US4085208A
Expired / Lapsed
US
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Process for preparing 4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitols and novel 1-epimers and 1-N-alkyl derivatives produced thereby; methods for the use of the 1-epimer derivatives as antibacterial agents and compositions useful therefor
Assignee: Merck Sharp & Dohme LLC
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Filing: 1976-06-21
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Granted: 1978-04-18
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Expires: 1996-06-21
Abstract
Abstract This invention relates to the preparation of novel 1-epi-aminoglycosides, useful as antibacterial agents, and also relates to the process for the preparation of known as well as novel 1-N-substituted aminoglycoside antibacterial agents.
Inventors
- 👤 Alan K. Mallams
- 👤 David Huw Davies
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-08 14:46
CPC Classifications
C; C07; C07H; C07H15/00; C07H15/20; C07H15/22; C07H15/222; C07H15/226; C07H15/234
Claims Analysis
Total Claims: 33
Claim 1
Independent Claim
155 words
A 1-epi-N-X-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol selected from the group consisting of 1-epi-N-X-gentamicin A, 1-epi-N-X-gentamicin B, 1-epi-N-X-gentamicin B 1 , 1-epi-N-X-gentamicin C 1 , 1-epi-N-X-gentamicin C 1a , 1-epi-N-X-gentamicin C 2 , 1-epi-N-X-gentamicin C 2a , 1-epi-N-X-gentamicin C 2b , 1-epi-N-X-gentamicin X 2 , 1-epi-N-X-kanamycin A, 1-epi-N-X-kanamycin B, 1-epi-N-X-3',4'-dideoxykanamycin B, 1-epi-N-X-sisomicin, 1-epi-N-X-verdamicin, 1-epi-N-X-tobramycin, 1-epi-N-X-Antibiotic G-52, 1-epi-N-X-Antibiotic G-418, 1-epi-N-X-Antibiotic 66-40B, 1-epi-N-X-Antibiotic 66-40D, 1-epi-N-X-Antibiotic JI-20A, 1-epi-N-X-Antibiotic JI-20B, the 5-epi, 5-epi-azido-5-deoxy, 5-epi-amino-5-deoxy analogs of the foregoing; and 1-epi-N-X-Antibiotic Mu-1, 1-epi-N-X-Antibiotic Mu-2, 1-epi-N-X-Antibiotic Mu-4, 1-epi-N-X-Antibiotic Mu-5; and the pharmaceutically acceptable acid addition salts thereof, wherein X is a substituent selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aralkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminohydroxyalkyl, alkylaminohydroxyalkyl and dialkylaminohydroxyalkyl, said X substituent having less than 9 carbon atoms with the proviso that, said aminohydroxyalkyl, alkylaminohydroxyalkyl and dialkylaminohydroxyalkyl substituents must have the amino and hydroxyl groups on different carbon atoms, and that neither substituent be on the carbon atom alpha to the 1-amino function.
Claim 2
Dependent Claim
155 words
A 1-epi-N-X-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol selected from the group consisting of 1-epi-N-X-gentamicin A, 1-epi-N-X-gentamicin B, 1-epi-N-X-gentamicin B 1 , 1-epi-N-X-gentamicin C 1 , 1-epi-N-X-gentamicin C 1a , 1-epi-N-X-gentamicin C 2 , 1-epi-N-X-gentamicin C 2a , 1-epi-N-X-gentamicin C 2b , 1-epi-N-X-gentamicin X 2 , 1-epi-N-X-kanamycin A, 1-epi-N-X-kanamycin B, 1-epi-N-X-3',4'-dideoxykanamycin B, 1-epi-N-X-sisomicin, 1-epi-N-X-verdamicin, 1-epi-N-X-tobramycin, 1-epi-N-X-Antibiotic G-52, 1-epi-N-X-Antibiotic G-418, 1-epi-N-X-Antibiotic 66-40B, 1-epi-N-X-Antibiotic 66-40D, 1-epi-N-X-Antibiotic JI-20A, 1-epi-N-X-Antibiotic JI-20B, the 5-epi, 5-epi-azido-5-deoxy, 5-epi-amino-5-deoxy analogs of the foregoing; and 1-epi-N-X-Antibiotic Mu-1, 1-epi-N-X-Antibiotic Mu-2, 1-epi-N-X-Antibiotic Mu-4, 1-epi-N-X-Antibiotic Mu-5; and the pharmaceutically acceptable acid addition salts thereof, wherein X is a substituent selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aralkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminohydroxyalkyl, alkylaminohydroxyalkyl and dialkylaminohydroxyalkyl, said X substituent having less than 9 carbon atoms with the proviso that, said aminohydroxyalkyl, alkylaminohydroxyalkyl and dialkylaminohydroxyalkyl substituents must have the amino and hydroxyl groups on different carbon atoms, and that neither substituent be on the carbon atom alpha to the 1-amino function.
Claim 3
Dependent Claim
15 words
A compound of claim 1 wherein said 6-aminoglycosyl is garosaminyl and said 1,3-diaminocyclitol is 2-deoxystreptamine.
Claim 4
Dependent Claim
14 words
A compound of claim 2 wherein said compound is 1-epi-N-X-4-O-(aminoglycosyl)-6-O-garosaminyl-2-deoxystreptamine, wherein X is hydrogen.
Claim 5
Dependent Claim
16 words
A compound of claim 2 wherein said compound is 1-epi-N-X-4-O-(aminoglycosyl)-6-O-garosaminyl-2-deoxystreptamine, wherein X has 2-4 carbon atoms.
Claim 6
Dependent Claim
11 words
A compound of claim 3 which is 1-epi-gentamicin C 1 .
Claim 7
Dependent Claim
11 words
A compound of claim 3 which is 1-epi-gentamicin C 1a .
Claim 8
Dependent Claim
8 words
A compound of claim 3 which is 1-epi-sisomicin.
Claim 9
Dependent Claim
8 words
A compound of claim 3 which is 1-epi-verdamicin.
Claim 10
Dependent Claim
11 words
A compound of claim 4 which is 1-epi-N-ethylgentamicin C 1 .
Claim 11
Dependent Claim
12 words
A compound of claim 4 which is 1-epi-N-(β-hydroxyethyl) gentamicin C 1 .
Claim 12
Dependent Claim
11 words
A compound of claim 4 which is 1-epi-N-propylgentamicin C 1 .
Claim 13
Dependent Claim
12 words
A compound of claim 4 which is 1-epi-N-(γ-aminopropyl) gentamicin C 1 .
Claim 14
Dependent Claim
12 words
A compound of claim 4 which is 1-epi-N-(δ-aminobutyl) gentamicin C 1 .
Claim 15
Dependent Claim
11 words
A compound of claim 4 which is 1-epi-N-ethylgentamicin C 1a .
Claim 16
Dependent Claim
12 words
A compound of claim 4 which is 1-epi-N-(β-hydroxyethyl) gentamicin C 1a .
Claim 17
Dependent Claim
11 words
A compound of claim 4 which is 1-epi-N-propylgentamicin C 1a .
Claim 18
Dependent Claim
12 words
A compound of claim 4 which is 1-epi-N-(γ-aminopropyl) gentamicin C 1a .
Claim 19
Dependent Claim
12 words
A compound of claim 4 which is 1-epi-N-(δ-aminobutyl) gentamicin C 1a .
Claim 20
Dependent Claim
8 words
A compound of claim 4 which is 1-epi-N-ethylsisomicin.
Claim 21
Dependent Claim
9 words
A compound of claim 4 which is 1-epi-N-(β-hydroxyethyl) sisomicin.
Claim 22
Dependent Claim
8 words
A compound of claim 4 which is 1-epi-N-propylsisomicin.
Claim 23
Dependent Claim
9 words
A compound of claim 4 which is 1-epi-N-(γ-aminopropyl) sisomicin.
Claim 24
Dependent Claim
9 words
A compound of claim 4 which is 1-epi-N-(δ-aminobutyl) sisomicin.
Claim 25
Dependent Claim
8 words
A compound of claim 4 which is 1epi-N-ethylverdamicin.
Claim 26
Dependent Claim
9 words
A compound of claim 4 which is 1-epi-N-(β-hydroxyethyl) verdamicin.
Claim 27
Dependent Claim
8 words
A compound of claim 4 which is 1-epi-N-propylverdamicin.
Claim 28
Dependent Claim
9 words
A compound of claim 4 which is 1-epi-N-(γ-aminopropyl) verdamicin.
Claim 29
Dependent Claim
9 words
A compound of claim 4 which is 1-epi-N-(δ-aminobutyl) verdamicin.
Claim 30
Independent Claim
182 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 anti-bacterially effective amount of a 1-epi-N-X-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol selected from the group consisting of 1-epi-N-X-gentamicin A, 1-epi-N-X-gentamicin B, 1-epi-N-X-gentamicin B 1 , 1-epi-N-X-gentamicin C 1 , 1-epi-N-X-gentamicin C 1a , 1-epi-N-X-gentamicin C 2 , 1-epi-N-X-gentamicin C 2a , 1-epi-N-X-gentamicin C 2b , 1-epi-N-X-gentamicin X 2 , 1-epi-N-X-kanamycin A, 1-epi-N-X-kanamycin B, 1-epi-N-X-3',4'-dideoxykanamycin B, 1-epi-N-X-sisomicin, 1-epi-N-X-verdamicin, 1-epi-N-X-tobramycin, 1-epi-N-X-Antibiotic G-52, 1-epi-N-X-Antibiotic G-418, 1-epi-N-X-Antibiotic 66-40B, 1-epi-N-X-Antibiotic 66-40D, 1-epi-N-X-Antibiotic JI-20A, 1-epi-N-X-Antibiotic JI-20B, the 5-epi, 5-epi-azido-5-deoxy, 5-epi-amino-5-deoxy analogs of the foregoing; 1-epi-N-X-Antibiotic Mu-1, 1-epi-N-X-Antibiotic Mu-2, 1-epi-N-X-Antibiotic Mu-4, 1-epi-N-X-Antibiotic Mu-5; and the pharmaceutically acceptable acid addition salts thereof, wherein X is a substituent selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aralkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminohydroxyalkyl, alkylaminohydroxyalkyl and dialkylaminohydroxyalkyl, said X substituent having less than 9 carbon atoms with the proviso that, said aminohydroxyalkyl, alkylaminohydroxyalkyl and dialkylaminohydroxyalkyl substituents must have the amino and hydroxyl groups on different carbon atoms, and that neither substituent be on the carbon atom alpha to the 1-amino function.
Claim 31
Independent Claim
182 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 anti-bacterially effective amount of a 1-epi-N-X-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol selected from the group consisting of 1-epi-N-X-gentamicin A, 1-epi-N-X-gentamicin B, 1-epi-N-X-gentamicin B 1 , 1-epi-N-X-gentamicin C 1 , 1-epi-N-X-gentamicin C 1a , 1-epi-N-X-gentamicin C 2 , 1-epi-N-X-gentamicin C 2a , 1-epi-N-X-gentamicin C 2b , 1-epi-N-X-gentamicin X 2 , 1-epi-N-X-kanamycin A, 1-epi-N-X-kanamycin B, 1-epi-N-X-3',4'-dideoxykanamycin B, 1-epi-N-X-sisomicin, 1-epi-N-X-verdamicin, 1-epi-N-X-tobramycin, 1-epi-N-X-Antibiotic G-52, 1-epi-N-X-Antibiotic G-418, 1-epi-N-X-Antibiotic 66-40B, 1-epi-N-X-Antibiotic 66-40D, 1-epi-N-X-Antibiotic JI-20A, 1-epi-N-X-Antibiotic JI-20B, the 5-epi, 5-epi-azido-5-deoxy, 5-epi-amino-5-deoxy analogs of the foregoing; 1-epi-N-X-Antibiotic Mu-1, 1-epi-N-X-Antibiotic Mu-2, 1-epi-N-X-Antibiotic Mu-4, 1-epi-N-X-Antibiotic Mu-5; and the pharmaceutically acceptable acid addition salts thereof, wherein X is a substituent selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aralkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminohydroxyalkyl, alkylaminohydroxyalkyl and dialkylaminohydroxyalkyl, said X substituent having less than 9 carbon atoms with the proviso that, said aminohydroxyalkyl, alkylaminohydroxyalkyl and dialkylaminohydroxyalkyl substituents must have the amino and hydroxyl groups on different carbon atoms, and that neither substituent be on the carbon atom alpha to the 1-amino function.
Claim 32
Dependent Claim
168 words
A pharmaceutical composition comprising an anti-bacterially effective amount of a 1-epi-N-X-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol selected from the group consisting of: 1-epi-N-X-gentamicin A, 1-epi-N-X-gentamicin B, 1-epi-N-X-gentamicin B 1 , 1-epi-N-X-gentamicin C 1 , 1-epi-N-X-gentamicin C 1a , 1-epi-N-X-gentamicin C 2 , 1-epi-N-X-gentamicin C 2a , 1-epi-N-X-gentamicin C 2b , 1-epi-N-X-gentamicin X 2 , 1-epi-N-X-kanamycin A, 1-epi-N-X-kanamycin B, 1-epi-N-X-3',4'-dideoxykanamycin B, 1-epi-N-X-sisomicin, 1-epi-N-X-verdamicin, 1-epi-N-X-tobramycin, 1-epi-N-X-Antibiotic G-52, 1-epi-N-X-Antibiotic G-418, 1-epi-N-X-Antibiotic 66-40B, 1-epi-N-X-Antibiotic 66-40D, 1-epi-N-X-Antibiotic JI-20A, 1-epi-N-X-Antibiotic JI-20B, the 5-epi, 5-epi-azido-5-deoxy, 5-epi-amino-5-deoxyanalogs of the foregoing; 1-epi-N-X-Antibiotic Mu-1, 1-epi-N-X-Antibiotic Mu-2, 1-epi-N-X-Antibiotic Mu-4, 1-epi-N-X-Antibiotic Mu-5, the pharmaceutically acceptable acid addition salts thereof, together with a non-toxic pharmaceutically acceptable carrier, wherein X is a substituent selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aralkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminohydroxyalkyl, alkylaminohydroxyalkyl and dialkylaminohydroxyalkyl, said X substituent having less than 9 carbon atoms with the proviso that, said aminohydroxyalkyl, alkylaminohydroxyalkyl and dialkylaminohydroxyalkyl substituents must have the amino and hdyroxyl groups on different carbon atoms, and that neither substituent be on the carbon atom alpha to the I-amino function.
Claim 33
Dependent Claim
168 words
A pharmaceutical composition comprising an anti-bacterially effective amount of a 1-epi-N-X-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol selected from the group consisting of: 1-epi-N-X-gentamicin A, 1-epi-N-X-gentamicin B, 1-epi-N-X-gentamicin B 1 , 1-epi-N-X-gentamicin C 1 , 1-epi-N-X-gentamicin C 1a , 1-epi-N-X-gentamicin C 2 , 1-epi-N-X-gentamicin C 2a , 1-epi-N-X-gentamicin C 2b , 1-epi-N-X-gentamicin X 2 , 1-epi-N-X-kanamycin A, 1-epi-N-X-kanamycin B, 1-epi-N-X-3',4'-dideoxykanamycin B, 1-epi-N-X-sisomicin, 1-epi-N-X-verdamicin, 1-epi-N-X-tobramycin, 1-epi-N-X-Antibiotic G-52, 1-epi-N-X-Antibiotic G-418, 1-epi-N-X-Antibiotic 66-40B, 1-epi-N-X-Antibiotic 66-40D, 1-epi-N-X-Antibiotic JI-20A, 1-epi-N-X-Antibiotic JI-20B, the 5-epi, 5-epi-azido-5-deoxy, 5-epi-amino-5-deoxyanalogs of the foregoing; 1-epi-N-X-Antibiotic Mu-1, 1-epi-N-X-Antibiotic Mu-2, 1-epi-N-X-Antibiotic Mu-4, 1-epi-N-X-Antibiotic Mu-5, the pharmaceutically acceptable acid addition salts thereof, together with a non-toxic pharmaceutically acceptable carrier, wherein X is a substituent selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aralkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminohydroxyalkyl, alkylaminohydroxyalkyl and dialkylaminohydroxyalkyl, said X substituent having less than 9 carbon atoms with the proviso that, said aminohydroxyalkyl, alkylaminohydroxyalkyl and dialkylaminohydroxyalkyl substituents must have the amino and hdyroxyl groups on different carbon atoms, and that neither substituent be on the carbon atom alpha to the I-amino function.
References Cited (Backward Citations)
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1981-04-17 | 1981-10-17 | 1982-04-18 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1985-04-17 | 1985-10-17 | 1986-04-18 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1989-04-17 | 1989-10-17 | 1990-04-18 | $7700.00 | Window Closed / Lapsed |