US4503040A
Expired / Lapsed
US
⏱️ 0.0 years remaining
6-(Aminoacyloxymethyl)penicillanic acid 1,1-dioxides as beta-lactamase inhibitors
Assignee: Pfizer Inc
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Filing: 1984-02-27
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Granted: 1985-03-05
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Expires: 2004-02-27
Abstract
Abstract Beta-lactamase inhibitors which are aminoacid esters of 6-alpha- and 6-beta-(hydroxymethyl)pencillanic acid 1,1-dioxides; pharmaceutically-acceptable salts thereof; conventional esters thereof which are hydrolyzable in vivo; bis-methanediol esters thereof; or mixed methanediol esters with said beta-lactamase inhibitors and sulbactam. Pharmaceutical compositions comprising said beta-lactamase inhibitors and a conventional beta-lactam antibiotic, said compositions useful in the treatment of bacterial infections. Compounds useful as intermediates in the synthesis of said beta-lactamase inhibitors. Antibacterial mixed bis-methanediol esters of said aminoacyloxymethyl penicillanic acid 1,1-dioxides and ampicillin or amoxicillin, also useful in the treatment of bacterial infections; and intermediates therefor.
Inventors
- 👤 Wayne E. Barth
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-27 04:41
CPC Classifications
C; C07; C07D; C07D499/00; C07D499/86; C07D499/861; A; A61; A61P; A61P31/00; A61P31/04
Claims Analysis
Total Claims: 59
Claim 1
Independent Claim
183 words
A compound having the formula ##STR19## wherein R is ##STR20## R 3 , R 4 and R 5 are each independently hydrogen or (C 1 -C 3 )alkyl; R 6 is hydrogen, (C 1 -C 6 )alkyl, phenyl or benzyl; or one of said (C 1 -C 6 )alkyl, phenyl or benzyl monosubstituted with --OR 3 , --SR 8 , --SO 2 R 8 , --NR 3 R 4 , --NHCOR 3 , --CONH 2 or --COOR 3 ; with the proviso that when said substituent is --COOH, n is 1 and R 1 is hydrogen; R 7 is hydrogen, hydroxy or --OCOR 3 ; R 8 is (C 1 -C 3 )alkyl; Y is --(CH 2 ) m --; --0--, --S--, ##STR21## m is 0, 1 or 2; and either n is 1 and R 1 is hydrogen, a radical group forming an ester hydrolyzable under physiological conditions, or 1,1-dioxopenicillanoyloxymethyl; or n is 2 and R 1 is --CH 2 --; a pharmaceutically-acceptable acid addition salt thereof, or a pharmaceutically-acceptable cationic salt thereof when n is 1 and R 1 is hydrogen.
Claim 2
Dependent Claim
183 words
A compound having the formula ##STR19## wherein R is ##STR20## R 3 , R 4 and R 5 are each independently hydrogen or (C 1 -C 3 )alkyl; R 6 is hydrogen, (C 1 -C 6 )alkyl, phenyl or benzyl; or one of said (C 1 -C 6 )alkyl, phenyl or benzyl monosubstituted with --OR 3 , --SR 8 , --SO 2 R 8 , --NR 3 R 4 , --NHCOR 3 , --CONH 2 or --COOR 3 ; with the proviso that when said substituent is --COOH, n is 1 and R 1 is hydrogen; R 7 is hydrogen, hydroxy or --OCOR 3 ; R 8 is (C 1 -C 3 )alkyl; Y is --(CH 2 ) m --; --0--, --S--, ##STR21## m is 0, 1 or 2; and either n is 1 and R 1 is hydrogen, a radical group forming an ester hydrolyzable under physiological conditions, or 1,1-dioxopenicillanoyloxymethyl; or n is 2 and R 1 is --CH 2 --; a pharmaceutically-acceptable acid addition salt thereof, or a pharmaceutically-acceptable cationic salt thereof when n is 1 and R 1 is hydrogen.
Claim 3
Dependent Claim
43 words
A compound of claim 1 wherein n is 1 and R 1 is: (5-methyl-1,3-dioxol-2-on-4-yl)methyl, 1H-isobenzofuran-3-on-1-yl, gamma-butyrolacton-4-yl, --CHR 9 OCOR 10 , or --CHR 9 OCOOR 10 , wherein R 9 is hydrogen or methyl and R 10 is (C 1 -C 6 )alkyl.
Claim 4
Dependent Claim
10 words
A compound of claim 2 wherein R 1 is 1-ethoxycarbonyloxyethyl.
Claim 5
Dependent Claim
10 words
A compound of claim 2 wherein R 1 is pivaloyloxymethyl.
Claim 6
Dependent Claim
16 words
A compound of claim 1 wherein n is 2 and R 1 is --CH 2 --.
Claim 7
Dependent Claim
13 words
The compound of claim 5 having the formula II wherein R is glycyl.
Claim 8
Dependent Claim
13 words
The compound of claim 5 having the formula (I) wherein R is trans-4-hydroxy-L-prolyl.
Claim 9
Dependent Claim
15 words
A compound of claim 1 wherein n is 1 and R 1 is hydrogen .
Claim 10
Dependent Claim
9 words
A compound of claim 8 wherein R is ##STR22##
Claim 11
Dependent Claim
16 words
A compound of claim 9 wherein R 3 , R 4 and R 5 are hydrogen.
Claim 12
Dependent Claim
9 words
A compound of claim 10 wherein R is D-alanyl.
Claim 13
Dependent Claim
9 words
A compound of claim 10 wherein R is L-alanyl.
Claim 14
Dependent Claim
9 words
A compound of claim 10 wherein R is L-glutaminyl.
Claim 15
Dependent Claim
9 words
A compound of claim 9 having the formula (I).
Claim 16
Dependent Claim
16 words
A compound of claim 14 wherein R is 2-amino-2-methylpropionyl, L-seryl, L-lysyl, L-(2-amino-4-methanesulfonylbutyryl), L-phenylalanyl, L-valyl or L-threonyl.
Claim 17
Dependent Claim
9 words
The compound of claim 15 wherein R is L-seryl.
Claim 18
Dependent Claim
9 words
The compound of claim 15 wherein R is L-lysyl.
Claim 19
Dependent Claim
10 words
The compound of claim 15 wherein R is L-phenyl- alanyl.
Claim 20
Dependent Claim
9 words
A compound of claim 8 wherein R is ##STR23##
Claim 21
Dependent Claim
14 words
A compound of claim 19 wherein R 3 is hydrogen and m is 1.
Claim 22
Dependent Claim
9 words
A compound of claim 20 having the formula (I).
Claim 23
Dependent Claim
9 words
The compound of claim 21 wherein R is L-prolyl.
Claim 24
Dependent Claim
9 words
The compound of claim 21 wherein R is trans-4-hydroxy-L-prolyl.
Claim 25
Dependent Claim
13 words
The compound of claim 20 having the formula (II) wherein R is L-prolyl.
Claim 26
Dependent Claim
9 words
A compound of claim 8 wherein R is ##STR24##
Claim 27
Dependent Claim
9 words
A compound of claim 8 wherein R is ##STR25##
Claim 28
Dependent Claim
26 words
A pharmaceutical composition for treating bacterial infections which comprises in a weight ratio of 1:3 to 3:1 a compound of claim 1 and a beta-lactam antibiotic.
Claim 29
Dependent Claim
79 words
A pharmaceutical composition of claim 27 wherein the beta-lactam antibiotic is amoxicillin, ampicillin, apalacillin azlocillin, azthreonam bacampicillin, carbenicillin, carbenicillin indanyl, carbenicillin phenyl, cefaclor, cefadroxil, cefaloram, cefamandole, cefamandole nafate, cefaparole, cefatrizine, cefazolin, cefmenoxime cefonicid cefodizime cefoperazone, ceforanide, cefotaxime, cefotiam cefotetan cefoxitin, cefsulodin, ceftazidime, ceftizoxime, ceftriaxone, cefuroxime, cephacetrile, cephalexin, cephaloglycin, cephaloridine, cephalothin, cephapirin, cephradine, cyclacillin, epicillin, furazlucillin hetacillin, levopropylcillin, mecillinam, mezlocillin, penicillin G, penicillin V, phenethicillin, piperacillin, pirbenicillin, pivampicillin, sarmoxicillin, sarpicillin, suncillin, talampicillin or ticarcillin; or a pharmaceutically acceptable salt thereof.
Claim 30
Dependent Claim
15 words
A pharmaceutical composition of claim 28 wherein n is 1 and R 1 is hydrogen.
Claim 31
Dependent Claim
28 words
A pharmaceutical composition of claim 28 wherein n is 1 and R 1 is: (5-methyl-1,3-dioxol-2-on-4-yl)methyl, 1H-isobenzofuran-3-on-1-yl, gamma-butyrolacton-4-yl, --CHR 9 OCOR 10 , or --CHR 9 OCOOR 10 .
Claim 32
Dependent Claim
11 words
A pharmaceutical composition of claim 30 wherein R 1 is pivaloyloxymethyl.
Claim 33
Dependent Claim
17 words
A pharmaceutical composition of claim 28 wherein n is 2 and R 1 is --CH 2 --.
Claim 34
Dependent Claim
10 words
A pharmaceutical composition of claim 28 wherein R is ##STR26##
Claim 35
Dependent Claim
10 words
A pharmaceutical composition of claim 28 wherein R is ##STR27##
Claim 36
Dependent Claim
17 words
A pharmaceutical composition of claim 28 wherein the beta-lactam antibiotic is ampicillin, hetacillin, pivampicillin, bacampicillin or talampicillin.
Claim 37
Dependent Claim
15 words
A pharmaceutical composition of claim 28 wherein the beta-lactam antibiotic is amoxicillin, sarmoxicillin or sarpicillin.
Claim 38
Dependent Claim
12 words
A pharmaceutical composition of claim 28 wherein the beta-lactam antibiotic is cefoperazone.
Claim 39
Dependent Claim
27 words
A method of treating a bacterial infection in a mammal which comprises administering to said mammal an antibacterially effective amount of a pharmaceutical composition of claim 28.
Claim 40
Dependent Claim
27 words
A method of treating a bacterial infection in a mammal which comprises administering to said mammal an antibacterially effective amount of a pharmaceutical composition of claim 29.
Claim 41
Dependent Claim
27 words
A method of treating a bacterial infection in a mammal which comprises administering to said mammal an antibacterially effective amount of a pharmaceutical composition of claim 30.
Claim 42
Dependent Claim
27 words
A method of treating a bacterial infection in a mammal which comprises administering to said mammal an antibacterially effective amount of a pharmaceutical composition of claim 31.
Claim 43
Dependent Claim
27 words
A method of treating a bacterial infection in a mammal which comprises administering to said mammal an antibacterially effective amount of a pharmaceutical composition of claim 32.
Claim 44
Dependent Claim
27 words
A method of treating a bacterial infection in a mammal which comprises administering to said mammal an antibacterially effective amount of a pharmaceutical composition of claim 33.
Claim 45
Dependent Claim
27 words
A method of treating a bacterial infection in a mammal which comprises administering to said mammal an antibacterially effective amount of a pharmaceutical composition of claim 34.
Claim 46
Dependent Claim
27 words
A method of treaing a bacterial infection in a mammal which comprises administering to said mammal an antibacterially effective amount of a pharmaceutical composition of claim 35.
Claim 47
Dependent Claim
27 words
A method of treating a bacterial infection in a mammal which comprises administering to said mammal an antibacterially effective amount of a pharmaceutical composition of claim 36.
Claim 48
Dependent Claim
27 words
A method of treating a bacterial infection in a mammal which comprises administering to said mammal an antibacterially effective amount of a pharmaceutical composition of claim 37.
Claim 49
Dependent Claim
125 words
A compound having the formula ##STR28## wherein R is ##STR29## R 3 , R 4 and R 5 are each independently hydrogen or (C 1 -C 3 )alkyl; R 6 is hydrogen, (C 1 -C 6 )alkyl, phenyl or benzyl; or one of said (C 1 -C 6 )alkyl, phenyl or benzyl monosubstituted with --OR 3 , --SR 8 , --SO 2 R 8 , --NR 3 R 4 , --NHCOR 3 , --CONH 2 or --COOR 3 ; R 7 is hydrogen, hydroxy or --OCOR 3 ; R 8 is (C 1 -C 3 )alkyl; Y is --(CH 2 ) m --, --O--, --S--, ##STR30## m is 0, 1 or 2; and R 11 is an acyloxy radical derived from a conventional beta-lactam antibiotic.
Claim 50
Dependent Claim
125 words
A compound having the formula ##STR28## wherein R is ##STR29## R 3 , R 4 and R 5 are each independently hydrogen or (C 1 -C 3 )alkyl; R 6 is hydrogen, (C 1 -C 6 )alkyl, phenyl or benzyl; or one of said (C 1 -C 6 )alkyl, phenyl or benzyl monosubstituted with --OR 3 , --SR 8 , --SO 2 R 8 , --NR 3 R 4 , --NHCOR 3 , --CONH 2 or --COOR 3 ; R 7 is hydrogen, hydroxy or --OCOR 3 ; R 8 is (C 1 -C 3 )alkyl; Y is --(CH 2 ) m --, --O--, --S--, ##STR30## m is 0, 1 or 2; and R 11 is an acyloxy radical derived from a conventional beta-lactam antibiotic.
Claim 51
Dependent Claim
49 words
A compound of claim 48 wherein R 11 is an acyloxy radical of the formula ##STR31## wherein Y 1 is hydrogen, hydroxy, (C 2 -C 7 )alkanoyloxy, (C 2 -C 7 )alkoxycarbonyloxy, benzoyloxy, or benzoyloxy monosubstituted with (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy or halo.
Claim 52
Dependent Claim
10 words
A compound of claim 49 wherein Y 1 is hydrogen.
Claim 53
Dependent Claim
10 words
A compound of claim 49 wherein Y 1 is hydroxy.
Claim 54
Dependent Claim
13 words
The compound of claim 50 of the formula (IV) wherein R is glycyl.
Claim 55
Dependent Claim
13 words
The compound of claim 50 of the formula (III) wherein R is trans-4-hydroxy-L-prolyl.
Claim 56
Dependent Claim
24 words
A pharmaceutical composition suitable for the treatment of an infection in a mammal which comprises a compound of claim 48 and a pharmaceutically-acceptable diluent.
Claim 57
Dependent Claim
25 words
A pharmaceutical composition suitable for the treatment of an infection in a mammal which comprises a compound of claim 49 and a pharmaceutically acceptable carrier.
Claim 58
Dependent Claim
25 words
A method of treating a bacterial infection in a mammal which comprises administering to said mammal an antibacterial amount of a compound of claim 48.
Claim 59
Dependent Claim
25 words
A method of treating a bacterial infection in a mammal which comprises administering to said mammal an antibacterial amount of a compound of claim 49.
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) | 1988-03-04 | 1988-09-03 | 1989-03-05 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1992-03-04 | 1992-09-03 | 1993-03-05 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1996-03-04 | 1996-09-03 | 1997-03-05 | $7700.00 | Window Closed / Lapsed |