain, 0-phenyI,optionally substituted by inductive atoms or groups or substituted or unsubstituted 0- benzyl, -NH2, -NHNH2 or -N3, and R2, R3 and R4 are hydrogen or -L-fucopyranosyI, but' at most one radical is v -L-fucopyranosyI, the compound in which R^ is -(CH2)XC0R^' w^ich x = 3 - 17 and R^ is C-j-Cg-a Ikoxy, 0-phenyl or 0-benzyl, being excluded if the glycosidic bond to the spacer is a /3-bond. 204379 - 24 - as described 2 2. A compound of the formula nn claim 1, in which R1 is -<CH2)NHC0(CH2>mC0R5, - <CH2) nC0NH (CH2) COR5 or -<CH2)xC0R5, in which n = 1 to 10, m - 1 to 10, x = 3 to 17 and R5 is -H, -OH, C-j-Cg-a Ikanoxy, -alke-noxy or -alkinoxy, in each case branched or straight-chain, 0-phenyI,optionally substituted by inductive atoms or groups, or substituted or unsubstituted 0-benzyl, -NH2, -NHNH2 or -Nj, and is hydrogen 2 ^ or 2,3,4-tri-O-benzyl-0* -L-f ucopy r a nosy I and Rand RJ 1 together are alkylidene. as described
23. A compound of the formula lYin claim 1, in which R1 is -<CH2)nNHC0(CH2)mC0R5, -<CH2>nC0NH(CH2>„- COR5 or -(CH2)xC0R5, in which n = 1 to 10, m = 1 to 10, x = 3 to 17 and R5 is -H, -OH, C-j-Cg-a Ikanoxy, -alke-noxy or -alkinoxy, in each case branched or straight-chain, 0-phenyl, optionally substituted by inductive atoms or groups, * or substituted or unsubst'ituted 0-benzyl, -NH2, -NHNH2 or -Nj, and R2 is hydrogen or 2,3,4-tri-0-benzyl-c^ -L-fucopyranosyI and R3 and R^ together are alkylidene; as described
24. A compound of the formula I^Tn claim 1, in which R1 is -CCH-) NHC0CCH-) COR5 , -(CH_) CONH(CH-) COR5 c n 2m 2n 2a or -(CH2)xC0R5, in which n = 1 to 10, m = 1 to 10, x = 3 to 17 and R5 is -H, -OH, ^-Cg-a Ikanoxy, -al- kenoxy or -alkinoxy, in each case branched or straight-chain, - 25 - 204379 0-phenyl, optionally substituted by inductive atoms or groups, , or substituted or unsubstituted 0- benzyl, -NH2, -NHNH2 or -N3, and R3 is hydrogen or 2,3,4-tri-0-benzyl-®\-L-fucopyranosyI, R^ is benzyl, benzyl-oxymethyl, methoxymethyl or allyl and R4 is benzyl, benzyloxymethyl or acyl. as described
25. A compound of the formula iVi n claim 1, in which R^ is a spacer bound to a natural or synthetic carrier, p 7 / preferably to an aminated matrix, and R , R and R are hydr0g_en"'or -L-fucopyranosy I, but at most one radical is -L-fucopyranosyI, a compound In which the spacer is -(CH2)xC0R5, in which x = 3 - 17 and R5 is a carrier, being excluded if the glycosidic bond to the spacer is a -bond. 26.. A process for the preparation of a compound of the as described _ . formula lyin claim 1, which comprises reacting a compound of the formula I in which R^ is to Cg-alkanyl, -alkenyl or -alkinyl, in each case branched or straight-chain, or a substituted or unsubstituted, alicycli'c or aromatic hydrocarbon radical or - (CH2>nNHC0(CH2)mC0R5, -(CH2) CONH(CH2)mC0R5 or -(CH2)xC0R5, in which n = 1 to 10, m = 1 to 10, x = 3 to 17 and R5 is C-j-Cg-a Ikanoxy, -alkenoxy or -alkinoxy, in each case branched or straight-chain, 0-phenyl, optionally substituted by inductive atoms or groups, or substituted or unsubstituted -26- •204379 0-benzyl, and R4 Is hydrogen and R2 and P3 together are alkylidene, or R2 is ~ hydrogen and R3 and R* together are benzylidene or alkylidene, or R3 is hydrogen, R2 is benzyl, benzyloxymethyI, methoxymethyl or allyl and R4 is benzyl, benzyloxymethyI or acyl, with 2,3,4- tri-0-benzyI- ucopyranosyl bromide or l-O-(N-methyl)- acetimidy1-2,3,4-tri-O-benzyI-^ -L-fucopyranose to give a 2 3 compound of the formula I in claim 1, in which R , R or is 2,3,4-tri-0-benzyl-»<-L-fucopyranosyI and in each case R3 and R4, R2 and R4 or R2 and R3, and R^ have the meaning given in this claim. t 2?* An agent for the chemotherapy and chemoprophyLaxis of malaria, which contains a compound of the formula I described in claim 1, tolerated by humans, and a pharma-ceutically acceptable auxiliary and/or additive. 2®- The use of a compound of the formula I as described in claim 1, in which R^ is a spacer attached to a solid, carrier, 2 A ' " . _ and R to R are hydrogen or »<-L-fucopyranosyI, but at .most on® radical is «v-L-fucopyranosyI, in a process for the preparation of a vaccine for malaria, which comprises incubating' this compound with intact merozoites or a merozoite lysate, lysing the intact merozoites, washing the carrier, e luting the bound product at a pH of 2.5 to 5 or of 8 to 11 or by J chaotropic change or by addition of N-acetyIglucosamine or *«-DGIcNAcOMe, if necessary further purifying the eluted product, and working up the product to a vaccine for active immunization against malaria. t BEHRINGWERKE AKTIENGESELLSCHAFT f/%'iBy Their Attorneys /iy HENRY HUGHES LIMITED By: I V V20'
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19823220426 DE3220426A1 (en) | 1982-05-29 | 1982-05-29 | CHEMICAL COMPOUND, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE FOR COMBATING THE MALARIA |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ204379A true NZ204379A (en) | 1985-08-30 |
Family
ID=6164901
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ204379A NZ204379A (en) | 1982-05-29 | 1983-05-27 | N-acetylglucosamine derivatives and pharmaceutical compositions |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0096293A1 (en) |
| JP (1) | JPS58225018A (en) |
| AU (1) | AU1510083A (en) |
| DE (1) | DE3220426A1 (en) |
| DK (1) | DK240583A (en) |
| IL (1) | IL68799A0 (en) |
| NZ (1) | NZ204379A (en) |
| ZA (1) | ZA833855B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3578866D1 (en) * | 1984-04-21 | 1990-08-30 | Sandoz Ag | 2,3-DIAMINO-2,3-DIDESOXYHEXOSE DERIVATIVES, METHOD FOR THEIR PRODUCTION AND THEIR USE. |
| DE3434039A1 (en) * | 1984-09-17 | 1986-03-27 | Behringwerke Ag, 3550 Marburg | GLYCOPEPTIDES, METHOD FOR THEIR PRODUCTION AND THEIR USE |
| CN101282956B (en) | 2005-10-04 | 2013-03-20 | 防卫研究与发展组织总干事 | Anti-malarial compound isolated from gomphostema niveum |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1792346C3 (en) * | 1968-08-22 | 1980-10-23 | Rotta Research Laboratorium S.P.A., San Fruttuoso Di Monza, Mailand (Italien) | Pharmaceutical preparation for the treatment of degenerative joint diseases |
| GB1544908A (en) * | 1975-07-08 | 1979-04-25 | Chembiomed Ltd | Artificial oligosaccharide antigenic determinants |
| CA1203532A (en) * | 1980-07-10 | 1986-04-22 | Chembiomed Ltd. | Synthesis of tumor antigenic determinant |
| DE3106815A1 (en) * | 1981-02-24 | 1982-09-09 | Behringwerke Ag, 3550 Marburg | "CHEMICAL COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS ANTIGENIC OR IMMUNADINE ORBANTS" |
-
1982
- 1982-05-29 DE DE19823220426 patent/DE3220426A1/en not_active Withdrawn
-
1983
- 1983-05-25 EP EP83105147A patent/EP0096293A1/en not_active Withdrawn
- 1983-05-26 IL IL68799A patent/IL68799A0/en unknown
- 1983-05-27 AU AU15100/83A patent/AU1510083A/en not_active Abandoned
- 1983-05-27 NZ NZ204379A patent/NZ204379A/en unknown
- 1983-05-27 ZA ZA833855A patent/ZA833855B/en unknown
- 1983-05-27 JP JP58092612A patent/JPS58225018A/en active Pending
- 1983-05-27 DK DK240583A patent/DK240583A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| EP0096293A1 (en) | 1983-12-21 |
| DE3220426A1 (en) | 1983-12-01 |
| JPS58225018A (en) | 1983-12-27 |
| DK240583D0 (en) | 1983-05-27 |
| DK240583A (en) | 1983-11-30 |
| AU1510083A (en) | 1983-12-01 |
| IL68799A0 (en) | 1983-09-30 |
| ZA833855B (en) | 1984-02-29 |
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