US4062947A
Expired / Lapsed
US
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Di-N-alkylaminoglycosides, methods for their manufacture and novel intermediates useful therein, method for their use as antibacterial agents and pharmaceutical compositions useful therefor
Assignee: Merck Sharp & Dohme LLC
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Filing: 1976-07-19
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Granted: 1977-12-13
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Expires: 1996-07-19
Abstract
Abstract 1,2'-di-N-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitols and 1,6'-di-N-alkyl-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitols and their acid addition salts are valuable as antibacterial agents. Also disclosed are 2'-N-alkyl-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol antibacterial agents which are also useful as intermediates in the preparation of the 1,2'-di-N-alkyl-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitols. Preferred compounds of this invention include 1,2'-di-N-ethylsisomicin and 1,6'-di-N-ethylsisomicin.
Inventors
- 👤 John J. Wright
- 👤 Peter J. L. Daniels
- 👤 Alan K. Mallams
- 👤 Tattanahalli L. Nagabhushan
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-06 12:23
CPC Classifications
C; C07; C07H; C07H15/00; C07H15/20; C07H15/22; C07H15/222; C07H15/226; C07H15/234; A; A61; A61P; A61P31/00; A61P31/04
Claims Analysis
Total Claims: 29
Claim 1
Independent Claim
128 words
A 1,2'-di-N-X and a 1,6'-di-N-X derivative of a 4,6-di-O-aminoglycosyl-1,3-diaminocyclitol having antibacterial activity, said 4-O-aminoglycosyl having amino groups, all of which are primary, said primary amino groups being on one or both of positions 2' and 6'; wherein X is a substituent selected from the group consisting of alkyl, alkenyl, cycloalkylalkyl, aralkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, aminohydroxyalkyl and alkylaminohydroxyalkyl, said substituent having 2 to 8 carbon atoms, the carbon in said substituent adjacent to the aminoglycoside nitrogen being unsubstituted, and when said substituent is substituted by both amino and hydroxyl functions, only one of said functions can be attached at any one carbon atom; wherein the substituents, X, in said 1,2'-di-N-X- and in said 1,6'-di-N-X derivatives may be the same or different; and the pharmaceutically acceptable acid addition salts thereof.
Claim 2
Dependent Claim
128 words
A 1,2'-di-N-X and a 1,6'-di-N-X derivative of a 4,6-di-O-aminoglycosyl-1,3-diaminocyclitol having antibacterial activity, said 4-O-aminoglycosyl having amino groups, all of which are primary, said primary amino groups being on one or both of positions 2' and 6'; wherein X is a substituent selected from the group consisting of alkyl, alkenyl, cycloalkylalkyl, aralkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, aminohydroxyalkyl and alkylaminohydroxyalkyl, said substituent having 2 to 8 carbon atoms, the carbon in said substituent adjacent to the aminoglycoside nitrogen being unsubstituted, and when said substituent is substituted by both amino and hydroxyl functions, only one of said functions can be attached at any one carbon atom; wherein the substituents, X, in said 1,2'-di-N-X- and in said 1,6'-di-N-X derivatives may be the same or different; and the pharmaceutically acceptable acid addition salts thereof.
Claim 3
Dependent Claim
16 words
A compound of claim 1 wherein X is a substituent having 2 to 4 carbon atoms.
Claim 4
Dependent Claim
21 words
A compound of claim 1 wherein said 6-O-aminoglycosyl is 6-O-garosaminyl and X is a substituent having 2 to 4 carbon atoms.
Claim 5
Dependent Claim
25 words
A compound of claim 1 wherein said 6-O-aminoglycosyl is 6-O-garosaminyl, said 1,3-diaminocyclitol is 2-deoxystreptamine and X is a substituent having 2 to 4 carbon atoms.
Claim 6
Dependent Claim
66 words
A compound of claim 3 which is a 1,2'-di-N-X-4-O-aminoglycosyl-6-O-garosaminyl-1,3-diaminocyclitol selected from the group consisting of: 1,2'-di-N-X-gentamicin C 1a , 1,2'-di-N-X-gentamicin C 2 , 1,2'-di-N-X-gentamicin C 2a , 1,2'-di-N-X-gentamicin X 2 , 1,2'-di-N-X-sisomicin, 1,2'-di-N-X-verdamicin, 1,2'-di-N-X-Antibiotic G-418, 1,2'-di-N-X-Antibiotic JI-20A, 1,2'-di-N-X-Antibiotic JI-20B, the 5-epi, 5-epi-azido-5-deoxy, 5-epi-amino-5-deoxy analogs, of the foregoing and, 1,2'-di-N-X-Anitibiotic Mu-1, 1,2'.sbsb.-X-Antibiotic Mu-2, 1,2'-di-N-X-Antibiotic Mu-4, 1,2'-di-N-X-Antibiotic Mu-5, X being a substituent having 2 to 4 carbon atoms.
Claim 7
Dependent Claim
29 words
A compound of claim 3 which is a 1,6'-di-N-X-4-O-aminoglycosyl-6-O-garosaminyl-1,3-diaminocyclitol selected from the group consisting of: 1,6'-di-N-X-gentamicin B, 1,6'-di-N-X-gentamicin B 1 , 1,6'-di-N-X-gentamicin C 1a , 1,6'-di-N-X-gentamicin C 2 ,
Claim 8
Dependent Claim
37 words
6'-di-N-X-gentamicin C 2a , 1,6'-di-N-X-sisomicin, 1,6'-di-N-X-verdamicin, 1,6'-di-N-X-Antibiotic JI-20A, 1,6'-di-N-X-Antibiotic JI-20B, the 5-epi, 5-epi-azido-5-deoxy, 5-epi-amino-5-deoxy analogs of the foregoing and, 1,6'-di-N-X-Antibiotic Mu-1, 1,6'-di-N-X-Antibiotic Mu-2, 1,6'-di-N-X-Antibiotic Mu-4, 1,6'-di-N-X-Antibiotic Mu-5, X being a substituent having 2 to 4 carbon atoms.
Claim 9
Dependent Claim
37 words
6'-di-N-X-gentamicin C 2a , 1,6'-di-N-X-sisomicin, 1,6'-di-N-X-verdamicin, 1,6'-di-N-X-Antibiotic JI-20A, 1,6'-di-N-X-Antibiotic JI-20B, the 5-epi, 5-epi-azido-5-deoxy, 5-epi-amino-5-deoxy analogs of the foregoing and, 1,6'-di-N-X-Antibiotic Mu-1, 1,6'-di-N-X-Antibiotic Mu-2, 1,6'-di-N-X-Antibiotic Mu-4, 1,6'-di-N-X-Antibiotic Mu-5, X being a substituent having 2 to 4 carbon atoms.
Claim 10
Dependent Claim
8 words
A compound of claim 5 which is 1,2'-di-N-ethylsisomicin.
Claim 11
Dependent Claim
8 words
A compound of claim 5 which is 1,2'-di-N-propylsisomicin.
Claim 12
Dependent Claim
8 words
A compound of claim 5 which is 1,2'-di-N-(δ-aminopropyl)sisomicin.
Claim 13
Dependent Claim
8 words
A compound of claim 5 which is 1,2'-di-N-(δ-aminobutyl)sisomicin.
Claim 14
Dependent Claim
8 words
A compound of claim 6 which is 1,6'-di-N-ethylsisomicin.
Claim 15
Dependent Claim
8 words
A compound of claim 6 which is 1,6'-di-N-propylsisomicin.
Claim 16
Dependent Claim
8 words
A compound of claim 6 which is 1,6'-di-N-(δ-aminopropyl)sisomicin.
Claim 17
Dependent Claim
8 words
A compound of claim 6 which is 1,6'-di-N-(δ-aminobutyl)sisomicin.
Claim 18
Dependent Claim
125 words
A 2'-N-X-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol selected from the group consisting of: 2'-N-X-gentamicin A, 2'-n-x-sisomicin, 2'-N-X-verdamicin, 2'-N-X-tobramycin, 2'-N-X-Antibiotic 66-40B, 2'-n-x-antibiotic 66-40D, the 5-epi, 5-epi-azido-5-deoxy, 5-epi-amino-5-deoxy analogs of the foregoing and the following; 2'-N-X-gentamicin C 1a , 2'-N-X-gentamicin C 2 , 2'-n-x-gentamicin C 2a , 2'-N-X-gentamicin X 2 , 2'-n-x-antibiotic G-418, 2'-n-x-antibiotic JI-20A, 2'-n-x-antibiotic JI-20B, and 2'-N-X-Antibiotic Mu-1, 2'-N-X-Antibiotic Mu-2, 2'-N-X-Antibiotic Mu-4and 2'-N-X-Antibiotic Mu-5; wherein X is a substituent selected from the group consisting of alkyl, alkenyl, cycloalkylalkyl, aralkyl, hydroxyalkyl, aminoalkyl, alklaminoalkyl, aminohydroxyalkyl, and alkylaminohydroxyalkyl, said substituent having 2 to 8 carbon atoms, the carbon in said substituent adjacent to the aminoglycoside nitrogen being unsubstituted and when said substituent is substituted by both hydroxyl and amino functions, only one of said functions can be attached at any one carbon atom.
Claim 19
Dependent Claim
125 words
A 2'-N-X-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol selected from the group consisting of: 2'-N-X-gentamicin A, 2'-n-x-sisomicin, 2'-N-X-verdamicin, 2'-N-X-tobramycin, 2'-N-X-Antibiotic 66-40B, 2'-n-x-antibiotic 66-40D, the 5-epi, 5-epi-azido-5-deoxy, 5-epi-amino-5-deoxy analogs of the foregoing and the following; 2'-N-X-gentamicin C 1a , 2'-N-X-gentamicin C 2 , 2'-n-x-gentamicin C 2a , 2'-N-X-gentamicin X 2 , 2'-n-x-antibiotic G-418, 2'-n-x-antibiotic JI-20A, 2'-n-x-antibiotic JI-20B, and 2'-N-X-Antibiotic Mu-1, 2'-N-X-Antibiotic Mu-2, 2'-N-X-Antibiotic Mu-4and 2'-N-X-Antibiotic Mu-5; wherein X is a substituent selected from the group consisting of alkyl, alkenyl, cycloalkylalkyl, aralkyl, hydroxyalkyl, aminoalkyl, alklaminoalkyl, aminohydroxyalkyl, and alkylaminohydroxyalkyl, said substituent having 2 to 8 carbon atoms, the carbon in said substituent adjacent to the aminoglycoside nitrogen being unsubstituted and when said substituent is substituted by both hydroxyl and amino functions, only one of said functions can be attached at any one carbon atom.
Claim 20
Dependent Claim
16 words
A compound of claim 15 wherein X is a substituent having 2 to 4 carbon atoms.
Claim 21
Dependent Claim
8 words
A compound of claim 16 which is 2'-N-ethylsisomicin.
Claim 22
Dependent Claim
8 words
A compound of claim 16 which is 2'-N-propylsisomicin.
Claim 23
Dependent Claim
8 words
A compound of claim 16 which is 2'-N-butylsisomicin.
Claim 24
Dependent Claim
9 words
A compound of claim 16 which is 2'-N-(δ-aminopropyl) sisomicin.
Claim 25
Dependent Claim
9 words
A compound of claim 16 which is 2'-N-(δ-aminobutyl) sisomicin.
Claim 26
Independent Claim
156 words
The method of eliciting an antibacterial response in a warm blooded animal having a susceptible bacterial infection which comprises administering to saidd animal a non-toxic antibacterially effective amount of a 1,2'-di-N-X and a 1,6'-di-N-X derivative of a 4,6-di-O-aminoglycosyl-1,3-diaminocyclitol having antibacterial activity, said 4-O-aminoglycosyl having amino groups all of which are primary, said primary amino groups being on one or both of positions 2' and 6'; wherein X is a substituent selected from the group consisting of alkyl, alkenyl, cycloalkylalkyl, aralkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, aminohydroxyalkyl and alkylaminohydroxyalkyl, said substituent having 2 to 8 carbon atoms, the carbon in aid substituent adjacent to the aminoglycoside nitrogen being unsubstituted, and when said substituent is substituted by both amino and hydroxyl functions only one of said functions can be attached at any one carbon atom; wherein the substituents, X, in said 1,2'-di-N-X-and in said 1,6'-di-N-X derivatives may be the same or different; and the pharmaceutically acceptable acid addition salts thereof.
Claim 27
Independent Claim
156 words
The method of eliciting an antibacterial response in a warm blooded animal having a susceptible bacterial infection which comprises administering to saidd animal a non-toxic antibacterially effective amount of a 1,2'-di-N-X and a 1,6'-di-N-X derivative of a 4,6-di-O-aminoglycosyl-1,3-diaminocyclitol having antibacterial activity, said 4-O-aminoglycosyl having amino groups all of which are primary, said primary amino groups being on one or both of positions 2' and 6'; wherein X is a substituent selected from the group consisting of alkyl, alkenyl, cycloalkylalkyl, aralkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, aminohydroxyalkyl and alkylaminohydroxyalkyl, said substituent having 2 to 8 carbon atoms, the carbon in aid substituent adjacent to the aminoglycoside nitrogen being unsubstituted, and when said substituent is substituted by both amino and hydroxyl functions only one of said functions can be attached at any one carbon atom; wherein the substituents, X, in said 1,2'-di-N-X-and in said 1,6'-di-N-X derivatives may be the same or different; and the pharmaceutically acceptable acid addition salts thereof.
Claim 28
Dependent Claim
144 words
A pharmaceutical composition comprising an antibacterially effective amount of a 1,2'-di-N-X and a 1,6'-di-N-X derivative of a 4,6-di-O-aminoglycosyl-1,3-diaminocyclitol having antibacterial activity, said 4-O-aminoglycosyl having amino groups all of which are primary, said primary amino groups being on one or both of positions 2' and 6'; wherein X is a substituent selected from the group consisting of alkyl, alkenyl, cycloalkylalkyl, aralkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, aminohydroxyalkyl and alkylaminohydroxyalkyl, said substituent having 2 to 8 carbon atoms, the carbon in said substituent adjacent to the aminoglycoside nitrogen being unsubstituted, and when said substituent is substituted by both amino and hydroxyl functions only one of said functions can be attached at any one carbon atom; wherein the substituents, X, in said 1,2'-di-N-X- and in said 1,6'-di-N-X derivatives may be the same or different; and the pharmaceutically acceptable acid addition salts thereof; together with a non-toxic pharmaceutically acceptable carrier.
Claim 29
Dependent Claim
144 words
A pharmaceutical composition comprising an antibacterially effective amount of a 1,2'-di-N-X and a 1,6'-di-N-X derivative of a 4,6-di-O-aminoglycosyl-1,3-diaminocyclitol having antibacterial activity, said 4-O-aminoglycosyl having amino groups all of which are primary, said primary amino groups being on one or both of positions 2' and 6'; wherein X is a substituent selected from the group consisting of alkyl, alkenyl, cycloalkylalkyl, aralkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, aminohydroxyalkyl and alkylaminohydroxyalkyl, said substituent having 2 to 8 carbon atoms, the carbon in said substituent adjacent to the aminoglycoside nitrogen being unsubstituted, and when said substituent is substituted by both amino and hydroxyl functions only one of said functions can be attached at any one carbon atom; wherein the substituents, X, in said 1,2'-di-N-X- and in said 1,6'-di-N-X derivatives may be the same or different; and the pharmaceutically acceptable acid addition salts thereof; together with a non-toxic pharmaceutically acceptable carrier.
References Cited (Backward Citations)
US3920628A
Cited
US4002742A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1980-12-12 | 1981-06-13 | 1981-12-13 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1984-12-12 | 1985-06-13 | 1985-12-13 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1988-12-12 | 1989-06-13 | 1989-12-13 | $7700.00 | Window Closed / Lapsed |