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US4053591A
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5-deoxy-4,6-di-o-(aminoglycosyl)-1,3-diaminocyclitols, methods for their manufacture, method for their use as antibacterial agents and compositions useful therefor
Assignee: Merck Sharp & Dohme LLC
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Filing: 1976-06-30
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Granted: 1977-10-11
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Expires: 1996-06-30
Abstract
Abstract 5-Deoxy-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitols, useful antibacterial agents, are prepared by the reaction of the corresponding 5-O-thioformyl-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol having all amino functions and all primary and secondary hydroxyl groups protected, with an organotin hydride (preferably tri-n-butylstannane) in an inert aprotic solvent under an inert atmosphere at temperatures of at least about 100° C, followed by removal of said hydroxyl and amino protecting groups.
Inventors
- 👤 Peter J. L. Daniels
- 👤 Stuart W. McCombie
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-24 23:28
CPC Classifications
C; C07; C07H; C07H15/00; C07H15/20; C07H15/22; C07H15/222; C07H15/226; C07H15/234; Y; Y10; Y10S; Y10S435/00; Y10S435/8215; Y10S435/822; Y10S435/863
Claims Analysis
Total Claims: 19
Claim 1
Independent Claim
166 words
A 5-deoxy-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol selected from the group consisting of 5-deoxygentamicin B, 5-deoxygentamicin B 1 , 5-deoxygentamicin C 1a , 5-deoxygentamicin C 2 , 5-deoxygentamicin C 2a , 5-deoxygentamicin X 1 , 5-deoxygentamicin X 2 , 5-deoxy-Antibiotic 66-40B, 5-deoxy-Antibiotic 66-40D, 5-deoxy-Antibiotic G-418, 5-deoxy-Antibiotic JI-20A, 5-deoxy-Antibiotic JI-20B, 5-deoxyverdamicin, 5-deoxykanamycin B, 5-deoxykanamycin C, 5,3',4'-trideoxykanamycin B, 5-deoxy-Aminoglycoside XK-88-5, 5-deoxytobramcyin; the 1-N-X derivatives thereof wherein X is a substituent selected from the group consisting of --CH 2 Z and ##STR8## wherein Z is a member selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, aminohydroxyalkyl, alkylaminohydroxyalkyl, phenyl, benzyl, and tolyl, said substituent Z having up to 7 carbon atoms and, when substituted by amino and hydroxy, bearing the substituents on different carbon atoms; the 2'-N-CH 2 Z, 6'-N-CH 2 Z, 1,2'-di-N-CH 2 Z and the 1,6'-di-N-CH 2 Z derivatives thereof wherein Z is as hereinabove defined; 5-deoxy-Antibiotic G-52 and the 1-N-X derivatives thereof wherein X is as hereinabove defined; and the pharmaceutically acceptable acid addition salts thereof.
Claim 2
Dependent Claim
166 words
A 5-deoxy-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol selected from the group consisting of 5-deoxygentamicin B, 5-deoxygentamicin B 1 , 5-deoxygentamicin C 1a , 5-deoxygentamicin C 2 , 5-deoxygentamicin C 2a , 5-deoxygentamicin X 1 , 5-deoxygentamicin X 2 , 5-deoxy-Antibiotic 66-40B, 5-deoxy-Antibiotic 66-40D, 5-deoxy-Antibiotic G-418, 5-deoxy-Antibiotic JI-20A, 5-deoxy-Antibiotic JI-20B, 5-deoxyverdamicin, 5-deoxykanamycin B, 5-deoxykanamycin C, 5,3',4'-trideoxykanamycin B, 5-deoxy-Aminoglycoside XK-88-5, 5-deoxytobramcyin; the 1-N-X derivatives thereof wherein X is a substituent selected from the group consisting of --CH 2 Z and ##STR8## wherein Z is a member selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, aminohydroxyalkyl, alkylaminohydroxyalkyl, phenyl, benzyl, and tolyl, said substituent Z having up to 7 carbon atoms and, when substituted by amino and hydroxy, bearing the substituents on different carbon atoms; the 2'-N-CH 2 Z, 6'-N-CH 2 Z, 1,2'-di-N-CH 2 Z and the 1,6'-di-N-CH 2 Z derivatives thereof wherein Z is as hereinabove defined; 5-deoxy-Antibiotic G-52 and the 1-N-X derivatives thereof wherein X is as hereinabove defined; and the pharmaceutically acceptable acid addition salts thereof.
Claim 3
Dependent Claim
9 words
A compound of claim 1 which is a 4-O-aminoglycosyl-6-O-garosaminyl-2,5-dideoxystreptamine.
Claim 4
Dependent Claim
27 words
A compound of claim 1 which is a 1-N-X-4-O-aminoglycosyl-6-O-garosaminyl-2,5-dideoxystreptamine wherein X is a --CH 2 Z substituent selected from the group consisting of ethyl, propyl, and δ-aminobutyl.
Claim 5
Dependent Claim
11 words
A compound of claim 2 which is 5-deoxygentamicin C 2 .
Claim 6
Dependent Claim
25 words
A compound of claim 1 which is a 1-N-X-4-O-aminoglycosyl-6-O-garosaminyl-2,5-dideoxystreptamine wherein X is a ##STR9## substituent selected from the group consisting of 3-amino-2-hydroxypropionyl, 4-amino-2-hydroxybutyryl, and 5-amino-2-hydroxyvaleryl.
Claim 7
Dependent Claim
26 words
A compound of claim 5 which is a 1-N-X derivative of 5-deoxygentamicin B selected from the group consisting of 1-N-(3-amino-2-hydroxypropionyl)-5-deoxygentamicin B, 1-N-(4-amino-2-hydroxybutyryl)-5-deoxygentamicin B, and 1-N-(5-amino-2-hydroxyvaleryl)-5-deoxygentamicin B.
Claim 8
Dependent Claim
33 words
A compound of claim 5 which is a 1-N-X derivative of 5-deoxygentamicin B 1 selected from the group consisting of 1-N-(3-amino-2-hydroxypropionyl)-5-deoxygentamicin B 1 , 1-N-(4-amino-2-hydroxybutyryl)-5-deoxygentamicin B 1 , and 1-N-(5-amino-2-hydroxyvaleryl)-5-deoxygentamicin B 1 .
Claim 9
Dependent Claim
20 words
A compound of claim 1 which is a 1,2'-di-N-CH 2 Z-4-O-aminoglycosyl-6-O-garosaminyl-2,5-dideoxystreptamine wherein CH 2 Z is ethyl, propyl, or δaminobutyl.
Claim 10
Dependent Claim
20 words
A compound of claim 1 which is a 1,6'-di-N-CH 2 Z-4-O-aminoglycosyl-6-O-garosaminyl-2,5-dideoxystreptamine wherein CH 2 Z is ethyl, propyl, or δ-aminobutyl.
Claim 11
Dependent Claim
85 words
The process for the preparation of a 5-deoxy-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol which comprises the reaction of the corresponding 5-O-thioformyl-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol having all amino functions protected by an amino protecting group, Y, and all primary and secondary hydroxyl groups protected by a hydroxy protecting group, R; with at least a molar equivalent of an organotin hydride in an inert aprotic solvent at a temperature of at least about 100° C and under an inert atmosphere; followed by removal of said amino protecting groups, Y, and said hydroxyl protecting groups R.
Claim 12
Dependent Claim
85 words
The process for the preparation of a 5-deoxy-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol which comprises the reaction of the corresponding 5-O-thioformyl-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol having all amino functions protected by an amino protecting group, Y, and all primary and secondary hydroxyl groups protected by a hydroxy protecting group, R; with at least a molar equivalent of an organotin hydride in an inert aprotic solvent at a temperature of at least about 100° C and under an inert atmosphere; followed by removal of said amino protecting groups, Y, and said hydroxyl protecting groups R.
Claim 13
Dependent Claim
11 words
The process of claim 10 wherein said organotin hydride is tri-n-butylstannane.
Claim 14
Dependent Claim
53 words
The process of claim 10 wherein said organotin hydride is tri-n-butylstannane, said 5-thioformyl-4,6di-O-(aminoglycosyl)-1,3-diaminocyclitol is a 5-thioformyl-4-O-aminoglycosyl-6-O-garosaminyl-2-deoxystreptamine having all amino functions protected by benzyloxycarbonyl or ethoxycarbonyl groups, and allprimary and secondary hydroxy groups protected by a member selected from the group consisting of benzoyl, acetyl and carbonyl derivatives of neighboring hydroxyl and amino groups.
Claim 15
Dependent Claim
79 words
The process of claim 10 for the preparation of 5-deoxysisomicin and 1-N-X derivatives thereof wherein X is a member selected from the group consisting of ethyl, propyl, and δ-aminobutyl, which comprises the reaction of 1,3,2',6'tetra-N-ethoxycarbonyl-5-O-thioformyl-2"-O-benzoyl-3",4"-N,O-carbonylsisomicin or a 1-N-X' derivative thereof wherein X' is ethyl, propyl, or amino-protected δ-aminobutyl, with at least a molar equivalent of tri-n-butylstannane in refluxing toluene under an atmosphere of argon followed by treatment of the 1,3,2',6'-tetra-N-ethoxycarbonyl-2"-O-benzoyl-3",4"-N,O-carbonyl-5-deoxysisomicin or 1-N-X' derivative thereof thereby formed with potassium hydroxide.
Claim 16
Independent Claim
202 words
The method of eliciting an antibacterial response in a warm-blooded animal having a susceptible bacterial infection which comprises administering to said animal a non-toxic, antibacterially effective amount of a member selected from the group consisting of a 5-deoxy-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol selected from the group consisting of 5-deoxygentamicin B, 5-deoxygentamicin B 1 , 5-deoxygentamicin C 1a , 5-deoxygentamicin C 2 , 5-deoxygentamicin C 2a , 5-deoxygentamicin X 1 , 5-deoxygentamicin X 2 , 5-deoxy-Antibiotic 66-40B, 5-deoxy-Antibiotic 66-40D, 5-deoxy-Antibiotic G-418, 5-deoxy-Antibiotic JI-20A, 5-deoxy-Antibiotic JI-20B, 5-deoxyverdamicin, 5-deoxykanamycin B, 5-deoxykanamycin C, 5,3',4'-trideoxykanamycin B, 5-deoxy-Aminoglycoside XK-88-5, 5-deoxytobramycin; the 1-N-X derivatives thereof wherein X is a substituent selected from the group consisting of --CH 2 Z and ##STR10## wherein Z is a member selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, aminohydroxyalkyl, alkylaminohydroxyalkyl, phenyl, benzyl, and tolyl, said substituent Z having up to 7 carbon atoms and, when substituted by amino and hydroxy, bearing the substituents on different carbon atoms; the 2'-N-CH 2 Z, 6'-N-CH 2 Z, 1,2'-di-N-CH 2 Z and the 1,6'-di-N-CH 2 Z derivatives thereof wherein Z is as hereinabove defined; 5-deoxy-Antibiotic G-52 and the 1-N-X derivatives thereof wherein X is as hereinabove defined; and the pharmaceutically acceptable acid addition salts thereof.
Claim 17
Independent Claim
202 words
The method of eliciting an antibacterial response in a warm-blooded animal having a susceptible bacterial infection which comprises administering to said animal a non-toxic, antibacterially effective amount of a member selected from the group consisting of a 5-deoxy-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol selected from the group consisting of 5-deoxygentamicin B, 5-deoxygentamicin B 1 , 5-deoxygentamicin C 1a , 5-deoxygentamicin C 2 , 5-deoxygentamicin C 2a , 5-deoxygentamicin X 1 , 5-deoxygentamicin X 2 , 5-deoxy-Antibiotic 66-40B, 5-deoxy-Antibiotic 66-40D, 5-deoxy-Antibiotic G-418, 5-deoxy-Antibiotic JI-20A, 5-deoxy-Antibiotic JI-20B, 5-deoxyverdamicin, 5-deoxykanamycin B, 5-deoxykanamycin C, 5,3',4'-trideoxykanamycin B, 5-deoxy-Aminoglycoside XK-88-5, 5-deoxytobramycin; the 1-N-X derivatives thereof wherein X is a substituent selected from the group consisting of --CH 2 Z and ##STR10## wherein Z is a member selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, aminohydroxyalkyl, alkylaminohydroxyalkyl, phenyl, benzyl, and tolyl, said substituent Z having up to 7 carbon atoms and, when substituted by amino and hydroxy, bearing the substituents on different carbon atoms; the 2'-N-CH 2 Z, 6'-N-CH 2 Z, 1,2'-di-N-CH 2 Z and the 1,6'-di-N-CH 2 Z derivatives thereof wherein Z is as hereinabove defined; 5-deoxy-Antibiotic G-52 and the 1-N-X derivatives thereof wherein X is as hereinabove defined; and the pharmaceutically acceptable acid addition salts thereof.
Claim 18
Dependent Claim
190 words
A pharmaceutical composition comprising an antibacterially effective amount of a member selected from the group consisting of a 5-deoxy-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol selected from the group consisting of 5-deoxygentamicin B, 5-deoxygentamicin B 1 , 5-deoxygentamicin C 1a , 5-deoxygentamicin C 2 , 5-deoxygentamicin C 2a , 5-deoxygentamicin X 1 , 5-deoxygentamicin X 2 , 5-deoxy-Antibiotic 66-40B, 5-deoxy-Antibiotic 66-40D, 5-deoxy-Antibiotic G-418, 5-deoxy-Antibiotic JI-20A, 5-deoxy-Antibiotic JI-20B, 5-deoxyverdamicin, 5-deoxykanamycin B, 5-deoxykanamycin C, 5,3',4'-trideoxykanamycin B, 5-deoxy-Aminoglycoside XK-88-5, 5-deoxytobramycin; the 1-N-X derivatives thereof wherein X is a substituent selected from the group consisting of --CH 2 Z and ##STR11## wherein Z is a member selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, aminohydroxyalkyl, alkylaminohydroxyalkyl, phenyl, benzyl, and tolyl, said substituent Z having up to 7 carbon atoms and, when substituted by amino and hydroxy, bearing the substituents on different carbon atoms; the 2'-N-CH 2 Z, 6'-N-CH 2 Z, 1,2'-di-N-CH 2 Z and the 1,6'-di-N-CH 2 Z derivatives thereof wherein Z is as hereinabove defined; 5-deoxy-Antibiotic G-52 and the 1-N-X derivatives thereof wherein X is as hereinabove defined; and the pharmaceutically acceptable acid addition salts thereof; together with a non-toxic pharmaceutically acceptable carrier.
Claim 19
Dependent Claim
190 words
A pharmaceutical composition comprising an antibacterially effective amount of a member selected from the group consisting of a 5-deoxy-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol selected from the group consisting of 5-deoxygentamicin B, 5-deoxygentamicin B 1 , 5-deoxygentamicin C 1a , 5-deoxygentamicin C 2 , 5-deoxygentamicin C 2a , 5-deoxygentamicin X 1 , 5-deoxygentamicin X 2 , 5-deoxy-Antibiotic 66-40B, 5-deoxy-Antibiotic 66-40D, 5-deoxy-Antibiotic G-418, 5-deoxy-Antibiotic JI-20A, 5-deoxy-Antibiotic JI-20B, 5-deoxyverdamicin, 5-deoxykanamycin B, 5-deoxykanamycin C, 5,3',4'-trideoxykanamycin B, 5-deoxy-Aminoglycoside XK-88-5, 5-deoxytobramycin; the 1-N-X derivatives thereof wherein X is a substituent selected from the group consisting of --CH 2 Z and ##STR11## wherein Z is a member selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, aminohydroxyalkyl, alkylaminohydroxyalkyl, phenyl, benzyl, and tolyl, said substituent Z having up to 7 carbon atoms and, when substituted by amino and hydroxy, bearing the substituents on different carbon atoms; the 2'-N-CH 2 Z, 6'-N-CH 2 Z, 1,2'-di-N-CH 2 Z and the 1,6'-di-N-CH 2 Z derivatives thereof wherein Z is as hereinabove defined; 5-deoxy-Antibiotic G-52 and the 1-N-X derivatives thereof wherein X is as hereinabove defined; and the pharmaceutically acceptable acid addition salts thereof; together with a non-toxic pharmaceutically acceptable carrier.
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
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| 3.5 Years (Year 4) | 1980-10-10 | 1981-04-11 | 1981-10-11 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1984-10-10 | 1985-04-11 | 1985-10-11 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1988-10-10 | 1989-04-11 | 1989-10-11 | $7700.00 | Window Closed / Lapsed |