GB1420879A - Pseudodi- and trisaccharides and methods for their preparation - Google Patents

Abstract

1420879 Pseudo di- and tri-saccharides, gentamicin derivatives and the preparation thereof SCHERICO Ltd 4 Oct 1973 [10 Oct 1972 20 Nov 1972 27 Aug 1973] 46431/73 Heading C2C Pseudotrisaccharides of the formula wherein R 1 represents hydroxy, R 2 represents hydrogen or hydroxy, R 3 represents hydroxy, amino or C 1-4 alkylamino, R 4 represents hydrogen or C 1-4 alkyl and R 5 represents hydroxy, amino or C 1-4 alkylamino, with the provisos (a) that when R 2 is hydroxy, R 4 is hydrogen or methyl and R 3 is amino, then R 5 is monosubstituted C 1-4 alkylamino, and (b) that when R 2 and R 3 are hydroxy, and R 4 is hydrogen or methyl, then R 5 is hydroxy or monosubstituted C 1-4 alkylamino, and pharmaceutically acceptable acid addition salts and Schiffs base oxazolidine derivatives thereof, may be obtained by condensing a selectively blocked garamine of the formula wherein each R 12 represents an amino protective group, and each R 11 represents hydrogen or a hydroxy protective group, and wherein R 12 in position 3<SP>1</SP> together with R 11 in position 4<SP>1</SP> may represent a protective group, and/or R 12 in positions 1 and 3 may together represent a protective group, e.g. a urea grouping, with a monosaccharide of the formula wherein hal represents halogen, R 14 represents -OR 13 and R 15 represents hydrogen or -OR 13 , X represents -OR 13 , -NRR 12 or an azido group, and Y represents -OR 13 , -NRR 12 or a nitroso group, R represents hydrogen or C 1-4 alkyl, and R 13 represents a hydroxy protective group, and when necessary subjecting the pseudotrisaccharide formed to one or two of the following steps in any appropriate order; (a) converting an oximino group in position 2<SP>1</SP> into group -NHR and/or an azido group in position 6<SP>1</SP> into -NH 2 ; (b) converting an oximino group in position 2<SP>1</SP> into hydroxy; or (c) converting a group -OR 13 in position 6<SP>1</SP> into a group -NHR; and subjecting the pseudotrisaccharide obtained from condensation or from one or two of steps (a) to (c) to an elimination of all protective groups present in the molecule, and, if desired, preparing a suitable salt or Schiffs base oxazolidine derivative. Gentamicin C 2a , a compound of Formula (I) wherein R 1 and R 2 are hydrogen, R 3 and R 5 are amino and R 4 is methyl, and which differs from gentamicin C 2 only in respect of the configuration at the 6<SP>1</SP>-carbon, is also claimed to be novel. The condensation of a compound of Formula (II) with a compound of Formula (III) may be effected in the presence of a catalyst such as mercuric cyanide or bromide, or silver carbonate, oxide, perchlorate or tosylate, optionally in the presence of a solvent. Conversion of the oximino group into the group -NHR may be effected by protection of the oximino group and subsequent reduction thereof, and where R is alkyl, the amino group formed upon reduction may be acylated with C 1-4 alkanoyl and the amide, so obtained, reduced. When the oximino group is acetylated and one or more hydroxy protective groups are acetyl, reduction may be effected with diborane. The amide group may also be formed by migration of an alkanoyl-hydroxy protective group to the amino group. Alternatively the oximino group may be converted into a keto group which is subsequently converted into a hydroxy group; the conversion of the oximino group into the keto group may be effected by means of levulinic acid, nitrous acid, titanium trichloride or thallium (III) nitrate, and conversion of the keto group into the hydroxy group may be effected by means of an alkali metal borohydride. Conversion of an azido group into an amino group may be effected by hydrogenation and the reaction may be carried out after conversion of the oximino group into the group -NHR. In step (c) above, conversion of the group -OR 13 into the group -NHR may be effected with RNH 2 or RNHNH 2 , or by transformation of the group -OR 13 into an azido group and subsequent reduction thereof. The elimination of all protective groups may be carried out by known methods such as hydrolysis, preferably in an alkaline medium, hydrogenolysis, or by means of hydrazine. Alkaline hydrolysis is preferably effected in reaction mixtures containing sodium hydroxide, sodium in ammonia, or ammonium hydroxide in methanol. The protected pseudotrisaccharide may be partially de-protected, e.g. with ammonium hydroxide, and subsequently fully de-protected in a stronger alkaline medium, e.g. sodium hydroxide. When the amino protective groups, together with the nitrogen atom to which they are attached in the 2-deoxy-D- streptamine ring, form carbamates and the deblocking is effected with a strong base, both amino groups in positions 1 and 3 may be protected with a bridging carbonyl group, i.e. to form a cyclic urea grouping, which may be removed in a very strong alkaline medium and preferably with hydrazine. Suitable protective groups may be selected from substituted or unsubstituted groups chosen from aryl, aralkyl, acyl, alkoxycarbonyl and aralkoxycarbonyl; specified amino protective groups include carbobenzoxy, t-butoxyearbonyl, 2,4-dinitrophenyl, 2,2,2-trichloroethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, acetyl, benzoyl, 2-iodo-ethoxycarbonyl, and p - methoxycarbobenzoxy; specified hydroxy protective groups include benzyl, p-nitrobenzyl and acetyl; or R 12 in position 3<SP>11</SP> together with R 11 in position 4<SP>11</SP> or both R 12 in positions 1 and 3 together may represent a carbonyl group. The monosaccharide starting materials of Formula III, wherein Y represents the nitroso group, may be prepared, for example, by reacting a nitrosyl halide with the corresponding monosaccharide having a 1,2- double bond. The pseudodisaccharides (also claimed to be novel) of the formula wherein R 10 is hydrogen or an amino protective group, R 11 is hydrogen or a hydroxy protective group and R 10 in position 3<SP>1</SP> and R 11 in position 4<SP>1</SP> together may represent a protective group, and/or R 10 in positions 1 and 3 together may represent a protective group, e.g. a urea grouping, may be obtained by selectively cleaving a compound of the formula and, when necessary, removing one or more protective groups and/or introducing one or more protective groups. The cleavage reaction may be effected by hydrolysis, under oxidative conditions, or by means of irradiation. The compounds of Formula (II) may be prepared by introducing the respective blocking group or groups into a compound of formula wherein R 14 is hydrogen or a hydroxy protective group more readily eliminatable than the other protective groups present in the molecule and wherein at least one of R 10 , R 11 and R 14 is hydrogen, followed, if desired, by elimination of the hydroxy protective group represented by R 14 . The pseudotrisaccharides exhibit antimicrobial, antiprotozoal, anthelmintic and antiviral activity and they may be formulated and applied in a known manner