2{41 -Deoxyaminoglycosides and 2{41 -epi-amino-3{41 -desamino derivatives thereof, methods for their manufacture and novel intermediates useful therein

Claim 2

A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A 2"-DEOXYAMINOGLYCOSIDE SELECTED FROM THE GROUP CONSISTING OF 2"-DEOXYGENTAMICIN A, 2"-DEOXYGENTAMICIN B, 2"-DEOXYGENTAMICIN B1, 2-DEOXYGENTAMICIN C1, 2"-DEOXYGENTAMICIN C1A, 2"-DEOXYGENTAMICIN C2, 2"-DEOXYGENTAMICIN C2A, 2"DEOXYGENTAMICIN X2, 2"-DEOXYSISONICIN, 2"-DEOXYVERDAMICIN, 2"-DEOXY-ANTIOBITIC JI-20-A, 2"-DEOXY-ANTIBIOTIC JI-20B, 2"-DEOXY-ANTIOBITIC G-418, 2"-DEOXYTOBRAMYCIN AND 3'',4'',2"-TRIDEOXYKANAMYCIN B; THE 3"-DESMETHYLAMINO-2"EPI-METHYLAMINO- OR 3"-DESAMINO-2"-EPI-AMINO DERIVATIVES THEREOF; MIXTURES OF SAID 2"-DEOXYAMINOGLYCOSIDE WITH THE 3"-DESMETHYLAMINO2"-EPI-METHLAMINO ANALOG THEREOF OR WITH THE 3-DESAMINO-2"-EPI:AMINO ANALOG THEREOF; AND THE NON-TPXIC PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS OF THE FOREGOING.

Claim 3

A 2''''-deoxyaminoglycoside of claim 1.

Claim 4

A 2''''-deoxyaminoglycoside of claim 1 which is 2''''-deoxysisomicin.

Claim 5

A 2''''-deoxyaminoglycoside of claim 1 which is 2''''-deoxyverdamicin.

Claim 6

A 2''''-deoxyaminoglycoside of claim 1 which is 2''''-deoxygentamicin C1.

Claim 7

A 2''''-deoxyaminoglycoside of claim 1 which is 2''''-deoxygentamicin C1a.

Claim 8

A 2''''-deoxyaminoglycoside of claim 1 which is a 2''''-deoxygentamicin C2.

Claim 9

A 2''''-deoxyaminoglycoside of claim 1 Which is 2''''-deoxygentamicin C2a.

Claim 10

A 3''''-desmethylamino-2''''-epi-methylamino analog of a 2''''-deoxyaminoglycoside of claim 1 which is 2''''-deoxy-3''''-desmethylamino-2''''-epi-methylaminogentamicin C2.

Claim 11

A per-N-lower alkanoyl-derivative of a 2''''-deoxyaminoglycoside of claim 1.

Claim 12

A compound according to claim 10 wherein the per-N-alkanoyl derivative is a per-N-acetyl derivative and wherein said 2''''-deoxyaminoglycoside is 2''''-deoxygentamicin C2, said compound being per-N-acetyl-2''''-deoxygentamicin C2.

Claim 13

A compound selected from the group consisting of a 2''''-O-hydrocarbonsulfonyl derivative of the following structural formulae I and II:

Claim 14

A compound selected from the group consisting of a 2''''-O-hydrocarbonsulfonyl derivative of the following structural formulae I and II:

Claim 15

A compound according to claim 12 wherein R3'''' is methyl and R5'''' is hydrogen.

Claim 16

A compound according to claim 12, formula I, wherein M is methyl, W2'' is -NHX, R3'', R4'' and R5'''' are hydrogen, R5'', R3'''' and R4'''' are methyl and W6'' is

Claim 17

A compound according to claim 12, wherein M is methyl; W2'' and W6'' are -NHX; R3'', R4'', R5'' and R5'''' are hydrogen; and R3'''' and R4'''' are methyl; said compound being per-N-X-2''''-O-methanesulfonylgentamicin C1a wherein X is a member selected from the group consisting of lower alkanoyl and carbobenzyloxy.

Claim 18

A compound according to claim 12, formula I, wherein M is methyl, W2'' and W6'' are -NHX; R3'', R4'' and R5'''' are hydrogen; R5'', R3'''' and R4'''' are methyl; the stereochemistry at C6'' being R; said compound being per-N-X-2''''-O-methanesulfonylgentamicin C2 wherein X is a member selected from the group consisting of lower alkanoyl and carbobenzyloxy.

Claim 19

A compound according to claim 12, formula I, wherein M is methyl; W2'' and W6'' are -NHX; R3'', R4'' and R5'''' are hydrogen; R5'', R3'''' and R4'''' are methyl; the stereochemistry at C6'' being S, said compound being Per-N-X-2''''-O-methanesulfonylgentamicin C2a wherein X is a member selected from the group consisting of lower alkanoyl and carbobenzyloxy.

Claim 20

A compound according to claim 12, formula II, wherein M is methyl and R5'' is hydrogen, said compound being per-N-X-2''''-O-methanesulfonylsisomicin wherein X is a member selected from the group consisting of lower alkanoyl and carbobenzyloxy.

Claim 21

A compound according to claim 12, formula II, wherein M is methyl and R5'' is methyl, said compound being per-N-X-2''''-O-methanesulfonylverdamicin wherein X is a member selected from the group consisting of lower alkanoyl and carbobenzyloxy.

Claim 22

A compound selected from the group consisting of a 2''''-deoxy-2''''-sulfhydryl-aminoglycoside derivative of following formulae I and II:

Claim 23

A compound selected from the group consisting of a 2''''-deoxy-2''''-sulfhydryl-aminoglycoside derivative of following formulae I and II:

Claim 24

A compound according to claim 20, Formula I, wherein A is ethyl, Y is acetyl, T2'' and T6'' are each acetamido; R3'', R4'', R5 '' and R5'''' are hydrogen; and R3'''' and R4'''' are each methyl; said compound being 2''''-deoxy-2''''-ethylthio-1,3,2'',6'',3''''-penta-N-acetylgentamicin C1a.

Claim 25

A compound selected from the group consisting of a 2''''-deoxy-3''''-desamino-2'''',3''''-epimino-aminoglycoside of following formulae I and II:

Claim 26

A compound selected from the group consisting of a 2''''-deoxy-3''''-desamino-2'''',3''''-epimino-aminoglycoside of following formulae I and II:

Claim 27

A compound according to claim 22, formula I, wherein R2'' is amino; R3'', R4'' and R5'''' are hydrogen: R5'', R3'''' and R4'''' are methyl; and R6'' is methylamino; said compound being 2''''-deoxy-3''''-desmethylamino-2'''',3''''-N-methylepimino-gentamicin C1.

Claim 28

A compound according to claim 22, formula I, wherein R2'' and R6'' are amino; R3'', R4'', R5'' and R5'''' are hydrogen; R3'''' and R4'''' are methyl; said compound being 2''''-deoxy-3''''-desmethylamino-2'''',3''''-N-methylepimino-gentamicin C1a.

Claim 29

A compound according to claim 22, formula I, wherein R2'' and R6'' are amino; R3'', R4'' and R5'''' are hydrogen; and R5'', R3'''' and R4'''' are methyl, the configuration at C6'' being R; said compound being 2''''-deoxy-3''''-desmethylamino-2'''',3''''-N-methylepiminogentamicin C2.

Claim 30

A compound according to claim 22, formula I, wherein R2'' and R6'' are amino; R3'', R4'' and R5'''' are hydrogen; and R5'', R3'''' and R4'''' are methyl, the configuration at C6'' being S, said compound being 2''''-deoxy-3''''-desmethylamino-2'''',3''''-N-methylepiminogentamicin C2a.

Claim 31

A compound according to claim 22, formula II, wherein R5'' is methyl, said compound being 2''''-deoxy-3''''-desmethylamino-2'''',3''''-N-methyl-epiminoverdamicin.

Claim 32

A compound according to claim 22, formula II, wherein R5'' is hydrogen, said compound being 2''''-deoxy-3''''-desmethylamino-2'''', 3''''-N-methylepiminosisomicin.

Claim 33

A compound selected from the group consisting of a 2''''-deoxy-3''''-desamino-2''''-epi-amino-3''''-epi-sulfhydrylaminoglycoside derivative of following formulae I and II:

Claim 34

A compound selected from the group consisting of a 2''''-deoxy-3''''-desamino-2''''-epi-amino-3''''-epi-sulfhydrylaminoglycoside derivative of following formulae I and II:

Claim 35

The process for preparing a 2''''-deoxy 4,6-di-(aminoglycosyl)-2-deoxystreptamine which comprises treating an antibacterially active 4,6-di-(aminoglycosyl)-2-deoxystreptamine having a 2''''-hydroxy function, the primary and secondary amino groups of which are protected by a lower alkanoyl, and protectable primary and secondary hydroxyl groups of which are converted to an O-protecting function selected from the group consisting of a triphenylmethyl ether of a primary hydroxyl group and a cyclic ketal or acetal of protectable neighboring hydroxyl groups; with a hydrocarbonsulfonyl halide having up to eight carbon atoms in a tertiary amine whereby is formed a 2''''-O-hydrocarbonsulfonylaminoglycoside intermediate; converting said 2''''-O-hydrocarbonsulfonylaminoglycoside intermediate to a 2''''-thio-2''''-deoxyaminoglycoside intermediate by treating a per-N-lower alkanoyl-2''''-O-hydrocarbonsulfonylaminoglycoside with an alkali metal salt of a lower alkylthiol in an anhydrous, polar, non-hydroxylic solvent, optionally followed by acid hydrolysis of any O-protecting functions present, whereby the 2''''-thio-2''''-deoxy intermediate formed is a 2''''-lower alkylthio-2''''-deoxy-per-N-lower alkanoylaminoglycoside; treating said 2''''-thio-2''''-deoxyaminoglycoside intermediate with a reductive desulfurization agent selected from the group consisting of Raney Nickel and aluminum amalgam, followed by alkaline hydrolysis of any amino protecting groups, whereby is obtained a 2''''-deoxyaminoglycoside.

Claim 36

The process for preparing a 2''''-deoxy 4,6-di-(aminoglycosyl)-2-deoxystreptamine which comprises treating an antibacterially active 4,6-di-(aminoglycosyl)-2-deoxystreptamine having a 2''''-hydroxy function, the primary and secondary amino groups of which are protected by a lower alkanoyl, and protectable primary and secondary hydroxyl groups of which are converted to an O-protecting function selected from the group consisting of a triphenylmethyl ether of a primary hydroxyl group and a cyclic ketal or acetal of protectable neighboring hydroxyl groups; with a hydrocarbonsulfonyl halide having up to eight carbon atoms in a tertiary amine whereby is formed a 2''''-O-hydrocarbonsulfonylaminoglycoside intermediate; converting said 2''''-O-hydrocarbonsulfonylaminoglycoside intermediate to a 2''''-thio-2''''-deoxyaminoglycoside intermediate by treating a per-N-lower alkanoyl-2''''-O-hydrocarbonsulfonylaminoglycoside with an alkali metal salt of a lower alkylthiol in an anhydrous, polar, non-hydroxylic solvent, optionally followed by acid hydrolysis of any O-protecting functions present, whereby the 2''''-thio-2''''-deoxy intermediate formed is a 2''''-lower alkylthio-2''''-deoxy-per-N-lower alkanoylaminoglycoside; treating said 2''''-thio-2''''-deoxyaminoglycoside intermediate with a reductive desulfurization agent selected from the group consisting of Raney Nickel and aluminum amalgam, followed by alkaline hydrolysis of any amino protecting groups, whereby is obtained a 2''''-deoxyaminoglycoside.

Claim 37

The process according to claim 30 wherein said antibacterially active 4,6-di-(aminoglycOsyl)-2-deoxystreptamine having a 2''''-hydroxy function is a member selected from the group consisting of sisomicin, verdamicin, a gentamicin selected from the group consisting of gentamicin A, gentamicin B, gentamicin B1, gentamicin C1, gentamicin C1a, gentamicin C2, gentamicin C2a, gentamicin X2 and mixtures thereof, tobramycin, 3'',4''-dideoxykanamycin B, Antibiotic JI-20-A, Antibiotic JI-20-B and Antibiotic G-418, whereby is obtained the corresponding 2''''-deoxyaminoglycoside antibiotic derivative selected from the group consisting of: 2''''-deoxysisomicin, 2''''-deoxyverdamicin, a 2''''-deoxygentamicin selected from the group consisting of 2''''-deoxygentamicin A, 2''''-deoxygentamicin B, 2''''-deoxygentamicin B1, 2''''-deoxygentamicin C1, 2''''-deoxygentamicin C1a, 2''''-deoxygentamicin C2, 2''''-deoxygentamicin C2a, gentamicin X2 and mixtures thereof, 2''''-deoxytobramycin, 3'',4'',2''''-trideoxykanamycin B, 2''''-deoxy-Antibiotic JI-20-A, 2''''-deoxy-Antibiotic JI-20-B, and 2''''-deoxy-Antibiotic-G-418.

Claim 38

The process according to claim 30 wherein the primary and secondary amino groups are protected by acetyl; wherein said hydrocarbonsulfonyl halide in a tertiary amine is methanesulfonyl chloride in pyridine; wherein said 2''''-thio-2''''-deoxyaminoglycoside intermediate is 2''''-ethylthio-2''''-deoxy-per-N-acetylaminoglycoside prepared by treating the corresponding per-N-acetyl-2''''-O-methanesulfonylaminoglycoside with the lithium salt of ethanethiol in anhydrous dimethylformamide.

Claim 39

The process for preparing a 2''''-deoxy-4,6-di-(aminoglycosyl)-2-deoxystreptamine which comprises treating an antibacterially active 4,6-di-(aminoglycosyl)-2-deoxystreptamine having a 2''''-hydroxy function and a 3''''-primary or secondary amino function, the primary and secondary amino groups of which are protected by a carbobenzyloxy group, and protectable neighboring primary and secondary hydroxyl groups of which are converted to a cyclic ketal or cyclic acetal function, with a hydrocarbonsulfonyl halide having up to eight carbon atoms in a tertiary amine; removing the carbobenzyloxy groups from the 2''''-O-hydrocarbonsulfonyl-per-N-carbobenzyloxyaminoglycoside thereby formed by treatment with hydrogen in the presence of a catalyst, or by cleavage with an alkali metal in liquid ammonia; converting the resulting 2''''-O-hydrocarbonsulfonylaminoglycoside to the corresponding 2''''-deoxy-3''''-desamino-2'''',3''''-epimino-aminoglycoside intermediate by spontaneous transformation or by heating in a lower alkanol either alone or together with an alkali metal salt of said alkanol, at temperatures in the range of from about 25* to about 100*C; cleaving the 2''''-deoxy-3''''-desamino-2'''',3''''-epiminoaminoglycoside thereby formed by (1) treatment with hydrogen in the presence of a catalyst, followed by acid hydrolysis of any acetal or ketal function; or (2) N-derivatization, followed by treatment of the resulting per-N-protected-2''''-deoxy-3''''-desamino-2'''',3''''-epiminoaminoglycoside with hydrogen in the presence of a catalyst, followed by acid hydrolysis of any acetal or ketal function and alkaline hydrolysis of said N-protecting groups; or (3) N-derivatization followed by quaternization with a benzyl halide of the epimino function, treatment of the resulting per-N-protected-2''''-deoxy-3''''-desamino-2'''',3''''-(N-methyl-N-benzyl) epiminoaminoglycoside quaternary halide salt with hydrogen in the presence of a cAtalyst followed by acid hydrolysis of any ketal or acetal functions and alkaline hydrolysis of said N-protecting groups; or (4) treatment with a sulfur nucleophile whereby is obtained a product mixture comprising a 2''''-deoxy-2''''-sulfhydryl-aminoglycoside and a 2''''-deoxy-3''''-desamino-2''''-epi-amino-3''''-epi-sulfhydryl-aminoglycoside or thiol hydrocarbon ether or thiol alkanoyl ester derivatives thereof wherein said hydrocarbon and said alkanoyl have up to 8 carbon atoms, followed by desulfurization of said product mixture and acid hydrolysis of any acetal or ketal functions or alternatively, followed by desulfurization of a per-N-protected derivative of said product mixture, thence acid hydrolysis of any ketal or acetal function followed by alkaline hydrolysis of said N-protecting groups; whereby is obtained a product mixture comprising a 2''''-deoxyaminoglycoside and a 2''''-deoxy-3''''-desamino-2''''-epi-aminoglycoside.

Claim 40

The process for preparing a 2''''-deoxy-4,6-di-(aminoglycosyl)-2-deoxystreptamine which comprises treating an antibacterially active 4,6-di-(aminoglycosyl)-2-deoxystreptamine having a 2''''-hydroxy function and a 3''''-primary or secondary amino function, the primary and secondary amino groups of which are protected by a carbobenzyloxy group, and protectable neighboring primary and secondary hydroxyl groups of which are converted to a cyclic ketal or cyclic acetal function, with a hydrocarbonsulfonyl halide having up to eight carbon atoms in a tertiary amine; removing the carbobenzyloxy groups from the 2''''-O-hydrocarbonsulfonyl-per-N-carbobenzyloxyaminoglycoside thereby formed by treatment with hydrogen in the presence of a catalyst, or by cleavage with an alkali metal in liquid ammonia; converting the resulting 2''''-O-hydrocarbonsulfonylaminoglycoside to the corresponding 2''''-deoxy-3''''-desamino-2'''',3''''-epimino-aminoglycoside intermediate by spontaneous transformation or by heating in a lower alkanol either alone or together with an alkali metal salt of said alkanol, at temperatures in the range of from about 25* to about 100*C; cleaving the 2''''-deoxy-3''''-desamino-2'''',3''''-epiminoaminoglycoside thereby formed by (1) treatment with hydrogen in the presence of a catalyst, followed by acid hydrolysis of any acetal or ketal function; or (2) N-derivatization, followed by treatment of the resulting per-N-protected-2''''-deoxy-3''''-desamino-2'''',3''''-epiminoaminoglycoside with hydrogen in the presence of a catalyst, followed by acid hydrolysis of any acetal or ketal function and alkaline hydrolysis of said N-protecting groups; or (3) N-derivatization followed by quaternization with a benzyl halide of the epimino function, treatment of the resulting per-N-protected-2''''-deoxy-3''''-desamino-2'''',3''''-(N-methyl-N-benzyl) epiminoaminoglycoside quaternary halide salt with hydrogen in the presence of a cAtalyst followed by acid hydrolysis of any ketal or acetal functions and alkaline hydrolysis of said N-protecting groups; or (4) treatment with a sulfur nucleophile whereby is obtained a product mixture comprising a 2''''-deoxy-2''''-sulfhydryl-aminoglycoside and a 2''''-deoxy-3''''-desamino-2''''-epi-amino-3''''-epi-sulfhydryl-aminoglycoside or thiol hydrocarbon ether or thiol alkanoyl ester derivatives thereof wherein said hydrocarbon and said alkanoyl have up to 8 carbon atoms, followed by desulfurization of said product mixture and acid hydrolysis of any acetal or ketal functions or alternatively, followed by desulfurization of a per-N-protected derivative of said product mixture, thence acid hydrolysis of any ketal or acetal function followed by alkaline hydrolysis of said N-protecting groups; whereby is obtained a product mixture comprising a 2''''-deoxyaminoglycoside and a 2''''-deoxy-3''''-desamino-2''''-epi-aminoglycoside.

Claim 41

The process according to claim 33 wherein said antibacterially active 4,6-di-(aminoglycosyl)-2-deoxystreptamine having a 2''''-hydroxy group is a member selected from the group consisting of sisomicin, verdamicin, tobramycin, 3'',4''-dideoxykanamycin B, Antibiotic JI-20-A, Antibiotic JI-20-B, Antibiotic G-418, and a gentamicin selected from the group consisting of gentamicin A, gentamicin B, gentamicin B1, gentamicin C1, gentamicin C1a, gentamicin C2, gentamicin C2a, gentamicin X2 and mixtures thereof, and wherein any protectable hydroxyl groups are protected by an O-isopropylidene function.

Claim 42

The process according to claim 33 wherein said hydrocarbonsulfonyl halide in a tertiary amine is methanesulfonyl chloride in pyridine; wherein said carbobenzyloxy groups are removed from said 2''''-O-methanesulfonyl-per-N-carbobenzyloxyaminoglycoside by treatment with hydrogen in the presence of palladium-on-charcoal; and said 2''''-O-methanesulfonylaminoglycoside is converted to said 2''''-deoxy-3''''-desmethylamino-2'''',3''''-epimino-aminoglycoside intermediate by heating said 2''''-O-methanesulfonylaminoglycoside in ethanol at reflux temperature in the presence of sodium methoxide and wherein said 2''''-deoxy-3''''-desamino-2'''',3'''' epimino-aminoglycoside is hydrogenolyzed by treatment in ethanol with hydrogen in the presence of Raney Nickel.

Claim 43

The process according to claim 33 wherein said antibacterially active 4,6-di-(aminoglycosyl)-2-deoxystreptamine having a 2''''-hydroxy function is gentamicin C2; wherein said hydrocarbonsulfonyl halide in a tertiary amine is methanesulfonyl chloride in pyridine; wherein said carbobenzyloxy groups are removed from said 2''''-O-methanesulfonyl-per-N-carbobenzyloxygentamicin C2 by treatment in ethanol with hydrogen in the presence of palladium-on-charcoal; and, wherein the thereby formed 2''''-O-methanesulfonylgentamicin C2 spontaneously converts to 2''''-deoxy-3''''-desmethylamino-2'''',3''''-N-methylepiminogentamicin C2.