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US4169141A
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1-Peptidyl derivatives of di-O-aminoglycosyl-1,3-diaminocyclitol antibacterial agents
Assignee: Merck Sharp & Dohme LLC
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Filing: 1978-01-30
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Granted: 1979-09-25
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Expires: 1998-01-30
Abstract
Abstract Disclosed herein are di-O-(aminoglycosyl)-1,3-diaminocyclitol antibacterial agents having on the 1-N-position of the 1,3-diaminocyclitol moiety a dipeptidyl or a tripeptidyl substituent. The compounds are useful antibacterial agents, as are their non-toxic pharmaceutically acceptable acid addition salts. Also disclosed are methods for preparing such agents from di-O-(aminoglycosyl)-1,3-diaminocyclitol antibacterial agents which are unsubstituted at the 1-N-position.
Inventors
- 👤 John G. Topliss
- 👤 Adriano Afonso
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-30 13:20
CPC Classifications
C; C07; C07H; C07H15/00; C07H15/20; C07H15/22; C07H15/222; C07H15/226; C07H15/234; C07K; C07K5/00; C07K5/04; C07K5/06; C07K5/06008; C07K5/06017; C07K5/06026; C07K5/06086; C07K9/00; C07K9/001; C07K9/005; A; A61; A61K; A61K38/00
Claims Analysis
Total Claims: 31
Claim 1
Independent Claim
183 words
1-N-peptidyl derivatives of 4,6-di-0-(aminoglycosyl)-1,3-diaminocyclitol antibacterial agents including the non-toxic pharmaceutically acceptable acid addition salts thereof wherein said peptidyl moiety is derived from a di or tripeptide having an acyl moiety selected from the group consisting of ##STR4## wherein R, R' and R" may be the same or different, are attached to carbon atoms which are in the L or D configuration, said R, R' and R" being members selected from the group consisting of hydrogen; C 1 -C 6 C 1 -C 6 alkyl including branched chain alkyl; HO--(CH 2 )--; HO--CH--(CH 3 ); HO--(CH 3 ) 2 ; NH 2 --(CH 2 )--; NH 2 --CH 2 --CH(OH)--(CH 2 )--; ##STR5## wherein A is a member of the group consisting of hydrogen and hydroxy; B is a member selected from the group consisting of hydrogen, bromo and iodo; D is a member selected from the group consisting of hydrogen and iodo; n is an integer from 1-5 and wherein R, R' and R" may be linked to the respective α-nitrogen to form a cyclic moiety selected from the group consisting of: ##STR6##
Claim 2
Dependent Claim
183 words
1-N-peptidyl derivatives of 4,6-di-0-(aminoglycosyl)-1,3-diaminocyclitol antibacterial agents including the non-toxic pharmaceutically acceptable acid addition salts thereof wherein said peptidyl moiety is derived from a di or tripeptide having an acyl moiety selected from the group consisting of ##STR4## wherein R, R' and R" may be the same or different, are attached to carbon atoms which are in the L or D configuration, said R, R' and R" being members selected from the group consisting of hydrogen; C 1 -C 6 C 1 -C 6 alkyl including branched chain alkyl; HO--(CH 2 )--; HO--CH--(CH 3 ); HO--(CH 3 ) 2 ; NH 2 --(CH 2 )--; NH 2 --CH 2 --CH(OH)--(CH 2 )--; ##STR5## wherein A is a member of the group consisting of hydrogen and hydroxy; B is a member selected from the group consisting of hydrogen, bromo and iodo; D is a member selected from the group consisting of hydrogen and iodo; n is an integer from 1-5 and wherein R, R' and R" may be linked to the respective α-nitrogen to form a cyclic moiety selected from the group consisting of: ##STR6##
Claim 3
Dependent Claim
25 words
A compund of claim 1 wherein the acyl moiety has the formula ##STR7## group wherein R and R' are as defined in said claim 1.
Claim 4
Dependent Claim
26 words
A compound of claim 1 wherein the acyl moiety has the formula ##STR8## group wherein R, R' and R" are as defined in said claim 1.
Claim 5
Dependent Claim
79 words
A 1-N-peptidyl derivative of a 4,6-di-0-(aminoglycosyl)-1,3-diaminocyclitol antibacterial agent of claim 2 selected from the group consisting of gentamicin A, gentamicin B, gentamicin B 1 , gentamicin C 1 , gentamicin C 1a , gentamicin C 2 , gentamicin C 2a , gentamicin C 2b , gentamicin X 2 , sisomicin, verdamicin, tobramycin, Antibiotic JI-20A, antibiotic JI-20B, Antibiotic Mu-1, Antibiotic Mu-2, Antibiotic Mu-4, Antibiotic Mu-5, Antibiotic Mu-6, Antibiotic G-52, Antibiotic G-418, Antibiotic 66-40B, Antibiotic 66-40D, kanamycin A and kanamycin B.
Claim 6
Dependent Claim
79 words
A 1-N-peptidyl derivative of a 4,6-di-0-(aminoglycosyl)-1,3-diaminocyclitol antibacterial agent of claim 3 selected from the group consisting of gentamicin A, gentamicin B, gentamicin B 1 , gentamicin C 1 , gentamicin C 1a , gentamicin C 2 , gentamicin C 2a , gentamicin C 2b , gentamicin X 2 , sisomicin, verdamicin, tobramycin, Antibiotic JI-20A, Antibiotic JI-20B, Antibiotic Mu-1, Antibiotic Mu-2, Antibiotic Mu-4, Antibiotic Mu-5, Antibiotic Mu-6, Antibiotic G-52, Antibiotic G-418, Antibiotic 66-40B, Antibiotic 66-40D, kanamycin A and kanamycin B.
Claim 7
Dependent Claim
49 words
A 1-N-peptidyl derivative of a 4,6-di-0-(aminoglycosyl)-1,3-diaminocyclitol antibacterial agent of claim 2 wherein said 4-0-(aminoglycosyl) moiety has a double bond briding the 4',5'-position of a compund selected from the group consisting of sisomicin, verdamicin, Antibiotic G-52, Antibiotic 66-40B, Antibiotic 66-40D, Antibiotic Mu-1,Antibiotic Mu-2, Antibiotic Mu-4, Antibiotic Mu-5 and Antibiotic Mu-6.
Claim 8
Dependent Claim
50 words
A 1-N-peptidyl derivative of a 4,6-di-0-(aminoglycosyl)-1,3-diaminocyclitol antibacterial agent of claim 3 wherein said 4-0-(aminoglycosyl) moiety has a double bond bridging the 4',5'-position of a compound selected from the group consisting of sisomicin, verdamicin, Antibiotic G-52, Antibiotic 66-40B, Antibiotic 66-40D, Antibiotic Mu-1, Antibiotic Mu-2, Antibiotic Mu-4, Antibiotic Mu-5 and Antibiotic Mu-6.
Claim 9
Dependent Claim
32 words
A compound of claim 6, said compound being a 1-N-dipeptidyl derivative of sisomicin selected from the group consisting of 1-N-(diglycyl)-sisomicin, 1-N-(L-leucyl-glycyl) sisomicin, 1-N-(glycyl-L-leucyl) sisomicin, 1-N-glycyl-L-seryl) sisomicin, 1-N-(L-seryl-glycyl)sisomicin, 1-N-(glycyl-L-α,γ-diaminobutyryl) sisomicin and 1-N-(L-α-γ-diaminobutyryl-glycyl) sisomicin.
Claim 10
Dependent Claim
10 words
A compound of claim 8, said compound being 1-N-(L-diglycyl) sisomicin.
Claim 11
Dependent Claim
10 words
A compound of claim 8, said compound being 1-N-(L-leucyl-glycyl) sisomicin.
Claim 12
Dependent Claim
10 words
A compound of claim 8, said compound being 1-N-(glycyl-L-leucyl) sisomicin.
Claim 13
Dependent Claim
10 words
A compound of claim 8, said compound being 1-N-(glycyl-L-seryl) sisomicin.
Claim 14
Dependent Claim
10 words
A compound of claim 8, said compound being 1-N-(L-seryl-glycyl) sisomicin.
Claim 15
Dependent Claim
10 words
A compound of claim 8, said compound being 1-N-(glycyl-L-α,ν-diaminobutyryl) sisomicin.
Claim 16
Dependent Claim
10 words
A compound of claim 8, said compound being 1-N-(L-α,γ-diaminobutyryl-glycyl) sisomicin.
Claim 17
Dependent Claim
15 words
A 1-N-(diglycyl) derivative of a compound of claim 4, said derivative being 1-N-(diglycyl) gentamicin B.
Claim 18
Dependent Claim
13 words
A compound of claim 7, said compound being a 1-N-tripeptidyl derivative of sisomicin.
Claim 19
Dependent Claim
10 words
A compound of claim 17, said compound being 1-N-(triglycyl) sisomicin.
Claim 20
Independent Claim
218 words
A method of eliciting an antibacterial response in a warm blooded animal having a bacterial infection caused by a susceptible bacteria which comprises administering to said animal a compound selected from the group consisting of 1-N-peptidyl derivatives of 4,6-di-0-(aminoglycosyl)-1,3-diaminocyclitol antibacterial agents including the non-toxic pharmaceutically acceptable acid addition salts thereof wherein said peptidyl moiety is derived from the group consisting of ##STR9## wherein R, R' and R" may be the same or different, are attached to carbon atoms which are in the L or D configuration, said R, R' and R" being members selected from the group consisting of hydrogen; C 1 -C 6 alkyl including branched chain alkyl; HO--(CH 2 )--; HO--(CH 3 )CH--; HO--(CH 3 ) 2 C--; NH 2 --(CH 2 )--; NH 2 --CH 2 --CH(OH)--(CH 2 )--; ##STR10## wherein A is a member of the group consisting of hydrogen and hydroxy; B is a member selected from the group consisting of hydrogen, bromo and iodo; D is a member selected from the group consisting of hydrogen and iodo; n is an integer from 1-5 and wherein R, R' and R" may be linked to the respective α-nitrogen to form a cyclic moiety selected from the group consisting of: ##STR11## and wherein the compound is administered at from about 7.5 to about 15 mg/kg/day.
Claim 21
Independent Claim
218 words
A method of eliciting an antibacterial response in a warm blooded animal having a bacterial infection caused by a susceptible bacteria which comprises administering to said animal a compound selected from the group consisting of 1-N-peptidyl derivatives of 4,6-di-0-(aminoglycosyl)-1,3-diaminocyclitol antibacterial agents including the non-toxic pharmaceutically acceptable acid addition salts thereof wherein said peptidyl moiety is derived from the group consisting of ##STR9## wherein R, R' and R" may be the same or different, are attached to carbon atoms which are in the L or D configuration, said R, R' and R" being members selected from the group consisting of hydrogen; C 1 -C 6 alkyl including branched chain alkyl; HO--(CH 2 )--; HO--(CH 3 )CH--; HO--(CH 3 ) 2 C--; NH 2 --(CH 2 )--; NH 2 --CH 2 --CH(OH)--(CH 2 )--; ##STR10## wherein A is a member of the group consisting of hydrogen and hydroxy; B is a member selected from the group consisting of hydrogen, bromo and iodo; D is a member selected from the group consisting of hydrogen and iodo; n is an integer from 1-5 and wherein R, R' and R" may be linked to the respective α-nitrogen to form a cyclic moiety selected from the group consisting of: ##STR11## and wherein the compound is administered at from about 7.5 to about 15 mg/kg/day.
Claim 22
Dependent Claim
35 words
A method according to claim 19 which comprises administering a compound of said claim wherein the acyl moiety has the formula ##STR12## and wherein R and R 1 are as defined in said claim 19.
Claim 23
Dependent Claim
35 words
A method according to claim 19 which comprises administering a compound of said claim wherein the acyl moiety has the formula ##STR13## and wherein R, R' and R" are as defined in said claim 19.
Claim 24
Dependent Claim
40 words
A method of eliciting an antibacterial response in a warm blooded animal having a bacterial infection caused by a susceptible bacterial which comprises administering to said animal from about 7.5 to about 15 mg/kg/day of a compound of claim 4.
Claim 25
Dependent Claim
40 words
A method of eliciting an antibacterial response in a warm blooded animal having a bacterial infection caused by a susceptible bacteria which comprises administering to said animal from about 7.5 to about 15 mg/kg/day of a compound of claim 5.
Claim 26
Dependent Claim
40 words
A method of eliciting an antibacterial response in a warm blooded animal having a bacterial infection caused by a susceptible bacteria which comprises administering to said animal from about 7.5 to about 15 mg/kg/day of a compound of claim 6.
Claim 27
Dependent Claim
40 words
A method of eliciting an antibacterial response in a warm blooded animal having a bacterial infection caused by a susceptible bacteria which comprises administering to said animal from about 7.5 to about 15 mg/kg/day of a compound of claim 7.
Claim 28
Dependent Claim
40 words
A method of eliciting an antibacterial response in a warm blooded animal having a bacterial infection caused by a susceptible bacteria which comprises administering to said animal from about 7.5 to about 15 mg/kg/day of a compound of claim 8.
Claim 29
Dependent Claim
11 words
A method according to claim 22 wherein 1-N-(diglycyl) sisomicin is administered.
Claim 30
Dependent Claim
12 words
A method according to claim 22 wherein 1-N-(diglycyl) gentamicin B is administered.
Claim 31
Dependent Claim
11 words
A method according to claim 25 wherein 1-N-(triglycyl) sisomicin is administered.
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) | 1982-09-24 | 1983-03-26 | 1983-09-25 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1986-09-24 | 1987-03-26 | 1987-09-25 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1990-09-24 | 1991-03-26 | 1991-09-25 | $7700.00 | Window Closed / Lapsed |