AZETIDINYL SULFONIC ACID AND ANALOGS

ACIDE AZETIDINYL SULFONIQUE ET SES ANALOGUES

English Abstract

ABSTRACT

Antibiotic activity is exhibited by .beta.-lactams
having the formula

Image ,

or an ester or salt thereof, wherein R1 is an acyl
group.

Claims

The embodiments of the invention in which an
exclusive property or privilege is claimed are de-
fined as follows:
1. A process for preparing a .beta.-lactam
having the formula
Image

or a pharmaceutically acceptable salt
thereof, wherein
R1 is an acyl group derived from a
carboxylic acid;
R2 is hydrogen or methoxy;
R3 and R4 are the same or different and
each is hydrogen, alkyl, alkenyl, alkynyl,
cycloalkyl, phenyl, substituted phenyl or a 4,
5, 6 or 7-membered heterocycle, or one of R3 and
R4 is hydrogen and the other is azido, halomethyl,
dihalomethyl, trihalomethyl, alkoxycarbonyl,
2-phenylethenyl, 2-phenylethynyl, carboxyl,
-CH2-X1, -S-X2, -O-X2,
Image or -A-?-NX6X7;
R5 and R6 are the same or different and each
is hydrogen, alkyl, alkenyl, alkynyl, phenyl,
substituted phenyl, cycloalkyl or a 4, 5, 6 or
7-membered heterocycle, or R5 and R6 together with
the carbon atom to which they are attached are
cycloalkyl or a 4, 5, 6 or 7-membered heterocycle,
or one of R5 and R6 is hydrogen and the other is
azido, halomethyl, dihalomethyl, trihalomethyl,
alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl,
carboxyl, -CH2-X1-, -S-X2, -O-X2 or

-A-?-NX6X7

39

X1 is azido, amino, hydroxy, alkanoylamino,
alkylsulfonyloxy, phenylsulfonyloxy, (substituted
phenyl)sulfonyloxy, phenyl, substituted phenyl,
cyano, -S-X2 or -O-X2;
X2 is alkyl, substituted alkyl, phenyl,
substituted phenyl, phenylalkyl, (substituted
phenyl)alkyl, alkanoyl, substituted alkanoyl,
phenylcarbonyl, (substituted phenyl)carbonyl or
heteroarylcarbonyl;
one of X3 and X4 is hydrogen and the other
is hydrogen or alkyl, or X3 and X4 when taken
together with the carbon atom to which they are
attached form a cycloalkyl group;
X5 is formyl, alkanoyl, phenylcarbonyl,
(substituted phenyl)carbonyl, phenylalkylcarbonyl,
(substituted phenyl)alkylcarbonyl, carboxyl,
alkoxycarbonyl, aminocarbonyl, (substituted amino)-
carbonyl, or cyano;
A is -CH=CH-, -CH2-CH=CH-, -(CH2)n-,
-(CH2)n'-O-, -(CH2)n'-NH-, -(CH2)n'-S-CH2;
n is 0, 1, 2 or 3;
n' is 1 or 2; and
X6 and X7 are the same or different and
each is hydrogen or alkyl, or X6 is hydrogen and
X7 is amino, substituted amino, acylamino or
alkoxy;
wherein the terms "alkyl and "alkoxy" refer
to groups having 1 to 10 carbon atoms;
the term "cycloalkyl" refers to cycloalkyl
groups having 3, 4, 5, 6 or 7 carbon atoms;
the term "substituted alkyl" refers to
alkyl groups substituted with one, or more
azido, amino, halogen, hydroxy, carboxy, cyano,
alkoxycarbonyl, aminocarbonyl, alkanoyloxy,
alkoxy, phenoxy, (substituted phenyl)oxy,
mercapto, alkylthio, phenylthio, (substituted
phenyl)thio, alkylsulfinyl, or alkylsulfonyl
groups;
the terms "alkanoyl", "alkenyl" and "alkynyl"
refer to groups having 2 to 10 carbon atoms;


the term "substituted alkanoyl" refers
to a group having the formula (substituted alkyl)

-?-

or phenylalkanoyl;
the term "substituted phenyl" refers to a
phenyl group substituted with 1, 2 or 3 amino,
halogen, hydroxyl, trifluoromethyl, alkyl (of 1
to 4 carbon atoms), alkoxy (of 1 to 4 carbon
atoms) or carboxyl groups;
the term "substituted amino" refers to a
group having the formula -NY1Y2 wherein Y1 is
hydrogen, alkyl, phenyl, substituted phenyl,
phenylalkyl or (substituted phenyl)alkyl, and Y2
is alkyl, phenyl, substituted phenyl,
phenylalkyl, (substituted phenyl)alkyl, hydroxy,
cyano, alkoxy, phenylalkoxy or amino;
the term "heteroaryl" refers to pyridinyl,
furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl,
1,2,4-triazolyl, imidazolyl, thiazolyl,
thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl,
tetrazolyl or one of the above groups substituted
with one or more halogen, hydroxy, nitro, amino,
cyano, trifluoromethyl, alkyl of 1 to 4 carbon
atoms, alkoxy of 1 to 4 carbon atoms,
alkylsulfonyl, phenyl, substituted phenyl,
2-furylmethyleneamino, phenylmethyleneamino,
substituted alkyl, wherein the alkyl groups has
1 to 4 carbon atoms, groups;
the term "a 4, 5, 6 or 7-membered
heterocycle" refers to pyridinyl, furanyl,
pyrrolyl, thienyl, 1,2,3-triazolyl,
1,2,4-triazolyl, imidazolyl, thiazolyl,
thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl,
tetrazolyl, azetinyl, oxetanyl, thietanyl,
piperidinyl, piperazinyl, imidazolidinyl,
oxazolidinyl, pyrrolidinyl, tetrahydro-
pyrimidinyl, dihydrothiazolyl, hexahydro-
azepinyl or one of the above groups

41

substituted with one or more oxo, halogen,
hydroxy, nitro, amino, cyano, trifluoromethyl,
alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4
carbon atoms, alkylsulfonyl, phenyl, substituted
phenyl, 2-furylmethyleneamino,
phenylmethyleneamino or substituted alkyl,
wherein the alkyl group has 1 to 4 carbon atoms,
groups, characterized by reacting a compound of
the formula
Image

with a R1 carboxylic acid or a reactive
derivative thereof.
2. A process in accordance with claim 1
wherein R1 is (Z)-2-amino-.alpha.-[(1-carboxy-1-methyl-
ethoxy)imino]-4-thiazoleacetyl.
3. A process in accordance with claim 1
wherein R2, R3, R4, R5 and R6 are each hydrogen
4. A process in accordance with claim 1
wherein R2, R3, R5 and R6 are each hydrogen and
R4 is methyl.
5. A process in accordance with claim 1
wherein R2, R4, R5 and R6 are each hydrogen and
R3 is methyl.
6. A compound having the formula
Image


or a pharmaceutically acceptable salt
thereof, wherein

42

R1 is an acyl group derived from a
carboxylic acid;
R2 is hydrogen or methoxy;
R3 and R4 are the same or different and
each is hydrogen, alkyl, alkenyl, alkynyl,
cycloalkyl, phenyl, substituted phenyl or a 4,
5, 6 or 7-membered heterocycle, or one of R3 and
R4 is hydrogen and the other is azido, halomethyl,
dihalomethyl, trihalomethyl, alkoxycarbonyl,
2-phenylethenyl, 2-phenylethynyl, carboxyl,
-CH2-X1, -S-X2, -O-X2,
Image or -A-?-NX6X7;

R5 and R6 are the same or different and each
is hydrogen, alkyl, alkenyl, alkynyl, phenyl,
substituted phenyl, cycloalkyl or a 4, 5, 6 or
7-membered heterocycle, or R5 and R6 together with
the carbon atom to which they are attached are
cycloalkyl or a 4, 5, 6 or 7-membered heterocycle,
or one of R5 and R6 is hydrogen and the other is
azido, halomethyl, dihalomethyl, trihalomethyl,
alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl,
carboxyl, -CH2-X1-, -S-X2, -O-X2 or
-A-?-NX6X7
X1 is azido, amino, hydroxy, alkanoylamino,
alkylsulfonyloxy, phenylsulfonyloxy, (substituted
phenyl)sulfonyloxy, phenyl, substituted phenyl,
cyano, -S-X2 or -O-X2;
X2 is alkyl, substituted alkyl, phenyl,
substituted phenyl, phenylalkyl, (substituted
phenyl)alkyl, alkanoyl, substituted alkanoyl,
phenylcarbonyl, (substituted phenyl)carbonyl or
heteroarylcarbonyl;
one of X3 and X4 is hydrogen and the other
is hydrogen or alkyl, or X3 and X4 when taken
together with the carbon atom to which they are
attached form a cycloalkyl group;

43

X5 is formyl, alkanoyl, phenylcarbonyl,
(substituted phenyl)carbonyl, phenylalkylcarbonyl,
(substituted phenyl)alkylcarbonyl, carboxyl,
alkoxycarbonyl, aminocarbonyl, (substituted amino)-
carbonyl, or cyano;
A is -CH=CH-, -CH2-CH=CH-, -(CH2)n-,
-(CH2)n'-O-, -(CH2)n'-NH-, -(CH2)n'-S-CH2;
n is 0, 1, 2 or 3;
n' is 1 or 2; and
X6 and X7 are the same or different and
each is hydrogen or alkyl, or X6 is hydrogen and
X7 is amino, substituted amino, acylamino or
alkoxy;
wherein the terms "alkyl and "alkoxy" refer
to groups having 1 to 10 carbon atoms;
the term "cycloalkyl" refers to cycloalkyl
groups having 3, 4, 5, 6 or 7 carbon atoms;
the term "substituted alkyl" refers to
alkyl groups substituted with one, or more
azido, amino, halogen, hydroxy, carboxy, cyano,
alkoxycarbonyl, aminocarbonyl, alkanoyloxy,
alkoxy, phenoxy, (substituted phenyl)oxy,
mercapto, alkylthio, phenylthio, (substituted
phenyl)thio, alkylsulfinyl, or alkylsulfonyl
groups;
the terms "alkanoyl", "alkenyl" and
"alkynyl" refer to groups having 2 to 10 carbon
atoms;
the term "substituted alkanoyl" refers
to a group having the formula (substituted alkyl)
-?-
or phenylalkanoyl;
the term "substituted phenyl" refers to a
phenyl group substituted with 1, 2 or 3 amino,
halogen, hydroxyl, trifluoromethyl, alkyl (of 1
to 4 carbon atoms), alkoxy (of 1 to 4 carbon
atoms) or carboxyl groups;

44

the term "substituted amino refers to a
group having the formula -NY1Y2 wherein Y1 is
hydrogen, alkyl, phenyl, substituted phenyl,
phenylalkyl or (substituted phenyl)alkyl, and Y2
is alkyl, phenyl, substituted phenyl,
phenylalkyl, (substituted phenyl)alkyl, hydroxy,
cyano, alkoxy, phenylalkoxy or amino;
the term "heteroaryl" refers to pyridinyl,
furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl,
1,2,4-triazolyl, imidazolyl, thiazolyl,
thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl,
tetrazolyl or one of the above groups substituted
with one or more halogen, hydroxy, nitro, amino,
cyano, trifluoromethyl, alkyl of 1 to 4 carbon
atoms, alkoxy of 1 to 4 carbon atoms,
alkylsulfonyl, phenyl, substituted phenyl,
2-furylmethyleneamino, phenylmethyleneamino,
substituted alkyl, wherein the alkyl groups has
1 to 4 carbon atoms, groups;
the term "a 4, 5, 6 or 7-membered
heterocycle" refers to pyridinyl, furanyl,
pyrrolyl, thienyl, 1,2,3-triazolyl,
1,2,4 triazolyl, imidazolyl, thiazolyl,
thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl,
tetrazolyl, azetinyl, oxetanyl, thietanyl,
piperidinyl, piperazinyl, imidazolidinyl,
oxazolidinyl, pyrrolidinyl, tetrahydro-
pyrimidinyl, dihydrothiazolyl, hexahydro-
azepinyl or one of the above groups
substituted with one or more oxo, halogen,
hydroxy, nitro, amino, cyano, trifluoromethyl,
alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4
carbon atoms, alkylsulfonyl, phenyl, substituted
phenyl, 2-furylmethyleneamino, phenylmethylene-
amino or substituted alkyl, wherein the alkyl
group has 1 to 4 carbon atoms, groups, whenever
prepared by the process of claim 1.



7. A compound in accordance with claim 6,
wherein R1 is (Z)-2-amino-.alpha.-[(1-carboxy-1-methyl-
ethoxy)imino]-4-thiazoleacetyl, whenever prepared
by the process of claim 2.
8. A compound in accordance with claim 6,
wherein R2, R3, R4, R5 and R6 are each hydrogen,
whenever prepared by the process of claim 3.
9. A compound in accordance with claim 6,
wherein R2, R3, R5 and R6 are each hydrogen and
R4 is methyl, whenever prepared by the process
of claim 4.
10. A compound in accordance with claim 6,
wherein R2, R4, R5 and R6 are each hydrogen and
R3 is methyl, whenever prepared by the process
of claim 5.
11. A .beta.-lactam having the formula

Image

or a pharmaceutically acceptable salt or ester
thereof, wherein
R1 is an acyl group derived from a carboxylic
acid;
R2 is hydrogen or methoxy;
R3 and R4 are the same or different and each
is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
phenyl, substituted phenyl or a 4, 5, 6 or 7-mem-
bered heterocycle, or one of R3 and R4 is hydrogen
and the other is azido, halomethyl, dihalomethyl,
trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-
phenylethynyl, carboxyl, -CH2-X1, -S-X2, -O-X2,

46


Image or -A-?-Nx6X7;

R5 and R6 are the same or different and each is
hydrogen, alkyl, alkenyl, alkynyl, phenyl, substitu-
ted phenyl, cycloalkyl or a 4, 5, 6 or 7-membered
heterocycle, or R5 and R6 together with the carbon
atom to which they are attached are cycloalkyl or a
4, 5, 6 or 7-membered heterocycle, or one of R5 and
R6 is hydrogen and the other is azido, halomethyl,
dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-
phenylethenyl, 2-phenylethynyl, carboxyl, -CH2-X1-,
-S-X2, -O-X2 or -A-?-NX6X7;
X1 is azido, amino, hydroxy, alkanoylamino, al-
kylsulfonyloxy, phenylsulfonyloxy, (substituted phe-
nyl)sulfonyloxy, phenyl, substituted phenyl, cyano,
-S-X2 or -O-X2;
X2 is alkyl, substituted alkyl, phenyl, substi-
tuted phenyl, phenylalkyl, (substituted phenyl)alkyl,
alkanoyl, substituted alkanoyl, phenylcarbonyl, (sub-
stituted phenyl)carbonyl or heteroarylcarbonyl;
one of X3 and X4 is hydrogen and the other is
hydrogen or alkyl, or X3 and X4 when taken together
with the carbon atom to which they are attached form
a cycloalkyl group;
X5 is formyl, alkanoyl, phenylcarbonyl, (substi-
tuted phenyl)carbonyl, phenylalkylcarbonyl, (substi-
tuted phenyl)alkylcarbonyl, carboxyl, alkoxycarbonyl,
aminocarbonyl, (substituted amino)carbonyl, or cyano;
A is -CH=CH-, -CH2-CH=CH-, -(CH2)n-, -(CH2)n'-O-,
-(CH2)n'-NH-, or -(CH2)n'-S-CH2;
n is 0, 1, 2 or 3;
n' is 1 or 2; and
X6 and X7 are the same or different and each is
hydrogen or alkyl, or X6 is hydrogen and X7 is amino,
substituted amino, acylamino or alkoxy;

47


wherein the terms "alkyl" and "alkoxy" refer
to groups having 1 to 10 carbon atoms;
the term "cycloalkyl" refers to cycloalkyl
groups having 3, 4, 5, 6 or 7 carbon atoms;
the term "substituted alkyl" refers to alkyl
groups substituted with one or more azido, amino,
halogen, hydroxy, carboxy, cyano, alkoxycarbonyl,
aminocarbonyl, alkanoyloxy, alkoxy, phenoxy, (sub-
stituted phenyl)oxy, mercapto, alkylthio, phenyl-
thio, (substituted phenyl)thio, alkylsulfinyl, or
alkylsulfonyl groups;
the terms "alkanoyl", "alkenyl" and "alkynyl"
refer to groups having 2 to 10 carbon atoms;
the term "substituted alkanoyl" refers to a
group having the formula (substituted alkyl)
-?-
or phenylalkanoyl;
the term "substituted phenyl" refers to a phe-
nyl group substituted with 1, 2 or 3 amino, halogen,
hydroxyl, trifluoromethyl, alkyl (of 1 to 4 carbon
atoms), alkoxy (of 1 to 4 carbon atoms) or carboxyl
groups;
the term "substituted amino" refers to a group
having the formula -NY1Y2 wherein Y1 is hydrogen,
alkyl, phenyl, substituted phenyl, phenylalkyl or
(substituted phenyl)alkyl, and Y2 is alkyl, phenyl,
substituted phenyl, phenylalkyl, (substituted phe-
nyl)alkyl, hydroxy, cyano, alkoxy, phenylalkoxy or
amino;
the term "heteroaryl" refers to pyridinyl,
furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-
triazolyl, imidazolyl, thiazolyl, thiadiazolyl, py-
rimidinyl, oxazolyl, triazinyl, tetrazolyl or one
of the above groups substituted with one or more
halogen, hydroxy, nitro, amino, cyano, trifluoro-

48



methyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1
to 4 carbon atoms, alkylsulfonyl, phenyl, substitu-
ted phenyl, 2-furylmethyleneamino, phenylmethylene-
amino, substituted alkyl, wherein the alkyl group
has 1 to 4 carbon atoms, groups; and
the term "a 4, 5, 6 or 7-membered heterocycle"
refers to pyridinyl, furanyl, pyrrolyl, thienyl,
1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thia-
zolyl, thiadiazolyl, pyrimidinyl, oxazolyl, triazi-
nyl, tetrazolyl, azetinyl, oxetanyl, thietanyl, pi-
peridinyl, piperazinyl, imidazolidinyl, oxazolidinyl,
pyrrolidinyl, tetrahydropyrimidinyl, dihydrothiazo-
lyl, hexahydroazepinyl or one of the above groups
substituted with one or more oxo, halogen, hydroxy,
nitro, amino, cyano, trifluoromethyl, alkyl of 1 to
4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alk-
ylsulfonyl, phenyl, substituted phenyl, 2-furylme-
thyleneamino, phenylmethyleneamino or substituted
alkyl, wherein the alkyl group has 1 to 4 carbon
atoms.
12. A compound in accordance with claim 11,
wherein R1 is (Z)-2-amino-.alpha.-[(1-carboxy-1-methyl-
ethoxy)imino]-4-thiazoleacetyl.
13. A compound in accordance with claim 11,
wherein R2, R3, R4, R5 and R6 are each hydrogen
14. A compound in accordance with claim 11,
wherein R2, R3, R5 and R6 are each hydrogen and R4
is methyl.
15. A compound in accordance with claim 11,
wherein R2, R4, R5 and R6 are each hydrogen and R3
is methyl.
16. A .beta.-lactam in accordance with claim 11, a
salt of [3S-[3.alpha.(Z),4.alpha.]]-[[3-[[(2-amino-4-thiazolyl)-
(methoxyimino)acetyl]amino]-4-methyl-2-oxo-1-azeti-
dinyl]oxy]methanesulfonic acid.
17. A .beta.-lactam in accordance with claim 11, a
salt of [3S-[3.alpha.(Z),4.alpha.]]-2-[[[1-(2-amino-4-thiazolyl)-
2-[[4-methyl-2-oxo-1-(sulfomethoxy)-3-azetidinyl]am-

49


ino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic
acid.
18. A .beta.-lactam in accordance with claim 11, a
salt of [3S-[3.alpha.(Z),4.beta.]]-2-[[[1-(2-amino-4-thiazolyl)-
2-[[4-methyl-2-oxo-1-(sulfomethoxy)-3-azetidinyl]am-
ino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic
acid.
19. A .beta.-lactam in accordance with claim 11, a
salt of [3S-[3.alpha.(R),4.beta.]]-[[3-[[[[(4-ethyl-2,3-dioxo-
1-piperazinyl)carbonyl]amino]phenylacetyl]amino]-4-
methyl-2-oxo-1-azetidinyl]oxy]methanesulfonic acid.
20. A .beta.-lactam in accordance with claim 11, a
salt of [3S-[3.alpha.(Z),4.beta.]]-[[3-[[(2-amino-4-thiazolyl)-
(methoxyimino)acetyl]amino]-4-methyl-2-oxo-1-azeti-
dinyl]oxy]methanesulfonic acid.
21. A pharmaceutical composition comprising a
.beta.-lactam having the formula
Image
or a pharmaceutically acceptable salt or ester there-
of, in admixture with a pharmaceutically acceptable
carrier therefor, wherein
R1 is an acyl group derived from a carboxylic
acid;
R2 is hydrogen or methoxy;
R3 and R4 are the same or different and each is
hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phe-
nyl, substituted phenyl or a 4, 5, 6 or 7-membered
heterocycle, or one of R3 and R4 is hydrogen and the
other is azido, halomethyl, dihalomethyl, trihalome-
thyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethy-




nyl, carboxyl, -CH2-X1, -S-X2, -O-X2, Image,
Image , or -A-?-NX6X7;

R5 and R6 are the same or different and each is
hydrogen, alkyl, alkenyl, alkynyl, phenyl, substitu-
ted phenyl, cycloalkyl or a 4, 5, 6 or 7-membered
heterocycle, or R5 and R6 together with the carbon
atom to which they are attached are cycloalkyl or a
4, 5, 6 or 7-membered heterocycle, or one of R5 and
R6 is hydrogen and the other is azido, halomethyl,
dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phe-
nylethenyl, 2-phenylethynyl, carboxyl, -CH2-X1-,
-S-X2, -O-X2 or -A-?-NX6X7;
X1 is azido, amino, hydroxy, alkanoylamino,
alkylsulfonyloxy, phenylsulfonyloxy, (substituted
phenyl)sulfonyloxy, phenyl, substituted phenyl,
cyano, -S-X2 or -O-X2;
X2 is alkyl, substituted alkyl, phenyl, sub-
stituted phenyl, phenylalkyl, (substituted phenyl)-
alkyl, alkanoyl, substituted alkanoyl, phenylcarbo-
nyl, (substituted phenyl)carbonyl or heteroarylcar-
bonyl;
one of X3 and X4 is hydrogen and the other is
hydrogen or alkyl, or X3 and X4 when taken together
with the carbon atom to which they are attached form
a cycloalkyl group;
X5 is formyl, alkanoyl, phenylcarbonyl, (sub-
stituted phenyl)carbonyl, phenylalkylcarbonyl, (sub-
stituted phenyl)alkylcarbonyl, carboxyl, alkoxycar-
bonyl, aminocarbonyl, (substituted amino)carbonyl,
or cyano;
A is -CH=CH-, -CH2-CH=CH-, -(CH2)n-, -(CH2)n'-O-,
-(CH2)n'-NH-, or -(CH2)n'-S-CH2;

51


n is 0, 1, 2 or 3;
n' is 1 or 2; and
X6 and X7 are the same or different and each is
hydrogen or alkyl, or X6 is hydrogen and X7 is amino,
substituted amino, acylamino or alkoxy;
wherein the terms "alkyl" and "alkoxy" refer to
groups having 1 to 10 carbon atoms;
the term "cycloalkyl" refers to cycloalkyl groups
having 3, 4, 5, 6 or 7 carbon atoms;
the term "substituted alkyl" refers to alkyl
groups substituted with one or more azido, amino, hal-
ogen, hydroxy, carboxy, cyano, alkoxycarbonyl, amino-
carbonyl, alkanoyloxy, alkoxy, phenoxy, (substituted
phenyl)oxy, mercapto, alkylthio, phenylthio, (substi-
tuted phenyl)thio, alkylsulfinyl, or alkylsulfonyl
groups;
the terms "alkanoyl", "alkenyl" and "alkynyl"
refer to groups having 2 to 10 carbon atoms;
the term "substituted alkanoyl" refers to a
group having the formula (substituted alkyl)

-?-
or phenylalkanoyl;
the term "substituted phenyl" refers to a phe-
nyl group substituted with 1, 2 or 3 amino, halogen,
hydroxyl, trifluoromethyl, alkyl (of 1 to 4 carbon
atoms), alkoxy (of 1 to 4 carbon atoms) or carboxyl
groups;
the term "substituted amino" refers to a group
having the formula -NY1Y2 wherein Y1 is hydrogen,
alkyl, phenyl, substituted phenyl, phenylalkyl or
(substituted phenyl)alkyl, and Y2 is alkyl, phenyl,
substituted phenyl, phenylalkyl, (substituted phe-
nyl)alkyl, hydroxy, cyano, alkoxy, phenylalkoxy or
amino;
the term "heteroaryl" refers to pyridinyl,

52


furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-
triazolyl, imidazolyl, thiazolyl, thiadiazolyl, py-
rimidinyl, oxazolyl, triazinyl, tetrazolyl or one of
the above groups substituted with one or more halo-
gen, hydroxy, nitro, amino, cyano, trifluoromethyl,
alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 car-
bon atoms, alkylsulfonyl, phenyl, substituted phenyl,
2-furylmethyleneamino, phenylmethyleneamino, substi-
tuted alkyl, wherein the alkyl group has 1 to 4 car-
bon atoms, groups; and
the term "a 4, 5, 6 or 7-membered heterocycle"
refers to pyridinyl, furanyl, pyrrolyl, thienyl,
1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thia-
zolyl, thiadiazolyl, pyrimidinyl, oxazolyl, triazi-
nyl, tetrazolyl, azetinyl, oxetanyl, thietanyl, pi-
peridinyl, piperazinyl, imidazolidinyl, oxazolidinyl,
pyrrolidinyl, tetrahydropyrimidinyl, dihydrothiazo-
lyl, hexahydroazepinyl or one of the above groups
substituted with one or more oxo, halogen, hydroxy,
nitro, amino, cyano, trifluoromethyl, alkyl of 1 to
4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alk-
ylsulfonyl, phenyl, substituted phenyl, 2-furylmeth-
yleneamino, phenylmethyleneamino or substituted al-
kyl, wherein the alkyl group has 1 to 4 carbon atoms.
22. A composition in accordance with claim 21,
wherein R1 is (Z)-2-amino-.alpha.-[(1-carboxy-1-methyl-
ethoxy)imino]-4-thiazoleacetyl.
23. A composition in accordance with claim 21,
wherein R2, R3, R4, R5 and R6 are each hydrogen
24. A composition in accordance with claim 21,
wherein R2, R3, R5 and R6 are each hydrogen and R4
is methyl.
25. A composition in accordance with claim 21,
wherein R2, R4, R5 and R6 are each hydrogen and R3
is methyl.
26. A composition in accordance with claim 21,
wherein the .beta.-lactam is a salt of [3S-[3.alpha.(Z),4.alpha.]]-

53


[[3-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]am-
ino]-4-methyl-2-oxo-1-azetidinyl]oxy]methanesulfonic
acid.
27. A composition in accordance with claim 21,
wherein the .beta.-lactam is a salt of [3S-[3.alpha.(Z),4.alpha.]]-2-
[[[1-(2-amino-4-thiazolyl)-2[[4-methyl-2-oxo-1-(sul-
fomethoxy)-3-azetidinyl]amino]-2-oxoethylidene]am-
ino]oxy]-2-methylpropanoic acid.
28. A composition in accordance with claim 21,
wherein the .beta.-lactam is a salt of [3S-[3.alpha.(Z),4.beta.]]-2-
[[[1-(2-amino-4-thiazolyl)-2-[[4-methyl-2-oxo-1-(sul-
fomethoxy)-3-azetidinyl]amino]-2-oxoethylidene]am-
ino]oxy]-2-methylpropanoic acid.
29. A composition in accordance with claim 21,
wherein the .beta.-lactam is a salt of [3S-[3.alpha.(R),4.beta.]]-
[[3-[[[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]am-
ino]phenylacetyl]amino]-4-methyl-2-oxo-1-azetidinyl]-
oxy]methanesulfonic acid.
30. A composition in accordance with claim 21,
wherein the .beta.-lactam is a salt of [3S-[3.alpha.(Z),4.beta.]]-
[[3-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]am-
ino]-4-methyl-2-oxo-1-azetidinyl]oxy]methanesulfonic
acid.

54

Description

~L2~3~
~ GCl98

-- 1

~ AZETIDINYL SULFONIC ACID AND ANALOGS
._
This invention is directed to a novel
family of ~-lactam antibiotics, and to the use
of such compounds as antibacterial agents.
It has been discovered that the B-lactam nucleus
can be biologically activated by a subs~ituent
R R
5~ ~ 6
havi~g the formula -O-C S03H (or salt thereof)
attached to the nitrogen atom i.n the nucleus.
R5~ ~ 6
~-Lactams having a -O-C~03H substituent
(or pharmaceutically acceptable sal~
thereof) in the l-position and an acylamino
substituent in the 3-position exhibit activity
against a range of gram-negative and gram-positive
bacteria.
Illustrative members of the novel family
of ~-lactam antibiotics of this invention are
those encompassed by the formula

I R2 -4
Rl-NH- I F 3 ~ ~R6

~C - N - O -C-SO H

or an ester or salt thereofO

3~ .



. 35


~.2535~3~
GC198


As used in formula I and throughout the
specification, the symbols are as defined below.
Rl is acyl;
R2 is hydrogen or methoxy;
R3 and R4 are the same or different and
each is hydrogen, alkyl, alkenyl, alkynyl,
cycloalkyl, phenyl, substituted phenyl or a
4,~,6 or 7-membered heterocycle (referred to
hereinafter as R7) or one of R3 and R4 is hydrogen
and the other is azido, halomethyl, dihalomethyl,
trihalomethyl, alkoxycarbonyl 2-phenylethenyl,
2-phenylethynyl, carboxyl, -CH2X~ X2,
13 X3 1l
- -X2 -o -f -x4 - S -f -X4 or -A-C-NX6X7 ;
lS X5 X5
Xl is azido, amino (-NH2), hydroxy, alkanoyl-
amino, alkylsulfonyloxy, phenylsulfonyloxy,
(substituted phenyl)sulfonyloxy, phenyl, substituted
phenyl, cyano, -S-X2 or --O-X2 ;
X2 is alkyl, substituted alkyl, phenyl,
substituted phenyl, phenylalkyl, (substituted
phenyl)alkyl, alkanoyl, substituted alkanoylj
phenylcarbonyl, (substituted phenyl)carbonyl or
heteroarylcarbonyl;
one of X3 and X4 is hydrogen and the other
is hydrogen or alkyl, or X3 and X4 when taken
together with the carbon atom to which they are
attached form a cycloalkyl group;
X5 is formyl, alkanoyl, phenylcarbonyl,
3~ (substituted phenyl)carbonyl, phenylalkylcarbonyl,
~substituted phenyl~alkylcarbonyl, carboxyl,

alkoxycarbonyl, aminocarbonyl (NH2-C~ substituted
amino~oarbonyl, or cyano l-C--N);


~ 3~
GC198

--3--

A is -CH=CH-, CH2-CH=C~ (C~2)-n ,
-(C~ ) , O-~ -tCH2)n~-NH-~ or (C~2~n, 2
n i~ 0, 1, 2 or 3;
n' is 1 or 2;
X6 and X7 are the same or different and each
is hydrogen or alkyl, or X6 is hydro~en and X7
is amino, substituted amino, acylamino or alkoxy; and
~5 and R6 are the same or different and
each is hydrogen, alkyl, alkenyl, alkynyl, phenyl,
substituted phenyl, cycloalkyl or R7, or R5 and
R6 together with the carbon atom to which they
are attached are cycloalkyl or R7, or one of R5
and R6 is hydrogen and the other is azido,
halomethyl, dihalomethyl, trihalomethyl,
lS alkoxycarbonyl, 2-pheny~eth~nyl, 2-phenylethynyl,

carbOxyl~ -CH2Xl, -S-X2~ --X2' or -A-C-NX~X7-
Listed below are definitions of various
terms used to describe the B-lactams of this
invention. These definitions apply to the
terms as they are used throughout the specification
(unless they are otherwise limited in specific
ins~ances) either individually or as part of a
larger group.
The terms "alkyl" and "alkoxy" refer to
both straight and branched chain groups. Those
groups having 1 to 10 carbon atoms are preferred.
The terms "cycloalkyl" and "cycloalkenyl"
refer to cycloalkyl and cycloalkenyl groups
having 3,4,5,6 or 7 carbon atoms.
The term "substituted alXyl" refers to
alkyl groups substituted with one, or more, azido
amino(-NH2), halogen, hydroxy, carboxy, cyano



~i3~
GC198
--4--

alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy,
phenyloxy~ (substituted phenyl)oxy, R7-oxy,
mercapto, al~ylthio, phenylthio, (suhstituted phenyl)-
t~io, alkylsulfinyl, or alkylsulfonyl groups.
The terms "alkanoyl", "alkenyl", "alkenyl"
and "alkynyl" refer to both straight and branched
chain groups. Those groups having 2 to 10 carbon
atoms are preferred.
The terms "halogen" and "halo" refer to
fluorine, chlorine, bromine and iodi.ne.
The term "protected carboxyl" refers to
a carboxyl group which has been esterified
with a conventional acid protecting group.
These groups are well known in the art; see,
for example, United States patent 4,14~,333,
issued March 13, 1979. The preferred protected
carboxyl groups are benzyl, benzhydryl, t-butyl,
and ~-nitrobenzyl esters.
The term "substituted phenyl" refers to
a phenyl group substituted with 1, 2 or 3
amino(-NH2~, halogen, hydroxyl, trifluoromethyl,
alkyl (of 1 to 4 carbon atoms), alko~y (of 1
to 4 carbon atoms), or carboxyl groups.
The expression "a 4,5,6 or 7-membered
heterocycle" (referred to as "~ ") refers to
substituted and unsubstituted, aromatic and
non-aromatic groups containing one or more
nitrogen, oxygen or sulfur atoms~ Exemplary
substituents are oxo~=O), halogen, hydroxy, nitro,
30- amino, cyano, trifluoromethyl, alkyl of 1 to 4



. 35

~ ;3~
GCl9
--5--

carbons, al~oxy of 1 to 4 carbons, alkylsulfonyl,
phenyl, substituted phenyl, 2-furylimino
O~_CH=N-
( ~ ), benzylimino and substituted alkyl
groups (wherein the alkyl group has 1 ~o 4 carbons)~
One type of 1-4,5,6 or 7-membered heterocycle" is
the "heteroaryl n . group. The term "h,eteroaryl n
refers to those 4,5,6 or 7-membered heterocycles
which are aromatic. Exemplary heteroaryl groups
are substituted and unsubstituted pyridinyl,
furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl,
1,2,4-triazolyl, imiaazolyl, thiazolyl,
thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl,
and tetrazolyl. Exemplary nonaromatic heterocycles
(i e., fully or partially saturated heterocyclic
groups)are substituted and unsubstituted azetinyl,
oxetanyl, thietanyl, piperidinyl, piperazinyl,
imidazolidinyl, oxazolidinyl, pyrrolidinyl,
tetrahydropyrimidinyl, dihydrothiazolyl and
hexahydroazepinyl. Exemplary of the substituted
4,5,6 or 7-membered heterocy~les are 1-alkyl-3-
azetinyl, 2-oxo-1-imidazolidinyl, 3-alkylsulfonyl-2-
oxo-l-imidazolidinyl, 3-benzylimino-2-oxo-1-

imidazolidinyl, 3-alkyl-2-oxo-1-imidazolidinyl,
3-phenyl (or substituted phenyl)-2-oxo-1-
imidazolidinyl, 3-benzyl-2-oxo-1-imidazolidinyl,




-$~

~3~ C198


3-(2-aminoethyl)-2-oxo-1-imidazolidinyl, 3-amino-
2-oxo-1-imidazolidinyl, 3-I (alkoxycarbonyl)amino~-
2-oxo-1-imidazolidinyl, 3-~2- I (alkoxycarbonyl~-
amino~e~hyl~-2-oxo-1-imidazolidinyl, 2-oxo-1-
pyrrolidinyl, 2-oxo-3-oxazolidinyl, 4-hydroxy-6-
methyl-2-pyrimidinyl, 2-oxo-1-hexahydroazepinyl,
2-oxo-3-pyrrolidinyl, 2-oxo-3-Euranyl, 2,3-dioxo-
l-piperazinyl, 2,5-dioxo-1-piperazinyl, 4-alkyl-
2,3-dioxo-1-piperazinyl, and 4-phenyl-2,3-dioxo-
l-piperazinyl.
The term "substituted amino" refers to a
group having the formula -NYlY2 wherein Yl is
hydrogen, alkyl, phenyl, substituted phenyl,
phenylalkyl or (substituted phenyl)alkyl, and
Y2 is alkyl, phenyl, substituted phenyl,
phenylalkyl, (substituted phenyl)alkyl, hydroxy,
cyano, alkoxy, phenylalkoxy, or amino (-NH2).
The term "substituted alkanoyl" includes
within its scope compounds having the formula

(substituted alkyl)-C- (wherein "substituted
alkyl" is defined above) and phenylalkanoyl.





~ 7 ~~

The term "acyl" refers -to all organic radicals
derived from an organic acid (i.e., a carboxylic acid) by
removal of the hydroxyl group. Certain acyl groups are, of
course, preferred but this preference should no-t be viewed as
a limi-tation of -the scope of this invention. Exemplary
acyl groups are those acyl groups which have been used in the
past to acylate ~-lactam antibiotics including 6-aminopeni-
cillanic acid and derivatives and 7-aminocephalosporanic acid
and derivatives; see, for example, ~halosporins and Penicillins,
edited by Flynn, Academic Press (1972), German Ofenlegungsschrift
2,716,677, published October 10, 1978, Belgian patent 867,994,
published December 11, 1978, United States patent 4,152,432,
issued May 1, 1979, United States patent 3,971,778, issued
July 27, 1976, United States patent 4,172,199, issued October
23, 1979, and British patent 1,348,894, published March 27,
1974. Portions oE these references describe various acyl
groups. The following list of acyl groups is presented to
further exemplify the term "acyl"; it should not be regarded
as limiting that term. Exemplary acyl groups are:
(a) Aliphatic groups having the formula

Ra 1,!
wherein Ra is alkyl; cycloalkyl; alkoxy; alkenyl;




f~
~ i ,,~,~, (

~3~
_ -8- GC198

~ycloalkenyl; cyclohexadienyl; or alkyl or alXenyl
substituted with one or more halogen, cyanor
nitro~ amino, mercapto, alkylthio, or cyanomethyl-

thio groups.
(b) Carbocyclic aromatic groups ha~ng theformula

RC
Rb~-~CH2)n-C-~



Rb ~ CH-C- ,
Re




2 D Rb ~<Rd ~1
CH2


Rc
b ~ C 2




~s6~ _

3~
GC198
_g_ .

R
Rb~d 2
~ S-CH~-C- c>r



~ H -S-C-

wherei~ n is 0, 1, 2 or 3; Rb, Rc, and Rd each
is independently hydrogen, halogen, hydroxyl,
nitro, amino, cyano, trifluoromethyl, alkyl
of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon
atoms or aminomethyl; and Re i5 amino, hydroxyl,
a carboxyl salt, protected carboxyl, foLmyloxy,
a sulfo salt, a sulfoamino salt, azido, halogen,
hvdrazino, alkylhydrazino, phenylhydrazino, or
~(alkylthio)thioxomethyl]thio.
20Preferred carbocyclic aromatic acyl groups
include those having the I ormula


25HO ~ CH -C-,

O

.. ~H2-C-,
30 ~
CH2 2




3~
GC198
--10--


. HO ~ H-C- (R~ is preferably

~e
a carboxyl salt or sulfo salt) and


CH-C- (Re is preIerably

a carboxyl salt or sulfo salt~. .
(c) Heteroaromatic yroups haviny ~he
formula

R~ ICH2)n

Rf-CH-C-

e
Rf--O--CH2--C-- ~
O

Rf-S-CH7-C- ,

O O
ll ~I
Rf-C -C-


wherein n is 0, 1, 2 or 3; Re is as aefined
ab~ve; and R~ is a substituted or unsubstituted
5-, 6- or 7-membered heterocyclic ring containing
1,2~3 or 4 (preferably 1 or 2~ nitrogen, oxygen
and sulfur atoms~ Exemplary heterocyclic




.G3~

~ ~3~
- GC198

rings are thienyl ! furyl, pyrrolyl, pyridinyl,
pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl,
thiadiazolyl and tetrazolyl. Exemplary substituents
are halogenl hydroxyl, nitro, amino, protected
S amino~ cyano, trifluoromethyl, alkyl~of 1 to 4
carbon atoms, alkoxy of 1 ~o 4 carbon atoms, or
R




HOOC - f H - C~2 - o-c -NH-
NH2
Preferred heteroaromatic acyl yroups
include those groups of the above formulas
wherein Rf is 2-amino-4-thiazolyl, 2-amino-5-
halo-4-thiazolyl, 4-aminopyrimidin-2-yl,
1~ 5-amino-1,2,4-thiadiazol-3-yl, 2-thienyl,
2-furanyl, or 6-aminopyridin-2-yl.
(d) [~(4-Substituted-2,3-dioxo-1-piper-
azinyl)carbonyl~amino]arylacetyl groups having
the formula
ll f--~
-C-CH-NH-C-N N-
R O ~ 0

wherein Rg is an aromatic group (including
carbocyclic aromatics such as those of the
formula Ic

and heteroaromatics as included within the
definition of Rf); and Rh is alkyl, substituted

~53~

_ GC198
-12-

alXyl ~wherein the alkyl group is substituted
with one or more halogent cyano, nitro~ amino
or mercapt~ groups), arylm~thyleneamino (i.e.,
-N=CH-Rg wherein R~ is as defined above),
Ol
arylcarbonylamino (i~e., -NH~C~Rg wherein R
is as defined above) or alkylcarbonylamino.
Preferred [[(~-substituted-2,3-dioxo-1-
piperazinyl)carbonyl~amino]arylacetyl groups
include those wherein ~ is ethyl, phenylmethylene-
amino or 2-furylmethyleneamino.
(e) ~Substituted oxyimino)arylacetyl groups
havinq the formula

O
--C-C=N-O-Ri
g

wherein R is.as de~ined above and Ri is hydrogen, Rc,
alkyl, cycloalkyl, al~ylaminocarbonyl, arylamino-

carbonyl (i.e., ~C~NH~Rg wherein Rg is as defined
above) or substituted alkyl (wherein the alkyl
group is substituted with 1 or more halogen~
cyano, nitro, amino, mercapto, alkylthio,
aromatic group (as defined by Rg), carboxyl
(including salts thereof), amido, alXoxycarbonyl,
phenylmethoxycarbonyl, diphenylmethoxvcarbonyl,
hydroxyalkoxyphosphinyl, dihydroxyphosphinyl,
hydroxy(phenylmethoxy)phosphinyl, or dialkoxy-
. phosphinyl substituents).



,~ .

5;3~
GC198
-13-

Preferred ~substituted oxyimino)arylacetyl
groups include those wherein R~ is 2-amino-4-
thiazolyl. Also preferred are those groups
wherein Ri is methyl, ethyl, carbo~yme~hyll 5 l-carboxy-l-methylethyl~ ~,2,2-trifluoroethyl or
l-carbo~ycyclopropy~. .. .
(~-3 (Acylamino)arylacetyl groups having
the formula o O
-C-CH-NH-C-R
R~

wherein Rg is as defined above and Rj is

Rb ~ (CH2)n-O-, ~mino, alkylamino, (cyanoalkyl)-

amino, amido, alkylamido, (cyanoalkyl)amido,
NH NH2 O
-cH2-NH-C ~ N ~CH-CH2--NH-CH

HO

~ \ ~ ~ ~ro2-N(CH2 C~2 OH)2, ~ rCH3,
OH

~ CH, or

~~ ~
HO ~ C-
o o


_ ~Cl9~ ~
-14-

Preferred (acylamino~arylacetyl groups of
the above formula incl~de those groups wherein
R is amino or amido~ Also preferred are
those groups wherein R is phenyl or 2-thienyl.
(g~ [[[3-Substituted-2-oxo-l-imidazoli-
dinyl]carbonyl]amino]arylacetyl groups having
the formula

I I
O O C
- C - C~-NH -C-N N-Rk
CH -CH2

wherein R is as defined above and Rk is
hydrogen, alkylsulfonyl, arylmethyleneamino
lS ~i.e., ~N=CH-Rg wherein R~ is as defined

above), -C-Rm (wherein Rm is hydrogen, alkyl
or halogen substituted alkyl), aromatic group
(as de~ined by Rg above), alky~ or substituted
alkyl (wherein the alkyl group is substituted
with one or more halogen, cyano, nitro, amino
vr mercapto groups).
Preferred [[3-substituted-2-oxo-l-imidazoli-
dinyl]carbonyl]amino]arylacetyl groups of the
above formula include those wherein Rg is phenyl
or 2-thienyl. Also preferred are those groups
wherein Rk is hydrogen, methylsulfonyl, phenyl-
methyleneamino or 2-furylmethyleneamino.




3~

~5350~ .
GC198
_

The terms "salt" and "salts" refer to
basic salts formed with inorganic and organic
bases. Such salts include ammonium salts, alkali
metal salts like sodium and potassilIm salts
(which are preferred)l alkaline earth metal
salts like the calcium and magnesiwn salts~ salts
with organic bases, e.~., dicyclohexylamine salt~
benzathine, N-methyl-D-glucamine, hydrabamine
salts, salts with amino acids like arginine,
lysine and the like. The nontoxic, pharmaceutically
acceptable salts are preferred, although other
salts are also useful, ~, in isolating or
purifying the product.

The salts are formed in conventional manner
by reactin~ the free acid form of the product
with one or more equivalents of the appropriate
base providing the desired cation in a solvent
or medium in which the salt is insoluble, or in
water and removing the water by freeze drying~
By neutralizing the salt with an insoluble acid
like a cation exchange resin in ~he hydrogen
form (e.g., polystyrene sulfonic acid resin like
Dowex 50, or with an aqueous acid and extraction
with an organic solvent, ~ ~, ethyl aceta~e,
dicloromethane or the like, the free acid form
can be obtained, and, if desired, another salt
formed.



3~

3~
GC198

.
-16-

~ -Lactarns having a -O-~C~SO H substituent
(or salt thereof) in the l-position and an amino
or acylamino substituent in the 3-posltion contain
at least one chiral center - the carbon atom
(in the 3-position of the ~-lactam nucleus) to
which the amino or acylamino substituent is attached.
This invention is directed to those 3-lactams
which have been described above, wherein the
stereochemistry at -the chiral center in the
3-position of the B-lactam nucleus is the same
as the configuration at the carbon atom in the
6-position of naturally occurring penicillins
~ ~, penicillin G) and as the configuration
lS at the carbon atom in the 7 position of naturally
occurring cephamycins, (e.g., cephamycin C).
With respect to the preferred ~-lactams
of formula I, the structural formulas have
been drawn to show the stereochemistry at the
chiral center in the 3-position.
Also included within the scope of this
invention are racemic mixtures which contain
the above-described 3-lactams.

~ 2~ GC198
..
-17-
R5 R6




~-Lactams having a -O-C-SO3H substituent
(or salt thereof) in the 1-position of the
~-lactam nucleus and an acylamino substituent
in the 3-position of the ~-lactam nucleus have
activity against a range of gram negative and
5~ ~ ~
gram-positive organisms. The O-C-SO3H
substituent (or salt thereof) is essential to
the activity of the compounds of this invention.
The compounds of this invention can be
used as agents to combat bacterial infections
(including urinary tract infections and respiratory
infections) in mammalian species, such as
domesticated animals (e.g., dogs, cats, cows,
horses, and the like) and humans.
For combating bacterial infections in
mammals a compound of this invention can be
administered to a mammal in need thereof in
an amount of about 1.4 mg/kg/day to about
35Q mg/kg/day, preferably about 14 mg/~g/day
; to about 100 mg/kg/day. All modes of adminis-
tration which have been used in the past to
deliver penicillins and cephalosporins to the
site of the infection are also contemplated
for use with the novel family of ~-lactams
of this invention. Such methods of administration
include oral, intravenous, intramuscular, and
as a suppository.

535 ~ ~ GC198
-18-

The ~-lactams of this invention can be
prepared from an amino acid having the formula

II OH
~R

~C - OH .
O
The amino group is first protected with a classical
protecting group (e.g., t-butoxycarbonyl, benzyloxy-
carbonyl, _-nitrophenylsulfenyl, etc.), ylelding
a compound having the formula

III
Al-NH-CH - C -R3

~C OH
O~

In formula III, and throughout the specification,
the symbol "Al" refers to a nitrogen protecting
group.
The carboxyl group of a protected amino
acid of formula XII is then reacted with an amine
having the formula
IV ~ 6
NH3-O ~C - SO3

The reaction proceeds in the presence of a coupling
agent such as l-ethyl-3-(3-dimethylaminopropyl)-
carbodiimide or dicyclohexylcarbodiimide, and
yields a salt of the compound having the formula



~25350:~ GC198

--19--

vIOH~\ R4
Al-NH-CH - C R3
C--NH O 5`c'R6o H
The hydroxyl group of a compound of formula V
(or a salt thereof) is converted to a leaving
group, using, for example, a classical reagent
such as methanesulfonyl chloride (methanesulfonyl
is referred to hereinafter as "Ms").
The fully protected compound having the
formula
VI ~ 4
Al-NH-CH- C - R3
~C - NH-O - C -SO3H ,
O
or a salt thereof,
is cyclized by treatment with base, e.g.,
potassium carbonate. The reaction is preferably
carried out in an organic solvent such as acetone,
under reflux conditions, and yields a compound
having the formula
VII _4
Al-N~-CH - C-R
¦ ¦ R5~ ~R~
~5 0
or a salt thereof.
Alternatively, cyclization of a compound
of formula V can be accomplished without first
converting the hydroxyl group to a leaving group.
Treatment of a compound of formula V (or a salt
thereof) with triphenylphosphine and diethyl-
azodicarboxylate or carbon tetrachloride and
~riethylamine, yields a compound of formula VII.

~2535~ GC198
-20-

Both of the methods disclosed above for
ring closure of a compound of formula V result
in the inversion of the stereochemlstry at the
carbon bonded to the R3 and R4 subs-tituents.
Deprotection of the 3-amino substituent
of a compound of formula VII can be accomplished
using art-recognized techniques. If, for example,
the protecting group is t-butoxycarbonyl,
trifluoroacetic acid can be used to deprotect
the amino group. If the protecting group is
benzyloxycarbonyl, catalytic (~ , palladium
on charcoal) hydrogenation can be used. If the
protecting group is o-nitrophenylsulfenyl,
~-toluenesulfonic acid can be used in combination
with ~-thiocresol. The deprotected compound has
the formula

VIII
R4
NH2~fH - IC R3R~ R6
~C - N -O - C - SO3H
or a salt thereof,

f~2~
GC198
-21-

and is a key intermedia~e for preparing the
compounds of this lnvention. The compounds of
formula VIII form an integral part of this
invention.
Well known acylation techniques can be
used to convert a compound of formula VIII to
the corresponding compound having the formula

IX R4
Rl~NH-CH - C-R
~C - N -O-~C~ ~O H
or a salt thereof.
Exemplary teehniques include reaction with a
carboxylic aeid (Rl-OH) or eorresponding carboxylic
aeid halide or earboxylie aeid anhydride. The
reactions with a earboxylie aeid proeeed most
readily in the presenee of a carbodiimide such
as dicyelohexylcarbodiimide and a substance
capable of forming a reaetive intermediate in situ
sueh as N-hydroxybenzotriazole or 4-dimethyl-
aminopyridine. In those instanees wherein the
acyl group (Rl) contains reactive functionality
(such as amino or carboxyl groups) lt may be
neeessary to first proteet these functional
groups, then carry out the aeylation reaetion,
and finally deproteet the resulting produet.

~2535~:~ GCl 9 8

-22-

The products of formula I wherein R2is methoxy can be prepared from the corresponding
compound of formula VII wherein Al is benzyloxy-
carbonyl~ Halogenating (preferably chlorinating)
the amide nitrogen of a compound of formula VII
(Al is benzyloxycarbonyl) yields a compound
having the formula
X O C1 R
~ CH2~O-C-N-CH - C-R3
1 - I o~-~C'R~O H

or a salt thereof.
Reagents and procedures of N-chlorinating amides
are known in the art. Exemplary reagents are
tert. - butyl hypochlorite, sodium hypochlorlte,
and chlorine. The reaction can be run in an
organic solvent (~ , a lower alkanol such
as methanol) or in a two phase solvent system
(e.g., water/methylene chloride) in the presence
of a base such as sodium borate decahydrate.
The reaction is preferably run at a reduced
temperature.
Reaction of a compound of formula X with
a methoxylating agent, ~y~, an alkali metal
methoxide, yields a compound (in combination
wi~h its enantiomer if R3 and R4 are the same
or if X is a racemic mixture) having the formula
XI

CH2-O-C-NH-l ¦ 3R R
~ C N -O - C - ~O H ,
or a salt thereof.



GC198
~35~
-23-

The reaction can be run in an organic solvent,
e.g., a polar organic solvent such as tetra-
hydrofuran, at a reduced ternperature.
Alternatively, a compound of formula VII,
wherein A1 ls benzyloxycarbonyl, can be converted
to a compound of formula XI using a single step
procedure. The methoxylating agent can first
be mixed with a compound of formula VII (Al is
benzyloxycarbonyl) and the N-chlorinating
reagent then added to the reaction mixture.
Conversion of a compound of formula XI
to the desired products of formula I can be
accomplished using the procedures described
above for the conversion of an intermediate
of formula VII to a product of this invention.
The starting materials oE formula II
are readily obtainable using art-recognized
procedures; see, for example Synthesls, pg. 216
(1979) and J. Org. Chem., 44:3967 (1979).
The following examples are specific
embodiments of this invention.

~ 3~ GC1~8
-24-

Example 1~3S-[3~(Z),4~]]-2 i [[1-(2-Amino-4-thiazolyl)-2-
[~4-methyl-2-oxo-1-(sulfome_noxy)-3-azetidinyl]-
amino]-2-oxoeth~lidene]amino]oxy]-2-methylpropanoic
acid, di~otassium salt
. .
A) minoxymethanesulfonic acid
Acetone oxime (1.46 g, 20 mmole) was added
to a suspension of a 60% mineral oil dispersion
of sodium hydride (0.8 g, 20 mmole) in 16 ml
of dry dimethylsulfoxide. This was followed by
-the portionwise addition of sodium bromomethane
sulfonate (3.94 g, 20 mmole). The reaction was
heated at 90-95C for 4 hours under nitrogen,
cooled and washed twice with 250 ml of ether.
Product solidified, was washed with 100 ml
of dichloromethane, filtered and dried over
P205 to yield 15.3 g of crude material. This
was dissolved in 20 ml of water, and tetra-
butylammonium hydrogen sulfate (7.5 g, 22 mmole)
was added. The resulting ion paired product
was extracted twice with 200 ml of dichloromethane.
The dichloromethane solution was drled (Na2SO4,
and concentrated _ vacuo. Hydrolysis of the
acetone oxime was accomplished by heating in
120 ml of 2N ~Cl at 130C for 4 hours. This
solu-tion was concentrated ln vacuo from water
twice and then from acetonitrile. The product
solidified upon addition of dichloromethane,
and was fil~ered and dried in vacuo to yield
2.5 g of the title compound.

~2535~ GC198

-~5-

B) O-Sulfomethyl-~-N-_-butoxycarbonyl-L-
__
threonine hydroxamate,potassium salt
-




Aminoxymethanesulfonic acid (1.14 g, 8.9 mmole)
was added to a solution of t-butoxycarbonyl-L-
threonine (1.96 g, 8.9 mmole) in 16 ml of
water and 4 ml of tetrahydrofuran at 0C.
The pH was adjusted to 4.5 wi~h lN ROH, and
l-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (1.87 g, 9.7 mmole) in 8 ml of
water was added dropwise. The reaction mixture
was stirred at ambient temperature for 2 hours,
and during this time, the pH was maintained
at 4 to 4.5 by occasional addition of lN H2SO~.
The product was ion paired with tetrabutyl-
ammonium hydrogensulfate (3.05 g, 8 mmole)
at pH 2.8 and extracted from the aqueous
solution wi ~ four 100 ml portions of dichloro~
methane. The dichloromethane solution was
dried (Na2SO4) and concentrated ln vacuo to
yield 4.5g of product as the tetrabutylammonium
salt. This was converted to the potassium
salt by ion exchange on 150 ml of Dowex 50X
(0.7 meq K~/ml), and after lyophilization,
2.63 g of th.e title compound was obtained.


~2~
GC198

-26-

Ç) O-Sulfomethyl-a-N-t-butoxycarbonyl-L~
(O-methanesulfonylthreonine)hydroxamate,_
tetrabutylammonium salt
To a parkial solution of O-sulfomethyl-~-
N-t-butoxycarbonyl-L-threonine hydroxamate,
potassium salt (2.37 g, 6.5 mmole) in 50 ml
of dry pyridine at 0-5C under nitrogen was
added dropwise 0.8 ml (excess) of methanesulfonyl
chloride. The reaction was stirred at room
temperature for 4 hours, and then concentrated
in vacuo. The residue was dissolved in lO ml
__
of water, and 2.0 g (6 mmole).of tetrabutyl
ammonium hydrogensulfate was added at pH 2.8.
The ion paired material was extracted with
chloroform. The chloroform was dried and
concentrated ln vacuo to yield 2.6 g of
crude product.

D) ~3S-(3a,4~?_]-3-~[(l,1-Dimeth~lethoxy~-
carbonvl]amino]-4-methY1-2-oxo-l-(sulfomethoxy)-
azetidine, potassium salt
O-Sulfomethyl-~-N-t-butoxycarbonyl-L-
(O-methanesulfonylthreonine)hydroxamate,
tetrabutylammonium salt (2.6 g, 4.0 mmole)
was dissolved in 5 ml of acetone and added
dropwise to a refluxing suspension of 2.2 g
of potassium carbonate in 65 ml of acetone.
Refluxing was continued for 3.5 hours and the
reaction was cooled, filtered, and concentrated
3~ in vacuo. The residue was dissolved in 10 ml
.
of 5 M pH 5.5 KH2PO4, and the pH was adjusted
to 2.~. Product was extracted four times with
lO0 ml portions of dichloromethane, and the
combined extract was dried and concentrated


~535~ GC198

-27~

in vacuo to yield 1.52 g of crude tetrabutyl-
ammonium lon paired B-lactam salt. The potassium
salt was obtained by ion exchange through 50 ml
of Dowex 50X (0.7 meq K /ml) to yield upon
lyophilization 0.53 g of crude material, which
was further purified by chromatography through
100 ml of HP-20 using water. The appropriate
fractions were conbined and lyophilized to yield
0.245 g of product.
Analysis Calc'd for ClOH17N27SK 1 2 H2O
C, 32.46; H, 5.28; N, 7.57; S, 8.66
Found: C, 32.52; ~, 4.76; N, 7.43; S, 8.30

E) [3S-(3~,4~)]-1-Sulfomethyl-3-amlno-4-methyl-2-
_o l-azetidine
[3S-(3~,43)]-3-[[(1,1-Dimethylethoxy~carbonyl]-
amino]-4-methyl-2-oxo-1-(sulfomethoxy)azetidine,
potassium salt (0.245 g, .68 mmole) was suspended
in 0.5 ml of dichloromethane and 0.5 ml of
anisole. mhe reaction mixture was cooled to
0 C, and trifluoroacetic acid (1.0 ml) was
added under nitrogen. The reaction mixture
was s~irred for 1 hour and then concentrated
in vacuo to a residue which was evaporated
from benzene twice. This was triturated with
ether, and the ether was decanted to give the
desired product as a white solid.

i3~
GC198
-28-

F) L3S-~3~(Z),4~]~-2-~L~1-(2=Ami 4-thiazolyl)-2-
[[4-methyl-2-oxo l-(sulfomethoxy)- _azetidinyl]-
_ninol-2-oxoethylidene]amino]oxy]-2-methylpropionic
acid, dlphenylmethyl ester, potassium salt
(Z)-2-Amino-~-[[2-(diphenylmethoxy)-1,1-
dimethyl-2-oxoethoxyl-imino]-4-thiazoleacetic
acid (0.30 g, .68 mmole) and 1-hydroxybenzotriazole
hydrate (0.10 g, .68 mmole) were dissolved in
~ ml of dry dimethylformamide under nitgoren.
This was cooled to 0 C, and N,N'-dicyclohexyl-
carbodiimide (0.14 g, .68 mmole) was added
portionwise. After addition, the reaction was
stirred at 0C for 1 hour. To this was added
a solution of the above crude 3-amino-1-(sulfo-
lS methoxy)azetidine (ca. 0.68 ~mole) in 10 ml
of dimethylformamide and O.S ml of N,N-diisopropyl-
ethylamine at 0 C. The reaction was stirred at
0C for 1 hour and then at room temperature
overnight. The solution was filtered, and the
filtrate was concentrated in vacuo. The residue
was dissolved in 50 ml of dichloromethane and
washed with 2 ml of water. Upon evaporation of
dichloromethane, 0.372 g of crude product was
obtained. This was passed through 30 ml of
Dowex S0 (0.7 meq K~/ml) using water, to yield
upon lyophilization 0.211 g of crude product,
contaminated with hydroxybenzotriazole.

3~
GC198
-29-

G) ~3S-~3~(Z),4~]]-2-l[~1-(2-Amino-4-thiazolyl)-2-
[[4-methyl-2-oxo-1-(sulfomethoxy)-3-azetidinyl]-
amino]-2-oxoeth.ylldene]amino]oxy]-2-methyl-
propanoic acid, dipotassium salt
[3S-[3~(Z),4~]]-2~~I[1-(2-Amino-4-thiazolyl)-2-
[[4 methyl-2-oxo-1-(sulfomethoxy)-3-azetidinyl]-
amino]-2-o~oethylidene]amino]oxy]-2-methylpropionic
acid, diphenylmethyl ester, potassium salt (0.211 g)
was dissolved in 1.8 ml of dichloromethane,
0.5 ml of anisole, and 1.5 ml of trifluoroacetic
acid, and stirred under nitrogen at 0C for
2 hours. The reaction mixture was condentrated
_ vacuo and evaporated from benzene twice.
The residue was washed with ether: ethyl acetate
lS (1:1) and with ether: acetonitrile (1:1) to
give a white solid. This was dissolved in
1.0 ml of pH 5.5 0.5 M KH2PO4, adjusted to
pH 6.5 with lN KOH, and chromatographed through
40 ml of HP-20 with water to give 53 mg of the
title compound, melting point 200C, dec.
AnalysiS Calc'd for C14H17N5OgS2 2 2
C, 28.44; H, 3.84; N, 11.85; S, 10.84
Found: C, 28.32; H, 3.36; N, 11.90; S, 10.37



GC198
-30-

Example 2
[2S-[2~,3~(Z)]]-[[3-[[(2~Amino-4-thiazolyl)-
(methoxyimino)ace-tyl]amino3-2-methyl-4-oxo-
l-azetidinyl]oxy]methanesulEonic acid
Following the procedure of ~xample 1, and
substituting an equimolar amount of (2)-2-amino-
~-[(methoxy)-imino]-4-thiazoleacetic acid for the
thiazoleacetic acid used in part (F) of Example 1,
the titled compound is prepared as the mono-
potassium salt as a hygroscopic solid after
dissolving in acetonitrile and removing the
acetonitrile under vacuum several times
IR - SO3 (1030 cm ); ~-lactam (1778 cm
Analysis: calc. for C11l114N5O7S2 3
calc. C-38.11; H-4.82; ~-15.92; S-12.56
found: C-37.94; H-5.36; N-15.92; S-12.56

Example 3
[2S-[2~,3~(R)]]-[[3-[[[[(4-Ethyl-2,3-dioxo-1-
piperazinyl)carbonyl]amino]phenylacetyl]amino]-
2-methyl-4-oxo-1-azetidinyl]oxy-meth~esulfonic
acid
Following the procedure of Example 1 and
substituting ~-[[(4-ethyl-2,3-dioxo-1-piperazinyl)-
carbonyl]amino]-phenylacetic acid for the thiazole-
acetic acid used in paxt (F) of Example 1, the ~itled
compound is obtained as the monopotassium salt as
a hygroscopic solid. IR - SO3 (1038 cm );
~-lactam (1775 cm 1)
30 Analysis calc- for C20H24N5O9SK-1-6~12O
calc.:C-41.53: H-4.74; N-12.11; S-5.54
found: C-41.53; H-4.46; N-11.13; S-5.61


Example 4
(S)-3-ben~oxycarbonylamino)-4-methyl-2-oxo-1-
(sulfomethoxy)-azetidine
Following the procedure of Example 1, parts
(A) through (D) and substituting benzyloxy-
carbonylserine for the t-butoxycarbonyl-L-
threonine used in part (B), the titled compound
is prepared as a potassium salt, IR --SO3 (1025 cm );
~-lactam (1775 cm ).

Example 5
(2~, 3~ sulfomethoxy-2-(aminocarbonyl)--3-
[[(l,l-dimethy].ethoxy)carbonyl]amino]-4-oxoazetidine
A. Er~thro-3-hydroxy-dl-aspartic acid
Erythro 3-hydroxy-dl-aspartic acid was prepared from
trans-epoxysuccinic acid as described by C.W. Jones et al.
(Can. J. Chem. 47,4363 (1969)). Trans-epoxysuccinic acid
was prepared from fumaric acid as described by G.B. Payne
et al. (J. Org. Chem. 24, 54 (1959)).
B ~-methyl erythro-3-hydroxy-dl-asparate
To a suspension of 5.0 g (33.5 mmol) of erythro-3-
hydroxy-dl-aspar-tic acid in 50 ml of dry methanol was
added 6 ml of conc. hydrochloric acid. The mixture was
refluxed for 3 hours, cooled to room temperature, and
evaporated in vacuo. The residue was taken up in 95
percent ethanol, and the pH was adjusted to 8.0 by
addition of pyridine. The white solid was filtered and
dried to give 5.2 g (95 percent yield) of desired methyl
ester having m.p. 210C. dec.
C. _Erythro-3-hydroxy-dl-asparagine
The above ~-methyl aspartate (4.0 g, 24.5 mmol~ was
dissolved in 40 ml of conc. ammonia and stirred overnight
at room temperature. The reaction mixture was evaporated
in vacuo to a solid which was dissolved in ho-t water.
The pEI was adjusted to 5.0 using 6NHCl, and the solution
was concentrated in vacuo to about 20 ml and then left

~253~

- 32 -
overnight at 5C. The white crystalline mass was
collec-ted and dried to give 3.4 g (95 percent yield)
of desired product having m.p. 233C dec.
D N-T-butoxycarbonyl-erythro-3-hydroxy-dl-
asparagine, potassium salt
Erythro-3-hydroxy-dl-asparagine (710 g, 47 mmol)
was suspended in 50 ml of water and solubilized by
addition of 3 N KOH. This solution was adjusted to pH
10.0 and maintained at -this pH while adding dropwise a
solution of di-t-butyldicarbonate (15.5 g, 71 mmol) in
20 ml of t-butanol. The reaction mixture was stirred
at pH 10.0 overnight at room temperature. The t-butanol
was removed in vacuo, and the aqueous remainder was
adjusted to pH 5.0 using 6N ~ICl. The solution was con-
centrated in vacuo to a small volume, and then the pH
was adjus-ted to 3.0 (6N HCl). Removal of solvent in
vacuo gave a solid (20 g) containing the desired
product in free acid form and in about quantitive yield,
along with inorganic salts. A portion (2.9 g) of this
solid was taken up in water and dilute KOH at pH 6.5
and chromatographed through 100 ml of HP20 resin using
water and then acetone-water (1:9) to give the desired
potassium salt as a residue ~1.8 g).
E Aminoxymethanesulfonic acid, tetrabutylammonium
salt
Tetrabutylammonium hydrogen sulfate (1.02 g, 3 mmol)
was added to a solution of 0.635G15 mmol) of aminoxymethane-
sulfonic acid in 2 ml of water, and the pH was adjusted to
10.0 using dilute KOH. The water was removed in vacuo,
and the residue was triturated with methylene chloride.
After filtration, the filtrate was dried over sodium
sulfate and evaporated to give the desired product as a
residue (1.06 g, 2.88 mmol).
F. 0-sulfomethyl-alpha-n-t-butoxycarbonyl-ery-thro-3-
hydroxy-dl-asparagine hydroxamate, ~otassium salt
N-t-butoxycarbonyl-erythro-3-hydroxy-dl-asparagine,


potassium salt (0.792 g., 2.77 mmol) was dissolved in
water (3 ml) and adjusted to pH 2.4 (dil. H2S04). The
solution was concentrated in vacuo to a residue, which
was concentra-ted from water (2 times~ and then from
benzene (2 times). Thls residue was dissolved in dry
acetonitrile (4 ml) and dry tetrahydrofuran (8 ml) and
cooled to 0C. To this stirred solution was added
0.424 g (2.77 mmol) of l-hydroxybenzotriazole monohydrate
followed by 0.572 g (2.77 mmol) of n,n'-dicyclohexyl-
carbodiimide. The mixture was stirred at 0C for 2 hours,
and then the above aminoxymethanesulfonic acid, tetra-
butylammonium salt (1.06 g, 2.88 mmol) in 5 ml of
acetonitrile was added dropwise. After the addition,
the reaction was stirred at 0C for 4 hours. The reaction
was filtered and concentrated in vacuo to a residue.
Water (10 ml) was added, and the residue was triturated at
0C until it solidiEied. The solid was removed by
filtration, and the aqueous filtrate was concentrated to
about 3 ml. The pH was adjusted to 4.0, and the fraction-
ation was performed over 80 ml of Dowex 50 (K) ion
exchange resin. Appropriate fractions were collected
and concentrated to a small volume. The pH was adjusted
to 3.4, and the solution was chromatographed over HP20
resin to give, after lyophilization, 502 mg (46 percent)
of desired product as a solid having m.p. 145C dec.
~nal. Calcd. for ClOH18N309SK.).71Il20: C, 29.42: H,4.80
N, 10.29: S,7.85
Found: C,29.42: H~.73: M, 10.04: S, 7.45
F O-sulfomethyl-alpha-n-t-butoxycarbonyl-erythro-3-
hydroxy-dl-asparagine hydroxamate, tetrabutyl-
ammonium salt
To a solution of the above asparagine hydroxamate,
potassium salt (104 mg, 0.263 mmol) in 1 ml of water was
added 2.63 ml of O.lm tetrabutylammonium hydrogen sulfate
in 0.5m ph 5.5 KH2P04 buffer. The solution was concen-
trated to dryness, and the residue was tritura-ted with
methylene chloride. Filtration and evaporation of the

- 34 -
methylene chloride gave the desired product as a residue
(156 mg, 0.26 mmol).
G. (2~, 3~)-1-sulfomethoxy-2-(aminoc_rbonyl)-3-
[[(l,l-dimethylethoxy)carbonyl]amino]-4-oxo-
azetidine, potassium salt
The above 0-sulfomethyl hydroxamate, tetrabutylammonium
salt (1~0 mg, 0.234 mmol) was dissolved in 1.6 ml of dry
methylene chloride and stirred with 1 g of dried 3 a
molecular sieves overnight. The solution was removed
via syringe and diluted with 0.8 ml of dry methylene
chloride. To this stirred solution at -50C under argon
was added 0.12 ml (0.85 mmol) of triethylamine followed
by dropwise addition of 0.08 ml ~0.42 mmol) of trifluoro-
methanesulfonic anhydride. The reaction was allowed to
warm to -30C over 1 hour, and then 0.06 ml of triethylamine
was added. ~fter 5 minutes, the reaction was concentrated
in vacuo, and the residue was dissolved in 2 ml of acetone.
The solution was cooled to 0C, and a solution of 79 mg
of potassium perfluorobutane sulfonate in 1 ml of acetone
was added. Ether was then added, and the solids were
collected by centrifugation. Treatment of this solid by
stirring with 2 ml of Dowex 50 (K) resin in water, fil-
tration and removal of the water in vacuo gave crude
desired potassium salt containing no amines. Chromatography
of this crude potassium salt on HP20 resin using water
gave 15 mg (20 percent yield) of desired potassium salt,
after lyophilization having m.p. 149C dec. and IR(KBR)
1786 reciprocal cm (~-lactam carbonyl) and 1696 reciprocal
cm (broab, amide and carbamate carbonyl).

GCl98
-35

Bv followinq the procedures previously descrikeA
the followinq comPounds are PrePared:
(3S-trans)-[[(2-Amino-4-thiazolyl)(methoxy-
imlno)acetyl]amino]-4-methyl-2-oxo-l-azetidinyl]-
oxy]methanesulfonic acid, monopotassium salt
(3S-trans)-[[(2-Amino-4-thiazolyl)[(2,2,2-
tri~luoroethoxy)imino]acetyl]amino]-4-methyl-2-oxo-l-
azetidinyl]oxy]methanesulfonic acid, mono-
pOtasSiUJn salt
(3S-trans)-[[(2-Amino-4-thiazolyl)[(2-amino-2-
oxoethoxy)imino]acetyl]amino]-4-methyl-2-oxo-l-
azetidinyl]oxy]methanesulfonic acid, monopotassium
salt
(3S-trans)-[[(2-Amino-4-thiazolyl)[(carboxy-
methoxy)imino~acetyl]amino]-4 methyl-2-oxo-l-
azetidinyl]-oxy]methanesulfonic acid, dipotassium
salt
(3S-trans)-[[(2-Amino-4-thiazolyl)[[(l-carboxy-
cyclopropyl)oxy]imino~acetyl]amino]-4-methyl-2-oxo-l-
azetidinyl]-oxy]methanesulfonic acid, dipotassium
salt
[3S-¦3~(R),4B]]-[[3-[(Aminophenylacetyl)-
amino]-4-methyl-2-oxo-l-azetidinyl]oxy]methane-
sulfonic acid, monopotassium salt
(3S-trans)-[[3-[(Phenylacetyl)amino]-4-
methyl-2-oxo-l-azetidinyl]oxy]methanesulfonic acid,
monopotassium salt
(3S-trans)-[[3-[(2-Thienylacetyl)amino]-4-
methyl-2-oxo-l-azetidinyl]oxy]methanesulfonic acid,
monopotassium salt
(3S-trans)-[[3-[(2,6-Dimethoxyphenyl)acetyl~-
amlno]-4-methyl-2-oxo-l-azetidinyl]oxy]methane-
sulfonic acid, monopotassium salt



~ ~i35~3~

-36- G~198



[3s-[3~(R)~4B]]-[[3-[[[[(Aminocarbonyl)-
amino]-2-thienylacetyl-amino]-4-methyl-2-oxo-1-
azetldinyl]-oxy]methanesulfonic acid, monopotassium
salt
[3S-[3(R),4~]]-[[3-[(Carboxyphenylacetyl)-
amino]-~-methyl-2-oxo-1-azetidinyl~oxy]methane-
sulfonic acid, dipotassium salt
[3S-[3~(+),4~]]-[[3-[(Phenylsulfoacetyl)-
amino]-4-methyl-2-oxo-1-azetidinylloxy]methane-
sulfonic acid, dipotassium salt
(3S-trans)]-[[3-¦[(2-Amino-4-thiazolyl)-
oxoacetyl]amino]-4-methyl-2-oxo-1-azetidinyl]-
oxy]methanesulfonic acid, monopotassium salt
[3S-[3a(R),4~]]-[[3-l[[[[2-Oxo-3-[(phenyl-
methylene)amino]-l-imidazolidinyl]carbonyl]amino]-
phenylacetyl]amino]-4-methyl-2-oxo-1-azetidinyl~oxy]--
methanesulfonic acid, monopotassium salt
[3S-[3~(Z),4~]]-[[3-[[2-Furanyl(methoxy-
imino)acetyl~amino]-4-methyl-2-oxo-1-azetidinyl]oxy]-
methanesulfonic acid, monopotassium salt
[3S(Z)]-[[3-l[(2-Amino-4-thiazolyl)(methoxy-
imino)acetyl]amino]-2-oxo-1-azetidinyl]oxy]methane-
sulfonic acid, monopotassium salt
[3S(Z)]-[[3-[[(2-Amino-4-thiazolyl)[(l-carboxy-
l-methylethoxy)imino]acetyl]amino]-2-oxo-1-
azetidinyl~oxy]methanesulfonic acid, dipotassium
salt
[3S(Z)]-[[3-[[(2-Amino-4-thiazolyl)[(2,2,2-
trifluoroethoxy)imino]acetyl]amino~-2-oxo-1-
azetidinyl]oxy]methanesulfonic acid, monopotassi~m
salt


-37- GCl9~

[3S~)]-[ L3-E [ (2-Amino-4-thiazolyl)[(2-amino-?-
oxoethoxy)imino]acetyl]amino]-2-oxo-1-azeti~inyl]-
oxy~methanesulfonic acid, monopotassium salt
[ 3s- [3~(5),4g]]-[[3-[[[(Aminocart)onyl)aminoJ-
2-thienylacetyl]amino]-2-oxo-1-azetidinyl]oxy]-
methanesul~onic acid, monopotassium salt
[ 3s- 13~ ( ~), 4 ~] ] - [ [ 3-[(Phenylsulfoacetyl)-
amino]-2-oxo-1-azetidinyl]oxy]methanesulfonic acid,
dipotassium salt
[3S-[3a(R),4B]]-[[3-[[[[(4-Ethyl-2,3-dioxo-1-
piperazinyl)carbonyl]amino]phenylacetyl]amino]-2-oxo-
l-azetidinyl]oxy]methanesulfonic acid,monopotassium
salt
[(3S(Z)]-i[3-[(Phenoxyacetyl)amino]-2-oxo-1-
azetidinyl]oxy]methanesulfonic acid, monopotassium
salt
(3S-cls)-[[(2-Amino-4-thiazolyl)~methoxy-
imino)acetyl]amino]-4-methyl-2-oxo-1-azetidinyl]-
oxy]methanesulfonic acid, monopotassium salt
(3S-cis)-[[(2-Amino 4-thiazolyl)[(2,2,2-
trifl~oroethoxy~imino]acetyl]amino]-4-methyl-2-oxo-1-
azetidinyl]oxy]methanesulfonic acid, mono-
potassium salt
(3S-cis)-[[(2-Amin~-4-thiazolyl)i(carboxy-
methoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-
azetidinyl]-o~y]methanesulfo.nlc acid, dipotassium
salt
(3S-cls)-[[3-[[(2-Amino-4-thiazolyl)](l-
carboxy-l-methylethoxy)imino]accetyl]amino]-2-oxo-4-
methyl-l-azetidinyl]oxy]methanesulfonic acid,
dipotassium salt
(3S-cis)-[[(2-Amino-4-thiazolyl)[[(l-carboxy-
cyclopropyl)oxy]imino]acetyl]aminoJ-4-methyl-2~oxo-1-
azetidinyl]-oxy]methanesulfonic acid, dipotassium
salt

~ ~35~

-3~- GC198

(3S-cis)-[[(2-Amino-4 thiazolyl)[(2-amino-2-
oxoethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-
azetidinyl]oxy]methanesulfonic acid, monopotassium
salt
[3S-[3a(R),4]]-[[3-[(Carboxyphenylacetyl)-
amino]-4-methyl-2-oxo-1-azetidinyl]oxy]methane-
sulfonic acid, dipotassium salt
[3S-[3a(R),4a]]-[[3-[[[[(4-Ethyl-2,3-dioxo-
l-piperazinyl)carbonyl]amlno]phenylacetyl]amino]-4-
methyl-2-oxo-1-azetiainyl]oxy]methanesulfonic acid,
monopotassium salt
[3S-[3a(S),4a]]-[[3-[[[(AminocarbonylJ-
amino]-2-thienylacetyl]-amino]-4-methyl-2-oxo-1-
azetidinyl]-oxy]methanesulfonic acid, monopotassiun,
salt
[3S-[;a(R),4a]]-[[3-[(Aminophenyl-
acetyl)-amino]-4-methyl-2-oxo-1-azetidinyl]oxy]-
methanesulfonic acid, monopotassium salt