Note: Descriptions are shown in the official language in which they were submitted.
'2~3~
X-7967A - 1 -
1-CARBA(DETHIA)CEPHALOSPORIN ANTIBIOTICS
In the field of antibacterial therapy, the
need for new chemotherapeutic agents is one that will
never extinguish. Mutant strains resistant to existing
antibacterial agents are encountered frequently. To
meet this need, considerable research effort continues
to focus on such new agents.
The present invention provides various 3-
(substituted or unsubstituted)thiazolo-l-carba(l-dethia)-
cephems (i.e., l-carba(1-dethia)cephalosporins) useful
as antibacterial agents against both gram-negative and
gram-positive bacteria. The present invention provides
7~-(acylamino-1-carba(1-dethia) 3-substituted-3-cephem-
4-carboxylic acids wherein the group at the 3-position
is a 4-thiazole ring optionally substituted in the
2-position by nitro, cyano, phenyl, amino, halo, C1-C6
alkyl, C1-C6 substituted alkyl, an optionally-substi-
tuted heterocyclic ring, substituted phenyl, or an acyl
group. Also provided are novel 7-amino intermediates
useful in the preparation of the compounds of the
present invention. Also provided is a pharmaceutical
2 ~ 9 ~
X-7967A - 2 -
formulation utilizing the compounds of the present
invention and a method for treating antibacterial
infections in man an other animals.
The present invention provides compounds of
Formula (1):
Rl-N
,~ X (1)
CO2H
wherein X i9 a group selected from amino, halo, cyano,
lS hydrogen, nitro, C1-C6 alkyl, C1-C6 substituted alkyl,
a C3 to C6 heterocyclic ring containing 1, 2, or 3
nitrogen atoms and 0 or 1 sulfur or oxygen atoms, said
ring optionally substituted by one or more groups
selected from halo, nitro, hydroxy, C1-C6 alkyl, or
Cl-C6 substituted alkyl;
phenyl, substituted phenyl or an acyl group of the
formula
O
Il
R"C-, wherein R" is C1-C6 alkyl, C1-C6 substituted
alkyl, phenyl, or substituted phenyl;
R3 is hydrogen, C1-C4 alkoxy, or a group of the formula
-NHCH0; and
R1 is an acyl group of the formula
0
R2-C-, wherein R2 is hydrogen; Cl-C6 alkyl, C1-C6 alkyl
X-7967A - 3 -
substituted by cyano, carboxy, halogen, amino, C1-C4
alkoxy, Cl-C4 alkylthio, or trifluoromethylthio; a
phenyl or substituted phenyl group represented by the
formula
a
a''' ~
wherein a and a' independently are hydrogen,
halogen, hydroxy, C1-C4 alkoxy, C1-C4
alkanoyloxy, C1-C4 alkyl, C1-C4 alkylthio,
amino, mono- or di(C1-C4 alkyl)amino, C1-C4
alkanoylamino, C1-C4 alkylsulfonylamino,
carboxy, carbamoyl, hydroxymethyl, amino-
methyl, or carboxymethyl;
a group represented by the formula
<,~(Z)m- CH2--
wherein a and a' have the same meanings as
defined above, Z is 0 or S, and m is 0 or 1;
. .
a heteroarylmethyl group represented by the formula
R~-CH2-
wherein R1 is thienyl, furyl, benæothienyl,
benzofuryl, indolyl, triazolyl, tetrazolyl,
oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl,
and such heteroaryl groups substituted by
2~5~
X-7967A - 4 -
amino, hydroxy, halogen, C1-C4 alkyl, Cl-C4
alkoxy, C1-C4 alkylsulfonylamino;
a substituted methyl group represented by the formula
R2-CH-
Q
wherein R2 is cyclohex-1,4-dienyl, or a
phenyl group or substituted phenyl group
represented by the formula
a
a~
wherein a and a' have the above defined
meanings, or R2 is Rl as defined above, and
Q is hydroxy, Cl-C4 alkanoyloxy, carboxy
sulfo, or amino;
or R2 is a keto group or an oximino-substituted group
represented by the formulae
R3-C- R3-C-
11 11
O N
OR4
wherein R3 is R1 or R2 as defined above and
R4 is hydrogen, C1-C4 alkyl, or a group repre-
sented by the formula
:
X-7967A - 5 -
-C-(CH2 ~nCOR5
b'
wherein b and b' independently are hydrogen,
or C1-C3 alkyl, and b and b' when taken together
with the carbon to which they are bonded form
a 3- to 6-membered carbocyclic ring, R5 is
hydroxy, C1-C4 alkoxy, amino, C1-C4 alkyl-
amino, or di(C1-C4 alkyl)amino, and n is 0,
1, 2, or 3;
or a pharmaceutically acceptable salt thereof.
In the above Formula (1), one preferred R2
group is a keto group or an oximino-substituted group
represented by the formulae
R3-C- R3-C-
11 11
O N
OR4
wherein R3 is Rl or R2 as defined above and
R4 is hydrogen, Cl-C4 alkyl, or a group repre-
sented by the formula
b
-C- ( CH2 ~nCORs
wherein b and b' independently are hydrogen,
: or Cl-C3 alkyl, and b and b' when taken together
with the carbon to which they are bonded form
2~3~9~
X-7967A - 6 -
a 3- to 6-membered carbocyclic ring, R5
y, C1 C4 alkoxy, amino, C1-C alkyl
amino, or di(C1-C4 alkyl)amino, and n is 0,
1, 2, or 3.
A preferred Rl group is (2-aminothiazol-
4-yl)methoximinoacetyl.
A further preferred R2 group is a substituted
methyl group represented by the formula
Rp-CH-
Q
wherein R2 is cyclohex-1,4-dienyl, or a
phenyl group or substituted phenyl group
represented by the formula
a ~ ~
<~ \~
a' ~
wherein a and a' have the above defined
meanings, or R2 is R1 as defined above, and
Q is hydroxy, C1-C4 alkanoyloxy, carboxy,
sulfo, or amino.
A preferred R1 group is D-phenyl-
glycyl.
As a further aspect of the present invention,
there are provided intermediates of Formula (2)
2~3~
X-7967A - 7 -
R1 b~
O ~ ~ X (2)
CO2R4
wherein: Rl' is hydrogen or an amino protecting group;
R4 is hydrogen or a carboxy protecting group;
R3' is hydrogen, Cl-C4 alkoxy, or a group of the formula
-NHCHO; and
X is a group selected from amino, halo, cyano, hydrogen,
nitro, Cl-C6 alkyl, Cl-C6 substituted alkyl, a C3 to C6
heterocyclic ring containing 1, 2, or 3 nitrogens and 0,
or 1 sulfur or oxygen atoms, said ring optionally
substituted by one or more groups selected from halo,
nitro, hydroxy, Cl-C6 alkyl, or Cl-C6 substituted alkyl;
phenyl, substituted phenyl, or an acyl group of the
formula
o
: R' " C-, wherein R " ' is Cl-C6 alkyl, Cl-C6 substituted
` alkyl, phenyl, or substituted phenyl. The compounds of
formula (2) are useful as intermediates to the anti-
bacterial agents of formula (1)
In the above Formula (1), the term "Cl to C6
alkyl" denotes such radicals as methyl, ethyl, n-propyl,
iso-propyl, n-butyl, sec-butyl, tert-butyl, amyl, tert-
amyl, hexyl and the like. The preferred "Cl to C6alkyl" group is methyl.
X-7967A - 8 -
The term "C1 to C6 substituted alkyl" denotes
the above Cl to C6 alkyl groups that are substituted by
one or two halogen, hydroxy, protected hydroxy, amino,
protected amino, Cl to C7 acyloxy, nitro, carboxy,
protected carboxy, carbamoyl, carbamoyloxy, cyano,
methylsulfonylamino, C1 to C4 alkoxy, phenyl, sub-
stituted phenyl, or a C3 to C6 heterocyclic ring
containing l, 2, or 3 nitrogen atoms and O or 1 sulfur
or oxygen atoms, said ring optionally substituted by
one or more groups selected from halo, nitro, hydroxy,
or C1-C6 alkyl. The substituted alkyl groups may be
substituted once or twice with the same or with different
substituents.
Examples of the above substituted alkyl groups
include cyanomethyl, nitromethyl, hydroxymethyl, trityl-
oxymethyl, propionyloxymethyl, aminomethyl, carboxymethyl,
allyloxycarbonylmethyl, allyloxycarbonylaminomethyl,
carbamoyloxymethyl, methoxymethyl, ethoxymethyl, t-butoxy
methyl, acetoxymethyl, chloromethyl, bromomethyl,
iodomethyl, 6-hydroxyhexyl, 2,4-dichloro(n-butyl),
2-amino(iso-propyl), 2-carbamoyloxyethyl chloroethyl,
bromoethyl, fluoroethyl, iodoethyl, chloropropyl,
bromopropyl, fluoropropyl, iodopropyl, phenylmethyl,
phenylethyl, phenyl (3-pyridyl)methyl, phenyl(3-
pyridyl)ethyl, and the like.
The term "C1 to Cg alkoxy" as used hereindenotes groups such as methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, t-butoxy and like groups.
The term "substituted phenyl" as used herein
denotes a phenyl group substituted with one or two
moieties chosen from the group consisting of halogen,
hydroxy, protected hydroxy, cyano, nitro, C1 to C6
X-7967A - 9 -
alkyl, C1 to C~ alkoxy, carboxy, protected carboxy,
carboxymethyl, protected carboxymethyl, hydroxymethyl,
protected hydroxymethyl, amino, protected amino,
aminomethyl, protected aminomethyl, trifluoromethyl
or N-(methylsulfonylamino).
Examples of the term "substituted phenyl"
include a mono- or di(halo)phenyl group such as 4-chloro-
phenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-
dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromo-
phenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-
fluorophenyl and the like; a mono- or di(hydroxy)phenyl
group such as 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-
dihydroxyphenyl, the protected-hydroxy derivatives
thereof and the like; a nitrophenyl group such as 3-
or 4-nitrophenyl; a cyanophenyl group, for example, 4-
cyanophenyl; a mono- or di(lower alkyl)phenyl group such
as 4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl,
4-(iso-propyl)phenyl, 4-ethylphenyl, 3-~n-propyl)phenyl
and the like; a mono- or di(alkoxy)phenyl group, for
example, 2,6-dimethoxyphenyl, 4-methoxyphenyl, 3-ethoxy-
phenyl, 4-(iso-propoxy)phenyl, 4-(t-butoxy)phenyl,
3-ethoxy-4-methoxyphenyl and the like; 3- or 4- tri-
fluoromethylphenyl; a mono- or dicarboxyphenyl or
(protected carboxy)phenyl group such as 4-carboxyphenyl
or 2,4-di(protected carboxy)phenyl; a mono- or di-
(hydroxymethyl)phenyl or (protected hydroxymethyl)-
phenyl such as 3-(protected hydroxymethyl)phenyl or
3,4-di(hydroxymethyl)phenyl; a mono- or di(aminomethyl)-
phenyl or (protected aminomethyl)phenyl such as 2-
(aminomethyl)phenyl or 2,4-(protected aminomethyl)-
phenyl; or a mono- or di(N-(methylsulfonylaminol)phenyl
such as 3-(N-(methylsulfonylamino))phenyl. Also, the
9 ~
X-7967A - 10 -
term "substituted phenyl" represents disubstituted
phenyl groups wherein the substituents are different,
for example, 3-methyl-4-hydroxyphenyl, 3-chloro-4-
hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-
hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 2-hydroxy-4-
chlorophenyl and the like. Preferred substituted phenyl
groups include the 2- and 3-trifluoromethylphenyl, the
4-hydroxyphenyl, the 2-aminomethylphenyl and the 3-
(N-(methylsulfonylamino))phenyl groups.
The terms "halo" and "halogen" refer to the
fluoro, chloro, bromo or iodo groups.
The term "pharmaceutically-acceptable salt"
encompasses those salts that form with the carboxylate
anions and includes salts formed with the organic and
inorganic cations discussed above. Furthermore, the
term includes salts that form by standard acid-base
reactions with basic groups (such as amino groups) and
organic or inorganic acids. Such acids include hydro-
chloric, sulfuric, phosphoric, acetic, succinic, citric,
lactic, maleic, fumaric, palmitic, cholic, pamoic,
mucic, D-glutamic, d-camphoric, glutaric, phthalic,
tartaric, lauric, stearic, salicyclic, methanesulfonic,
benzenesulfonic, sorbic, picric, benzoic, cinnamic, and
like acids.
The term "carboxy-protecting group" as used
herein refers to one of the ester derivatives
of the carboxylic acid group commonly employed to block
or protect the carboxylic acid group while reactions are
carried out on other functional groups on the compound.
Examples of such carboxylic acid protecting groups
2 ~
X-7967A - 11 -
include 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxy-
benzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl,
2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylene-
dioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl,
2,2',4,4'-tetramethoxybenzhydryl, t-butyl, t-amyl,
trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4 "-
trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl,
t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl,
~-(trimethylsilyl)ethyl, ~-(di(n-butyl)methylsilyl)ethyl,
p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl,
allyl, cinnamyl, 1-(trimethylsilylmethyl)prop-1-en-3-yl,
and like moieties. The species of carboxy-protecting
group employed is not critical so long as the derivatized
carboxylic acid is stable to the condition of subsequent
reaction(s) on other positions of the molecule and can
be removed at the appropriate point without disrupting
the remainder of the molecule. In particular, it is
important not to subject the carboxy-protected molecule
to stxong nucleophilic bases or reductive conditions
employing highly activated metal catalysts such as Raney
nickel. (Such harsh removal conditions are also to be
avoided when removing amino-protecting groups discussed
below.) A preferred carboxylic acid protecting group is
the allyl group. Similar carboxy-protecting groups used
in the cephalosporin, penicillin and peptide arts can
also be used to protect a carboxy group substituents~
Further examples of these groups are found in E. Haslam,
"Protective Groups in Organic Chemistry", J.G.W. McOmie,
Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, and
T.W. Greene, "Protective Groups in Organic Synthesis",
John Wiley and Sons, New York, N.Y., 1981, Chapter 5.
~ $ ~
X-79~7A - 12 -
A related term is "protected carboxy", which refers
to a carboxy group substituted with one of the above
carboxy-protecting groups.
The term "amino-protecting group" as used
herein refers to substituents of the amino group
commonly employed to block or protect the amino
functionality while reacting other functional groups
on the compound. Examples of such amino-protecting
groups include the formyl group, the trityl group, the
t-butoxycarbonyl group, the phthalimido group, the
trichloroacetyl group, the chloroacetyl, bromoacetyl
and iodoacetyl groups, urethane-type blocking groups
such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl,
2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl,
3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl,
2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,
3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,
4-cyanobenzyloxycarbonyl, 2-(4-xenyl)iso-propoxycar-
bonyl, l,l-diphenyleth-1-yloxycarbonyl, 1,1-diphenyl-
prop-l-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl,
2-~p-toluyI)prop-2-yloxycarbonyl, cyclopentanyloxy-
carbonyl, 1-methylcyclopentanyloxycarbonyl, cyclo-
hexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl,
2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)-
ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl,
2-(triphenylphosphino)ethoxycarbonyl, 9-fluorenyl-
methoxycarbonyl ("FMOC"), 2-(trimethylsilyl)ethoxy-
carbonyl, allyloxycarbonyl, l-(trimethylsilylmethyl)-
prop-l-enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl,
4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxy-
carbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropyl-
2 ~
X-7967A - 13 -
methoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl, iso-
bornyloxycarbonyl, 1-piperidyloxycarbonyl and the like;
the benzoylmethylsulfonyl group, the 2-(nitro)phenyl-
sulfenyl group, the diphenylphosphine oxide group and
like amino-protecting groups. The species of amino-
protecting group employed is not critical so long as the
derivatized amino group is stable to the condition of
subsequent reaction(s) on other positions of the mole-
cule and can be removed at the appropriate point without
disrupting the remainder of the molecule. Preferred
amino-protecting groups are the allyloxycarbonyl, the
t-butoxycarbonyl, and the trityl groups. Similar
amino-protecting groups used in the cephalosporin,
penicillin and peptide art are also embraced by the
above terms. Further examples of groups referred to
by the above terms are described by J.W. Barton, "Pro-
tective Groups In Organic Chemistry", J.G.W. McOmie,
Ed., Plenum Press, New York, N.Y., 1973, Chapter 2, and
T.W. Greene, "Protective Groups in Organic Synthesis",
John Wiley and Sons, New York, N.Y., 1981, Chapter 7.
The related term "protected amino" defines an amino
group substituted with an amino-protecting group dis-
cussed above.
In Formulae (1) and (2) above, when X is a
C3-C6 heterocyclic ring containing 1, 2, or 3 nitrogen
atoms and 0 or 1 sulfur or oxygen atoms, (i.e., a
heterocyclic ring containing from 3 to 6 carbon atoms,
1, 2, or 3 nitrogen atoms and 0 or 1 sulfur or oxygen
atoms) said ring optionally substituted by one or more
halo, nitro, hydroxy, C1-Cff alkyl, or Cl-C6 substituted
alkyl groups, examples of such rings include pyrrolyl,
furanyl, 4-nitrothiazol-2-yl, imidazolyl, pyridinyl,
pyrimidinyl, pyrazinyl, morpholinyl, oxazolyl, thiazolyl,
203~3~
X-7967A - 14 -
thiadiazolyl, oxadiazolyl, l-methyl-3-pyridyl, 2-methyl-
3-pyridyl, 3-methyl-4-nitro-imidazol-2-yl, and the like.
One intermediate (VI) can be prepared
according to the following Scheme (A)
OCH2CNH~
~L Cf~
CO2CH2 ~NO2
I~i,
~ OCH2CN
H~ ~
l CH2
o _N~ 11 OCH2CH,
co2CH2 ~N2
l ~U)
OCH2CNH~
OCH2CHJ
~N ~ tOCH2CH3
2 5 C02CH2 ~N2
o l~lU~
3 0 ~ OCH*
N~,_~
OCH2CH~
~OCH*H3 ~ [V)
CO2CH2 ~3No7
'
:
~3~
X-7967A - lS -
o
OCH2CN~ ~
FIN~ j~CH~ (V)
CO2CH2 ~NO~
I~v~
0
+ ~CH2CNH~
~N~CI12Elr ~Vl)
C0*H2 aNO2
I ~vi~
According to Scheme A, p-NO2 benzyl-7~-phenoxy-
acetylamino-l-carba(l-dethia)-3-trifluoromethanesulfonyl-
oxy-3-cephem-4-carboxylate (which can be prepared
according to the method of Evans et al., U.S. Patent
No. 4,673,737, incorporated herein by reference) is
reacted with a compound of the formula CH2=C(OCH2CH3)-
(Sn(X)3), wherein X is methyl or n-butyl, LiCl, and
. - (CH3CN~2PdCl2 in a polar organic solvent, preferably
N,N'-dimethylformamide to provide (II~. Further details
of this type of transformation can be found in Cook et
al. U.S. Patent No. 4,855,418, incorporated herein by
reference. Compound (II~ can then be converted to the
3-(2-bromo-1,1-diethoxyethyl~ compound (III) with
Br2/CCl4 in ethanol/CH2Cl2 using a base such as 2,6-
lutidine.
Reactions (iii) and (iv) depict a methodwhereby the 7-phenoxyacetyl group may be replaced by
the t-butoxycarbonyl group. First, compound (III) is
~.
~3~
X-7967A - 16 -
acylated with di-tert-butoxydicarbonate in the presence
of a base such as dimethylaminopyridine.
Secondly, the phenoxyacetyl group is displaced
with a base such as LioH in a polar solvent such as
tetrahydrofuran. Further description of this exchange
can be found in Blaszczak et al., European Patent Appli-
cation No. 88306996.5.
Finally, the 3-bromomethylcarbonyl compound
(VI) can then be prepared from compound V by an acid
catalyzed hydrolysis reaction with, for example, acetic
acid in acetonitrile/water.
Compounds of Formula (1) can then be made
from intermediate (VI) above by the following Scheme (B):
ol
+ OCH2CNH~r~
--N~ CH2Bt ( Vl )
COqCU2 aNO2
'I (vi)
~ OCH2CNH ~
p ~ ~ ~v~)
COqCH2 ~NO2
(V~i)
11
+ OCH2CNH~
O
CO2H
I
2 ~3 ~
X-7967A - 17 - ~
R1-NH ~
~ N ~ ~ X
CO2H
In the above step (vi), the 3-(2-substituted)
thiazolo compounds may be synthesized by reaction of
intermediate (VI) with a compound of the formula
S
Il
H2N-C-X,
wherein X is as defined in Formula 1, above. Thus,
with the desired 3-(2-substituted thiazol-4-yl) sub-
stituent in place, and with the de-esterification of
the 4-p-nitrobenzyl ester occasionally occurring under
the previously defined reaction conditions, the 4-
carboxy position may be re-esterified to the 4-allyl
ester using allyl bromide, NaI, (CH3CH2CH2CH2)4NHS04,
and NaHCO3 in N,N'-dimethylformamide. If deesterifi-
cation does not occur under these conditions, the
p-nitrobenzyl protecting group may be removed by
zinc reduction in a solvent mixture of N,N'-dimethyl-
formamide/tetrahydrofuran/acetic acid or N,N'-dimethyl-
formamide/tetrahydrofuran in HCl and reesterified as
described above to the 4-allyl ester. The resulting
amino protected, carboxy protected "nucleus" (i.e.,
formula (2)) can then be treated with p-toluenesulfonic
acid H2O or trifluoroacetic acid to remove the 7-t-
butoxycarbonyl group to provide the 7-amino 4-carboxy
2~3~
X-7967A - 18 -
protected intermediate. Further, the 7-amino group can
then be acylated with an activated form of the desired
R1 substituent using standard procedures well-known in
the ~-lactam art. Finally, all remaining amino and~or
carboxy protecting groups can then be removed using
conventional methodology.
The 7~-acylamino-7~-substituted-l-carbacephalo-
sporins represented by Formula (1) wherein R3 is C1-C~
alkoxy can be prepared according to the method described
by Koppel, U.S. Patent No. 3,994,885, incorporated herein
by reference.
T~e 7~-formamido substituted compounds wherein
R3 is -NHCHO can be obtained by the method described by
Millner, U.S. Patent No. 4,539,159 incorporated herein
by reference. According to this method, a 7~-acylamino-
or 7~-protected amino-7~-methylthio-substituted 1-
carbacephalosporin is reacted with anhydrous ammonia or
an ammonium salt in the presence of mercuric acetate to
form the corresponding 7~-amino derivative. The latter
is formylated to the 7a-formamido derivative.
One skilled in the art will appreciate that
although the above manipulations utilized phenoxyacetyl
and t-butyloxycarbonyl as amino protecting groups and
the p-nitrobenzyl group as carboxy-protecting group,
there are many which would be equally efficacious.
The 1-carbacephalosporins provided by the
invention form salts with suitable bases, in partic-
ular, the pharmaceutically-acceptable, non-toxic salts.
The C-4 carboxy group of the 1-carbacephalosporin can
form salts with the alkali and alkaline earth metal
hydroxides, carbonates and bicarbonates. Examples of
such pharmaceutically-acceptable salts are the sodium,
2~6~ ~
X-7967A - 19 -
potassium, calcium and magnesium salts. Salts also may
be formed with amines such as dibenzylamine, cyclohexyl-
amine, triethylamine, ethanolamine, di-ethanolamine and
like amines. Likewise, when the 1-carbacephalosporin
is substituted by two or more carboxy groups, di- and
tri-salts are obtained by conventional salt-forming
methods.
The pharmaceutically-acceptable, non-toxic
salts can be useful forms of the antibiotics for pre-
paring antibiotic formulations.
This invention also provides a method for
- treating infectious diseases in man and other animals
caused by bacteria and pharmaceutical formulations
suitable for administration in the treatment method.
The therapeutic method of this invention comprises
administering to man or other animals an antibiotically
effective non-toxic dose of a compound represented by
Formula (1) or a pharmaceutically acceptable salt
thereof.
An antibiotically effective amount is an
amount between about 25 mg and about 2 grams. The
compound or salt may be administered in a single
. dose or in multiple doses throughout the day. Treat-
ment may continue for a week to ten days or longer
depending upon the duration of the infection. The
particular dose and regimen can depend on such factors
as the weight and age of the patient, the particular
causative organism, the severity of the infection, the
general health of the patient, and the tolerance of the
individual to the antibiotic.
9 ~
X-7967A - 20 -
The l-carbacephalosporins may be administered
parenterally, orally, subcutaneously or rectally. AS
with other ~-lactam antibiotics, the method of this
invention may be used prophylactically to prevent
infections after exposure or before possible exposure,
e.g., preoperatively. The antibiotic 1-carbaceph-
alosporins may be administered by conventional methods,
e.g., in capsules, tablets, by syringe, or by intra-
venous drip.
The pharmaceutical formulations of the inven-
tion comprise an antibiotically effective non-toxic
amount of a l-carbacephalosporin represented by Formula
(1) or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.
Formulations for oral administration include
capsules, tablets, lozenges and liquid suspensions.
The antibiotic or a salt thereof in the form of a dry
powder can be encapsulated in gelatin capsules for
oral use. The antibiotic may also be blended with
an excipient, e.g., a stabilizer, prior to filling.
Capsules may contain between about 100 mg and about
500 mg to provide unit dosage formulations.
Tablets containing between about 100 mg and
500 mg of the antibiotic or a pharmaceutically accept-
able salt thereof can be formulated by conventionalmeanæ and may contain in addition a binding agent,
disintegrating agent, stabilizing agent, antioxidant,
etc.
Liquid preparations of the antibiotic may be
prepared for infant and geriatric use. Pediatric sus-
pensions can be formulated with the antibiotic oral
2 ~ 3 ~
X-7967A - 21 -
excipients such as suspending agents, flavoring agents,
stabilizers and the like. Solutions of the antibiotics
likewise may be formulated with solubilizing agents,
flavoring agents, sugar, water, etc.
Parenteral formulations of the antibiotics
for injection are formulated with Water-for-Injection,
Ringer's solution, physiological saline or glucose
solution. The antibiotic also may be administered in
an intravenous fluid by the drip method.
For parenteral use, the antibiotic or a phar-
maceutically acceptable salt thereof, can be made up
preferably in dry crystalline powder form or as a
lyophilized powder and filled into vials. Such vials
may contain between about 100 mg and about 2 grams of
antibiotic per vial.
The following Experimental Section provides
further examples of the various aspects of the present
invention but is not to be construed as limiting the
scope therefor.
Experimental Section
. Preparation 1
p-Nitrobenzyl 7~-phenoxyacetylamido-1-carba(l-dethia)-
3-trifluoromethanesulfonyloxy-3-cephem-4-carboxylate
The title compound can be prepared according
to the method of Evans and Sjogren, U.S. Patent No.
4,673,737, incorporated herein by reference.
~3~
X-7967A - 22 -
PreParation 2
Trimethyl(l-ethoxy-e~hen-l-yl)stannane
(Ref: Organometallics, Vol. 1, No. 6, 1982, J.
Soderquist)
A 19.18 ml (14.48 g, 200.36 mmol) sample of
ethoxyethylene was dissolved in 100 ml of tetrahydrofuran,
cooled to -78C, and treated with a solution of t-butyl-
lithium (94.1 ml, 150.56 mmol, 1.6M) over 20 min. under
argon. The reaction mixture was then allowed to warm
to 0C over 35 min. and added via cannula to a -78C
solution of 20.0 g (100.4 mmol) of chlorotrimethyi-
stannane in 40 ml of tetrahydrofuran and allowed to
warm to room temperature gradually. After an additional
50 min., the mixture was guenched with saturated NH4Cl
solution (400 ml) and extracted with diethyl ether (500
ml). The ether solution was then dried over anhydrous
Na2SO4, filtered and concentrated to provide the crude
product as a yellowish liquid (23.8 g; 100%). The
crude product was then distilled at 40-41C and about
4 mm Hg to provide 12.05 g of the title compound.
lH NMR (300 MHz, CDCl3) ~4.65 (s, lH), 4.10 (s, lH),
3.70 (g, 2H), 1.25 (t, 3H~, and 0.18 (s, 9H).
2 ~
X-7967A - 23 -
Preparation 3
p-Nitrobenzyl 7~-phenoxyacetylamino-1-carba(l-dethia)-
3-(l-ethoxy-ethen-1-yl)-3-cephem-4-carboxylate.
A 1.0 g (1.77 mmol) sample of the title
compound of Preparation 1, a 0.142 g (3.34 mmol) sample
of lithium chloride, and a 0.043 g (0.167 mmol) sample
of dichloropalladium (II) diacetonitrilate were dissolved
in 3 ml of dimethylformamide and treated with 0.435 g
(1.84 mmol) of trimethyl (l-ethoxy-ethen-l-yl)stannane.
The reaction was then gently warmed with a hot air gun
for about 10 seconds, and allowed to stir at room
temperature for about one hour. The reaction mixture
was poured into 100 ml 1:1 mixture of ethyl acetate/
diethyl ether and 100 ml 10:1 mixture Brine/satd.
NaHCO3 solution. Organics were separated and dried over
Na2SO4, filtered, and concentrated ln vacuo. Resultant
crude dark oil was then diluted with 2 ml CH2Cl2 and
5 ml diethyl ether and 20 ml of hexane. A dark oil
again resulted. Supernatant was decanted and to it was
added an additional 40 ml hexane. Desired precipitated
as a solid which was filtered and washed with hexane and
dried to give 87 mg of the desired compound. The dark
oil was chromatographed on 50 g of silica gel using
15-25% ethyl acetate/CH2Cl2 as eluent. The resulting
product fractions were concentrated ln vacuo and treated
with ~0 ml Et2O to provide 550 mg of the title compound
(total yield 637 mg, 74%).
~3~L~
X-7967A - 24 -
lH NMR: (300 MHz, CDC13) ~8.20 (d, J= 9Hz, 2H), 7.60 (d,
J= 9Hz, 2H), 7.35 (t, J= 8Hz, 2H), 7.10 (m, 2H~, 6.90
(d, J= 8Ez, 2H), 5.45 (dd, J= 5,7Hz, lH), 5.37 (AB, 2H),
4.58 (S, 2H), 4.21 (d, J= 3 Hz, lH), 4.18 (d, J= 3Hz,
lH), 3.95 (m, lH), 3.75 (m, 2H), 2~70 (dd, J= 4, 18Hz,
lH), 2.30 (m, lH), 2.05 (m, lH), 1.50 (m, lH) and 1.25
(t, J= 7Hz, 3H)
IR: (CHCl3) 3028, 1772, 1734, 1691, 1524, 1496, 1389,
1299, 1277, and 1207 cm 1
MS: m/e 521 (M )
Analysis Calculated for C27H27N3O8:
Calc.: C, 62.18i H, 5.22; N, 8.06;
Found: C, 62.43; H, 5.36; N, 8.30.
Preparation 4
p-Nitrobenzyl 7~-phenoxyacetylamino-1-carba(l-dethia)-
3-(2-bromo-1,1-diethoxyethyl)-3-cephem-4-carboxylate
A 570 mg sample of the material from Prepara-
tion 4 was dissolved in 4.5 ml of ethanol/2 ml of
CH2Cl2 and cooled to 0C. The solution was then treated
with 0.153 ml (1.312 mmol) of 2,6-lutidine and 1.1 ml
(1.1 mmol) of a 1.0 M Br2/CCl4 solution. The resulting
mixture was then poured into a mixture of saturated
sodium bicarbonate solution and 1:1 ethyl acetate/diethyl
ether. The organic layer was separated, dried over
2 ~ 3 i~
X-7967A - 25 -
anhydrous Na2S0~, filtered, and concentrated to provide
a yellow foam which was used directly in the next step.
A 25 mg sample of the above product was
purified over a silica gel (2.5 g) column using 7%
ethyl acetate/CH2Cl2 as eluent to provide 20 mg of the
title compound.
lH NMR (300 NHz, CDCl3) ~8.23 (d, J= 9Hz, 2H), 7.60 (d,
J= 9Hz, 2H) 7.35 (t, J= 8Hz, 2H), 7.10 (m, 2H), 6.95 (d,
J= 8Hz, 2H), 5.35 (AB, 2H) 5.32 (dd, J= 5, 7Hz, lH), 4.58
(s, 2H), 3.95 (m, lH) 3.3-3.6 (2m, 4H), 2.48 (dd, J= 2,
16Hz, lH), 2.20 (m, lH) 2.05 (m, lH) 1.45 (m, lH) 1.16
(t, J= 4Hz, 3H) and 1.10 (t, J= 4Hz, 3H)
IR: (CHCl3) 3019, 1772, 1751, 1749, 1695, 1349, 1290,
}206 and 1073 cm 1
MS: m/e 646 (M + 1)
Analysis Calculated for CpgH32N309Br:
Calc.: C, 53.88; H, 4.99; N, 6.50;
Found: C, 53.59; H, 4.75; N, 6.77.
.,
Preparation 5
p-Nitrobenzyl 7~-phenoxyacetyl-t-butyloxycarbonylamino-
l-carba(l-dethia)-3-(2-bromo-1,1-diethoxy)-3-cephem-4-
carboxylate
A 700 mg sample of the product of preparation
4 ~as dissolved in 10 ml of CH2C12 at room temperature
2 ~ 3 ~
X-7967A - 26 -
and treated with 0.256 ml (1.126 mmol) of di-tert-butyl
dicarbonate, followed by 132 mg (1.08 mmol) of 4-
dimethylaminopyridine and stirring for 30 min. An
additional 50 ~1 of di-tert-butyl dicarbonate was added
and the reaction stirred for about 30 min. The reaction
mixture was chromatographed directly over a silica gel
column (40 g) using 20-30% ethyl acetate/CH2Cl2 as eluent
to provide 730 mg (90.5%) of the title compound.
lH NMR: (300 MHz, CDCl3) ~8.23 (d, J= 9Hz, 2H), 7.62 (d,
J= 9Hz, 2H), 7.30 (t, J= 8Hz, 2H), 7.0 (m, 2H), 6.95 (d,
J= 8Hz, 2H~, 5.70 (d, J= 4Hz, lH~, 5.35 (AB, 2H), 5.18
(d, J= 3Hz, 2H), 3.86 (m, lH), 3.35-3.7 (m, 4H), 2.5 (dd,
J= 2, 18Hz, lH), 2.18 (m, lH), 1.85 (m, lH) 1.55 (s, 9H)
1.50 (m, lH) 1.16 (t, J= 4Hz, 3H) and 1.10 (t, J= 4Hz, 3H)
IR: (CHCl3) 3019, 1791, 1747, 1349, 1226, 1205, and
1145 cm~l
MS: m/e 672 (M -OC4Hg)
Analysis Calculated for C34H40N3O11Br:
Calc.: C, 54.70; H, 5.40; N, 5.63;
Found: C, 53.55; H, 4.48, N, 6.42.
2~3~9~
X-7967A - 27 -
Preparation 6
p-Nitrobenzyl 7~-t-butyloxycarbonylamino-1-carba
(l-dethia)-3-(2-bromo-1,1-diethoxyethyl-3-cephem-4-
carboxylate
A 750 mg (O.957 mmol) sample of the product
of Preparation 5 was dissolved in 8 ml of tetrahydro-
furan, treated with 0.85 ml (0.85 mmol) of 1.0 M
lithium hydroxide soln. and sonicated. A further 0.155
ml portion of lithium hydroxide was added and sonication
continued for 30 min. The reaction mixture was then
poured into 50 ml of saturated sodium bicarbonate/75 ml
ethyl acetate solution. The organic phase was separated
and dried over anhydrous Na2 S04, filtered, and concen-
trated to provide 410 mg of the product as a foam after
column chromatography over silica gel (8% ethyl acetate/
CH2Cl2 ) -
The above chromatography provided 176 mg of
starting material which was re-submitted to the above
conditions to obtain 102 mg of the title compound.
Total yield = 512 mg (86.6%).
1~ NMR: (300 MHz, CDCl3) ~8.23 (d, J= 9Hz, 2H), 7.61 (d,
J= 9Hz, 2H), 5.35 (AB, 2H), 5.01 (m, lH), 5.09 (m, lH),
3.85 (m, lH), 3.3-3.6 (m, 4H), 2.47 (dd, J= 2, 16Hz,
lH), 2.20 (m, lH), 2.10 (m, lH), 1.43 (s, 9H), 1.12 (t,
J= 4Hz, 3H), and 1.08 (t, J= 4Hz, 3H)
IR: (CHCl3) 1769, 1741, 1716, 1524, 1349, 1224, 1207,
and 1160 cm 1
~ ~ 3 ~
X-7967A - 28 -
MS: 611 (M )
Analysis Calculated for C2 6H3~N3OgBr:
Calc.: C, 50.99; H, 5.60; N, 6.86;
Found: C, 51.99; H, 5.16; N, 7.67.
Preparation 7
p-Nitrobenzyl 7~-t-butoxycarbonylamino-1-carba(l-dethia)-
3-(2-bromomethylcarbonyl)-3-cephem-4-carboxylate
A 125 mg (0.204 mmol) sample of the product
of Preparation 6 was dissolved in 1.2 ml of acetonitrile/
0.25 ml of acetic acid/0.05 ml H2O and stirred for about
2 hours. The reaction mixture was then poured into
~50 ml) saturated sodium bicarbonate solution/(100 ml)
1:1 ethyl acetate/diethyl ether solution. The organic
phase was separated, dried over anhydrous Na2SO4,
filtered, and concentrated to provide 111 mg (about
100%) of the title compound as a white solid.
1H NMR: (300 MHz, CDCl3) ~8.20 (d, J= 9Hz, 2H), 7.62 (d,
J= 9Hz, 2H), 5.33 (AB, 2H), 5.28 (dd, J= 4,7Hz, lH), 5.25
(d, J= 4Hz, lH), 4.03 (AB, 2H), 3.87 (m, lH), 2.80 (dd,
J= 4,18Hz, lH), 2.45 (m, lH), 2.13 (m, lH) 1.57 (m, lH),
and 1.4 (s, 9H)
IR: (CHCl3) 3019, 1782, 1718, 1525, 1369, 1291, and
1159 cm 1
MS: m/e 480 (M+-C4Hg)
X-7967A - 29 -
Analysis Calculated for C22H24N3O8Br:
Calc.: C, 49.08; H, 4.49; N, 7.81;
Found: C, 49.29; H, 4.64; N, 7.62.
ExamPle 1
7~-t-butoxycarbonylamino-1-carba(1-dethia)-3-(2-phenyl-
thiazolo)-3-cephem-4-carboxylic acid
A 75 mg (0.140 mmol) sample of p-nitrobenzyl
7~-t-butoxycarbonylamino-1-carba(1-dethia)-3-bromo-
methylcarbonyl)-3-cephem-4-carboxylate (Preparation 7)
was dissolved in 1.5 ml of isopropanol and 1 ml of
1,1,2-trichloroethane, followed by the addition of 20
mg (0.146 mmol) of phenylthiocarbamate. The reaction
mixture was then heated to about 65C for 1.5 hours.
The reaction mixture was concentrated ln vacuo and
treated with 3 ml of diethyl ether/4 ml hexane. The
resulting solid (85% yield) was dried to provide the
title compound.
Example 2
7,B-t-butoxycarbonylamino-l-carba(l-dethia)-3-(2-(4-NO2-
- 3-methylimidazol-2-yl)-thiazol-4-yl-3-cephem-4-carboxylic
acid
A 127 mg sample of p-nitrobenzyl 7~-t-butoxy-
carbonylamino-1-carba(1-dethia)-3-bromomethylcarbonyl-
4-carboxylic acid was reacted with 4-NO2-3-methyl
imidazolo thiocarbamate in a manner analogous to that
of Example 1. Column chromatography ethylacetate/CH2Cl2
with a trace of acetic acid provided 85 mg of the title
compound.
X-7967A - 30 -
Example 3
p-Nitrobenzyl 7~-t-butoxycarbonylamino-1-carba(l-dethia)-
3-(2-(phenyl)(2-pyridyl)methylthiazol-4-yl)-3-cephem-4-
carboxylate
The title compound was prepared in a manner
analogous to that of Example 1 (without deesterification)
utilizing phenyl-2-pyridylthiocarbamate 710 mg (97.3%)
lH NMR: (300 MHz, CDC13) ~8.60 (dd, J= 4, 9Hz, lH), 8.05
(d, J= 9Hz, 2H), 7.60 (m, 9H), 5.83 (d, J= 4Hz, lH), 5.15
(m, 3H), 4.70 (m, lH), 3.90 (m, lH), 2.92 (dd, J= 4, 18Hz,
lH), 2.50 (m, lH), 2.20 (m, lH) 1.70 (m, lH) and 1.~8
(s~ 9H)
Example 4
7~-t-butoxycarbonylamino-1-carba(l-dethia)-3-(2-
phenylthiazol-4-yl)-3-cephem-4-carboxylic acid
A 430 mg (0.746 mmol) sample of p-nitrobenzyl
7~-t-butoxycarbonylamino-1-carba(l-dethia)-3-(2-phenyl-
thiazol-4-yl)-3-cephem-4-carboxylate was dissolved in 5
ml dimethylformamide/6 ml tetrahydrofuran/4 ml acetic
acid along with 200 mg (2.98 mmol) of Zn. Upon comple-
tion, the reaction mixture was diluted with CH2Cl2 and
filtered through filter (celite) aid. The organic phase
was then washed sequentially with H2O, lN HCl, and
NaHCO3 solution. The NaHCO3 solution was layered with
CH2Cl2, acidified to a pH of 2. The CH2Cl2 layer was
separated and the aqueous portion extracted with CH2C12.
2 ~ a
X-7967A - 31 -
The combined CH2Cl2 portions were dried over anhydrous
Na2SO4, filtered, and concentrated. Crystallization
over diethyl ether/hexane provided 270 mg (82.3%) of
the title compound.
Example 5
p-Nitrobenzyl 7~-t-butoxycarbonylamino-1-carba(l-
dethia)-3-(2-aminothiazol-4-yl)-3-cephem-4-carboxylate
A 600 mg (1.115 mmol) sample of p-nitrobenzyl-
7~-t-butoxycarbonylamino-1-carba(l-dethia)-3-(bromo-
methylcarbonyl)-3-cephem-4-carboxylate was dissolved in
15 ml of isopropanol/10 ml 1,1,2-trichloroethane along
with 0.146 ~1.25 mmol) of 2,6-lutidine followed by 88.4
15 mg (1.16 mmol) of thiourea. -
Workup analogous to that described above
provided 220 mg of the title compound.
lH NMR: (300 MHz, CDCl3) 88.22 (m, 2H), 6.90 (m, lH),
6.58 (m, lH) 6.10 (s, 2H) 5.35 (m, 3H), 3.85 (m, lH),
2.85 (m, lH), 2.58 ~m, lH), 2.40 (m, lH), 1.80 (m, lH),
and 1.45 (s, 9H)
ExamPle 6
p-Nitrobenzyl 7~-t-butoxycarbonylamino-1-carba(l-
dethia)-3-(2-(2,3-dihydroxyphenyl)thiazol-4-yl)-3-
cephem-4-carboxylate
In a manner analogous to preceding examples,
3,4-dihydroxyphenylthiocarbamate was utilized to provide
the title compound (380 mg).
2~3~
X-7967A - 32 -
lH NMR: (300 ~Hz, CDCl3) ~7.90 (m, 2H), 7.40 (m, lH),
7.12 (m, 3H), 6.98 (s, lH), 6.84 (m, lH), 5.20 (m, 4H),
4.05 (m, lH), 2.84 (dd, J= 4, 18Hz, 1~) 2.35 (m, lH),
2.15 (m, lH), 1.75 (m, lH), and 1.45 (s, 9H)
Example 7
p-Nitrobenzyl 7~-t-butoxycarbonyl-l-carba(l-dethia)-3-
(2-(2,3-di-(t-butyldimethylsilyloxy)phenyl)thiazol-4-yl~-
3-cephem-4-carboxylate
A 370 mg sample of the compound produced
in Example 6 above was dissolved in 4 ml of dimethyl-
formamide and treated with 184 mg of t-butyldimethyl-
silylchloride and 85 mg of imidazole and stirred for
about 24 hours. An additional 180 mg of t-butyl-
dimethylsilyl chloride and 90 mg of imidazole were
added and the solution stirred an additional 24 hours.
The reaction mixture was then diluted with
100 ml of ethyl acetate and 100 ml of H2O. The organic
phase was separated and washed with lO0 ml of saturated
NaHCO3 solution. The organic phase was then dried over
anhydrous Na2SO4 and purified over (50 g) silica gel
using ethyl acetate as eluent. Further chromatography
over silica gel (25% ethyl acetate/hexane) provided
320 mg of p-nitrobenzyl 7~-t-butoxycarbonylamino-1-
carba(1-dethia)-3-(3,4-di(t-butyldimethylsilyloxy)-
phenylthiazol-4-yl-3-cephem-4-carboxylate.
X-7967A - 33 -
H NMR: (300 MHz, CDCl3) ~8.0 (d, J= 9Hz, 2H), 7.32
(m, 2H), 7.22 (d, J= 9Hz, 2H), 7.05 (s, lH), 6.80
(m, lH), 5.28 (AB, 2H), 5.22 (m, lH), 5.05 (m, lH~,
3.95 tm, lH), 2.95 (dd J= 4, 18Hz, lH), 2.55 (m, lH),
2.20 (m, lH), 1.70 (m, lH), 1.42 (s, 9H) 1.0 (s, 9H),
0.97 (s, 9H), 0.23 (s, 6H), and 0.20 (s, 6H)
Example 8
Allyl 7~-t-butoxycarbonylamino-1-carba(1-dethia)-3-(2-
(2,3-di-(t-butyldimethylsilyloxy)phenyl)-3-cephem-4-
carboxylate
A. Removal of p-nitrobenzyl ester
A 320 mg (0.382 mmol) sample of the title
compound from Example 7 was dissolved in 2.5 ml of
dimethylformamide/3 ml of tetrahydrofuran and 2.5 ml of
acetic acid, treated with 100 mg (1.53 mmol) of Zn dust
and stirred for 20 min. The reaction mixture was then
treated with an additional 1 ml of acetic acid and 100
mg of Zn. After lh, the reaction mixture was filtered,
diluted with ethyl acetate and washed with water. The
organic phase was then dried and concentrated in vacuo
azeotroping any remaining dimethylformamide away with
toluene (5 times) to provide the title compound as a
foam (220 mg, 82%) (some desilylation occurred)~
B. Formation of allyl ester
A 215 mg (0.306 mmol) sample of the product
from part A above is reacted with allyl bromide in
2 ~
X-7967A - 34 -
dimethylformamide in the presence of tetra-n-butyl-
ammonium hydrogen sulfate, sodium bicarbonate and
sodium iodide to provide the title compound.
Example 9
Allyl 7~-t-butoxycarbonylamino-1-carba(l-dethia)-3-
(2-phenylthiazol-4-yl)-3-cephem-4-carboxylate
A 103 mg 0.234 mmol) sample of 7~-t-butoxy-
carbonylamino-1-carba(l-dethia)-3-(2-phenylthiazol-
4-yl)-3-cephem-4-carboxylic acid, prepared according to
the foregoing examples, was dissolved in a small amount
of N,N-dimethylformamide, treated with 60 mg (0.70 mmol)
of NaHC03 and stirred for 10 min. The reaction mixture
15 was then treated with 83 mg (0.246 mmol) of tetra-n-
butylammonium hydrogen sulfate, allowed to stir for
10 min., followed by treatment with 26 ~1 (0.294 mmol)
of allyl bromide (followed by a additional 10~1) and
109 mg (0.725 mmol) of NaI. After stirring at room
temperature overnight, the reaction mixture was poured
into 30 ml of saturated NaHC03 solution and 50 ml of
ethyl acetate. The organic phase was separated and
washed (2x30 ml) with 0.5 N HCl solution, dried over
anhydrous Na2 S04, filtered and concentrated ln vacuo to
25 provide the title compound. (100 mg, 89.3%, isolated as
a solid from diethyl ether/hexane.)
lH NMR: (300 MHz, CDCl3) ~7.90 (m, 2H), 7.40 (m, 3H),
7.15 (s, lH), 5.78 (m, lH), 5.10 (m, 4H), 4.65 (ABX, 2H),
30 3.90 (m, lH), 2.95 (dd, J= 4, 18Hz, lH), 2.50 (m, lH),
2.20 (m, lH), 1.70 (m, lH) and 1.45 (s, 9H).
.
.
~ 3
X-7967A - 35 -
IR: (CHCl3) 1769, 1718, 1506, 1369, 1248, and 1161 cm 1
MS: m/e 482 (M + 1)
AnalysiS Calculated for C2sH27N3sS:
Calc.: C, 62.35; H, 5.65; N, 8.73;
Found: C, 64.23; H, 5.81; N, 8.93.
Examples 10-18
According to the general methodolo~y of
Example 9 and the preceding Examples, the followin~
compounds were prepared.
10. Allyl 7~-t-butoxycarbonylamino-l-carba-
(1-dethia)-3-[2-(5-nitrothiazol-2-yl)thiazol-4-yl]-3-
cephem-4-carboxylate
lH NNR: (300 MHz, CDCl3) ~8.55 (s, lH), 7.43 (s, lH),
5.85 (m, lH), 5.25 (m, 3H), 5.10 (m, lH), 4.75 (ABX,
2H), 4.95 (m, lH), 2.98 (dd, J= 4, 18Hz, lH), 2.55
(m, lH), 2.23 (m, lH), 1.70 (m, lH) and 1.45 (s, 9H)
IR: (CHCl3) 2976, 1772, 1719, 1390, 1351, 1251, and
1159 cm 1
MS: m/e 534 (M + 1)
Analysis Calculated for C22H23NsO7S2:
Calc.: C, 49.52; H, 4.35; N, 13.13;
Found: C, 50.90; H, 4.33; N, 13.23.
X-7967A - 36 -
11. Allyl 7~-t-butoxycarbonylamino-1-carba-
(l-dethia)-3-[2-(4-fluorophenyl)thiazol-4-yl]-3-cephem-
4-carboxylate
lH NMR: (300 MHz, C~C13) ~7.90 (m, 2H), 7.19 (s, lH),
7.12 (m, 2H), 5.8 (m, lH), 5.15 (m, 4H), 4.70 (ABX, 2H),
3.90 (m, lH), 2.95 (dd J= 4, 18Hz, lH), 2.50 (m, lH),
2.20 (m, lH), 1.70 (m, lH), and 1.45 (s, 9H)
IR: (KBr) 3019, 2977, 1770, 1719, 1393, 1336, and
1157 cm
MS: m/e 499 (M )
Analysis Calculated for C25H26N3O5SF:
Calc.: C, 60.10; H, 5.25; N, 8.41;
Found: C, 62.52; H, 5.57; N, 8.42.
12. Allyl 7~-t-butoxycarbonylamino-1-carba-
(l-dethia)-3-[2-(4-pyridyl)thiazol-4-yl]-3-cephem-
4-carboxylate
; 1H NMR: (300 MHz, CDCl3) ~8.72 ((d, J= 9Hz, 2H), 7.75
(d, J= 9Hz, 2H), 7.30 (s, lH), 5.80 (m, lH), 5.20
(m, 4H), 4.70 (ABX, 2H), 3.95 (m, lH), 3.0 (dd J= 4,
18Hz, lH), 2.58 (m, lH), 2.25 (m, lH), 2.25 (m, lH),
1.75 (m, lH), and 1.50 (s, 9H)
IR: (CHCl3) 3020, 1771, 1718, 1505, 1393, 1348, 1248,
and 1161 cm 1
~3~
X-7967A - 37 -
MS: m~e 482 (M )
A~alysis Calculated for C2~H2GN~O5S --
Calc.: C, 59.74; H, 5.43; N, 11.61;
Found: C, 58.47; H, 5.23; N, 11.25.
13. Allyl 7~-t-butoxycarbonylamino-1-carba-
(l-dethia)-3-[2-(3-methyl-4-nitroimidazol-2-yl)thiazol-
4-yl]-3-cephem-4-carboxylate
lH NMR: (300 MHz, CDCl3) ~8.10 (s, lH), 7.40 (s, lH),
5.62 (m, lH), 5.25 (m, 3H), 5.08 (d, J= 8Hz, lH), 4.70
(d, J= 6Hz, 2H), 4.48 (s, 3H), 3.95 (m, lH), 3.0 (dd
J= 4, 18Hz, lH), 2.58 (m, lH), 2.25 (m, lH), 1.75
(m, lH), and 1.48 ~s, 9H)
IR: (CHCl3) 3018, 1772, 1719, 1530, 1472, 1365, 1270,
and 1161 cm 1
MS: m/e 530 (M )
14. Allyl 7~-t-butoxycarbonylamino-1-carba-
(l-dethia)-3-[2-(1,1-(2-pyridyl)(phenyl)methyl)thiazol-
4-yl]-3-cephem-4-carboxylate
lH NMR: (300 MHz, CDCl3) ~8.60 (d, J= 4Hz, lH) 7.63 (t,
J- 9Hz, lH), 7.30 (m, 5H), 7.18 (m, 2H), 7.13 (s, lH),
7.11 (6, lH), 5.86 (s, lH), 5.85 (s, lH), 5.65 (m, lH),
5.10 (m, 4H), 4.53 (d, J= 6Hz, lH), 4.47 (d J= 6Hz, lH),
4.28 (dd, J= 5, 15Hz, lH), 4.20 (dd, J= 5, 15Hz, lH),
3.88 (m, lH), 2.90 ~m, lH), 2.45 (m, lH), and 1.45
(s, 9H)
2 ~
X-7967A - 38 -
IR: (CHCl3) 3019, 1769, 1718, 1496, 1393, 1369, 1247,and 1160 cm 1
MS: m/e 572 (M+)
Analysis Calculated for C3lH32N40sS:
Calc.: C, 65.02; H, 5.63; N, 9.78;
Found: C, 65.01; H, 5.60; N, 9.52.
15. Allyl 7~-t-butoxycarbonylamino-1-carba-
(l-dethia)-3-[2-(p-nitrophenyl)thiazol-4-yl]-3-cephem-
4-carboxylate
lH NMR: (300 MHz, CDCl3) ~8.30 (d, J= 9Hz, 2H) 8.05 (d,
15 J= 9H~, 2H) 7.30 (s, lHl, 5.80 (m, lH), 5.20 (m, 4H),
4.68 (ABX, 2H), 3.g5 (m, lH), 3.0 (dd J= 4, 18Hz, lH),
2.55 (m, lH), 2.25 (m, lH), 1.70 (m, lH), and 1.45
(s, 9H)
20 IR: (CHCl3) 3020, 1771, 1719, 1525, 1348, 1248, and
1161 cm
MS: m/e 527 (M + 1)
Analysis Calculated for C25H26N407S;
Calc.: C, 57.03; H, 4.98; N, 10.64;
Fou~d: C, 57.48; H, 4.82; N, 11.33.
16. ~llyl 7~-t-butoxycarbonylamino-1-carba-
30 (1-dethia)-3-[2-(3,4-(t-butyldimethylsilyloxy)phenyl)-
thiazol-4-yl]-3-cephem-4-carboxylate
2 ~ L `3 ~
X-7967A - 39 -
lH NMR: (300 MHz, CDCl3~ ~7.35 (m, 2H), 7.05 (s, lH),
6.85 (d, J= 9Hz, lH), 5.75 (m, lH), 5.15 (m, 4H), 4.65
(ABX, 2H), 3.90 (m, lH), 2.95 (dd J= 4, 18Hz, lH~, 2.48
(m, lH), 2.18 (m, lH), 1.70 (m, lH), 1.45 (s, 9H), 1.02
(s, 9H), 1.0 (s, 9H), 0.24 (s, 6H), and 0.21 (s, 6H)
IR: (CHCl3) 2931, 1768, 1718, 1520, 1472, 1392, 1297,
1254 and 1161 cm 1
10 MS: m/e 742 (M + 1)
Analysis Calculated for C37H55N307SSi2:
Calc.: C, 59.89; H, 7.47; N, 5.66;
Found: C, 62.22; H, 7.57; N, 5.65.
17. Allyl 7~-t-butoxycarbonylamino-1-carba-
(l-dethia)-3-[2-(2-furenyl)thiazol-4-yl]-3-cephem-4-
carboxylate
20 lH NMR: (300 MHz, CDCl3) ~7.48 (d, J= 2Hz, lH), 7.10
(s, lH), 6.95 (m, lH), 6.5 ~m, lH), 5.80 (m, lH), 5.15
(m, 4H), 4.68 (ABX, 2H), 3.90 (m, lH), 2.95 (dd J= 4,
18Hz, lH), 2.S0 (m, lH), 2.20 (m, lH), 1.70 (m, lH),
and 1.45 (s, 9H)
IR: (CHCl3) 3019, 1770, 1718, 1502, 1393, 1249, and
1160 cm
MS: m/e 472 (M+ + 1)
Analysis Calculated for C2 3H25N3O6S:
Calc.: C, 58.59; H, 5.34; N, 8.91;
Found: C, 59.83; H, 5.27; N, 8.41.
2 ~
X-7967A - 40 -
18. Allyl 7~-t-butoxycarbonylamino-1-carba-
(l-dethia)-3-[2-(3-pyridyl)thiazol-4-yl]-3-cephem-4-
carboxylate
lH NMR: (300 MHz, CDCl3) ~9.1 (d, J= 2Hz, lH), 8.65 (d,
J= 4Hz lH), 8.18 (m, lH), 7.38 (m, lH), 7.22 (s, lH), 5.80
(m, lH), 5.2 (m, 4H), 4.70 (ABX, 2H), 3.95 (m, lH), 3.0 (dd
J= 4, 18Hz, lH), 2.52 (m, lH), 2.20 (m, lH), 1.70 (m, lH),
and 1.48 (s, 9H)
IR: (CHCl3) 3025, 1771, 1717, 1602, 1246, and 1162 cm 1
MS: m/e 482 (M )
Analysis Calculated for C24H26N4O5S:
Calc.: C, 59.74; H, 5.43; N, 11.61,
Found: C, 59.90; H, 5.62; N, 11.63.
19. Allyl 7~-t-butoxycarbonylamino-1-carba-
20 (1-dethia)-3-[2-(allyloxycarbonylamino)thiazol-4-yl]-3-
cephem-4-carboxylate
In a procedure analogous to Example 9 above,
the title compound was prepared in 38% yield.
25 lH NNR: (300 MHz, CDCl3) ~8.70 (s, lH), 5.90 (m, 2H),
5.30 (m, 6H), 4.72 (d, J= 6Hz, 2H), 4.65 (d, J= 6Hz, 2H)
4.90 (m, lH), 3.85 (dd J= 4, 18Hz, lH), 2.38 (m, lH),
2.10 (m, lH), and 1.45 (æ, 9H)
30 IR: (CHCl3) 3018, 1769, 1722, 1549, 1237, and 1207 cm 1
MS: m/e 504 (M )
2 ~
X-7967A - 41 -
Analysis Calculated for C23H28N4O7S:
Calc.: C, 54.75; H, 5.59; N, ll.10;
Found: C, 54.93; H, 5.31; N, 11.94.
Coproduced in this reaction was allyl 7~-t-butoxy-
carbonylamino-l-carba(l-dethia)-3-[2-[(allyloxy-
carbonyl)(allyl)]amino]-thiazol-4-yl-3-cephem-4-
carboxylate (45%).
lH NMR: (300 MHz, CDCl3) ~6.80 (s, lH), 5.90 (m, 2H),
5.25 (m, 5H), 5.05 (d, J= 8Hz, lH), 4.78 (d, J= 6Hz, 2H),
4.65 (d, J= 6Hz, 2H), 3.87 (m, lH), 2.88 (dd J= 4, 18Hz,
lH), 2.40 (m, lH), 2.15 (m, lH), 1.65 (m, lH), and 1.45
(s, 9H)
IR: (CHCl3) 3020, 1768, 1712, 1504, 1393, 1242, and
1157 cm~l
MS: m/e 544 (M )
Analysis Calculated for C26H32N4O7S:
Calc.: C, 57.34; H, 5.92; N, 10.29;
- Found: C, 57.08; H, 5.86; N, 10.09.
It was subsequently discovered that the use
of NaH in l-molar eguivalency as base resulted in the
desired mono-allylated product.
~ ~ 3 ~
X-7967A - 42 -
Example 20
Allyl 7~-[(2-allyloxycarbonylaminothiazol-
4-yl)-Z-methoximinoacetylamino]-1-carba(l-dethia)-3-
[2-(4-fluorophenyl)thiazol-4-yl]-3-cephem-4-carboxylate
A. Deprotection
An 80 mg (O.16 mmol) sample of allyl 7~-t-
butoxycarbonylamino-l-carba(l-dethia)-3-[2-(4-fluoro-
phenyl)thiazol-4-yl]-3-cephem-4-carboxylate was dis-
solved in 1 ml of CH2C12 and 1 ml of trifluoroacetic
acid. The solution was concentrated ln vacuo to provide
a foam which was again treated with trifluroracetic
acid and concentrated out of acetonitrile. From the
resulting foam (CH2Cl2/diethyl ether/hexane) was
obtained a tan solid.
B. Acylation
In another container, a 46 mg (0.16 mmol)
sample of (2-allyloxycarbonylaminothiazol-4-yl)-Z-
methoximino acetic acid was dissovled in a small amount
of CH2Cl2 and treated with 28 mg (0.16 mmol) of 2-
chloro-4,6-dimethoxytria2ene and cooled to 0C. The
reaction mixture was then diluted with an additional
1 ml of CH2Cl2 and treated with 19 ~1 (0.168 mmol)
of N-methylmorpholine and stirred for about 40 min.
An additional 19 ~1 g N-methylmorpholine was added,
followed by addition of the product from Part A, above,
using about 2 ml of CH2Cl2 as wash. After 2 hours, the
reaction mixture was concentrated ln vacuo and purified
by column chromatography (silica gel, 30-40% ethyl
acetate/CH2Cl2) to provide 42 mg of the title compound.
2~3~
X-7967A - 43 -
lH NMR: (300 MHz, CDCl3) ~9.38 (s, lH), 7.90 (m, 2H),
7.20 (s, lH), 7.12 (m, 2H), 5.85 (m, 3H), 5.25 (m, 4H),
4.70 (m, 4H), 4.10 (m, lH), 4.05 (s, 3H), 3.05 (dd,
J= 4, 18Hz, lH), 2.60 (m, lH), 2.30 (m, lH), and 1.95
(m, lH)
Examples 21-30
~The following compounds were prepared in a
manner analogous to that used in Example 20.
21. Allyl 7~-[(2-allyloxycarbonylamino-
thiazol-4-yl)-Z-methoximinoacetylamino]-l-carba(l-
dethia)-3-[(2-phenyl)thiazol-4-yl]-3-cephem-4-
carboxylate
lH NMR: (300 MHz, CDCl3) ~9.40 (s, lH), 7.90 (m, 3H),
7.40 (m, 2H), 7.20 (s, lH), 7.10 (s, lH), 5.95 (m, lH),
5.80 (m, lH), 5.60 (m, lH), 5.20 (m, 4H), 4.70 (m, 4H),
4.10 (m, lH), 4.05 (s, 3H), 3.0 (dd J= 4, 18Hz, lH),
20 2.60 (m, lH), 2.30 (m, lH), and 1.95 (m, lH)
22. Allyl 7~-[2-(allyloxycarbonylamino-
thiazol-4-yl)-Z-methoximinoacetylamino]-l-carba(l-
dethia)-3-[(pyridyl)thiazol-4-yl]-3-cephem-4-carboxylate
lH NMR: (300 MHz, CDCl3) ~9.55 (s, lH), 9.10 (s, lH),
8.65 (d, J= 6Hz, lH) 8.20 (d, J= 9Hz, lH), 8.05 (s, lH),
7.38 (m, lH), 7.30 (s, lH), 7.10 (s, lH), 5.95 ~m, lH),
5.80 (m, lH), 5.75 (m, lH), 5.25 (m, 4H), 4.70 ~m, 4H),
30 4.10 (m, lH), 4.05 (s, 3H), 3.0 (dd J= 4, 18Hz, lH), 2.60
(m, lH), 2.30 (m, lH), and 1.95 (m, lH)
2~3~
X-7967A - 44 -
23. Allyl 7~-[2-(allyloxycarbonylamino-
thiazol-4-yl]-Z-methoximinoacetylamino]-l-carba(l-
dethia)-3-[(1-methyl-2-pyridyl)thiazol-4-yl]-3-cephem-
4-carboxylate iodide
A 58 mg sample of the title compound of
Example 22 was dissolved in 0.9 ml of N,N-dimethyl-
formamide and treated with 17~1 (0.278 mmol) of methyl-
iodide. Crystallization by addition of diethyl ether/
hexane to the reaction mixture provided 56 mg (95%
yield) of the title compound.
lH NMR: (300 MHz, CDCl3) ~9.15 (s, lH), 8.80 (d, J= 9Hz,
lH), 8.70 (d, J= 6Hz, lH), 8.10 (m, lH), 7.70 (s, lH),
7.60 (d, J= 9Hz, lH), 7.25, (s, lH), 5.95 (m, lH), 5.75
(m, lH), 5.55 (m, lH), 5.25 (m, 4H), 4.65 (m, 4H), 4.35
(s, 3H), 4.05 (m, lH), 3.95 (s, lH), 3.05 (dd J= 4,
18Hz, lH), 2.55 (m, lH), 2.10 (m, lH), and 1.85 (m, lH)
24. Allyl 7~-[2-(allyloxycarbonylamino-
thiazol-4-yl]-Z-methoximinoacetylamino]-l-carba(l-
dethia)-3-[2-[5-nitrothiazol-4-yl]thiazol-4-yl]-3-
cephem-4-carboxylate
lH NMR: (300 MHz, CDCl~) ~9.30 (s, lH), 8.55 (s, lH),
7.80 (s, lH), 7.45 (s, lH), 7.15 (s, lH), 5.90 ~m, 2H),
5.70 (m, lH), 5.30 (m, 4H), 4.70 (m, 4H), 4.10 (m, lH),
4.05 (s, 3H), 3.0 (dd J= 4, 18Hz, lH), 2.60
(m, lH), and 1.90 (m, lH)
(using p-toluenesulfonic acid H2O in place of
trifluoroacetic acid)
2~6~ ~
X-7967A - 45 -
25. Allyl 7~-[(2-triphenylmethylaminothiazol-
4-yl)-Z-triphenylmethoximinoacetylamino]-l-carba(1-dethia~-
3-[2-[4-nitro-3-methylimidazol-2-yl]thiazol-4-yl-3-cephem-
4-carboxylate
(using p-toluenesulfonic acid H2O in place of
trifluor~acetic acid)
lH NMR: (300 MHz, CDCl3) ~8.05 (s, lH), 7.25 (m, 30H),
6.62 (s, H), 6.58 (d, J= 6Hz, lH), 6.43 (s, lH), 5.85
(m, lH), 5.45 (m, lH), 5.20 (m, 2H), 4.70 (m, 2H), 4.40
(s, 3H), 4.0 (m, lH), 2.58 (dd, J= 4, 18Hz, lH), 2.35,
(m, lH), 2.10 (m, lH), and 1.45 (m, lH)
26. Allyl 7~-[(2-allyloxycarbonylamino-
thiazol-4-yl]-Z-methoximinoacetylamino]-1-carba(1-
dethia)-3-[2-[(phenyl)(2-pyridyl)methyl]thiazol-4-
yl]-3-cephem-4-carboxylate
~H NMR: (300 MHz, CDCl3) ~9.60 (s, lH), 8.60 (d, J=
4Hz, lH), 8.05 (s, lH), 7.60 (m, lH), 7.25 (m, 5H), 7.20
(m, lH), 7.12 (s, lH), 7.0, (s, lH), 5.80 (m, 3H), 5.20
(m, 4H), 4.50 (m, 4H), 4.10 (m, lH), 4.0 (s, 3H), 2.90
(m, lH), 2.50 (m, lH), 2.20 (m, lH), and 1.90 (m, lH)
2~3~
X-7967A - 46 -
27. Allyl 7~-[(2-allyloxycarbonylamino-
thiazol-4-yl-Z-methoximinoacetylamino]-l-carba(l-dethia)-
3-[2-(4-nitrophenyl)thiazol-4-yl]-3-cephem-4-carboxylate
(using p-toluenesulfonic acid-H2O instead of
trifluoroacetic acid)
lH NMR: (300 MHz, CDCl3) ~9.60 (s, lH), 8.25 (d, J= 8Hz,
2H), 8.18 (s, lH), 8.05 (d, J= 8Hz, 2H), 7.35 (s, lH),
7.05, (s, lH), 5.90 (m, 3H), 5.25 (m, 4H), 4.70 (m, 4H),
4.15 (m, lH), 4.05 (s, 3H), 3.0 (dd, J= 4, 18Hz, lH),
2.60 (m, lH), 2.30 (m, lH), and 1.95 (m, lH)
28. Allyl 7~-[(2-allyloxycarbonylamino-
thiazol-4-yl]-Z-methoximinoacetylamino]-l-carba(1-
dethia)-3-[2-allyloxycarbonylaminothiazol-4-yl]-3-
cephem-4-carboxylate
lH NMR: (300 MHz, CDCl3) ~9.60 (s, lH), 8.52 (s, lH),
8.10 (s, lH), 7.02 (s, lH), 6.80 (s, lH), 5.90 (m, 3H),
5.70 (m, lH), 5.25 (m, 6H), 4.70 (m, 6H), 4.05 (m, lH),
4.0 (s, 3H), 2.88 (dd, J= 4, 18Hz, lH), 2.43 (m, lH),
2.20 (m, lH), and 1.90 (m, lH)
29. Allyl 7~-[(2-allyloxycarbonylamino-
thiazol-4-yl]-Z-methoximinoacetylamino]-l-carba(l-
dethia)-3-[2-(3,4-(t-butyldimethylsilyl)oxy)phenyl-
thiazol-4-yl]-3-cephem-4-carboxylate
2 ~ 3 ~
X-7967A - 47 -
lH NMR: (300 MHz, CDCl3) ~9.45 (s, lH), 7.95 (s, lH),
7.35 (m, 2H), 7.12 (s, lH), 6.84 (m, lH), 5.95 (m, lH),
5.75 (m, 2H), 5.25 (m, 4H), 4.65 (m, 4H), 4.10 (m, lH),
4.02 (s, 3H), 3.0 (dd, J= 4, 18Hz, lH), 2.55 (m, lH),
2.25 (m, lH), 1.90 (m, lH), 1.0 (s, 9H), 0.97 (s, 9H),
0.23 (s, 6H), and 0.18 (s, 6H)
30. Allyl 7~-~(2-allyloxycarbonylamino-
thiazol-4-yl)-Z-methoximinoacetylamino]-l-carba(l-
10 dethia)-3-[2-(2-furyl)thiazol-4-yl]-3-cephem-4-
carboxylate
lH NMR: (300 MHz, CDCl3) ~9.55 (s, lH), 8.05 (s, lH),
7.48 (s, lH), 7.15 (s, lH), 7.05 (s, lH), 6.95 (m, lH),
15 6.52 (m, lH), 5.85 (m, 3H), 5.25 (m, 4H), 4.70 (m, 4H),
4.10 (m, lH), 4.02 (s, 3H), 3.0 (dd, J= 4, 18Hz, lH),
2.55 (m, lH), 2.25 (m, lH) and 1.95 (m, lH)
Example 31
Sodium 7~-[(2-aminothiazol-4-yl)-Z-methox-
iminoacetylamino]-l-carba(l-dethia)-3-[2-(2-phenyl)-
thiazol-4-yl]-3-cephem-4-carboxylate
A 27 mg (0.0417 mmol) sample of allyl 7~-
t(2-allyloxycarbonylaminothiazol-4-yl)-Z-methoximino-
acetylamino]-1-carba(l-dethia)-3-[2-(phenyl)thiazol-4-
yl]-3-cephem-4-carboxylate was dissolved in 1.5 ml of
CH2Cl2, treated with 0.878 mg (0.0013 mmol) of bis
triphenylphosphine Pd(II) dichloride and 6 ~1 (0.0917
mmol) of tri-n-butyltinhydride and stirred for 10 min.
~ ~ 3 ~
X-7967A - 48 -
The reaction mixture was then treated with an additional
5.0 ~l of tri-n-butyltinhydride. After 10 min., the
reaction mixture was quenched with a solution of 10 ~l
concentrated HCl in 0.5 ml of CH3CN. The resulting
mixture was treated with 10 ml of diethyl ether and
10 ml hexane and centrifuged (2X). The resulting solid
was dried under vacuum to provide 16.0 mg of the free
acid of the title compound (93% pure by HPLC) in 73.7%
yield.
A 130 mg (0.248 mmol) of the above was suspended
in about 7 ml H20 and 2 ml CH3CN. A solution of 25 mg
(0.297 mmol) of NaHC03 in 1.5 ml of H20 was prepared
and added. The resulting solution was sonicated and
passed through an HP20SS column eluting with 8% CH3CN-18%
CH3CN/H20. The desired fractions were concentrated and
the resulting title compound washed with diethylether/
hexane to provide 125 mg (99.8% pure).
1H NMR: (300 MHz, d6-DMSO) ~9.2 (d, J= 9Hz, 2H), 7.85
(m, 2H), 7.65 (s, lH), 7.40 (m, 3~), 7.15 (s, 2H), 6.70
(s, lH), 5.25 (m, lH), 3.80 (s, 3H), 3.75 (m, lH), 2.95
(dd, J= 4, 18Hz, lH), 2.35 (m, lH), 1.90 (m, lH), and 1.70
(m, lH).
IR (KBr): 3500-3100, 1733, 1648, 1591, 1557, 1539, 1405
and 1376 cm
MS: m/e 547 (M + 1)
Analysis calculated for c23Hl9N6oss2Na:
Calc.: C, 50.54; H, 3.50; N, 15.38;
Found: C, 50.33; H, 3.76; N, 15.17.
2~3 r~ 1 ~ 3~
X-7967A - 49 -
Examples 32-38
Examples 32-38 were prepared by methodology
analogous to that of Example 31.
32. Sodium 7~-~(2-aminothiazol-4-yl)-Z-
methoximinoacetylamino]-l-carba(l-dethia)-3-[2-(2-
furyl)thiazol-4-yl]-3-cephem-4-carboxylate
lH NMR: (300 MHz, d6-DMSO) ~9.25 (d, J= 9Hz, lH), 7.80
(s, lH), 7.65 (s, lH), 7.20 (s, 2H), 6.95 (m, lH), 6.70
(s, lH), 6.60 (m, lH), 5.25 (m, lH),3.80 (s, 3H), 3.75
(m, lH), 3.85, (dd, J= 4, 18Hz, lH), 2.32 (m, lE), 1.85
(m, lH) and 1.65 (m, lH)
IR (KBr): 3500-3200, 1744, 1647, 1595, 1538, 1404, 1383
and 1035 cm
MS: m/e 537 (M + 1)
Analysis calculated for C2lHl7N6O6S2Na:
Calc.: C, 47.01; H, 3.19; N, 15.66;
Found: C, 41.14; H, 2.95; N, 11.02.
.-- Residue: 12.74%
33. 7~-[(2-Aminothiazol-4-yl)-Z-hydroxy-
iminoacetylamino]-l-carba(l-dethia)-3-[2-(4-nitro-3-
methylimidazol-2-yl)thiazol-4-yl]-3-cephem-4-carboxylic
acid
2~3~
X-7967A - 50 -
H NMR: (300 MHz, d6-DMSO) ~9.15 (d, J= 9Hz, lH), 8.15
(s, lH), 7.88 (s, lH), 7.08 (s, 2H), 6.65 (s,lH), 5.40
(m, lH), 4.30 (s, 3H), 3.80 (m, lH), 3.90 (dd, J= 4, 18Hz,
lH), 2.38 (m, lH), 1.95 (m, lH) and 1.7~ (m, lH)
IR (KBr): 3500-3100, 1754, 1617, 1528, 1397, 1365,
1339, 1268 and 1209 cm 1
MS: m/e 560 (M + 1)
Analysis calculated for C2 oH17Ns7 S2
Calc.: C, 42.93; H, 3.06; N, 22.53;
Found: C, 42.47; H, 3.38; N, 20.77.
34. 7~-[(2-aminothiazol-4-yl)-Z-methox-
iminoacetylamino]-l-carba(1-dethia)-3-[2-(1-methyl-
3-pyridyl)thiazol-4-yl]-3-cephem-4-carboxylic acid
1H NMR: (300 MHz, D2O) ~9.30 ~s, lH), 8.90 (d, J= 8Hz,
lH), 8.78, (d, J= 6Hz, lH), 8.10 (m, lH), 7.65 ~s, lH),
6.95 (s, lH), 5.50, (d, J= 6Hz, lH), 4.45 (s, 3H), 4.10
(m, lH), 4.0 (s, 3H), 3.95, (m, lH), 2.58 (m, lH), 2.20
(m, lH), and 1.80 (m, lH)
IR (KBr): 3200, 1758, 1674, 1532, 1384, 1203, and
1168 cm~1
MS: m/e 540 (M + 1)
X-7967A - 51 -
35. Sodium 7~-[(2-aminothiazol-4-yl)-Z-
methoximinoacetylamino~-1-carba(1-dethia)-3-[2-(4-nitro-
phenyl)thiazol-4-yl]-3-cephem-4-carboxylate
lH NMR: (300 MHz, d6-DMSO) ~9.25 (d, J= 9Hz, lH), 8.25
(d, J= 9Hz, 2H), 8.15 (d, J= 9Hz, 2H), 7.85 (s, lH), 7.15
(s, 2H), 6.72 (s, lH), 5.25 (m, lH), 3.80 (s, 3H), 3.75
(m, lH), 2.95 (dd, J= 4, 18Hz, lH), 2.40 (m, lH), 1.90
(m, lH), and 1.70 (m, lH)
IR (KBr): 3400-3200, 1733, 1649, 1594, 1523, 1402,
1345, 1050 and 851 cm 1
MS: m/e 592 (M + 1)
Analysis calculated for C23H18N7O7S2Na:
Calc.: C, 46.70; H, 3.07; H, 16.57;
Found: C, 46.06; H, 3.05; N, 15.75.
Residue: 5.84%
36. 7~-[(2-aminothiazol-4-yl)-4-methox-
iminoacetylamino]-l-carba(l-dethia)-3-[2-(5-nitro-
thiazol-2-yl)thiazol-4-yl]-3-cephem-4-carboxylic acid
25 lH NMR: (300 MHz, d6-DMSO) ~9.35 (d, J= 9Hz, lH), 8.90
(s, lH), 8.02 (s, lH), 7.40 (s, 2H), 6.78 (s, lH), 5.45
(m, lH), 3.90 (m, lH), 3.80 (s, 3H), 2.95 (dd, J= 4,
18Hz, lH), 2.40 (m, lH), 2.0 (m, lH), and 1.70 (m, lH)
30 IR (KBr): 3419, 1764, 1629, 1524, and 1350 cm 1
MS: m/e 532 (M - C2 )
~ ~ ,C~
X-7967A - 52 -
Analysis calculated for C20Hl6N8O7S3:
Calc.: C, 41.66; H, 2.80; N, 19.43;
Found: C, 41.38; H, 2.90; N, 17.16.
S 37. 7~-[(2-aminothiazol-4-yl)-Z-methoximino-
acetylamino]-l-carba(l-dethia)-3-[2-(4-fluorophenyl)-
thiazol-4-yl]-3-cephem-4-carboxylic acid
lH NMR: (300 MHz, d6-DNSO~ ~9.45 (d, J~ 9Hz, lH), 7.95
(m, 2H), 7.65 (s, lH), 7.35 (m, 2H), 6.83 (s, lH), 5.50
(m, lH), 3.95 (m, lH), 3.90 (s, 3H), 2.95 (m, lH), 2.40
(m, lH), 2.0 (m, lH), and 1.75 (m, lH)
IR (KBr): 3400-3000, 1762, 1673, 1631, 1517, 1389,
1234, and 1046 cm 1
MS: m/e 543 (M + 1)
Analysis calculated for C23H1gN6O5S2F:
Calc.: C, 50.92; H, 3.53; N, 15.49;
Found: C, 48.53; H, 3.66; N, 13.87.
38. 7~-[(2-aminothiazol-4-yl)-Z-methox-
iminoacetylamino]-l-carba(1-dethia)-3-[2-(phenyl)(2-
pyridyl)methyl)thiazol-4-yl]-3-cephem-4-carboxylic acid
H NMR: (300 MHz, d6-DMSO) ~9.28 (d, J= 9Hz, lH), 8.50
(d, J= 4Hæ, lH), 7.70 (m, lH), 7.50 (s, lH), 7.45 (m, lH),
7.25 (m, 8H), 6.72 (s, lH), 5.90 (s, lH), 5.40 (m, lH),
3.80 (s, 3~), 2.85 (dd, J= 4, 18Hz, lH), 2.30 (m, lH),
1.90 (m, lH), and 1.65 (m, lH)
`' ,c~ q~
X-7967A - 53 -
IR (KBr): 3400-3000, 1758, 1671, 1619, 1589, 1532,
and 1379 cm 1
MS: m/e 616 (M + 1)
Analysis calculated for C29H25N705S2:
Calc.: C, 56.57; H, 4.09; H, 15.93;
Found: C, 55.11; H, 4.09; N, 15.30.
Example 39
Sodium 7~-[(2-aminothiazol-4-yl)-Z-methox-
iminoacetylamino]-l-carba(l-dethia)-3-(2-aminothiazol-
4-yl)-3-cephem-4-carboxylate
1H NMR: (300 MHz, d6-DMS0) 89.20 (d, J= 9Hz, lH), 7.15
(s, 2H~, 6.70 (s, lH), 6.60 (s, 2H), 6.55 (s, lH), 5.20
(m, lH), 3.78 (s, 3H), 3.62 (s, lH), 2.64 (dd J= 4, 18Hz,
lH), 2.15 (m, lH), 1.75 (m, lH) and 1.60 (m, lH)
IR (KBr): 3500-3100, 1744, 1661, 1607, 1591, 1527,
1382, 1350, and 1034 cm 1
. MS: m/e 485 (M )
Analysis calculated for C17H~6N705S2Na:
Calc.: C, 42.06; H, 3.32; N, 20.20;
Found: C, 42.38; H, 3.33; N, 18.59.
- 2~3~
X-7967A - 54 -
Exam~le 40
Sodium 7~-~(2-aminothiazol-4-yl)-Z-methox-
iminoacetylamino]-l-carba(l-dethia)-3-[2-(3,4-dihydroxy-
phenyl)thiazol-4-yl]-3-cephem-4-carboxylate
1H NMR: (300 MHz, d6-DMSO) ~9.50 (s, lH), 9.25 (d, J= 9Hz,
lH), 7.48 (m, lH), 7.28 (m, lH), 7.15 (m, 3H), 6.75 (d,
J= 8Hz, lH), 6.70 (s, lH), 5.25 (m, lH), 3.80 (s, 3H), 3.72
(m, lH), 2.90, (dd, J= 4, 18 Hz, lH), 2.35 (m, lH), 1.88
(m, lH), and 1.65 (m, lH)
IR (KBr): 3341, 3226, 2223, 1648, 1628, 1600, 1587,
1365, 1253, and 1159 cm 1
+
15 MS: m/e 579 (M + 1)
Analysis calculated for C23H1gN6O7S2Na:
Calc.: C, 47.75; H, 3.31; N, 14.55;
Found: C, 42.41; H, 3.24; N, 12.35.
Residue: 7.69%
Exam~le 41
7~-(D-phenylglycylamino)-l-carba(l-dethia)-
25 3-(2-aminothiazol-4-yl)-3-cephem-4-carboxylic acid
H NMR: (300 MHz, D20) 87.60 (m, 5H), 6.60 (s, lH), 5.50
~(d, J= 4Hz, lH), 5.22 (s, lH), 4.0 (m, lH), 2.70 (dd,
J= 4, 18Hz, lH), 2.35 (m, lH), 1.78 (m, lH) and 1.35
(m, lH)
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