Process for the production of a cyclic ureido-derivative of a deoxystreptamine-containing antibiotic and products thereof

Claim 2

The cyclic ureido-derivative of a deoxystreptamine-containing antibiotic of the formula: ##SPC19## wherein R a is an aminoglycoside present in the molecule other than on the deoxystreptamine moiety thereof, R b and R c are each hydrogen or an aminoglycoside present in the molecule of the antibiotic other than on the deoxystreptamine moiety thereof.

Claim 3

A compound according to claim 1, wherein one of R b and R c is an aminoglycoside.

Claim 4

A compound according to claim 1, wherein R b and R c are both hydrogen.

Claim 5

A compound according to claim 1, wherein said antibiotic is selected from the group consisting of kanamycin A, kanamycin B, kanamycin C, neamine, neomycin B, neomycin C, paromamine, paromomycin I, paromomycin II, ribostamycin, lividomycin A, lividomycin B, gentamicin A and gentamicin C.

Claim 6

A compound according to claim 4, wherein said antibiotic is selected from the group consisting of kanamycin A, kanamycin B, kanamycin C, neamime, paromamine and ribostamycin.

Claim 7

The cyclic ureido-derivative of kanamycin A represented by the formula: ##SPC20##

Claim 8

The cyclic ureido-derivative of kanamycin A represented by the formula: ##SPC20##

Claim 9

The cyclic ureido-derivative of kanamycin B represented by the formula: ##SPC21##

Claim 10

The cyclic ureido-derivative of kanamycin B represented by the formula: ##SPC21##

Claim 11

The cyclic ureido-derivative of neamine represented by the formula: ##SPC22##

Claim 12

The cyclic ureido-derivative of neamine represented by the formula: ##SPC22##

Claim 13

The cyclic ureido-derivative of paromamine represented by the formula: ##SPC23##

Claim 14

The cyclic ureido-derivative of paromamine represented by the formula: ##SPC23##

Claim 15

The cyclic ureido-derivative of ribostamycin represented by the formula: ##SPC24##

Claim 16

The cyclic ureido-derivative of ribostamycin represented by the formula: ##SPC24##

Claim 17

A process for the production of cyclic ureido-deoxystreptamine-containing antibiotics of the formula: ##SPC25## wherein R a is an aminoglycoside present in the molecule of the antibiotic other than on the deoxystreptamine moiety thereof and R b and R c are each hydrogen or an aminoglycoside present in the molecule of said antibiotic other than on the deoxystreptamine moiety thereof, which comprises reacting in an inert solvent: (a) an alkali metal base or an alkaline earth metal base in an amount sufficient to provide an alkaline reaction mixture, with (b) a urethane derivative of said antibiotic of the formula: ##SPC26## wherein R 1 , R 2 and R 3 are each amino-protected derivatives of R a , R b and and R c , respectively in which all of the aminoglycoside groups originally present therein are substituted with an amino-protecting group of the formula --CO--OR 4 wherein R 4 is alkyl of 1-5 carbon atoms, alkenyl of 2-5 carbon atoms, aralkyl, cycloalkyl, aryl or a monovalent heterocyclic group, to: i. convert the two protected amino groups --NH--CO --OR 4 in the deoxystreptamine moiety of said urethane derivative into the cyclic ureido form, and simultaneously ii. liberate said amino-protecting groups from R 1 , R 2 and R 3 whereby the aminoglycoside members of R a , R b and R c are regenerated.

Claim 18

A process for the production of cyclic ureido-deoxystreptamine-containing antibiotics of the formula: ##SPC25## wherein R a is an aminoglycoside present in the molecule of the antibiotic other than on the deoxystreptamine moiety thereof and R b and R c are each hydrogen or an aminoglycoside present in the molecule of said antibiotic other than on the deoxystreptamine moiety thereof, which comprises reacting in an inert solvent: (a) an alkali metal base or an alkaline earth metal base in an amount sufficient to provide an alkaline reaction mixture, with (b) a urethane derivative of said antibiotic of the formula: ##SPC26## wherein R 1 , R 2 and R 3 are each amino-protected derivatives of R a , R b and and R c , respectively in which all of the aminoglycoside groups originally present therein are substituted with an amino-protecting group of the formula --CO--OR 4 wherein R 4 is alkyl of 1-5 carbon atoms, alkenyl of 2-5 carbon atoms, aralkyl, cycloalkyl, aryl or a monovalent heterocyclic group, to: i. convert the two protected amino groups --NH--CO --OR 4 in the deoxystreptamine moiety of said urethane derivative into the cyclic ureido form, and simultaneously ii. liberate said amino-protecting groups from R 1 , R 2 and R 3 whereby the aminoglycoside members of R a , R b and R c are regenerated.

Claim 19

A process according to claim 11, wherein the deoxstreptamine-containing antibiotic is selected from the group consisting of cyclic ureido derivatives of kanamycin A, kanamycin B, kanamycin C, neamine, neomycin B, neomycin C, paromamine, paromomycin I, paromomycin II, ribostamycin, lividomycin A, lividomycin B, gentamicin A and gentamicin C.

Claim 20

A process according to claim 12, wherein the deoxystreptamine-containing antibiotic is selected from the group consisting of kanamycin A, kanamycin B, kanamycin C, neamine, paromamine and ribostamycin.

Claim 21

A process according to claim 11, wherein R 4 is alkyl of 1-5 carbon atoms, alkenyl of 2.5 carbon atoms, cyclopentyl, phenyl, benzyl, p-nitrobenzyl or furfuryl.

Claim 22

A process according to claim 13, wherein said base is barium hydroxide.

Claim 23

A process according to claim 11, in which the deoxystreptamine-containing antibiotic is selected from the group consisting of cyclic ureido derivatives of kanamycin A, kanamycin B, kanamycin C, neamine, neomycin B, neomycin C, paromamine, paromomycin I, paromomycin II, ribostamycin, lividomycin A, lividomycin B, gentamicin A and gentamicin C, further comprising preparing said urethane derivative by reacting said antibiotic with a member selected from the group consisting of a chloroformate of the formula Cl--CO--OR 4 , a nitrophenyl carbonic acid ester of the formula p-NO 2 --C 6 H 5 -O--CO--R 4 , an N-hydroxysuccinimide carbonic acid ester of the formula: ##SPC27## an azidoformate of the formula N 3 --CO--OR 4 wherein R 4 has the above-indicated values.

Claim 24

A process according to claim 16, wherein said urethane derivatives are prepared in a reaction mixture containing an acid binding agent.