Abbott Laboratories Corporation

Jerry R Martin

John S Tadanier

Paulette Collum

Paul Kurath

Paulette Johnson

Robert Hallas

James B McAlpine

Ronald E Carney

Alford M Thomas

Daniel T Chu

Alex M Nadzan

Leslie A Freiberg

Daniel Ambrose Dunnigan

Alma W Goldstein

Norman E Wideburg

John S Tananier

Daniel I Chu

Described is a method for the preparation of 6'-modified fortimicin compounds including 6'-epi fortimicin by converting 1,2-di-N-protected fortimicin B into 4,6'-di-N-substituted alkoxycarbonyl-1,2'-di-N-protected fortimicin B which is further converted to 1,2'-di-substituted fortimicin B-4,5-carbamate, a compound whose substitution pattern is particularly suited to modification at the 6'-amino group and novel compounds thereof.

6'-Modified fortimicin compounds

2-Deoxyfortimicin A, 2-deoxy-4-N-alkyl fortimicins and 2-deoxy-4-N-acyl fortimicins represented by the formula ##STR1## wherein R is selected from the group consisting of acyl, aminoacyl, N-monoloweralkylaminoacyl, N,N-diloweralkylaminoacyl, hydroxy-substituted aminoacyl, an amino acid residue, hydroxyacyl, loweralkyl, aminoloweralkyl, N-monoloweralkylaminoloweralkyl, hydroxyloweralkyl, N-N-diloweralkylaminoloweralkyl or hydroxy-substituted aminoloweralkyl, and the pharmaceutically acceptable salts thereof; intermediates therefor; and pharmaceutical compositions containing the compounds of this invention.

(1,2',6'-Tri-N-(2-O-methanesulfonylsalicylidine)-4,5-(2-O-methanesulfonyl

2-Deoxyfortimicin A, 4-N-alkyl and 4-N-acyl-2-deoxyfortimicin B

2-Deoxyfortimicin, A, 2-deoxy-4-N-alkyl fortimicins and 2-deoxy-4-N-acyl fortimicins represented by the formula ##STR1## wherein R is selected from the group consisting of acyl, aminoacyl, N-monoloweralkylaminoacyl, N,N-diloweralkylaminoacyl, hydroxy-substituted aminoacyl, an amino acid residue, hydroxyacyl, loweralkyl, aminoloweralkyl, N-monoloweralkylaminoloweralkyl, hydroxyloweralkyl, N-N-diloweralkylaminoloweralkyl or hydroxy-substituted aminoloweralkyl, and the pharmaceutically acceptable salts thereof; intermediates therefor; and pharmaceutical compositions containing the compounds of this invention.

2-O-Methanesulfonylfortimicin B

A 1,2-modified fortimicin A or B represented by the formulae I, II and III: ##STR1## wherein R is hydrogen or loweralkyl; and R.sub.1 is selected from the group consisting of hydrogen, loweralkyl, aminoloweralkyl, diaminoloweralkyl, N-lower-alkylaminoloweralkyl, N,N-diloweralkylaminoloweralkyl, hydroxyloweralkyl, amino hydroxyloweralkyl, N-loweralkylaminohydroxyloweralkyl, N-N-diloweralkylaminohydroxyloweralkyl, acyl, aminoacyl, hydroxy-substituted aminoacyl, diaminoacyl, hydroxyacyl, hydroxy-substituted diaminoacyl, N-loweralkylaminoacyl, N, N-diloweralkylaminoacyl, hydroxysubstituted-N-loweralkylaminoacyl and hydroxy-substituted-N, N-diloweralkylaminoacyl, and the pharmaceutically acceptable salts thereof. The compounds are broad spectrum antibiotics.

1,2-Modified fortimicins A and B, intermediates therefor and method for

What is described is 2-epi-fortimicin A, 2-epi-fortimicin B or a 2-epi-fortimicin B derivative represented by the formula: ##STR1## wherein R.sub.1 is hydrogen or loweralkyl; R.sub.2 is hydrogen or hydroxy; R.sub.3 is methyl or hydrogen; and R.sub.4 is selected from the group consisting of hydrogen, loweralkyl, aminoloweralkyl, diaminoloweralkyl, N-loweralkylaminoalkyl, N,N-diloweralkylaminoloweralkyl, hydroxyloweralkyl, aminohydroxyloweralkyl, N-loweralkylaminohydroxyloweralkyl, N,N-diloweralkylaminohydroxyloweralkyl, acyl of the formula ##STR2## wherein R.sub.5 is loweralkyl, aminoacyl, diaminoacyl, hydroxyacyl, N-loweralkylaminoacyl, N,N-diloweralkylaminoacyl, hydroxy-substituted aminoacyl or an amino acid residue other than those defined above and the pharmaceutically acceptable salts thereof useful in the treatment of infections.

2-Epi-fortimicin A and derivatives

A new fortimicin antibiotic, 2-deoxyfortimicin B, intermediates useful in the preparation of the compound, methods of making and using the compound and compositions containing 2-deoxyfortimicin B.

2-O-Substituted sulfonyl derivatives of fortimicin B

1,2-Epiminofortimicin B

It has been found that dipeptides containing a 3-fluoro-D-alanine N-terminus are powerful antibacterials and produce a highly useful synergistic effect with antibiotics.

Antibacterial peptides

2-Deoxyfortimicin A, 2-deoxy-4-N-alkyl fortimicins and 2-deoxy-4-N-acyl fortimicins represented by the formula ##STR1## wherein R is selected from the group consisting of acyl, aminoacyl, N-monoloweralkylaminoacyl, N,N-diloweralkylaminoacyl, hydroxy-substituted aminoacyl, an amino acid residue, hydroxyacyl, loweralkyl, aminoloweralkyl, N-monoloweralkylaminoloweralkyl, hydroxyloweralkyl, N-N-diloweralkylaminoloweralkyl or hydroxysubstituted aminoloweralkyl, and the pharmaceutically acceptable salts thereof; intermediates therefor; and pharmaceutical compositions containing the compounds of this invention.

Fortimicin intermediates for producing 2-deoxyfortimicins

Fortimicin B-4,5-carbamates represented by the formula: ##STR1## wherein R is hydrogen or an amine-protecting group; R.sub.1 is hydrogen or an amine-protecting group; R.sub.2 is hydrogen or loweralkoxycarbonyl; and R.sub.4 is hydrogen or loweralkoxycarbonyl. The compounds are useful as intermediates in the preparation the 2-epi-fortimicins.

4,5-Carbamates of fortimicin B

A 1,2-modified fortimicin A or B represented by the formulae I, II and III: ##STR1## wherein R is hydrogen or loweralkyl.

2-O-Hydrocarbonsulfonyl-4,5-oxazolidine fortimicin B derivatives

A 1,2-carbamate of fortimicin B and derivatives represented by the formula: ##STR1## wherein: R is hydrogen or monocyclicaryloxycarbonyl, R.sub.1 is hydrogen or monocyclicaryloxycarbonyl; and R.sub.2 is selected from the group consisting of loweralkyl, loweralkoxycarbonyl aminoloweralkyl, hydroxyloweralkyl, hydroxy-substituted aminolowerakyl, an amino acid residue, and N-protected amino acid residue, or when R and R.sub.1 are hydrogen, R.sub.2 can also be hydrogen; and the acid addition salts thereof when R,R.sub.1 or R.sub.2 are hydrogen or an unprotected aminoacid residue.

1,2-Carbamates of fortimicin B and derivatives

It has been found that dipeptides containing a 3-halo-D-alanine C-terminus are powerful antibacterials and produce a highly useful synergistic effect with antibiotics.

Growing community of inventors

Waukegan, IL, United States of America

Jerry R Martin