Note: Descriptions are shown in the official language in which they were submitted.
5~
This invention relates to intermediates and their
preparations. More particularly, it is concerned with intenmed-
iates for new cephem ccmpounds.
This application is a division oE Canadian Patent
Application Serial No. 331,128 f.iled July 4, 1979.
More esp~cially the new cephem ccn~ounds are 7-
su~stituted-3-cephem~4 carboxylic acid and phar~ceutically
acceptable salt thereof~ which hAve antimicrobial ac-tivitiec"
intermediate for preparing the same and processes for and can be
used prophylactically and therapeutically for treatment of
infectious dlseases in`human ~eing and animals.
Accordingly, the intermediates of this invention
provide:
new 7-subst.ituted-3-cephem-4-carbQxylic aci.d and
p~ maceutically accept~ble salt thereo.E, wh:ich exhibit ~xcc~:llent
antimicrobial activities against a w.ide variet~ oE pathocJenic
microorganisms includ mg Gram negative and Gram positive bacter;ia.
In accorclance with one aspect of -the invention th~re
is provided a compound oE ~le ~ormula (I~)
Rl ~ ~ -C00~
S ' (IA)
OR
wherein R is amino or protected amino and R is lower c~lky~, or
a salt thereof.
In accordance with another aspect of the invention there
is provided a process for preparing a ccmpound of formula (IA), as
defIned above, cc~mprises subjectLng a cc~n?ound of the formula:
CoCOSR7
Rl~N~
., ~
.. ~
la
wherein R a is a protected amino ancl R7 is lower alkyl, to
hydrolysis c~ld fur~her reacting the res~ting c~po~l with a
compour~l of the formLla:
R2-ONH2
~herein R2 is as def~ned above or a salt-~lereof; or subjecting
a compo~ld of the .formula:
Rla~ ~ N
oR2
where~n R2 is as defined a~ove and Rla is a protected amino, or
a salt thereof, to elimlnati~n reaction oE the protective group
of anLilo.
m e intermediates of the inYention are useful for
preparation of pharmaceutically active 7-su~sti-tu-tecl-3-cephem-4-
carboxylic acids or pharmaceutically acceptable salts thereof.
~ e 7-~substituted-3~cephel~-4-ccu-lx~Yylic acids are novel
and can be represented by the following general formula (I).
C-cON~ 4 ~)
o OR - R
~erein R is a~ino or a protectecl c ~ no,
R is lower aLkyl,
R3 is hydrogen or lc~wer aIkyl,
R4 is hydrogen, acyloxy(lc~wer)aLkyl,
acylthio(lower)alkyl or ca heterocyclicthio-
(lower)alkyl which may be substituted wlth
suitable ~ bstituent(s) and
R is cclrbQxy or a protected carboxy.
The 7-substitutecl-3-cephe~4-carboxylic acids(I) can
be prepcared by the follc~wing processes.
~2~
- j -
Process_
H~ ~ S R3 + R~ C-CO~
~ N ~ R ~s-N 11
R5 ~ 2
OR
~II) (III)
or its reactive derivative or its reactiYe deri~a-
at the amino group or a tive at the carboxy
la salt ~hereof group or a sait thereof
R ~ ~ C-CONH ~ S ~ R3
g~2
(I~
or a salt thereo~
Process 2
1 N - 3 Elimination of the
R ~ C-C~NH~ rS ~_ R pro.ective glOUp
s~N N ~ N ~ R4 f carboxy
~R2 R5a
~Ia3
or a salt thereof
Rl ~- C - CONEl~
3~ 5 2 COOH
OR
(Ib!
OT a sal. thereoT
Proc~ss 3
S N O ~ N ~ A-R4
OR R5
~Ic~ ~IV)
or a salt thereof or its reactive derivative
at the mer~apto grUF
N O ~ ~ A-S-R4b
~R2 R
~Id)
or a sal~ thereof
Process 4
-
3 Elimination of the
C-CON~ s R protective group of
S~ ~ R4~ amino
oR2 R
(Ie)
or a salt thereof
R ~'s~ C-CONH ~ -
~ 2 Ri
(I,~
or a sal~ ~hereof
-- 5
wherein R , R , R , R4 and R are each as defined above;
R is a protected carboxy;
R4a is a group whlch can be substituted by a
o p R4b S ~herei R4b i -c 1 or a
heterocyclic group which m~y be sub~-tituted
with suit~le substituent(s);
A is lower alkylene;
~ ~ is as defined above;
R is a heterocyclicthio(lower)alXyl substituted
~ith protected a~no(lower)alkyl or protected amino; and
R4d is a heterocyclicthio(lower)alkyl substituted
with amino(lc~r)alkyl or amino.
Among the starting compo~ds are the novel intermediates
of this .invention .ulcluding the compounds ~III), which c~l be
prepared by the following preF~arations:
IIltroduction
. (i~ halogena~lon 6 of the protective
N-H Cli) MSCN VI ~ COOR group o~ amino
H2N-C-COOR6 ~ ~2N~S~
~ V) ~ V~
o~ a salt the~eo
R7 - SC;12S - ~7
~S~ ~ ~ \ ~OCH
{~)
~VIII)
~X~
Acid and/or 1 N ~ COCOS~
acid anhydride > R ay ~ Hydrolysis
~43 (XI) (5)
2 Elimination
R -OlYH~ of the p~otective
XI I ] group of amino
t_~ ~ z
\ OR
X: I ) 2 ~ I I I a)
\or a salt. thereo~
~- .
-~C - COOH
--~ H2N~/ s~N N
) 2
~IIIb)
2 5 T
'
âû
elein R- is ~ de~ ed above~
R6 is a protective g~oup of carbox~,
l~I is an al~cal~ metal,
1 ~7S~f~
-- 7 --
la .
R lS a protectecl amlno and
R is a lower aIkyl.
In ccxnpounds (I) and the intermediates (IA) ~.e.(III),
in the scheme the partial struct~e represeIIte~ ~y the forn~lla:
- C - C O
N
O - ~
is to ~e understoocl to include both of the gecxnetrical structures
represented ~y the fonmNla:
- C - CO - C - CO -
N _ O _ ~2 and R2 N
~A) tA')
Ih this spec:ification, with re~ard to all the compound~ h~vinc3
the above m~n-tiQned partial structure, the c~ ~ounds hav~lg -the
gecme~rical structure shawn by the form~la (A) are referred to
as `'syn isomPr" and the cQmpounds having the alternative one
shown by the fonnula ~Al) as "anti iscxmer".
~ egardLng the o~jec~t compound of the formula (I) and
the starting ccxn?ound of the formula (III) as mentioned
above, is is also to be understood that said object and
starting cc~pounds may incl~de tautc~ric isaners relating -to
t~eir thiadiazolyl group. That is, in case that the group
represented by the formula:
Rl ~ ~ (whe~ei~ Rl is amino OT a pro~ectcd amino) in
foT~ula of said object and s-arting compounds Lake the
~cr~ul~
Rl S' (B) (wherein Rl ~s as de~ined above),
~T ~
sald group of .he formula: Rl,~S~N Y
alte~na~ively ~epresented by its tautomeTic formula:
~ ~7S ~
g .
~ YS~ ~B') ~wherein Rl is imino or a pro~ected
imino). That is, both of the said group ~B) and ~B')
may be in ~he sta~e of e~uilibrium as so-called tau~o-
S me~ic orms which can be represented by the following
equilibrium:
R S ~ ~ S ~N
(B) (B )
~wherein Rl and Rl are each as defined above).
In the present specification ir3clucling claims
and e~amples, the object and starting compounds having
said group are represented by using one of ~h~
expressions ~herefor~ namely the ormula:
'~ N ~- "
,4 N only ~or the convenient sake.
~,1 S'
(~)
~0 Suita~le pharmaceu~ically acceptable salts o
the object compound (I) are con~entional non-toxic
salts and may include an inorganic salt, for example,
a metal salt such as an alkali me~al salt (e g.,
sodium salt, potassium salt, etc.) and an alkaline earth
metal salt (e.g., calcium sal~, magnesium salt, etc~
ammonium salt etc.;
an organic ~alt, for example~ an organic amine salt
~e.g., trimethylamine sal~, triethyla~ine salt, pyridine
salt, procaine salt, picoline salt, dicyclohexylamine
salt, ~ dibenzylethyl ne-diamine salt, N-methylglu-
camine salt J diethanolamine salt, trieth~nola~ine salt,
tris~hydroxymethylamino)meth~ne s21t, phenylethyl-
benzylamine salt, ~iben~ylethyle~ed~2~i~s s21~ ~ etc.
etc.:
an organic carboxylic or sulfonic acid salt (e.g.
4;~
ace~ate, maleate, tartrate~ methanesulfona~e, oen_ene-
sulfonate, toluenesulfonate, etc.); an inorganic acid
sal~ ~e.g., hydrocnloride, hydrobromide, sulfate,
phosphate, etc.);
5 a sal~ with a basic or acidic amino acid (e ~., arginine,
aspartic acid, glutamic acid, lysine, etc.) and ~he like.
In ~he above and subsequent descriptions o the
pres~nt specification, sui~able examples c~d
illustration of the vaTious d~finitions which the present
~ inventio~ intends to include within the scope thereof
a~e explained in detall as follows.
~ he ~erm "lower" is used to intend a group ha~ing
1 to 6 carbon atom(s), unless othsrwise provided.
Suitable protected amino may include an acylamino
and amino gTOUp subs~ituted by a conventional
prop~ective group other ~han the acyl group, such aLs
ar~low~alky:l~e.g" benzy~, trityl, etc,) ar~lower)-
alkylidene~e,g,, ben~y}idene, etc.), lower alkylidene
substituted with lower alkoxycarbonyl or di~lower~-
alkylamino~e.g., 1-ethoxycarbonyl-2-propylidene,
dimethylaminomethylene, etc.), p}io~phono or the like,,
Suitable protected imino may include an acylimino
and imino group substituted by a conventional
protective group other than the acyl group such as
aforesaid ar(lower)alkyl or the like.
Suitable ac~l and acyl moiety in the terms
"acylamino","acylimino", r'acyloxy~lower)al~yl" and
"acylthio(lowe~)alkyl" may include carbamoyl J aliphatic
acyl group and acyl group containing an aroma~ic or
aO heterocyclic ring. And, suitable examples of the
said acyl may be lower alkanoyl (e.g., formyl, acetyl,
p~opionyl, butyrJl, isobuty-yl, valeryl, isovaleryl,
oxalyl, succinyl, pivaloyl, etc.), preferably one
having 1 to 4 CarDon a~om~s), more preferably one
;5 having 1 tO ~ carbQn atom~s);
- 10 -
lower alkoxycarbonyl having 2 to 7 carbon ato~s (e.g., methoxy-
carbonyl, ethoxycarbonyl, propoxycarbonyl, l-cycloproplethoxy-
carbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl,
pentyloxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl, etc.),
preferably one hdving 3 to 6 carbon atoms; lower alkanesulfonyl
(e.g., mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl,
butanesulfonyl, etc.): arenesulfonyl (e.g., benezenesulfonyl,
tosyl, etc.); aroyl (e.g., benzoyl, toluoyl~ naphthoyl, phthal-
oyl, indancarbonyl, etc.); ar(lower) alkanoyl (e.g., phenylacetyl,
phenylpropionyl, etc.); ar(lower) alkoxycarbonyl (e.g., benzyloxy-
carbonyl, phenethyloxycarbonyl, etc); and the like.
The acyl and acyl moiety as stated above may have 1 to ~ ~,
suitable substituent(s) such as halogen (e.g., chlorirle, brumine,
iodine or fluorine), hydroxy, cyano, ni-tro, lower alkcxy (e.g.,
methoxy, ethoxy, propoxy, isopropoxy, etc.), lower alkyl (e.g.,
methyl, ethyl,propyl, isopropyl, butyl, etc.), lower alkenyl
(e.g., vinyl, allyl, etc.), aryl (e.g., phenyl, tolyl, etc.),
or the like.
Suitable lower alkyl and lower alkyl moiety in the terms
"acyloxy(lower)alkyl", "acylthio(lower)alkyl" and "heterocyclic-
thio(lower)alkyl" may include one having 1 to 6 carbon atom(s),
such as methyl, ethyl, propyl, isopropvl, butyl, isobutyl, tert-
butyl, pentyl, tert-pentyl, hexyl or the like, preferably one
having 1 to 3 carbon atom(s).
Suitable protected carboxy may include esterified
carboxy in which said ester may be the ones such as lower alkyl
ester (e.g., methyl ester, ethyl ester, propyl ester, isopropyl
ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester,
. .
5~
- 11 -
t-pentyl ester, hexyl ester, l-cyclopropylethyl ester, etc.),
wherein lower alkyl moiety may be preferably one having 1 to 4
carbon atom(s); lower alkenyl ester (e.g., vinyl ester, allyl ester,
etc.); lower alkynyl ester (e.g., ethynyl ester, propynyl ester,
etc.); mono(or di or tri)-halo(lower)alkyl ester (e.g., 2-
iodoethyl ester, 2,2,2-trichloroethy'l ester, etc.); lower alkanoy-
loxy(lower)alkyl ester (e.g., acetoxymethyl ester, propionyl-
oxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester,
pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl
ester, 2-propionyloxyethyl ester, etc.); lower alkaneslllfonyl-
(lower)alkyl ester (e.g., mesy'lmethyl ester, 2-rnesylethyl ester,
etc.); ar(lower) alkyl ester, for example, phenyl(lower)a'lkyl
ester which may be substitu-ted with one or more suitable sub-
stituent(s) (e.g., benzyl ester, 4-me-thoxybenzy'l ester, 4-nitro-
benzyl ester, phenethyl ester, trityl ester, diphenylmethyl ester,bis(methoxyphenyl)methyl ester, 3,4-~dimethoxybenzyl ester,
4-hydroxy-3,5-ditertiarybutylbenzyl ester9 etc.); aryl es-ter
which may have one or more suitable substituent(s) (e.g., phenyl
ester, tolyl ester, tertiarybutylphenyl ester, xylyl ester, mesityl
ester, cumenyl ester,etc.), and the like.
Preferable example of protected carboxy may be lower alk-
oxycarbonyl ~e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
butoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, hexyloxycar-
bonyl, etc.) having 2 to 7 carbon atoms, preferably one having 2 to
5 carbon atoms and phenyl(lower)alkoxycarbonyl which ~ay be sub-
stituted with nitro (e.g., 4-nitrobenzyloxycarbonyl, benzyloxycarbonyl,
4-nitrophenethyloxycarbonyl, etc.)~
.ca'
7 ~ 3
- 12 -
Suitable heterocyclic group and heterocyclic moiety
in the term "a heterocyclicthio(lower)alkyl" means saturated or
unsaturated, monocyclic or polycyclic heterocycli~ group contain-
ing at least one hetero-atom such as an oxygen, sulfur, nitro~en atom
and -the like. And, especially preferably heterocyclic group may be
heterocyclic group such as unsaturated 3 to 8-membered hetero-
monocyclic group containing 1 to 4 nitrogen atom(s), for example,
pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, and its N-
oxide, pyrimidyl, pyrazinyl, pyradazinyl, triazolyl (e.g., 4H-l,
2,4-triazolyl, lH-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), te-tra-
zolyl (e.g~, lH-tetrazolyl, 2H-tetrazolyl, etc.), etc.; saturated
3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen
atom(s), for example, pyrrolidinyl, imidazolidinvl~ piperidino,
piperazinyl, etc.; unsaturated condensed heterocyclic group con-
taining 1 to 5 nitrogen atom(s), for example, indolyl, isoindolyl,
indolizynyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, ben-
zotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl, dihydrotria-
zolopyridazinyl, etc.; unsaturated 3- to 8-membered heteromono-
cyc~ic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen
atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl, (e.g., 1,2,
4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc.;
saturated 3 to 8-membered heteromonocyclic group containing 1 to 2
oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morbholinyl,
etc., unsaturated condensed heterocyclic group containing 1 to 2 oxy-
gen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl,
benzoxadiazolyl, etc.; unsaturated 3 to 8-membered heteromonocyclic
group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s),
-$ ~ `
., .~ . ..
- 13 -
for example, thia~olyl, thiazolinyl, thiadiazolyl (e.g., 1,2,4-
thiadiazolyl~ 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.),etc.;
sa-turated 3 to 8-melnbered heteromonocyclic group containing 1 to 2
sulFur atom(s) and 1 to 3 nitrogen atom(s), -for example, tlliazoli-
dinyl, etc.i unsaturatecl 3 to 8-membered heteromonocyclic group
containing a sulfur atom, for example, thienyl, etc.; unsa-turated
condensed heterocyclic group containing 1 to 2 sulfur atom(s) and
1 to 3 nitrogen atom(s), for example, benzothiazolyl~ benzothiadia-
zolyl, etc., and the like; wherein said heterocyclic group may be
substituted with one or two suitable substitllent(s) such as lower
alkyl(e.g., methyl, ethyl, propyl, isopropyl, butyl, isot)utyl, pentyl,
hexyll etc.), pre-ferably one having 1 to 3 carbon atom(s); lower
alkythio (e.g.~ me-thylthio, ethylthio, propylthio, etc.); lower
alkenyl (e.g., vinyl, allyl, butenyl, etc.), preFerably one h~ving
2 to 3 carbon atoms; lower alkenylthio (e.g., vinylthio, allylthio,
butenylthio, etc.~, preferably one having 2 to 3 carbon atoms; aryl
(e.g., phenyl, tolyl, etc.); halogen (e.g., chlorine, bromine,
iodine or fluorine); amino; di(lower)alkylamino(lower)alkyl (e.g.,
dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, di-
ethylaminopropyl, diethylaminobutyl, etc.), carboxy(lower)alkyl (e.g.,carboxymethyl, carboxyethyl, carboxypropyl, etc.), preferably one
having 2 to 4 carbon atoms; esterified carboxy(lo~er)alkyl wherein
the esterified carboxy moiety is exemplified above, a~ino(lower~
alkyl (e.g., aminornethyl, aminoethyl, aminopropyl, l-aminomethyl-
ethyl, aminobutyl, etc.), preferably one having 1 to 3 carbon atom(s).
- 14 -
.
pro ~ec~ed amino ~lo~ er) al~cyl wherei!l ~he pro ~ec~ed
amino and lo~er alkyl moieties are each as e~cemplified
above, preferably lo~er alko:~cycarbonylamino(lower)-
alkyl ~e, g ., methoxycarbonylaminomethyl, ethoxycarbony:l -
S aminomethyl ~ t-butoxyearbonylaminomethyl, t-buto~-
carbonylaminoethyl, t-buto~ycarbonylaminopropyl~
buto~ycarbo~ylaminomethylethyl9 etc~), more pr~erably
one ha~ing ~ to 9 carbon atom~
or lower alkanoylamino (lower) al~;yl ~e . g ., acetyl-
aminomethyl 3 acetylaminoethyl, acetylaminopropyl) 1- -
acetylaminomethylethyl, etc.~ more pre~erably one having
2 to 5 carbon a-tcms; carbo~y;
esteriied carboxy as exempli~ied above, pre~er~bly
lower alkoxycarbonyl, more prefarably one havlng 2 to ~ -
1~ c~bon atoms; lower alkoxy~lo~er)alkyl ~e.g.,
methoxymethyl, methoxyethyl, methaxyp ropy1 J e ~ho~ymethyl,
ethoxyethyl, e~ . preferably one having 2 to 5 carbon atoms
hydroxy~lower)alkyl~e.g., hydroxy-
methyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, etc.),
prefe~bly one having 1 to 3 carbon atom(s); -
lower alkylthio~lower~alkyl ~e.g., methylthiomethyl,
methylthioethyl, methylthiopropyl, ethylthiomethyl,
etc,),`preferably one having 2 to 3 carbon atoms
sulfo~lower)alkyl (e,g,, sulfomethyl, sulfoet:hyl~
sulfopropyl, sulfobutyl, etc.~, prefarably one having 1
to ~ carbon atom(s); acyl~lower)alkyl w~erein
the acyl and lower alkyl moieties are each as
exemplified above, preferably lower alkanesulfonyl-
~lower)al~yl ~e.g., mesylmethyl; mesyiethyl, ethane-
sulfonylmethyl, etc.),more pre~erab~ one ha~ing 2 to
3 c2rbon a~o~s; acylamino~lower)al~yl wherein
the acyl ~nd lower al~yl moie~ies a.e e~c~
exe~oli~ied above, pre~erably lower al~anesul_cnyl-
~m~o~lower)al~yl ~e,g., mesylaminomethylJ mesyl-
a5 ami~oethyl, mesylaminopropyl, e~hanesul~cnyla~ino-
S~'~3
- 15 -
methyl, etc.), more pr~aferably 0~2 ~a~ng 2 to ~ carbon
atom~; carbo;cy(lower)alkylthio ~e.g., carboxy-
methylthio, c~rbo~yethylthio, etc.), preferably one
having 2 to 3 carbon a-,oms; 020; halotlower~ l (e.g. ~
chloromethylt c}~oroeth~l~ diohloroethyl, trl chloroeth~l,
trif~uoro~ethgl, trich:Loromethyl, tri~ oroethyl, ~tc. ),
preferabl~ triha~otlower)alk~l~ more pre~erably one
havlng 1 to 2 carbon atom(s~; ~ower aI~,rlami~o (e.g.,
methylamino~ ethylamino, propylamino, ilsopropylamino,
etc~, pre~erab-y one having 1 to 2 carbon atom(s);
protected amino as exempli~ied above; or the like O
Suitable lower alkylene may include straight or
branched bivalen~ aliphatic hydrocarbon residue having
1 to 6 carbon atom~s), such as methylene, ethylenev
methylethylene, propylene, tri~athylene, 2-methyltri-
methyle~e or the like~ and preferably one having 1 to
4 carbon a~om(s)~ mo~e pre~erably one having 1 ~o 2
carbon ~tom(s) and the most pre~erably one having 1
carban atom~
Suitable protected amino(lower)alkyl, protected am~o
and amino(lower)al~yl being the substituent of a he~erocyclic-
thio(lower)a~nJl ~or R4c and R4d ~an be each referred to the
ones as e~emplified above~ ~
Suitable protective g~oup of carboxy may be
referred to the ones exemplified as aforementioned
ester moiety in the esterified carboxy group. Preferable
example of protective group of carboxy may be lower alkyl
2S mentioned above.
Suitable alkali metal may include sodium, potassium,
3~ lithium, etc.
Preferred èmbodiments of the objecL com?o~nd ~I)
are as follows.
PreIerred embodiment of Rl is amino, acylamino ~more
preferably lower alXanoylamino)1 di~lower)alkylamino-
3i ~lower)alkylidene~mino or ~hos~honoamino;
- 16 -
R2 is lower alkyl; R is hydrogen or lower alkyl; R4 is hydrogen;
acyloxy(lower)alkyl [ nlore pre-ferably lower alkanoyloxy(lower)
alkyl or carbamoyloxy(lower)alkyl, most preferably lower alkan-
oyloxymethyl or carbamoyloxyrnethyl~; acylthio(lower)aIkyl [more
preferably lower alkanoylthio(lower)alkyl, mos-t preferdbly lower
alkanoylthiomethyl]; tetrazolylthio(lower) alkyI (more preferably
tetrazolythiomethyl) substituted with lower alkyl, lower alkenyl,
lower alkoxy(lower)alkyl, lower alkylthio(lower)alkyl, hydroxy-
(lower)alkyl, amino(lower)alkyl, lower alkoxycarbonylamino(lower)-
alkyl, lower alkanoylamino(lower)alkyl, di(lower)alkylamino(lower)-
alkyl, sulfo(lower)alkyl or carboxy(lower)alkyl; -thiadiazolythio-
(lower)alkyl (more preFerably thiadiazolylth-iomethyl) which iIIay be
substituted with lower alkyl, lower alkoxy(lower)alkyl~ lower
alkylthio(lower)alkyl, lower alkenylthio, carboxy, lower alkoxy-
carbonyl, hydroxy(lower)alkyl, amino(lower)alkyl, lower alkoxycarbon-
ylamino(lower)alkyl, amino, lower alkylamino, halo(lower)alkyl, car-
boxy(lower)alkylthio, lower alkanesulfonyl(lower)alkyl, lower alkane-
sulfonylamino(lower)alkyl or carboxy(lower)alkylthio; -triazolylthio
(lower)alkyl ( more preferably triazolylthiomethyl) substituted with
lower alkyl, lower alkenyl or lower alkoxy(lower)alkyl; pyrazin-
ylthio(lower)alkyl (more preferably pyrazinylthiomethyl); thia-
zolinylthio(lower)alkyl (more preferably thiazolylthiomethyl);
tetrazolopyridazinylthio(lower)alkyl (more preferably tetrazolo-
pyridazinylthiomethyl); or dihydrotriazolopyridazinylthio(lower)-
alkyl (more preferably dihydrotriazolopyridazinylthiomethyl) sub-
stituted with oxo and carboxy(lower)alkyl;
na~
- 17 -
j and R5 is carboxy or phenyl(lower)-
alkoxycarbonyl substituted with nitro.
The processes for preparing the object compounds
are explained in details in the ~ollowing
Process 1
i
i The objec~ compound (I~ can be prepared ~y
:! reacting ~he compo~d (II) or its reacti~e derivati~e
.~ . at the amino group or a salt thereof with the compound
~III) or its reactive derivative at t:he carboxy gTOUp
~3 10 or a salt thereof.
Suitable reacti~e der~vative at the ami~o group
; o the compound (II) may include conventional reactive
3 derivative used in amidation, for e~ample~ Schi~I's
base type imino or its tautomeric enamine typ~ isomer
~3 15 foTmed by the reaction of the compound ~II) with
a carbonyl compou~d; a silyl derivative ormed by the
reac~ion of the compound ~ with a silyl compo~ld
such as bis ~trimethylsilyl)acetamide, trimethylsilyl-
acetamida or the like; a derivative formed by reaction
of the compound tII) with phosphorus trichloride or
phosgene, and the like.
~ Suitable salt of the compound ~II) may include
.~3 an acid addition salt such as an organic acid salt
:~ ~e.g.,-acetate, maleate~ tartrate, ben~enesulfonaLe,
tolue~esulfonate, etc.) or an inorganic acid salt
`~ ~e . g ., hydTochloride, hydrobromide, sulfate, phosphate,
etc.);
.
_5
,
`'9
....
- 18 -
a metal salt ~e.g., sodium salt, potassium salt, cal-
cium salt, magnesium salt, e~c.); ammonium salt; an
organic amine salt (e.g., triethylamine salt,
dicyclohe~ylamine salt~ etc.), and the like.
Suitable reacti~e derivative at the carboxy
~roup of the compound ~III) may include an acid halide,
an acid anhydride, an activated amide;, an ac~ivated
ester9 and the like. The suitable example may be an
acid chlorid~; an acid azide; a mixed acid anhydride
with an acid such as subs~ituted phosphoric acid (e.g.,
dialkylphosphori~ acid, phenylphosphoric acid, diphenyl-
phosphoric acid, dibenzylphosphoric acid, halogenated
phosphoric acid, etc.), dialkylphosphorous acid,
sul~urous acid, thiosulfuric acid, sulfuric acid,
alkylcarbonic aid, aliphatic carboxylic acid ~e.g.,
pivalic acid, pen~anoic acid, isopentanoic acid,
~ -e~hylbutyric acid, acetic acid or trichloro~
acetic acid, etc.) or aromatic ca~boxylic acid ~e.g.,
be~oic acid~ etc~); a symmetrical acid anhydride; an
~0 acti~ated amide with imidazole, dimethylpyra701e, tria-
zol~ or tetrazole; or an activated ester (e.g., cya~o-
methyl ester, methoxymethyl ester, dimethyliminomethyl
~(CH3)2N = CH-] ester, vinyl ester, propargyl esterp
p-nitrophenyl es~er, 2,4-dinitrophenyl es~er, trichloro-
phenyl ester, pentachlorophenyl ester, mesyl phenyl
ester, phenylazophenyl ester, phenyl thioester, p-
nitrophenyl thioester, p-cresyl thioester, carboxy-
methyl thioester, pyranyl ester, pyridyl ester, piperidyl
ester, 8-quinolyl thioester, or an ester ~ith N,N-
dimethylhydroxylamine, 1-hydroxy-2-~lH~-pyridone, N-
hydrox~succinimide~ N-hydroxyphthalimide or l-hydro~y-
6-cnloro-lH-benzotria~ole, ~nd the like. These .
~e~ctive deriva.ives can be optionally selected from
them according to the kind of the compound ~ to be
3a used.
'7~
- 19 -
The salts of the compound (III) may be salts
wi~h an inorganic base such as an alkali metal sal~s
(e.g.) sodium or potassium salt), or an alkaline earth
me~al salt ~e.g., calcium or magnesium salt), a salt
with an org~ic base such as trimethylamine, trie~hyl~
amine, pyridi~e, a salt with an acid ~e.g , hydrochloric
acid or hydrobromic acid) or the like.
The reaction is usually carried out in a con-
~entional solvent such as water> acetone, dioxane,
acetonitrile, chloro~orm, methylene chloride, ethylene
chloride, tetrahydrofuran, ethyl ace~a~e, N,N-dimethyl-
formamide, pyTidine or any other organ:ic solvent which
does not adversely influence to the reaction. Among
t~ese solvents, hydrophilic solvents may be used in a
lS mixture with water.
When ~he compound ~III) is used in free acid form
- or its salt form in the reaction, ~he reaction is
preferably carried out in the presence of a con~entional
condensing agent such as N,N-dicyclohexylcarbodiimide;
2~ N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclo-
hexyl-N'-~4-diethylaminocyclohexyl)carbodiimide; ~,N-
diethylcarbodiimide; ~,N-diisopropylcar~odiimide; N-
ethyl-N'-~3-dimethylaminopropyl)carbodiimide; N,N-
carbonylbis(2-methylimidazole); pentamethylene-ketene-
N-cyclohexylimine; diphenyl~etene-N-cyclohexylimine;
ethoxyacetylene; ethyl polyphosphate; isopropyl poly-
phosphate; diethyl phosphorochloridite; phosphorus
oxychloride; phosphorus trichloride; phosphorus
pentachloride; thionyl chloride; o~alyl chloride;
triphenylphosphine; N-ethyl-7-hydroxybenzisoxazolium
fluoroborate; N-ethyl-5-phenyliso~a~olium-3'-sulfonate;
l-(p-chloroben enesulfonyloxy)-6-chloro-lH-ben~otria-ole;
so-called Vilsmeier reagent, for e~ample ~chloromethylene)
dimethylammonium chloride produced by the reaction o~
;5 dimethylformamide with thionyl chloride or phosgene,
- 20 -
a compound produced by the reaction of dimethylfornlanlide wi-th
phosphorus oxychloride, etc.; or the like.
The reaction may be also carried out in the presence of
an inorganic nr an organic base such as an alkali metal hydrnx-ide,
S an alkali metal bicarbonate, alkali metal carbonate, alkali metal
acetate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine,
N,N-di(lower)alkylbenzylamine, N,N-di(lower)alkylaniline as exempli-
fied below, or the like. When the base or the condensing agent is in
liquid, it can be used also as a solvent. The reaction temperature
0 i5 not critical, and -the reaction is usllally carried out under
cooling or at ambient temperature.
In -the present reaction~ a syn-isomer oF the object
compound (I) can be ob-tained pre-ferably by contlucting -the reaction
of the compound (Il) with a syn-isomer of thé starting compound ~III). -
In the present reaction, amino group for R1 in the compound
~III) may be converted into a protected amino ~roup to give the
compound (I) wherein R1 is a protected amino in the course oF the
reaction according to reaction conditions, and this case is also inc-
luded within the scope of the present reaction.
Process 2
The object compound(Ib) or a salt thereof can be prepared
by subjecting the compound(Ia) or a salt thereof to elimination
reaction of the protective group of carboxy.
Suitable salt of the compound ~Ia) can be referred to the
acid addition salt exemplified for the compound (II~.
The present reaction is carried out in accordance with a
conventional method such as hydrolysis, reduction or the like.
~,
j.. ,.. ,_
~ 5
- 21 -
In case that the protecti~e group is an ester,
the protective group can be eliminated by hydrolysis.
Hydrolysis is pre~erab}y carried out in the presence o~
a base or an acid. Suitable base may include an inor-
5 ganic base and an organic base such as an alkali metal~e.g., sodium, potassium; etc.~, an alkaline earth
metal ~e.g., magnesium, calcium, etc.), ~he hydroxide
or carbonate or bicarbonate thereo~ ~rialkylamine
~e.g.9 trimethylamine, triethylamin~, etc.), picoline,
1,5-diazabicyclo~4,3,0~none-5-ene, 1,4-diazabicyclo~2,
2,2loctane~ 1,8-diazabicyclo[5,4,0]undecene-7, or the
like. Suitable acid may include an organic acid (e.g.
formic acid, acetic acid, propionic acid, trifluoro-
acetic acid, etc~) and an inorganic acid ~e~g., hydro-
chlo~ic acid, hydrobromic acidJ sulfuric acid, etc.).
The reaction is usually carried out in a sol-
ven~ such as water, an alcohol ~e,g , methanol, ethanol,
etc.), a mixture th~reo~ or any other solvent which does
not ad~ersely influence to the reaction. A liquid base
or acid can be also used as the solvent. The reaction
temperature is not critical and the reaction is usually
carried ou~ under cooling to warming.
Reduction can be applied preferably for elimination
of the protective group such as 4-nitroben~yl, 2-
iodoethyl, 2,2,2-trichloroethyl, or the like. The
reduction method applicable for the elimination reaction
may include, for example, reduction by using a
combination of a metal (e.g., zinc, zinc amalga~, etc.)
or a salt of chrome compound (e.g., ~hromous chloride,
;0 chromous acetate, etc.) and an organic or i~organic
acid (e.g., acetic acid, propionic acid, hydrochloric
acid, etc.); and conventional catalytic reauction in the
presence ol a con~entional metallic catalyst (e.g. 9
palladium-carbon, etc.).
:'
~'75
- 22 -
Process 3
-
The object compound ~Id) or a sal~ thereo can be
prepared by reacting the compound ~Ic) or a salt thereof
wi~h the compound ~IV) or its reactive derivati~e at the
mercapto gTOUp.
Suitable salt of the compound (Ic) can be referred
to the ones exemplified for the compound (II).
Suitable reactive derivative at the mercapto group
of the compound (IV) may include a metal salt such as an
alkali metal salt (e.g., sodium salt, potassium sal~,
etc.) or the like.
The presen~ reaction may be carried out in a solvent
such as water, phosphate buffer, acetone) chloro~orm,
nitToben~ene, methylene chlor~de, eth~lene chloride,
dimethylformamide, m~thanol, ethanol, ether, tetrahydro-
uran, dime~hylsulfoxide, or any other organic s~lvent
which does not adversely a~ect the reaction, preerably
in ones having str~ng polarities. Among the solvents
hydrophilic solvents may be used in a mi~ure with
water. The reaction is preferably carried out in
around neutral medium. ~Yhen the compound (Ic) or the
compound ~IV~ is used in a free form3 the reaction is
preferably conducted in the presence of a base, for
example, inorganic base such as alkali metal
~ydroxide, alkali metal carbonate, alkali metal bicarbonate,
organic base such as ~rialkylamine, and the like. The
reaction temperature is not critical, and the leacti.on
is usually carried out at ambient temperature, under
waTming or under slightly heating.
Process 4
The object compound ~If) or a salt thereof can be
prepa ed by subJecting the compound (Ie) or a sal Lhereof
to elimination reaction of the protective group of amino.
Suitable salt of the compound (Ie) may include a
~5 metal salt, ammonium salt, an organic amine salt and
,
- 2i -
the like as aforemen~ioned.
The present elimination reaction is carried out in
accordance with a conventional method such as hydrolysis;
reduction; a method by reacting ~he compound ~Ie)
wherein the pretec~ive group is acy} group with imino-
halogenating agent and ~hen with iminoe~herifying a~ent,
and, i necessary~ subjecting the resultin~ compound to
hydrolysis; or ~he like. The hydrol~sis may include a
me~hod using an acid or base or hydrazLne and the like.
These methods may be selected depending on the kind of
the protecti~e g~oups to be eliminated.
Among th~se methods, hydrolysis using an acid is
one o the common and preferable method for eliminating
the protecti~e group such as substituted or ~substituted
alkoxycarbonyl (e.g., t-pentyloxycarbonyl, t-buto.~-
carbonyl, etc.), alkanoyl ~e.g., formyl, etc.)~
cycloalkoxycarbonyl, substituted or unsubstituted
aral~oxycarboxyl (e.~., bcn~yloxycarbonyl, subs~ituted
benzyloxycarbonyl, e~c.)~ substituted phenylthio,
~0 substituted aralkylidene, subs~ituted alkylidene,
substituted cyGloalkylidene, ar~lower)alkyl (e.g.,
benzyl, trityl, et~.) or the like.
Suitable acid may include an organic or an
inorganic acid, for example, formic acid, trifluoro-
2i acetic acid, ~enzenesulfonic acid, p-toluenesul~onic
acid, hydrochloric acid and the like, and preferable
acid is,for example, formic acid, trifluoroacetic acid,
hydrochloric acid, etc. The acid suitable foT ~he
reaction can be selected according to the kind of
protective group to be eliminated. When ~he elimination
reaction is conducted with the acid, it can be carTied
out in the presence or absence of a solvent. Suitable
solvent may include a conventional organic solvent,
wate~ or a mixture thereof. ~hen trifluoroacetic acid
is used, the eliminatl~n reaction may preferably be
,
- 2~ -
carried out in the presence o-f anisole
The hydrolysis using hydrazine is commonly applied
for eliminating the protectlve group, for example,
succinyl or phthaloyl.
The hydrolysis with a base is preerably applied
for eliminating acyl group ~ or example, haloalkanoyl
~e.g,, dichloroacetyl~ ~rifluoroacetyl~ etc ) etc.
Suitable base may inc~ude, ~or example 3 an inorganic
base such as alkali me~al hydroxide ~e.g., sodi~m
hydroxide, potassium hydroxide, e~c.), alkaline
earth metal hydroxide (e.g., ~agnesium hydroxide,
calcium hydroxide, etc.), al~ali metal carbonate (e g.,
sodium carbonate~ potassium carbonate, etc.), alkaline
earth metal carbonate ~e.g., magnesium carbonate, calcium
carbonate, etc.), alkali metal bicarbonate ~e.g., sodium
bicarbonate, potassium bicarbonate, etc.), alkali
metal acetate ~e.g., sodium aceta~e, potassium ace~ate,
etc.)~alkaline earth metal phosphate ~e.g., magnesium
phosphate, calcium phosphate, etc.), alkali metal
hydTogen phosphate (e.g. J disodium hydrogen phcsphate,
dipotassium hydrogen phosphate, etc.), or the like,
and an organic base such as trialkylamine ~e.g.,
trimethylamine9 triethylamine, etc ), picoline, N-metnyl-
pyrrolidine, N-methylmorpholine, 1,5-diazabicyclo~4,~,0~-
non-5-ene, 1-4-diazabicyclo~2,2,2]octane, 1~5-diazabi-
cyclo~5,4,0~undecene-5-or the like. The hydrolysis
using a base is often carried out in water, a conventional
organic solvent or a mixture thereof.
Among the protective group, the acyl group can be
generally eliminated by hydrolysis as mentioned above
or by the other conventional hydrolysis. In case
that the acyl group is halogen substituted-alXo~ycarbonyl
or 8-quinolyloxycarbonyl, they are eliminated by
treating wi~h a heavy metal such as copper, zinc or
the like.
- 25 -
The reductive elimination is generally applied For
eliminating the pro-tective group, for example, haloalkoxy-
carbonyl ~e.g., -trichloroethoxycarbonyl, etc.), ~ubstituted
or unsubstituted aral~oxycarbonyl (e.g., benzyloxycarbonyl,
substituted benzyloxycarbonyl, etc.), 2-pyri~ylmethoxycarbonyl,
etc. Suitable reduction may include, for example, reduction with
an alkali metal borohydride (e.g., sodium borohydride, etc.),
and the like.
The reaction temperature is not critical and may be
suitably selected in accordance with the kind oF the protective
group of the amino group and the elimination metho~l as mentioned
above, and the present reaction is preFerably carrietl out under
a mild condi-tinn such as under cooling, at ambient temperature or
slightly elevated temperature
The present reaction includes, within its scope, the
cases that the protected carboxy group for R5 is transformed into
the free carboxy group in the course of the elimination reaction as
mentioned above or in the post-treatment of the reaction mixture
or reaction product.
The preparation for preparing the starting compound (III)
are explained below in detail.
Preparation (1)
The compound (VII) can be prepared by reacting the com-
pound (V) or a salt thereof with halogenating agent and the
compound (VI).
Suitable halogenating agent to be used in the present
reaction may include bromine, chlorine and the like.
3':~
- 26 -
The present reaction i 5 preferablY carried out in the pres-
ence of a base such as an inorganic base or an organic base, for ex-
ample, alkali metal carhonate, alkali metal alkoxide, trialkylarnine,
or the like. The present reaction is usually carried Ollt in a sol-
vent such as an alcohol te.g., methanol, ethanol, etc.) or any other
solvent which does not adversely affect the reaction. The reaction
tem?erature is not critical and the reaction is usually carried out
under cooling or at ambient temperature. In this reaction, R6 of
the compound (~) rnay be converted into other protective gro~p of
carboxy according to reaction conditions and kinds o-F the protect-
ive group and it is included wi-thin the scope oF the present re-
actiorl.
Preparation_(2)
The compound (VIII) can be prepared by subjecting the com
pound (~II) to introduction reaction of the protective group of amino.
The present process can be carried out in a canventional
manner and when the protective group of amino to be introduced into
the amino group is acyl, the reaction can be carried out in sub-
stantially the same manner as that of Process l. Accordingly, the
detailed explanation therefore is to be referred to said Process l.
Preparation (3)
The compound (X~ can be prepared by reacting the compound
(VIII) with the compound (IX). This process is usually carried out
in the presence of base such as an alkali metal hydride (e.g.,sod-
ium hydride, potassium hydride,etc.), an alkaline earth metal hydride
(e.g., calcium hydride, etc.) and the like, and usually carried out
in a solvent such as dimethylformamide or any other solvent which
3~ does not adversely affect the reaction. The reaction temperature
5~ 3
- 27 -
is not critical and the reaction is usually carried out under
cooling, at ambient -temperature or under warming.
Prepara_ on (4
The compound (XI) can be prepared by reacting the compound
(X) with an acid and/or acid anhydride such as acetic acid andlor
acetic anhydride. The reaction of this process can preferably be
carried out in the presence of alkali metal perhaloate (e.g.,
- sodium perchlorate, sodium periodate, potassium perchlorate, etc.),
alkaline earth metal perchlorate, (e.g., magnesium perchlorate,
calcium perchlorate, etc.) and the like, and an acid such as an
organic acid (e.g., formic acid, acetic acid,etc.) or an inorganic
acid (e.g., hydrochloric acid).
The reaction temperature is not critical ancl the reac-tion is
usually carried out under warming.
Preparations (S) and (7)
The preparation (5) and (7) can be carried out in a oon-
ventional manner as shown in Process 2 or 4.
In the preparation (5), according to reaction conditions,
there may be obtained the product having Rla or the product having
amino group instead of R , and they are subsequently reacted with
the compound ~XII) or a salt thereof to give the compound (IIIa) or
(IIIb), respectively, as shown in Preparation (6).
Preparation (6)
Suitable salt of the compound (XII) is a conventional acid
salt such as an inorganic acid salt (e.g., hydrochloride, etc.) and
an organic acid salt (e.g., p-toluenesulfonic acid salt, etc.).
~hen salt of said compound (XII) is used in this process , the
reaction is usually carried out in the presence of a base such as an
t~ 30
7; .~ "~
~3
- 28 -
alkali metal ilydroxide (e.g.~ sodium hydroxide, potassium hy-
droxide, etc.~. The reaction is usually carried out in a solvent
such as water, an alcohol (e.g., methanol, ethanol,etc.) or any
other solvent which cloes not adversely affect the reaction. The
reaction -temperature is no-t critical and the reaction is usually
carried out at ambient temperature
In the aforementioned reac-tions and/or in the post
treatment of the reactions of the present invention, the aforementioned
tautomeric isomers may occas;onally be transFormed into other taut-
omeric isomers and sucll case is also included in the scope of the
present invention.
In case that the object compound (I) is obtained in a
form of the free acid at 4 position and/or in case that the object
compound (I) has free amino gnoup, it may be optionally transformed
1~ into its pharmaceutically acceptable salt as aforemen-tioned by a
conventional method.
The object compound (I) and pharmaceutically acceptable
salt thereof of the present invention are all novel compounds which
exhibit high antibacterial activity, inhibiting the growth of a wide
variety of pathogenic microorganisms including Gram-positive and
Gram-negative bacteria and are useful as antibacterial agents.
No~, in order to show the utility of the object compound
(I), with regard to some representative compounds of this invention,
the test data on the in vitro anti-bacterial activity are shown in
the following.
Test Compounds
~1) 7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl) aceta-
mido]-3-(1-methyl-1H-tetrazol-5-ylthio-methyl)-3-cephem-4-carboxylic
acid (syn isomer)
~"
- 29 -
(2) 7-[?-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)ace-talnitlo~
-3-(l,3,4-thiadiazol-2-ylthiomethyl~-3-cephem-4-carboxylic ac-id (syn
isomer~
(3) 7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamidol
-3-[l-(2-aminoethyl)-lH-te-trazol-5-yl]thiomethyl-3-cephem-4-carboxylic
acid (syn isomer)
(4) 7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]
-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn
isomer
(5) 7 [2-Methoxyimino-2-(S amino-1,2,4-thiadiazol-3-yl)(lcet.llllicl()]
-3-[1-(2-hydrnxyethyl)-l~l-tetrazol-5-yl]thiomethyl-3-cephem-~l-carboxylic
acid (syn isorner)
(6) 7-[2-Methoxyimino-2-(5-dmino-l,2,~--thiadiazol-3-yl)-acetanlitlo]
-3-(tetrazolo[1,5-b]pyridazin-6-yl-thiome-thyl-3-cephem-4-carboxylic
acid (syn isomer)
(7) 7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]
-3-(1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn
isomer)
(8) 7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido~
-3-(l-allyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid
(syn isomer)
~9) 7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]
-3-cephem-4-carboxylic acid (syn isomer)
(10) 7-[2-Methoxyimino-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]
-3-[1-(3-aminopropyl)-lH-tetrazol-5-yl]-thiomethyl-3-cephem-4-carboxylic
acid (syn isomer)
7~3~3
Tes t Me th od
-
In vitro antibacterial activity was determined by
the two-fold agar-plate dilution method as described
below.
S One loopful of an overnight culture o each test
strain in Trypticase-so~ broth (10~ viable cells per ml.)
was streakea on heart inusion agar (HI-agar)
containin~ graded concentrations of te:st compounds, and
minimal inhibitory concentration (MIC) was expressed in
terms of ~g/ml . a~ter incubation at 37 C for 20 hours.
?~
,
- 31 -
)- ~C~ ts ~ W ~o
20~ . ~3 ~ ~ ~ U~
~ . .
c~ I n c~ ~n o ~7
I ~ ~ ~ O C rt rt
~' _~ I_ O~ 0~ ~D ~
O ~ ~_ ~D ~- C~ ~ ~ ~n
oq ~ W ~'~ Y~ ~
3 ~z: ~ ~- P ,_
o ~ ~ ;~ ~ ,~............. ~t
o v, p~' 4
P ~D
_ . .___
a~ o o o w ,_
:~ ~ ~ ,_
o o o C~ ,-~
,_ , ~ ,_ o l_
Ul W
~ O ~ O G~ ~_
~ ~ ,_ ~ ~ ~U7 ~n ~
W C~ o o ~ ,_
~_ ~ U~'
C~ o o
. ' . ~ O ~ ~ ~n
- ~n ~ n ~
. . , O . O W 1~ H
u, ~ w I_ i- n
W o ~ o ~-- o ~_
. . . . . .
-- ~1 ~n ~3
tD ~ CO G~ -~ O
. . . .
o~ o o o
~ ~ ~ Y Y __
Ul ~D ,~0 W _~
~ o o o r~) ~D
~J o r~ o
~_ _~
~ o. o o ~ ~
~I L~.
~ . ~ . ... . . .. . .. ..... .. . . .
- ~2 -
For therapeutic adminis~ration, the object compoun~
~I) of the present invention is used in the form of
conven~ional pharmaceutical preparation which contains
said compounds, as an active ingredient, in admixture
5 with a pharmaceutically acceptable carriers such as an
organic or inorganic solid or liquid e~xcipient which is
suitable for oral, parenteral or external administration.
The pharmaceu*ical preparations may be in solid form such
as capsule, tablet, dragee, oin~ment or suppository, or
in liquid form such as solution, suspension, or emulsion.
If needed, ~he~e may be included in the above prepara~ions
auxiliary substances~ stabilizing agents, wetting or
emulsi~ying agents, bufers ~ld the other commonly use~
additi~es.
While the dosage o~ the compounds may vary from
and also depend upon the age, conditions o~ the patient,
a kind of disease, a kind of the compound (I) ~o be
applied, etc.l an average si~gle dose of about 50 mg.,
100 mg., 250 mg, and 500 mg. of the object compound
~I) of the present invention has proved to be effective
in treating diseases infected by pathogenic bacteria.
In general, daily dose between 5 mg. and about
3,000 mg. or even more may be administered to a
patient.
The following Preparations and Examples are
giYen for the purpose of illustra~ing the present
inYention:-
S~
-~3 ~
PreParation 1:
Preparation of Methyl 5-zmino-1,2,~-thiadiazole-
3-carboxyla~.e.
To a solution of l-e~hoxycarbonylformamidine.
hyarobromide ~16.6 g.) in absolute meth~mol ~84 ml)
~as added a solution of sodium ~1.93 g)
in absolute methanol ~42 ml) at 0C. To the mixture
were added al~ernately bromine ~12.8 g) and a solution
of sodium ~1.93 g) in absolute methanol ~42 ml) at
0C and then to ~he suspension was added potassium
thiocyana~e ~8.1 g) in absolute methanol ~100 ml~.
The reaction mixture was stirred for an hour at 0C
and for an additional 6 hours a~ ambient temperature.
The mix~ure was filtered throu~h cellulose powder and
the ~iltrate was evzporated to dryness. The residue
was dissolved in a mixture uf ethyl ace~ate ~ld water,
and ~hen ~-he ethyl acetate layer was separated and
dried over anhydrous magnesium sulfate. The solvent
~ was evaporated and the residue was triturated with
-diethyl ether to give the title compound (9.0 g), mp.
2~Z ~o 205C.
I.R. ~Nujol~*: 3400, 3250 3 31Q0, 1710,
1610, 1540 cm~
N.M.R. (d6-DMSO)
~ : ~.85 (3H, s), 8.25 (2H, s)
Preparation 2:
Preparation of Methyl 5-formamido-1,2,4-
thiadiazole-3-carboxylate.
To a mixture of formic acid (33 g~ and acetic
anhydride ~22 g) was added methyl 5-amino-1,~,4-
thiadia~ole-3-carboxylzte ~6.2 g~, and then the
mixlure wzs stirred for 2 days a~ ambient temperature.
The reaction mix~ure was concentrated under reduced
pressure and the residue was triturated with a mix~ure
*trade mark
of diethyl ether ~nd n-hexane to give the title
compound ~7.~ g), mp. 210 to 215C.
I.R. ~Nujol) : 3100, 1720, 1680 cm 1
N.M~R. ~d6-DMS0)
~ : 3.90 ~3H, s), 8.85 ~lH, s~
Preparation 3:
_
Preparation of 5-Formamido-3-(2-I~etnylthio-2-
methylsulfinylacety~-1,2,4-thiadia7O1e.
To a mix~ure of methyl 5-formamido-1~2,4-
thiadiazole-3-car~oxylate (9.2 g~ ~nd methyl methyl-
thiomethyl sulfoxide (6.1 g) in N,N-dime~hylformamide
~100 ml) was added 50~ sodium hydride (7.1 g) wi~h
cooling in an ice-bath. The mixture was stirTed for
an hour at ambient temperature and or ~n addi ~ional
lS one hour a~ 40C. After cooling to ambient ~empera-
ture, methylene chloride ~300 ml) was added to tne
reaction mixture, and the resulting precipitates
were collected by ~ ration and washed wi~h
mèthylene chloride. The precipitates were added to
a stirred mix~ur~ of hydrochloric acid ~14.7 ml),
ice-water ~200 ml) and methylene chloride (2~0 ml).
An insoluble material was filtered off and the
methylene chloride layer was separated from the
filtrate. The solution was. dried over anhydr~us
magnesium sulfate, evaporàted and the Tesidue was
triturated with diethyl ether to give the title
compound (4.~ g) 9 mp. 130 to 132C.
I.R. ~Nujol) : 3100, 1680, 1670 cm l
- N.M.R. (d6-DMSO)
: 2.22 }~3H, 2s)
2.28
2.68} ~2H, ?S)
2.85
3~o
5.70 } ~1~, 2s)
5 .80
. 8.86 ~l~I, s)
a Preparation 4:
Preparation of S-methyl ~5-formamido-1,2J4-
~hiadia~ol-3-yl~thioglyoxylate.
A mi~ture of 5-ormamido-3-(2-methylthio-2-
methylsulfinylace~yl~^l,2,4-~hiadia~ole (0.85 g) and
sodium perioda~e ~V.Z g) in glacial acetic acid
~10 ml~ was stirred for 45 minutes at 70C. The
reaction mixture was evaporated and the residue was
dissolved in a mixture of ethyl acetate and water.
The mixture was adjusted to p~ 7 with an a~ueous
solu~ion o sodium bicarbonate and treated with an
aqueous solution of sodium thiosulfate. The org~nic
layer was separated, dried ove~ anhydrous magnesium
sulfate and evapora~ed to dryness. The residue was
tritura~ed with a mixture of die~hyl ether and
petroleum ether to gi~e the ~itle compound (280 mg),
mp. 186 to 187C.
I.R. (Nujol) : 3100, 1680, 1660 cm 1
N.M.R. (d6-DMSO)
~ : 2.55 (3H, s}, 8.95 ~lH, s)
Preparation 5:
Preparation of 2-Methoxyimino-2-~5-formamido-
1,2,4-thiadiazol-3-yl)acetic acid (syn isomer).
A mixture of S-methyl (5-formamido-1,2,4-
- thiadiazol-3-yl)thioglyoxylate (231 mg) in methanol
(2 ml) and lN-aqueous solution of potassium hydroxide
(3.5 ml) was s.irred for an hour at ambient tempera-
ture. The mixture was adjusted to pH 7.6 with 1
hydrochloric acid, followed by an addition OI O-
methylhydroxylamine hydrochloride (90 mg) and stir-
;5 ring for 3~ minutes a~ ambient temperature.
36 -
The reaction mixture was neutralized with an aqueous
- solution of sodium bicarbonate and concentra~ed to
remoYe meth~nol. The concen~ra~ed aqueous solution
was adjusted to pH 4 ~i~h hydrochloric acid and
i washed with ethyl ace~a~e. The aqueous layer was
adjusted to p~ 1 with hydrochloric acid, satura~ed
wi~h sodium chloride and extracted with e~hyl acetate.
The extract was evaporated to dryness and the residue
was triturated with diethyl ether, collected by
filtra~ion and then dried to give the ~itle compound
~80 mg), mp. 1~5 to 186C.
I .R. (Nu jol) : 3150~ 1720, 1690 cm 1
N.M.R. ~d6-DMSO~
~ : 3 ~8 (3H, s), 8 84 ~lH, s)
Preparation 6:
Preparatio~ o 2-Methoxyimino-2-(5-ormamido-
4-thiadiazol-3-yl)acetic acid (syn isomer)
A mixture o~ 5-formamido-3-(2-me~hyl~hio-2-
methylsulfinylace~yl)-1,2,4-thiadia~ole ~3.2 g) and
sodium periodate (0.8 g) in glacial acetic acid
~32 ml) was stirred for 4S minutes at 70C. The re-
sulting mixture was evaporated and the residue was
wasned with n-hexane and then thereto were added
methanol (20 ml) and 1~ aqueous solution of potassium
hydroxide ~40 ml). The solution was stirred for a~
hour at ambient temperature. The reaction mixture
was adjusted to pH 8 with lN hydrochloric acid9
followed by an addition of O-methylhydroxylamine
hydrochloride ~0.96 g~ and stirring for an hour at
ambient temperature. The ~eaction mixture w~s neu-
trali ed with an aqueous solution of sodium bicarbonate
and concent-ated to remove methanol. The resu}ting
aqueous solution was washed with ethyl acetate,
adjusted to pH 1 with 10% hydrochloric acid,
saturated with sodium chloride and extracted ~ith
.
~ ~7 ~
wi~h ethyl acetate. The extract was dried o~e~
anhydrous magnesium sulfate, evaporated; and the
residue was tritura~ed wi~h diisopropy:l e~her ~o
give the title compound ~1.02 g), mp. 185 t~ 1~6C.
Preparation_7:
Preparation of 2-~le~hoxyimino-2-~5-amino-1~2,4-
thiadiazol-3-yl) acetic acid (sy~ isomer).
A solution of 2-methoxyimino-2-(5-fo~mamido-
1,2,4-thiadiazol-3-yl)ace~ic acid ~syn isome~)(1.4 g)
in lN aqueous solution of sodium hydroxide ~19.1 ml)
was heated at 50 to 55C or an hour. To the solut-
ion was added conc.hydrochloric acid (1.9 ml) under
cooling in an ice-bath. The mixture was saturated
with sodium chloride and extracted with e~hyl acetate,
The extract was dTied over anhydrous magnesium sul~ate
and evaporated to dryness. The residue was tri~urated
with diethyl ether to gi~e ~he title compound (0,9 g),
mp. 180 to 182C (dec.).
I.R. (Nujol~ : 3450, 3250, 3100~ 1715, 1610,
1530 cm~
N.M.R. ~d6-DMSO)
~ : 3.90 (3H, s), 8.10 (3H~ broad s)
Preparation 8
A mixture of 5-fQrmamido-3-~2-methylthio-2-
methylsulfinylacetyl) 1,2,4-thiadiazole (10 g) and
sodium periodate ~2.0 g) in glacial ~cetic acid
~50 ml) was stirred for 50 minutes at 70C. The sol-
vent was e~aporated and the residue was washed with
n-hexane. To the residue was added lN aqueous
solu.ion of sodium hydroxide (160 ml) and the mixture
was stirred for an hour at ambient temperature. To
Lhe reac.ion mixture was added O-ethylhydroxylamine
nydrochloride (3.~ g) and the solution was adjusted
to pH 3 to 4 with 10% hydrochloric acid and then
3; stirred for an hou~ at ambient tempera~ure. After
`L~ lf'l~
an insoluble material was filtered off, the iltrate
was was~ed with ethyl ace~a~e, adjusted to pH 1 with
10~ hydrochloric acid and extrac~ed with ethyl acetate.
The extract was dried over magnesium sulfa~e and
evaporated to dryness~ The residue was ~riturated
with a mixture o~ dîethyl e~her and diisopropyl ether
to giYe 2-ethoxyimino-2-~5-~ormamido-;L,294-thiadiazol-
3-yl)acetic acid (syn isome~(4.5 g), mp. 165 to 168C
~dec.),
lQ I.R. ~Nujol) : 3450, 3170, 3050, 1730, 1690;
1595, 1565 cm~
N.M.R. (d6-DMSO~
: 1.30 ~3H, t, J=7Hz), 4.30 (2H, q,
J=7Hz~, 8.87 ~lH, s)
1~ Preparation 9
The ollowing compounds were obtained according
to a similar manner ~o that of Preparation 8.
Propoxyimino-2^~5-i~ormamido-112,4-thiadiazol-
3-yl)acetic acid ~syn isomer)g mp,168 to 170C ~dec.).
I.R. ~Nujol) : 3250, 3140, 1720, 1690,
1590, 1530 cm
N.M.R. (d~- DMSO)
- ~ : 0.90 ~3H, t, J=6Hz3, 1.4-1.9 (2H, m),
4.17 (2H, t, J=6Hz), 8.85 (lH, s)
(2) 2-Isopropoxyimino-2-(5-foTmamido-1,2,4-thiadiazol-
3-yl)acetic acid (syn isomer), mp. 180 to 182C ~dec.).
I.R. (Nujol) : 3230, 1720, 1690, 1590, 1530 cm l
N.M.R. (d6- DMSO~
~ : 1.25 (6H, d~ J=6Hz), 4.2-4.7 ~lH~ m),
8.85 ~lH, s)
_ 3 ~ ~r
't:~3'~l3
-39 ~
Preparation lO
A mixture of 2-e~hoxyimino-2-~5-~orm~mido-l,Z,4~
thiadiazol-3-yl)acetic acid (syn isomer}~4.4 g) and lN
a~ueous solution o~ sodium hyd~o~ide (54 ml) was stirr~d
for 2 hours at 50 to 55~C. The mi~ture was cooled in an
ice bath, acidiied with hydrochloric acid ~5.4 ml) and
extracred with ethyl acetate. The extract was dried over
magnesium sulfate and e~aporated to dryness. The residue
was triturated with diethyl ether to give 2-ethoxyirnino-
2-~-amino-1,2,4-thiadiazol-3-yl)acetic acid ~syn isomer)
(2.92 g), mp. 168 to 170C ~dec.).
I.R. ~Nujol~ : i450, 3370, 3250, 3150, 1665,
1610, 1530 cm
N.M.R. ~d6-DMSO)
O : 1.22 (3H, t, J=7Hz~, 4.17 ~2H, ~, J=7H_),
8.17 (2H, broad s)
r~
The following compounds were obtained accor-l~g to
a similar ma~ner to that of P~eparation '0.
(1) 2-Propoxyimino-2-~5-amino-1,2,4-thiadia_ol-~-
3a yl~acetic acid ~syn isomer~ mp. 100 to 10~C ~dec.~.
7~j~L'
-- ~0 --
I I.R. ~ujol): 3620, 352Q, 3350, ~l~Q, 260n,
¦ 250Q~ 1720~ 16~Q, 15S0 cm~
N.M.R. ~d6-D~IS0~
0~ ~3H, t, J=6H~); 1,3-Z.0 (2~, m),
4.13 ~2H, t, J~6~2), 8,17 (2H~ broad, ~)
~2~ Z-Isopropoxyimina-2-(S-amino-1,2,~-thiadia~ol-
3-yl)ace~ic acid ~syn isomer), mp. 152 to l~SC ~dec.).
I.R. (Nujol) : ~450, 3300, 3200, 173Q,
1620, 1530 cm 1
N.M.R. ~d6-DMS0)
2 ~6H, d, J=6Hz), 4.1-4.6 ~lH~ m),
8.20 ~H, broad s~
PreparatiOn 12
A mixture of 7-aminocephalosporanic acid ~14.il g),
5-al}ylthio-1,3,4-thiadia~ole-2-.hiol ~14 g), sodium
~ bicarbcnate tlO.6 g), water (3; ml) and pH 6.4 phos-
phate buffer solution ~105 ml) was sti~-ed for ~ hou.s
a. 6_ to 70C. To the retction mi~ture ~-as ~.dded
ethyl ~cetate ~50 ml) and th~ mi~tu.e was adjus~ed ;o
pH ~ with hydrochloric acid. P~ecipitates were col-
~5 lected by filtration, washea witn water, me.hanol and
; ~
_.~,_ _ . . .. _ _ _ _ _ _ ~.. . _ _ , . .. , ... , .. , . _ _ .. = . . _ . ... . _ . . . .. _ . _ . . .
acetone, and dried to give pale brown powder of
crude 7 amino-~-t5-allylthio-1,3,4-thiadiazol-2-yl)-
thiomethyl-3-cephem-4-carboxylic acid ~13.4 g).
Said powder ~10 gJ was dissolved in a mixture o
methanol ~100 ml) and conc.hydroch~oric acid (70 ml)
and filtered. The filtrate was treated w:ith an
activated charcoal and adjusted to pH 3 with aqueous
ammonia. Ethyl acetate ~50 ml) was added thereto
and precipitates were collected by fil~ration, washed
with water and acetone, and dried to gi~e puTe object com-
pound ~5.2 g), mp. 195 to 197C.
I.R. (Nujol): 3150~ 2700-2500, 1800) 1610,
1550-1510, 1040, 720 cm~
~ion 1~
(1) A solution of methyl N-(3-methoxypropyl)dithlo-
caTbama~e (100.2 g) in ethanol (300 ml) was added
dropwise a~ 3C ovor 30 minutes to ~ solution o
hydr~zine hydrate ~28 g~ in ethanol (200 ml). The
mixture was stirred for 4.5 hours at 70~C. The react~
ion mixture was concentrated and to the ~esidue were
added water and diethyl e~her. The diethyl ether
extract was dried over magnesium sulf~te and evapo-
rated in vacuo to give pinkish oil of 4-~3-
methoxypropyl)thiosemicarbazide (89.S g).
N.M.R.~CDCQ3)
: 1.87 ~H, m), 3.33 (3H, s), ;.3-3.8
(4H, m), 4.0 (2H, broad s), 7.~ (lH,
broad s)
~2) A mixture of 4-~3-methoxypropyl)thiosemicarbazide
(89.g g) and formic acid (450 ml) was refluxed with
stirring for 8.5 hours at 105C. Formic acid ~as re-
moved in vacuo from the reaction mixture and to .he
residue were added ethyl acetate (800 ml) and ~ater
~200 ml). The separated organic layer was ~Tashed with
5% aqueous solution of sodium bicarbonate and w-ith
.
3l~
an aqueous solution of sodium chloride, dried over
magnesium sulfate and concentrated ~o give orange oil
t77.52 g). To the oil were added a solution o
sodium hydroxide (26 g) in water t260 ml) and methanol
~40 ml), and then methanol was distilled of under
reduced pressure. To the residue was added water
(lO0 ml), and the mixture was adjusted to pH 3 or 4
with 10~ hydrochloric acid and extracted with ethyl
aceta~e ~150 ml x 2). The extracts were dried over
magnesium sulfate and evaporated to gi~e orange oil
~40.32 g), The oil was purified by column chromatography
on silica gel (500 g) using e~hyl acetate as eluent
~o give oil of 4-~3-methoxypropyl)-4H-1,2/4-tria~ole-
3-thiol ~8.95 g).
N.M.R. ~CDCQ3)
: ~,14 (2H, m)~ 3.40 t3H~ s), 3,47
(~H, t~ J~7Hz), 4~18 (2H, t, J~7~z),
7-94 tlH~ S)
~l) A solution o N-t3-aminopropyl)acetamide ~146 g)
in dioxane (710 ml) was added to a solutian of 97~
sodium hydroxide ~5~ g) in water t620 ml) and then
carbon disulfide t96 g) was added dropwise thereto
over 35 minu~es at-l to 3C. The mixture was stirred
for 1 hour at 0 to 2C. To the mixture containing
sodium N-(3-acetamidopropyl)dithiocarbamate was added
dropwise methyl iodide (179 g) over 35 minutes at
0 to aC and then the resulting mixture was stirred
for 3 hours at the same ~emperature. Dioxane was dis-
tilled off in vacuo from the reaction mixture and theresidue was exLracted writh ethyl acetate ~iO0 ml,
200 ml x 4). The extracts were dried over magnesium
sulfate and concentrated in vacuo to give oil of
methyl N-(;-acetamidopropyl)dithiocarbamate (19a.18 g3.
;~ ~2) A mix.ure of a solution of methyl N- ~a-
~2 ~
.~t~7~
acetamidopropyl)dithiocarbamaLe ~193 g~ in dioxane(610 ml) and a solution of sodium a~ide `~79.4~ g)
in water ~SOQ ml) was refluxed under stirring for
4 hours. Dioxane was distilled of~ and the rem~ining 2queou~
S la~er wa~ washed wi~h diethyl ether ~lS0 ml x 2) J
adjusted to pH 1 with 17~5% hydrochloric ac:id, and
cooled in an ice bath. Precipltates were collected by
filtration and washed with ice-water to give white
powder of ~-(3-acetamidopropyl)~ tetra-ol-S-thiol
~91~?5 g)~ mp. 152 to 154C.
N.M.R. (d6-DMSO)
: 1.87 ~3H, s), 1.97 ~2H, m), 3.17
~2H, m), 4.~8 ~2H~ ~ J=7~z),
7.9 ~lH, broad s)~ lS,0 (lH, broad s)
lS (3) A mixture of 1-(3-acetamidopropyl)-lH-te~razole-
5-thio~ (85 g) and 6N hydrochloric acid (1 Q) was
refluxed for 7S minutes under stirring, The r~ction
mixture was concentrated in vacuo and precipitates
were collected by iltration and washed wi~h hexane
and dlethyl ether to give 1-(3-aminopropyl)-lH-
~etrazole-S-*hiol hydrochloride ~67.15 g).
N.M.R. (D2O)
: 2.45 ~2H,.m), 3.23 (2H, t, J=7Hz)~
~ 4.50 ~2H, t, J=7Hz)
ZS (4) A solution of 2-t-butoxycarbonyloxyimino-2-
phenylacetonitrile (12.3 g) in dioxane (30 ml) was
added under ice-cooling to a stirred solu~ion of
1-t3-aminopropyl)-lH-tetrazole-5-thiol hydrochloride
(9.78 g) and triethylamine ~.ll.l g) in a mixture of
dioxane (25 ml) and water (25 ml), and then the
resulting mixture ~'25 stirred for 1.75 hours at
ambient temperature. Dioxane was distilled off and
to the residue were added diethyl ether-and a small
- amount o water. Alter shaking,the aqueous layer
was separated and the organic layer was extracted
4~
~wice with 10% potassi~m carbonate. The extracts
combined with the separated aqueous layer were
washed three times with diethyl ether, ad3usted to
pH 1 with hydrochloric acid and extracted with
S diethyl ether. The extrac~ was washed wi~h water,
dried and evaporated in ~acuo. The residual oil
(10 . 92 g) was pulYerized with diisopropyl ether to
give 1-~3-(N-~-butoxycarbonylamino)propyl~-lH-
te~ra,-ole-5-thiol (9.6 g)~ mp. 75 ~0 770CD
I.R. (Nujol) : 3380, 3260, 1650, 1530, 1170,
lQ50 c~ 1
N.M.R. (CDCQ3)
: 1.50 (9H, s), 2.14 (2H, m), 3.25
(2H, m), 4,39 (2H, ~) J-7H~),
lS 4 . 9-6 ~ 7 (lH, broad)
Pr~~:
(1) To .a mixture o:~ methyl 5-amino-l ~2 ,4-thiadia;~ole-
3-carboxylate ~Z6 g~, conc.hydrochloric acid (49û ml)
and a small amount o~ copper was added dropwise over
40 minutes a solution of sodium nitrite ~22.5 g) in
water ~28 ml) at -10 to -15C.
The mixture was stirred for 1~5 hours at the same
temperature and for 30 minutes at 50C. The reaction
` mixture was poured into ice-water (500 ml) and extracted
wi~h ethyl acetate. The extract was washed) dried
and concentrated to gi~e white powder of me~hyl S-
chloro-1,2,4-thiadiazole-3-carboxylate ~8.9 g).
I.R. ~u~ol): 1730, 1430, 1385, 1320, 1220,
1065, 980, 830 cm 1
N.M.R. (CDCQ3)
ô : 4 . 01 ~3H, s)
~2) A mi~;ure o, me~hyl 5-chloro-1,2,4-thiadia-ole-
3-czrboxylate ~7. 80 g), thiourea (3.32- g), tetra-
hydrofuran ~24 ml) and water ~8 ml) was gent-y boiled
for 6.5 hours . The reac~ion mixture was post-treated
_ 45 -
according to conven~ional manner to give yellow
powder of methyl 5-mer~pto-1,2 ,4- thiadiazole-3-
carboxylate (7~1 g)~ mp. 126 to 127C.
I.R. ~Nujol) : 1730, 1430, 1360~ 1270, 1060 cm 1
N.M.R. ~d6-DMS0)
~ : 3,91 (3H, s), 9.a3 ~lH, m)
(1) Trichloromethylsulfur monochloride ~88.33 g) was
added at 0C to a solution of 2-ally~.sothiourea
hydrobromide ~93.6 g) in water ~285 ml) and ~hen a
solution of sodium hydroxide (76 g) in water (300 ml)
was added dropwise thereto over 4 hours with stirring.
After stirring for 1 hour, the reaction mixture was
post-treated according to conventional manner to
give reddish brown oil of 3-allylthio-5 chloro-
1~2,4-thiadiazole (84 g), bp. 105 to 111C/13mmHg.
I.R~ t~ 1450j 1220, 1070 cm 1
N.M.R~ (CDC~3)
~ ~ 3.gO (2H~ d, J=6H~), 5~1S-5,47 (2H,
m), 5.67-~.34 ~lH, m)
(2) A mixture of.3-allylthio-5-chloro-1,2J4-
thiadiazole (15 . O g), thiourea (5.95 g), tetra-
hydrofuran (45 ml) and wa~er (15 ml) was gently
boiled for 8.5 hours at 65~C, The reaction mixture
was post-treated according to conventional manner
~o give powder of 3-allylthio-1,2,4^thiadiazole-5-
thiol (8.5 g), mp. 107 to 108C.
I.R.(Nujol) : 1510,1430, 1170, 1095, 900 cm 1
.
- /l o
Preparation 17
solution of ~-(2-ami~oprop~l)acet~lde
~82.9 g) in dioxane (415 ml~ was added to a solution
of 97~ sodium hydroxide ~29.S g) in wat~r (3~0 ml}.
To the miXtuTe was added dropwise at 0 to 5C over
25 minutes carbon disulide ~5~.5 g), ater which the
mixture was stirred or 1 hour at 0 to 5C. Methyl
iodide (101.5 g) was added dropwise over 30 minutes
at 0 ~o 3C to the resultant mixture and the mixture
was stirred or 3 hours at the same temperature. The
reaction mixtuTe was concentrated ~nd extTacted with
ethyl acetate (20~ ml, 100 ml x2~. The extracts were
dried over magnesium sulfate and evaporated to give
oil ~16~.2 g). The oil was sub jected to column
chromatography on silica gel (900 ~) and succcssively
eluted with a mixture o~ benzene a~d ethyl acetate
~1:1) and ethyl acetate ~o give oil o a m:ixture of
methyl N-(2-acetamidopropyl~dithiocarbamate and methyl
N-~l-(acetamidomethyl)ethyl3dithiocarbamate (114~1 g~.
I. R. (Film) : 340~-3200, 1730, 1670-1630,
1560-150~, 1310~ 1280, 1250,
llS0, 960 cm~l
(2) A mixture of methyl N-~2-acetamidopTopyl)-
dithiocarbamate and methyl N-[l-(acetamidomethyl)ethyl]-
dithiocarbamate (100 g) in dioxane (300 ml) and a
solution of sodium azide (41 g) in water ~270 ml~ were
stirred for 4.5 hours under reflux. The reaction
mixture was concentrated to half ~olume undeT reduced
pressure, washed with diethyl ether and aci~ified ~ith
concentrated hydrochloric acid. The resulting pre-
cipitate was collected by filtration and washed with
diethyl etheT to give pale yellow powder of l-[I-
(acetamidome.nyl)ethyl]~ tetlazole-5-thiol (26.~? g),
mp 176 to 178C.
~ 58 ~
I.R. ~Nujol) : 3420, 2850~ 1640, 1550, 1520,
l3901 1350, 1310~ 1210~ 1050,
990 cm~
~.M.R, (d6-DMSO9~ 40 (3H, d, J=7H2)~
1.75 (~H, s), 3.51 ~2H, m), 4.~1 ~lH, m),
8.00 (lH, t, J=6Hz)
t3~ A mixture of l-[l-(acetamidomèthyl)ethyl~-lH-
tetrazole-5-thiol ~23 g) and ~N aqueous hyd~ochloric
acid ~300 ml) was refluxed for 2 hours unde~ stirring
and e~apora~ed to dryness. The residue was triturated
with diethyl ether to give 1-[1- ~aminomethyl)ethyl]-
lH-tetra~ole-5-thiol hydrochloride ~19 g~, mp 208 to
210C
I.R, tNUjol) : 2800-2400~ 1610, 1600, 1510, 1285,
1200, 1050 cm 1
N M~R~ (D2J~) ~ 1.62 t3~l, d~ J=7Hz), 3.70 ~2H, m~
5.~3 ~1H) m)
(4) To a solution of 1- [1- (aminomethyl)ethyl ~ -lH-
tetrazole-S-thiol hyd~ochloride ~17 g) and triethylamine
~19.33 g) in 50% aqueous dioxane ~80 ml) was added a
solution of 2-t-butoxycarbonyloxyimino-2-phenylacetonitrile
~21.4 g) in dioxane (S0 ml) under cooling in an ice
bath. The mixture was stirTed for 1.5 hours at
ambient tempera~ure and concentrated to third volume.
The aqueous solution was washed with diethyl ether
and the washings were reextracted with aqueous solution
of potassium carbonate. The two aqueous solutions
weTe combined, washed with diethyl ether and mixed with
ethyl acetate~ The mixture was acidified with 10%
hydrochlo~ic acid and the organic layer was separated
out. The solution ~as dried over magnesium sulfate
and e~-aporated to dryness. The residue was triturated
3~ ~ith n-hexane to give l-[l-{~N-t-butoxycarbonylamino)-
5i ~ L~ ~
-- 48 --
methyl}ethyl]-lH-tetrazole-S-thiol (l9.1S g) ! mp 156
to lS8C.
I.R. ~Nujol): 3270, 3070, 2850, 1660, 1530,
1500, 139Q, 1340, 1~00, 1180, 1040 cm~
N.M.R. ~d6-DMS0, ~ : 1, 40 (9H> s) p 1.52 (3H, d
J=7Hz), 3. 41 (2H, m), 4 . 95 (lH, m~,
7 . 05 ~lH, m)
: ~ 2 5
'
:`
- ~9 - .
Example 1:
Preparation of 7-[2-~5ethoxyimino-2-(5-formamido-
1~2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-lH-
tetrazol-5-ylthiome~hyl~-3-cephem-4-carboxylic acid
(syn isomer).
A mixture of N,N-dimethyl~ormamide (6 ml~ and
phosphorus oxychloride ~918 mg) was stirred or 30
minutes ~t ambient temperature. To the mixture w~re
added me~hylene chloride ~6 ml) and 2-methoxyimino-Z-
~5-formamido-1,2, 4- thi adiazol-3-yl)acetic acid (syn
isomer) (1.1 g) at -15 to -10C, followed by stirring
for 30 minutes at the same temperature. A mixture of
7-amino-3-~1-methyl-lH-tetrazol-5-ylthiomethyl)-3-
cephem-4-carboxylic acid (1.97 g) and trimethyl-
silylacetamide (6 g~ in methylene chloride (60 ml) was
warmed to make ~ clear solution. The solution was
cooled to -15C and added to the above obtained solut-
ion The reaction mixture ~as stirred Eor an hour a~
0C and pouTed into a cold a~ueous solution o~ sodium
bicarbonate. The a~ueous layer was separated, adjusted
to pH 2 with 10% hydrochloTic acid and ext~acted with
ethyl acetate. The extract ~as dried over anhydTous
mag~esium sulfate and evaporated to dryness. The
residue was triturated ~ith diethyl ether to give a
crude produc~ of the title compound ~2.75 g). The
crude material was dissolved in an aqueous solution of
sodium bicarbonate and reprecipitated with diluted
hyd~ochloric acid to give the pure title compound
(1.5 g), mp. 170 to 175C (dec.~.
I. R. ~Nujol) : 3300, 1780, 1680 cm 1
N.M.R. (d6-DMS0, 3) : 3.90 (2H, broad s)j
3.95 (3H, s), 4.00 (3H, s), 4.33 ~2H,
broad s), 5.17 (lH, d3 J=4Hz),
5.87 (lH, 2d, J=4, 8Hz), 8.83 (lH, s),
9.70 (lH, d, J=8Hz)
- 50 -
Example 2
Preparation of 7-[2-Methoxyimino-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetamldo]-3-(1-methyl~
tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylio acid
(syn isomer).
A mixture of 2-methoxyimino-2-(5-amino-l,Z,4-
thiadiazol-3-yl)acetic acid (syn isomer)(lO0 mg) and
phospho~us oxychloride ~306 mg) in methylene chloride
~5 ml) was stirred for 30 minutes at ambient temperaturei
To the mixture was added N,N-dime~hylfGTmamide (O.Z ml~
under cooling in an ice-bath, followed by stirring for
30 minutes. A mixture of 7-amino-3-(1-methyl-lH- -
tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid
(300 mg) and trimethylsilylacetamide ~0.9 g~ in
methylene chloride ~9 ml~ was warmed to ma~e a clear
solution. The solution was cooled in an ice-bath and
~dded to the above obtained solu~iong followed by
stirring for 30 minutes at 0C. The reaction mixt~re
was poured into a cold aque~us solution of sod;um
bicarbonate. The aqueous layer was separated, adjusted
to pH 1 with 10~ hyd~ochloric acid and extracted with
ethyl acetate. The extract was dTied over anhydrous
magnesium sulfate and evaporated ~o dryness. The
residue was triturated with diethyl etheT to give a
crude product of the title compound (120 mg~. The crude
m~terial was dissolved in an aqueous solution of sodium
bicarbonate and reprecipitated with diluted hydrochloric
acid to give the pure title compound (60 mg), mp. 170
to 175~C ~dec.).
I.R. (Nujol) : 3300, 177Q, 1660, 1610, 1520 cm 1
N.M.R. ~d6-DMS0, ~) : 3.73 ~2H; broad s~,
3.97 ~6H, s), 4.33 (2H, broad s),
5.13 (lH, d, J=4Hz), 5.83 (lH~ 2d,
J=4, 8.5H~), 8.12 (2H, s), 9.57 (lH,
d, J=8.5Hz)
~, `
5~ .3
- 51 -
Example 3
Preparation of 7-[2-Me~hoxyimino-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetamido]cephalosporanic acid
(syn isomer).
A mixture of 2-methoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetic acid (syn isomer~(1 21 g} and
phosphorus oxychloride ~3~67 g) in methylene chlor:Lde
~30 ml) was stirred for an hour at ambient te~perature,
cooled and there~o was added N,N-dimethylformamide
~2.4 ml), followed by stirrin~ Eor an additional 30
minutes under ice-cooling. A mixture of 7-amino-
cephalosporanic acid ~2.94 g) and trime~hylsilylacetamide
~10 g) in methylene chloride ~50 ml) was warmed to make
a clear solution. The solution was cooled in an ice-bath
and added ~o the above obtained solution, followed by
stirring for 30 minutes at 0 to 5C. Ihe reaction mix-
ture was poured into a mixture of a saturated a~ueous
solution of sodium bicarbonate ~60 ml) and ice. The
aqueous layer ~200 ml., pH 7 to 8) was separated and
thereto was added ethyl acetate. The resulting ~ixture
was-adjusted to pH 1 with 10% hydrochloric acid,
saturated wi~h sodium chloride and filtered to remove
an insoluble material. The ethyl acetate layer was
separated, dried over magnesium sulfate and evaporated.
~5 The residue was triturated with diethyl ether to give a
cr~de product of the title compound (2.4 g). The crude
material was dissolved in an aqueous solution of sodium
bicaTbonate, trea~ed with activated charcoal ~100 mg),
adjusted to pH 2 with 10~ hydrochloric acidO The p~e-
cipitates weTe collected by iltration, washed withice-water and dried to give the title compound (1.2 g),
mp. 180 to 185C (dec.).
I.R. (Nujol) : 3350, 1780, 1730, 1580, 1620,
1530 cm 1
5 2
.~I.R. (d6-DMS0, ~) : 1.97 ~3H, s), 3.50 (2H, s),
3.87 (3H, s), {4 67 (2~, ABq, J=14~7),
5.08 (lH, d~ J=4H7)~ 5.77 (lH~ 2d,
J=4, 8.5~z), ~.06 (2H7 s), 9.50 (1~l,
dl J=8.5Hz~
Exa~le 4
Prepa~ation of 7-~2-Methoxyimino~2-(5-amino-
1,2,4-thiadiazol-3-yl)acetamidol-3-carbamoyloxymethyl-
3-cephem-4-carboxylic acid (syn isomer).
A mixture of 2-methoxyimino-~-(5-amino-1,2J4-
thiadiazol-3-yl)acetic acid (syn isomer)(l.01 g) and
phosphorus oxychloride (3.06 g) in methylene chloride
(25 ml) ~Tas stirred for 2 hours at ambient tempera~tuTe,
cooled to 0C and thereto was added NJN-d.ime~hyl-
formamide ~2.0 ml), followed by s~irring for an
additional 45 minutes at O~C. A mixture o~ 7-amino-
3-carbamoyloxymethyl-3-cephem-~-carboxylic acid (4.9
g) and t~imethylsilylacetamide (ll g) in methylene
chloride ~100 ml) was warm~d ~o mc~ke a clear solution~
The solution was cooled to -15C and added to the
above ob~ained solu~ion9 followed by stirring for 30
mi~utes at 0C. The reaction mixture was poured into
a cold aqueous solution of sodium bicarbonate.
The aqueous layer was separated and thereto was added
e~hyl acetate. The resulting mixture was adjusted to
pH 2 with 10% hydTochloric acid, filtered to remov~ an
insoluble material and then saturated with sodium
chloride. The ethyl acetate layer was separated,
dried over magnesium sulfate and evaporated. The
residue was triturated with diethyl ether to give ;a
crude product of the title compound (l.Z g). The
crude material ~as dissolved in an aqueous solution
of sodium bicarbonate, and reprecipitated ~-ith 10%
3~ hydrochloric acid. The precipitates were collected ~y
- 53
filtration9 washed ~ith water and dried to give the
title compound (0 ~ ~5 g), mp. lSS to 190C ~dec.) .
I.R, ~Nujol) : 3350, 1780~ 1720, 1680, 1620,
1530 cm~l
N.M.R. ~d6-D~SO~ 3.52 (2H, s), 3.92 ~3H, s),
{ 4 62 (2~1 ABq, J--l2Hz)
5.14 (lH, d, J=4Hz), 5.~0 ~lH, 2d,
J-4,8Hz}, 6.58 (2H, s), 8~10 ~2H9 s),
9 . 54 (lH, d, J=BHz~
PrepaTation of 7- [2-Methoxyimino-2- ~5-amino-
1, 2, 4 - thi adi ar. ol - 3-yl ) ace tami do ] - 2 - methyl - 3- cephem- 4 -
i~ carboxylic acid (syn isomer).
A mixture of 2-methoxyimino-2-t5-amino-1,2,4-
thiadiazol-3-yl)acetic acid ~syn isomer)(1.21 g) and
phosphorus oxychloride ~3.67 g~ in methylene &hloride
~30 ml) was stirred for two hours at ambient temperature7
cooled to oac and theTeto was added N,N-dimethylformamide
~2.4 ml), followed by stirring for an additio~al 45
~inutes at 0C. A mixture of 7-amino-2-methyl-3-
cephem-4-ca~boxylic acid (3.0~ g) and trimethylsilyl-
acetamide tlO g) in methylene chloride (50 ml) was
warmed to make a clear solution~ The solution was
cooled to -15~C and added to the above obtained solut-
ion, followed by stiTTing for 30 minutes at ODC.
The reaction mixture was poured into a cold aqueous
solution of sodium bicarbonate. The aqueou~ layer
was sepa~ated and the~eto was added ethyl acetate.
The Tesulting mixture was adjusted to pH 2 with 10%
hydrochloric acid and the ethyl acetate layeI was
separated, dried over anhydrous magnesium sulfate and
then evaporated. The residue was tTiturated with
diethyl ether to give a crude pToduct of the title
~7
- 54 -
compound (2.2 g). The crude ma~erial was dissol~ed
in an aqueous solution of sodium bicarbonate, adjusted
to pH 2 with 10% hydrochloric acid. The precipitates
~ere collected by filtration, washed ~ith ice-water
and dried ~to giYe the title compound (1 6 g), mp. 175
to 180C (dec.).
I~R. ~Nujol) : 3350, 1775~ 1675, 1630, 1530 cm 1
N.M.R. ~d6-DMS0, ~} : 1.43 (3H, d, J=6Hz) t
3.6-3.9 (lH, m)~ 3.93 (3H, s), 5.07
(lH, d, J=4Hz)~ 5.87 ~LH~ 2d, J=4,8
6.53 (lH9 d, J=5Hz), 8.08 (2H, s),
9.55 (lH, d9 J=~Hz~
E ~
Preparation of 4-Nitrobenzyl 7-~2-metho~rimino-
2-(5-amino-1,2,4-thiadi~zol-3-yl)acetamido]-3-cephem-
4-carboxylate (syn isomer) (I) c~nd 4-nitrobenzyl 7-[2-
methoxyimino-2-{S-{N'-~N,N-dimethylaminomethylene~-
amino}-1,2,4-thiadia~ol-3-yl~acetamido]-3-cephem-4-
carboxylat~ (syn isomer)~II).
A mix~ure of 2-methoxyimino-2-~5-ami~o-1,2,4-
thiadiazol-~-yl)acetic acid (syn isomer)(l.~l g~ and
phosphorus oxychloride (3.S7 g) in methylene chloride
(30 ml) was stirred for 2 hours at ambient temperature 9
cooled to 0C and theTeto was added N,~-dimethylormamide
(2.4 ml~ J followed by stirring for an additional 45
minutes at 0C. A mixture of 4-nitrobenzyl 7-amino-
3-cephem-4-carboxylate ~2.68 g) and trimethylsilyl-
acetamide ~8 g) in methylene chloride (80 ml~ was
stirred for 2 hours at ambient temperature to make a
clear solution. The solution was cooled to 0C and
added to the above obtained solution, followed by
stirring for 30 minutes at 0 to 5C. The reaction
mixture was poured into a cold aqueous solution of
sodium bicaTbonate. The methylene chloride layer was
-- 55 --
sepaTated, dried over magnesium sulfate and evaporated.
The residue ~as triturated ~-Tith diethyl ether tD give
a mixture of crud~ product o:f the title compound (I)
and ~II) (3.7 g). The c~ude powder was su~jected to
5 column chromatography on silica gel using sthyl acetate
as an eluent to :Eirstly give the title compound (I)
(1.0 g), mp. 150 to 155~C. From subseq,uen~ fractions,
there was obtained the title compound (II) (1.1 g),
~. 115 to 120~C. The title cor~pound ~I) has the
10 following ~.R. and N.M.R. spectra;
I.R. ~Nujol): 3300, 177OJ 1720, 1670, 1620"
1510 cm~l
N.M.R. (d6-DMSO, ô) : 3.63 ~2H, broad d, J=3Hz~l,
3.93 (3H, s), 5.17 (lH, d, J=4Hz),
5.43 (2H) s), 5,92 tlH, 2d, J-~,9Hz~,
6.67 ~lH~ t) :J=3Hz), 7.70 ~2H, d, J- 8Hz),
8.08 (2H, s), 8~23 ~2H, d~ J=8Hz),
9.55 (lH, d, J=9Hz)
The title compound tII) has the :following I.R~ and
20 N.M.R. spectra;
I.R. (Nujol): 3300~ 1770, 1720, 167û, 1610 cm 1
N.M.R. (d6-DMSQ, ~) : 3.07 ~3H, s), 3.20 ~3H, s),
3.63 (2H, broad d, J=3Hz3 7 3.97 (3H, s),
5.17 ~lH, d, J=4Hz), 5.43 (2H, s),
5.93 (lH, 2d, J=4,8Hz), 6.67 (lH, t~
J=3Hz), 7.70 ~2H, d, J=8Hz3, 8.23 (2H,
d, J=8Hz~, 8.47 (lH, s), 9.60 ~lH, d~
J=8Hz)
5~
-~6 -
Example 7
A mixture o~ 2-ethoxyimino-2-~5-amino-1,2,4-
thiadia~ol-3-yl)acetic acid tsyn isomer)(l.3 g) and
phosphorus oxychloride (3.67 g) in methylene chloride
(30 ml~ uas s~isred for 2 hours at ambient ~emperatu~e
and then cooled to -~ to -15C. To the cold mixture
was added dimethylformamide (2.4 ml) and the mixture
was stirr~d for 45 minutes a~ -8 to -10C. On the
o~har hand, a mixture of 7-amino-3-~1,3,4-thiadiazol-
2-yl)thiomethyl-3-cephem-4-carboxylic acid (2.~ g3
and trimethylsilylacetamid~ ~8 g) in me~hylene chloride
~40 ml) was warmed ~o make a solution. The solution
was cooled ~o -25C and added to the above activated
mixture. The reaction mixture was stirred for 30
minutes at -8 to -10~C and po~ed into a cold a~ueous
solution of sodium bicarbonate. The mixtu~e was
stirred for 30 minu~es at ambient temperature and the
aqueous larer was s~parated out. The a~ueous solut-
ion was adjusted to pH 1 with 10~ hydrochloric acid
and extracted with ethyl acetate. The extract was
dried oYe~ magnesium sulfate and evaporated to dry-
ness. The residue was tri~ura~ed with diethyl ether
to gi~e a crude 7-[2-ethoxyimino-2-(S-amino-1 9 2,4-
thiadia~ol-3-yl)acetamido~-3-~1,3,4-thiadiazol-2-yl)-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer)
~.6 g). The crude product was dissolved in an
aqueous solution o~ sodium bicarbonate and repreci-
pita~ed with an addition of 10% hydrochloric acid to
give pure object compound ~1.92 g). mp 150 to 155C
~dec.)
I. R. ~ujol) : 3350, 3230, 1775, 1680, 1620,
1530 cm~l
N.M.R. (d6-DMSO, ô~ : 1.27 ~3H, t, J=7H ),
- 3.72 ~2H, broad s), 4.22 (2H, q, J=7H~)
;5 4.32 and 4.55 t2H, ABq, J=l~Hz),
,
57 -
5.17 (lH,d3 J=5H~), 5.83 (lH, dd,
J=5 and 8Hz), 8.13 (~H, broad s)
9.56 ~lH, d, J=8Hz), 9.57 ~lH, s)
Example 8
A mix~ure of 2-isop~opoxyimino-2-~5-amino-1,2,4-
thiadia~ol-3-yl)acetic acid (syn isome~)(1.38 g) and
phosphorus oxychloride (3~67 g) in methylene chloride
~30 ml) was stirred for l.S hours at ambient tem-
peratu~e and then cooled to -12 to-15C.
To the cold mixture was added dimethylformamide
~2.4 ml) and ~he mixture was stirred for 45 minutes
a~ -8 to -10C. On the other hand~ a mixture of
7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-
4-carboxylic acid (~.9 g) and trimethylsilylsc~tamid~
(8 g) in methylene chloride ~40 ml~ was warmed to
make a solution. The solution was cooled to -25C
and added to the above activated mixture. The re-
acti~n ~ixture was stirred for 30 minutes at ^10~C
and poured into a cold aqueous s~lution o~ sodium
bicarbonate. The mixtu~e was stirred for 30 minutes
at ambient temperature and the aqueous layPr was
separated out. The aqueous solution was adjusted ~o
pH 1 with 10~ hydrochloric acid and extTacted with
ethyl acetate. The extract was dried over magnesium
sulfate and evaporated to dryness. The ~esidue was
triturated with diethyl ether to give a crude 7-[2-
isopropoxyimino-2-:~5-amino-1,~,4-thiadiazol-3-yl~-
acetamido]-3~ 34-thiadiazol-2-yl~thiomethyl-3-
cephem-4-carboxylic acid ~syn isomer)~2.25 g).
The crude product was dissolved in a mixture of
acetone and e~nyl acetaLe. The acetone was evapo-
rated and the precipi,ates were collected by filt-
ration to give the same object compound (1.53 g),
which was dissolved in an aqueous solution of sodium
bicarbonate and reprecipitated with an addition of
s~
~ 5~ ~
10~ hydrocnlaric acid ~o giYe pure object compound
3 g). mp 145 to 150C Cdec.)
I.R, ~ujol) : ~370, 32~0, 1780, 1680, 16~5,
1~30 cm~
S N.M.R. ~d6-DMS0, ~ : 1.25 ~H, d, J=6H~
3.68 ~2H, broad s?, 4.2-4.~ ~lH, m)g
4.28 and 4~55 (2H, ABq9 J~13H7), 5.13
: (lH~ dy J=SHz)~ 5.8U (lH, ddr J~S and
~Hz) 8.1~ ~H3 broad s), 9.S0 ~lH, d~
J=8Hz~, 9.53 (lH, s)
Exam~le_g
- A mixture of phosphorus pe~tachloride ~250 mg)
and methylene chloride ~S ml~ was stirred for 10
mi~utes a~ ambie~t temperature. 2-Isopropoxyiminoo
Z-(5-ami~o-lgZ,4-thiadiazol-3-yl)acetic acid (syn
isomer~ 0 mg) was added thereto at -15C and ~he
mixtuTe was stiIred ~or 4S minutes a. -10 to -lâC~
A solu~ion of 7-aminocephalosporanic acid (350 mg~
- 25 and ~rime~hylsilylacetamid~ (1 g) în methyle~e
chlcride ~5 ~1) was added thereto at -15C and the
mixture was stirred f~r 30 minutes at -10C. To the
reaction mix;ur~ were ~dded a saturated aqueous
solution of sodium bicarbona e (8 ml) and water (10
_~ ml), and then methylene chloride was evapora~ed.
To the aqueous layer W25 added ethyl ace~a~e, and
the mi~ture ~'2S adjusted to pH 2 with 10% hydrochloric
acid and tne~ extracted wi~h ethyl acetate. The
ex~rac~ was dried over magnesium sulfate an~ ccncent-
rated. Tne residue was triturated with diethyl ether
a~
- 59 ~
and precipitates were collec~ed by filtration to
gi~re 7- [2-isopropoxyimino-2- C5-amino-1, 2, 4-~hiadi~zol -
3-yl)ace~amido~cephalospora}lic acid ~syn isomer)
~4aO mg) . mp lSO ~o l~5C. ~dec.~
a I. R. ~Nujol): aaOO, 1?80, 1125, l660, 15?0 cm l
N.M.R. ~d6-DMSO, ~ O ~6H, d, J-6Hz) ~
2.û8 ~3H, s) ~ 3.62 ~2H, broad s), 4 .33 -
4.67 ~lH~ m~, 4~77 and 5.03 (2H, A~,
J~13Hz), 5.22 ~lH, dy J-4Hz), 5.87 ~lH9
dd, J-4 and 8Hz~ ~ 8 ,i7 (2H, s~ " 9.53 ~lH,
d" J=8Hz)
- -
aO
, ?~S~
- 60 -
Example 10
To a cold solution of phosphorus pentachloride
(2.5 g) in methylene chloride (60 ml) was added
2-ethoxyimino-2-(5-amino-1,2 9 4-thiadia~ol-3-yl)acetic
5 acid tsyn isomer)~2.16 g) at -15C ancl th~ mixture
was stirred for 30 minutes a~ the same temperature.
On the other hand, a mixture of 4-nitloberLzyl 7-amino-
3-cephem-4-carboxylate (4.0 g) and trimethylsilyl-
acetamide (12 g) in me~hylene chloride (60 ml) was
warmed to make a clear solution and then cooled to
-10C. The solution was added to the above activated
mixture and the mixture was stiTred for 0.5 hour at
O to 5~. The reaction mixture was poured into cold
aqueous solution (150 ml) o sodi~l bicarbonate (7.0 g).
The organic layer was dried o~er magnesi~ sulate
and evaporated to d~yness. The residue was pulverized
with diethyl ~ther and precipitates ~Yere collected by
filtration and dried ~o give 4-nitrobenzyl 7-~2-
e~hoxyimino-2-(5-amino-1,2,4-thiadia201-3-yl)acetamido]-
3-cephem-4-carboxylate ~syn isomer)~5.5 g), mp. 120 to
125 DC (dec.).
Nujol) : 3300, 177Q, 1720, 1670, 1620,
1605, 1520 cm~l
N.M.R. ~d6-D~ISO, ~) : 1.23 (3H, t, J=7Hz),
3.50-3.70 ~2H, m), 4.33 (2H, q, J=7Hz),
5.10 (lH, d, J=4Hz) 9 5.37 (2H, s),
5.88 ~lH, dd3 J=4 and 8Hz), 6.60 (lH,
t, J=4Hz), 7.63 (2H, d, J=8Hz),
8.07 (2H~ s~, 8.17 ~2H~ d, J=8Hz),
9.50 (lH, d~ J=8Hz~
Exam~le 11
The following compounds were prepared by similar
man~ers to those described in Examples 1 to 10.
(1) 7-~2-Methoxyimino-2-~5-amino-1,2~4-
61 -
thiadiaz~l-3-yl)acetamido]-3-~5-methyl-1,3,4-
thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic
acid ~syn isomer), mp. 175 to 180C (dec.).
I.R. (Nujol) : 3350, 1780~ 1680, 1625, 1530 cm 1
N.M.R. (d6-DMSO, ~) : 2 72 (3H, s), 3.70 (2H, s),
4.00 ~3H, s)~ 4.25, 4.53 (2H, ABq,
J=14Hz), 5.16 (lH, d, J=4H~), 5.83 (lH,
2d, J=4,8Hz~, 8.13 t2H, s) ) 9.58 tlH,
d~ J=8Hz)
(2) 7-[2-Methoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido~-3- (1 9 3,4-thiadiazol-2-
ylthiomethyl~-3-cephem-4-carboxylic acid (syn isomer),
mp. 172 to 177C ~dec.).
I.R. ~Nujol) : 3350, 1775, 1680, 1625, 1530 cTn 1
N.~5.R. ~d6-DMSO, ~) : 3.80 ~2H~ s), 4.00 (3H, s),
4.38, 4.67 ~2H, ABq, J=14Hz),
5.22 (lH, d, J=SHz) 9 S.gO ~lH, 2dt
J=5~8Hz), 8.20 (2H, s~, 9.63 ~lH, s),
9.67 ~lH, dJ J=8Hz)
~3) 7-[2-Methoxyimino-2-~5-amino-132~4-thiadiazol
3-yl)acetamido~-3-~1-allyl-lH-tetrazol-5-ylthiomethyl)-
3-cephem-4-carboxylic acid (syn isomer), mp. 170 to
172~C (dec.)~
I.R. ~Nujol) : 3350, 1780, 1680, 1625, 1530 cm 1
N.M.R. (d6-DMS0, ~) : 3.67 (2H, s), 3.93 (3H, s) 9
{4 43 (2H, ABq, J=13Hz), 4.9-S.S (SH, m)~
5.6-6.3 ~2H9 m), 8.10 (2H, s),
9~53 (lH, d~ J=8Hz)
(4) 7-~2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-
3-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer),
mp. 190 to 195C ~dec.).
I.R. (Nujol) : 3350~ 1775, 1680, 1630, 1530 cm 1
- 62 -
. ~) 7-12-Propoxyimino-2-~5-amino-1,2,4-
ehiadiazol-~-yl)~cetamido~- J- (1 ~ 3, ~ -thiadiazol-2-
yl)thiome~hyl-3-cephem-4-carboxylic acid (syn
isomer). mp 1~0 to l~aC (dec.~
I. R. ~Nujol~ ; 33~0, 3230, 1780, 1680,
16~5, 1530 cm 1
N.M.R. ~d6-DMSO~ D.92 ~3H, t, J-6Hz~,
1.3-2.1 (2H~ m), ;.12 (2H, t, J=6Hz)~
. 3.7~ (2H, broad s~, 4133 and 4.58
~2H, ABq, J=13H~) 9 5.17 ~lH~ d, J-5Hz),
5.82 (lH, dd, J=5 and 8Hz), 8.12 (2H,
broad s) J 9.5~ ~lH~ d, 3-8Hz), 9.57 ~lH,
s)
~6 ) ~-~2-Methoxyimino-2-(s-amino-l~2~4-
thiadiazol-3-yl)acetamido]-3-~5~N-t-butoxycarboTlyl-
amino)me~hy}-1,3~4-~hiadiazol-2-yl}thlomethyl-3
cephem-4-caTboxylic acid ~syn isomer), mp 150 to
lSS~C ~dec.)
I. R. ~Nujol~ : 33S0J 3250, 1780, 1670 cm 1
N.M.R. ~d6-DMS0, ~) : 1.40 ~9H, s), 3.70 ~2~,
broad s)~ 3.93 ~3H) s), 4.30 and 4.53
20 . t2H, ABq, J313Hz); 4.53 ~2H, d, ~SHz),
5.17 ~lH, d, J-4Hz), 5.83 ~lH7 dd, J=4
~nd 8H~), 8.13 (2H, s~, 9~57 ~lH~ ~,
J=8Hz)
(7 ) 7-[2-Methoxyimino-2-~S-amino-1,2 9 4-
Z5 thiàdia~ol-3-yl)acetamido]-3-t5-allylthio 1,3,4-
thiadiazol-2wyl)thiome~hyl-3-~ephem-4-ca~boxylic
acid (syn isomer). mp 160 to 165C ~dec~)
I. R. (Nujol~ : 33503 32~09 1780, 1680,
. 1620 cm
3~ . N-M-R- (d6-DMS07 ~) : 3.70 ~2H, broad s),
a.9;- 4.0 ~2H, m), 3.93 (3Hl 5~-
4.27 and 4.50 (2H, ABq, J=14Hz),
5.15 (lH, d~ J=4H_) ~ S .1-5 .5 ~2H, m),
5.6-6.2 ~lH, m)~ 5.83 (tH, dd, J=4 and
8Hz~, 8.1~ ~2H, s), 9.57 ~lH, d, J38H~
.
'~ ~>~5
64
~ 8 ) 7-[2-Methoxyimino-2-(5-amino-l~2J4~
thiadia~ol-3-yl~acetamido~-3-acetylth:Lomethyl-3-
cephem-4-ca~boxylic acid (syn isomer), mp 178 to
182C (dec.)
I. R. ~Nujol) : 3350, 3250, 1780,, 16B0, 1620 cm 1
N.M.R. (d6-DMSO~ 2.83 t3H, t~) ~ 3.27 and
3~57 t2H, ABq, J=18Hz)~ 3.83 t3H, s),
3.73 and 3.97 (2H9 ABq, J~=13Hz) 9 5.04
tlH, d, J=4Hz) 9 5.72 (lH, dd, J=4 a~d
8Hz~, 8.07 (2H7 s), 9.47 (lH, d, J=8Hz)
(9 ~ 7-~2-Methoxyimino-2-(5-amino^1,2,4-
thiadia~ol-3-yl)ace~amido]-3-pyra~inylthiomethyl-3-
cephem-4-carboxylic acid (syn isomer). mp 170 to
174C (dec.)
I. R. (Nujol) : 3350, 3250, 1780, 16809 1620
153~ cm~l '
~O) 7-~2-M~hoxyimino~ 5-amino 1~2~4-
thiadiazol-3-yl)acetamido]-3-~2-thia~o~in-2~yl~-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
mp 175 to 180~C (dec.)
I. R. (Nujol) : 3350, 3~50, 1780, 16~0, 1620,
1530 cm 1
(11) 7-~2-Methoxymino-2-(5-amino-1,2,4-~hia- -
diazol-3-yl)acetamido]-3-(~etrazolo[1,5-blpy~idazi:n-
6-yl)thiomethyl-3-cephem-4-carboxylic acid ~sy~
isomer). mp 175 to 180C ~dec.)
I. R. (Nujol) : 3400, 325Q3 1885, 1725, 1670,
1640, 1540 c,m 1
~12) 7-~2 Methoxyimino-2-(S-amino-1,2,4-
thiadia~ol-3-yl)acetamido]-3-[1-{2-(N-t-butoxy-
~arbonylamino)ethyl~lH-tet~azol-5-yl]thiomethyl-3-
cephem-4-carboxylic acid (syn isomer). mp 200 to
205C ~dec.)
~ Nujol~ : ~300, 17~0, 1700, 1680, 1620,
1520 cm 1
- 65 -
~ ) 7- [2-~ethoxyimino-2- (5-amino-1,2,4^
thiadiaæol-3-yl)acetamidQ] ~3- (l-propyl~lH-tetra~ol
5-yl)thiome~hyl-3-cephem-4-carboxylic acid ~syn
isomeT). mp liS to 160aC Cdec.)
I. R. (Nujol) : 3350, 32503 1780, 16B0,
1630~ 1530 cm~l
~4) 7-[2-Methoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl~acetamido]-3-~1-(3-methoxypropyl)-
lH-tetrazol-5-yl]*hiomethyl-3-cephem-4-carboxylic
acid ~syn isomer~. mp 165 ~o 1~7C (dec.)
I. R. (Nujo~ : a350, 3250, 1780, 1680)
1620~ 1530 cm~l
~5) 7-~2-Methoxyimino-2-(5-amino-1,2l4-
thiadiazol-3-yl)ace~amido]-a-(3-me~hyl-1,2,4-
lS thiadiazol-5-yl)thiome~hyl-3-cephem-4-carboxylic
acid (syn isomer). mp 178 to 182C (dec.)
I. R. ~Nujol) : 3350, 3250, 1780, 1680,
1630~ 1530 rm 1
~6 ) 7-[2-Me~hoxyimino-2-(S-amino-1,2,4-
~ thiadiazol-3-yl) acetamido~ - 3- (5 -methoxymethyl-1,3,4
thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic
acid tsyn isomer), mp 170 to 174C (dec.)
I. R. ~Nujol): 3350, 3250, 1780, 1680,
1630~ 1530 cm l
(17) 7-[2-Methoxyimino-2-( 5-amino-19 2,4-
thiadiazol-3-yl)acetamido]- 3 - ~ 5 -methylthiomethyl-
1~3,4 -thiadia-ol - 2 -yl) thiomethyl-3-cephem-4-
carboxylic acid (syn isomer). mp 173 to 175C ~dec.)
I.R. ~Nujol): 3350, 3250, 1780, 1680p
1630, 1~30 cm 1
(18) 7~ [2 -Methoxyimino- 2- ~5-amino-1,2,4 -
thiadia20l -3-y~)acebamido~ -3-(4-propyl-4H-1,2,4-
triazol-3-yl~thiomethyl-3-c~phem-4-carboxylic acid
(syn isomer). mp 182 to 184C (dec.)
I. R. (~ujol): 33~0, 3250, 1780, 1680, 1620,
1530 cm-l
~S~ ~3
- 66-
(19) 7-E2-~ethoxyimino-2-(5-amino-l~Z,4-
thiadiazol-3-yl)acetamidol-3~ methylthiomethyl-
lH-tetrazol-S-yl)thiomethyl-3-cephem^4-carboxylic
acid ~syn isomer). ~p 175 to 178aC ~dec.~
I. R. (Nujol) : 3350J 3250, 178Q, 1680, 1620,
1530 cm~l
(20) 7-~2-Methoxyimino-2-(5-amino-1,~,4-
~hiadiazol-3-yl)ace~amidol-3~ isopropyl-lH-
tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer)~ mp 180 to 182C (dec.)
I. R. (Nujol) : 3350, 3250, 1780, 1680,
1~30, 1530 cm 1
~1) 7-[2-Methoxyimino-2-~5-amino-1,2,4-
thiadia201-3-yl)acetamido]-3-[1-~2-hydroxyet}lyl~-lH-
tetrazol-5-yl]~hiomethyl-3-cephem-4-carboxylic acid
(syn isomer). mp 170 to 175C ~dec.~
I R. (Nujol) : 3350 9 3250g 1780, 1680,
1625 J 1530 cm 1
~2~ 7-~2-Methoxyimino~ S-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-~5-~2-hydroxyethyl)-
1,3,4-thiadiazol-2-yl]thiomethyl-3-cephem-4-
carboxylic acid (syn isomer) mp 175 to 180C ~dec.)
I. R. ~Nujol) : 3350, 32S0, 1780, 1680, 1630,
1530 cm~l ~
(23) 7-12-Methoxyimino-~-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-(5-propyl-1,3,4-
thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer). mp 177 to 180C (dec.)
I. R. (Nujol) : 3350, 3250, 1780, 168G,
1630, 1530 cm^l
(24~ 7-[2-Methoxyimino-2-~5-amino-1,2,4-
thiadiazol-3-yl)acetamido] -3- ~5-hydroxymethyl-1,3,4-
thiadiazol-2-yl3thiomethyl-3-cephem-4-carboxylic
acid (syr. isomer). mp 165 to 170C (dec.3
I. R. (Nujol) : 3350J 3250, 1780~ 1680, 1620,
1530 cm~l
-67 ~
(2~ 7-[2-Methoxyimino-2-(5-amino-1,2 94 -
thiadia~ol-3-yl)acetamido~-3-~5 methanesul~onamido-
methyl-1,3,4-thiadiazol-2-yl)thiomethy:L-3-cephem-
4-carboxylic acid ~syn isome~). mp 170 ~o 17SC
(dec,)
Io ~. tNUjol) : 3350, 3250, 1780, 16~0,
1620, 1530 cm l
(26) 7-~2-Me~hoxyimino-2-(5-amino-192 7 4-
thiadiazol-3-yl~acetamido]-3-(3-allylt.hio-1,2,4-
1~ thiadiazol-5-yl~thiomethyl-3-cephem-4-carboxylic
acid ~syn isomer). mp 170 ~o 173C ~dec.)
I, R. ~Nu~ol~ : 3a50, 3250, 1780, 16~0,
16~0, 1530 c~-l
~27) 7-~2-Methoxyimino-2-(5-amino-1,2,4-
thiadia~ol-3-yl)acetamido~-3-(S mesylmethyl-~,3,4-
thiadiazol-2-yl~thiomethyl-3~cephem-4-ca~boxylic
acid (syn isomer)~ mp 175 to 180C (dec.)
I. R. (Nujol~ : 3350, 3~50, 17~0, ~680,
1620, 1530 cm 1
~0 (28~ Sodîum 7:E2,~ethoxyimino-2-~5-amino-
1~ 2, 4 -thiadiazol 3 -yl) ace~amido] - 3- ~1 -sul:Eon~ tomethyl -
lH-tetrazol-5 -yl)thiomethyl-3-cephem-4-caTboxylic
acid ~syn isomer). mp 205 to 210C (dec.)
I. R. (Nujol) : 3350, 3250, 1780, 1680,
1530 cm 1
~2~) 7-[2-Methoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-(4-methyl-4H-1,2,4-
triazol- 3 -yl) thiomethyl-3-cephem-4 -carboxylic acid
~syn isomer)~ mp 180 to 185C (dec.)
I. R. (Nujol) : 3350, 3250, 1780, 1680,
1620, 1530 cm~l
5O~ 7-[2-Methoxyimino-2-t5-amino-19 2,4-
*hiadiazol-i-yl)acetamido~-3-[1-{ 2 - (N, N - dimethylamino)-
ethyl~lH- tetra z ol - 5 -yl ~ thiomethyl-3-cephem-4-
carboxylic acid (syn isomer). mp 185 to 190C (dec.)
s~
_ 68~
I. R. tNujol) : ~350, 3250, 1780, 1680,
1620, 1530 cm~
~l) 7-~2-Methoxyimino-2-(5-amino-1~2,4-
thiadiazol-3-yl)acetamido]-3-[4-(3-methoxypropyl)-
4H-1,2,4-tria~ol-3-yl]thiomethyl-3-cephem-4-
caTboxylic acid ~s~n isomer). mp 175 to 180C (dec.)
I, R. (Nujol) : 3350, 3250, 1780, 1680,
1620~ 1530 cm l
(32) 7-[2-Methoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl~ac~amido]-3-~5-C2-aminoethyl)-1,3,4-
thiadiazol-2-yl~thiomethyl-3-cephem-4-carboxylic
acid ~syn isomer). mp 205 to 210C (dec.)
I. R. ~Nujol) : 3200, 1770, 1670, 1620,
1530 cm 1
t33) 7-[2-Methoxyimino-2-~5^amino 1,2,4-
thiadia~ol-3~yl~acetamido]-3-~5-aminomethyl-1,3~4-
thiadiazol-2-yl)~hiome~hyl-3-cephem-4-carboxylic
acid ~syn isomer). mp 2~0 to ~15C ~dec,)
I. R. ~Nujol) : 3350, 32Q0, 1770, 1680, 1620 cm 1
~34) 7-~2-Methoxyimino-2-(5-amino 1,2,4-
thiadiazol-3-yl)acetamido]-3~ (2-aminoethy~)-lH-
tet~azol-5-yllthiomethyl-3-cephem-4-carboxylic acid
(syn isomer). mp 200 to 205C ~dec.)
I. R. (Nujol) : 3350, 3200, 1775l 1670,
25 1620, 1530 cm
~35) 7-~Z-Ethoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido]cephalosporanic acid
~syn isome~). mp 140 to 156~C (dec.)
I. R. (Nujol) : 3370, 32S0, 1780, 1730, 1680~
1620, 1530, 1380, 1240, 1040 cm
5~ 3
- 69 -
N.M.R. (d6-DMS0, o~ : 1.23 (3H, t, J=7Hz), 2.00
(3H, s~, 3.7 (2t~, m~, 4.17 (211, q, J=7Hz),
4.63 and 5.00 (2H, ABq, J=12Hz), 5.10 (lH,
d, J=4.5Hz), 5.80 ~lH, dd, J=4.5 and 8 O~lz),
8.1 (2H, broad s), 9.53 (lH, d, J=8H,)
~36) 7-[2-~thoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]
-3-[1-(3-(N-t-butoxycarbonylamino)propyl)-lH-tetrazol-5-ylJthiomethyl-
3-cep~em-4-carboxylic acid (syn isomer). mp 183 to 188C (dec.)
I.R. (Nujol) : 3370, 3240, 1780, 1690, 1630,
1530, 1380, 1260, 1170, 1040 cm~
(37) 7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acletarllido~
-3-[1-(2-(N-t-butoxycarbonylamino)ethyl)-lH-tetrazol-5-ylJ-thiomethyl-
3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3360, 3240, 1780, 1690, l630
1530, 1375, 1250, 1170, 1040 cm~l
~38) 7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]
-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer). mp 156 to 159C (dec.)
I.R. (Nujol) : 3360, 3250, 1780, 1680,
1625, 1380, 1080,-1040 cm~l
,~ .
, .,~
7o -
~9) 7~2-~thoxyimin~-2-~5-amino-1,2,4-
thiadia2O1-3;yl)àcetamido]-3-[i-~2-~N,N-dimethylamino)-
e~hyl}-lH-tetra~ol-5-yl~thiomethyl-3-cephem-4-
carboxylic acid (syn isomer). mp 177 to 180C (dec.)
I.R. (Nujol) 3380, 3250, 1775, 1670, 1620,
1535, 1380, 1040 cm~l
(40) 7-~2-Ethoxyimino-2-~5-amino-~,2l4-
thiadia~ol-3-~l)acetamido]-3-(1-allyl-lH-tetrazol-5-
yl)~hiomethyl-3-cephem-4-carboxylic acid (syn isomerj.
mp 160 to 165C (dec.)
I.R. ~Nujol) : 3380, 3250t 1780~ 1680, 1630,
1530, 1380, 1040 cm~l
(4~ 7-[2-Ethoxyimino-2~5-amino-1,2,4-
thiadiazol-3-yl)acetami~o]-3-(te~razolo[1,5-b]pyridazin-
lS 6-yl)thiom~thyl-3-cephem-4 carboxylic acid ~syn
isomer). mp 180 to 185C (dec.)
I,R. (Nuj~ 3350t 3240, 178OJ 1680, 1620,
1530, 1380, 1040 cm 1
~42) 7-~2-Ethoxyimino-2-t5-amino-1,2,4-
thiadia~ol~3-yl)acetamido]-3-tS-aminomethyl-1~3,4-
thiadiazol-2-yl)thioMethyl-3-cephem-4-carboxylic
acid ~Syll isomer). mp 198 to 205C (dec,)
I.R. ~Nujol) : 33509 3250, 1775, 1680, 1620,-
1535, 1380, 1040 cm l
(43) 7-[2-Ethoxyimino-2-~5-amino~ ,4-
thiadiazol-3-yl)acetamido]-3-[1-(2-hydroxyethyl)-lH-
tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid
(syn isomer). mp 170 to 173C (dec.)
I.R. (Nujol) : 3350, 3240, 178Q, 1675, 1625,
1530, 1380, 1040, 720 cm 1
(44) 7-[2-Methoxyimino-2-(5-amino-1,2,4-
thiadia~ol-a-yl)acetamido]-3-(4-zllyl-4H-1,2,4-
tria~ol-3-yl)thiomethyl-3-cephem-4- aIboxylic acid
(syn isomeI). mp 185 to l90~C (dec.)
I.R. tNu~ol) : 33~0, 3250, 1780, 1680, 1625,
1530 cm~l
-71 -
~4~ 7-L2-Methoxyimino-2-~5-amino-1,2J4-
thiadia301-3-yl)acetamido]-3 ~3-methoxycarbonyl-
1,2~4-thiadiàzol-5-yl)thiomethyl~-cephem-4-
carboxylic acid ~syn isomer). mp 180 to 185C ~dec.)
S I.R. ~Nujol) : 3;50, 3250, 1780, 1740~ 1680,
1620, ~530 cm~l
~46) 7~ Methoxyimino-~-(5-amino 1,~,40
thiadiazol-3-yl)acetamido~-3-(3-caIboxy 1,~,4-
thiadiazol-5-yl)thiomethyl-3-cephem-4 carboxylic
acid (syn isomer)~ mp 175 to 1~0C ~dec.)
I.R. (Nujol) : 3350, 32$0, 1780, 1730, 1680
1620g 15~0 cm 1
(47) 7 ~2-E~hoxyimino-~-(5-amino-1,2,4-
thiadiazol~i-yl)acetamidol-3-[1-~3-aminoprupyl)-
lH-tetra201-S-yl]thiomethyl-3-cephem-4 carboxylic
acid tSyn isomer~. mp lB2 ~o 185C ~dec.)~
I~R. ~Nujol) : 3350, 3200, 1770, 1670, 1620,
- 1530, 1380, 1040 cm 1
~48) 7-~2-Ethoxyim;no-2-~5-amino-l,Z,4-
aO thiadia~ol-3-yl)ac~tamido]-3-~ 2-aminoethyl~-lH-
tetTazol-5--yl~thiomethyl-3~cephem-4-carboxylic acid
(syn isomer). mp 195 to 210~ ~ (d~c~).
Nujol) : a3403 3210, 1770, 1675, 1620,
liaO, 1;80, 1040 cm 1
~ S ~t3
- 72 ~-
(49) 4-Nitrobenzyl 7- [2-isopropoxyimino-2-(5-
amino 1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-
carboxylate (syn isomar), mp~ 145 to 150C ~dec.).
I.R. ~Nujol): 330Q, 1775, 1720, 1670, 1620,
1600, 1520 cm 1
N.M.R. (d6-D~S0, ~ : 1.27 (6H, d, J=7Hz)~
3.53-3. 77 ~2H3, m), 4.17-4.67 (lH~ m),
5.17 tlH~ d, J-4Hz), 5.42 (2H, s) "
5.93 ~1~, dd, J=4 and 8Hz),
6.67 (lH, t, J-4Hz~, 7.86 ~?H, d, J=8Hz),
8.13 (2~, s), 8~23 ~2H, d~ J=8Hz),
9.53 tlH, d, Ja8Hz)
(50) 7 - ~2- Is opropoxyimino-Z-~5-amino-1,2,4-
thiadiazol- 3-yl) acetamido] - 3- [5-~N-t-butoxycarbonyl.-
ami~o)methyl-1,3,4-thiadiazol-2-yl3thio}nethyl-3-
cephem- 4 -carb oxylic acid ~syn isomer), mp. 140 to
145C (dec.),
I .R. ~Nuj ol) : 3300, 1780) 1670, 1620~ 1530 cm 1
N .M.R. ~d6-DMSO~ 18 ~6H, d , J-6Hz),
1.32 (9H, s), 3. 62 ~2H, b~oad s),
4.17-4.73 ~5H~ m), 5.17 ~lH, d, J=4Hz),
S . 84 (lH, dd~ J=4 and 8Hz), 8.18 (2H,
s), 9.63 (lH, dJ J=BHz)
~51) 7-L2-I^sopropoxyimino-2-(5-amino-l~2~4-
thiadiazol-3-yl)acetamido3-3-(1-carboxymethyl-lH-
tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid
~syn isomer), mp. 175 to 18QC (dec.).
I.R. (Nujol) : 3300, 3200, 1770~ 1720~ 1680,
1620, 1520 cm 1
~52) 7-[2-~lethoxyimino-2-~5-amino-1,2,4-
thiadiazol-3-yl)acetamido3-3-(5-carboxymethylthio-
1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer), mp. 150 ~o 155C ~dec.).
I.R. ~Nujol) : 3350, 3250, 1780, 1720, 1680,
1620, 1530 cm 1
~53) 7-[2-Isopropo~yin~no-2-(5-amino-1~2,4-
thiadiazol-3-yl)acetamido]-3-(1-methyl-lH-t~trazol-
5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn
isomer), mp. 170 to 175C (dec.).
I.R. ~Nujol) : 3350, 3250, 1780) 16~0, 1620,
1530 cm 1
t5~) 7-[2-I~sopropoxyimino-2-~5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonyl-
amino)ethyl3-lH-tetTazol-5-yl~thiomethyl-3-cephem-4-
carboxylic acid ~syn isomer~, mp 142. ~o 147C (dec.).
I.R. (Nujol) : 3350~ 3250, 178û~ 1690, 1630,
1530 cm 1
(55) 7- [2-Isopropoxyimino-2-~5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-~tetra~olo[1,5-b~pyri.-
dazin-6-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp. 165 to 170~ ~dec.).
I.R. ~Nujol~ : 33~0, 3200, 1775, 1710, 16707
1625, lS25 cm~l
(56) 7- [2-Isopropoxyimino-2-~S-amino-1,2~4-
thiadiazol-3-yl~acetamido~-3-(1-allyl-lH-tetrazol-5-
yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) 9
mp. 135 to 140C (dec.).
I.R. (Nujol) : 3350, 3230j 1780, 1680, 1625J
1530 cm 1
(57) 7- [2-Methoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl~acetamido]-3-(5-trifluoromethyl-1,3~4-
thiadlazol-2-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer), mp. 150 to 155C (dec.)~
I.R. (ldujol) : 3300, 3200, 1770, 1670, 162û,
1520 cm~l
(58) 7- [2-Methoxyimi~o-2-(5-amino-l,Z,4-
thiadiazol-3-yl)acetamido]-3-[Z-carboxymethyl-3-oxo-
2,a-dihydro-1,2~4-triazolo[4,3-b]pyridazin-6-yl}-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer),
mp. 205 to 210C (dec.).
- ~ 3
t~.3
-- 74 --
I.R. tNujol): 3300, 1765, 1710, 1680, 1620,
1550, 1520 cm 1
(59) 7- [Z-Methoxyimino- 2 - (S - amino~ 2, 4 -
thiadia~ol-3-yl)acetamido~-3-(5-methylamino-1,3~4-
thiadiazol-2-yl) thiomethyl- 3-cephem-4-carboxylic
acid (syn isomer), mp. 17~ to 180C (dec.).
I.R. (Nujol): 3450, 3370, 3250, 1775, 1710,
1680, 1630, 1560 cm 1
~60) 7- [2-Methoxyimino-2-(5-amino-1~2,4-
thiadiazol-3-yl)acetamido]-3-~5-aminv-1~394-
thiadiazol-~-yl)thiomethyl-3-cephem-4-carboxylic
acid tsyn isomer), n~. 165 to 170C (dec.).
I.R. ~Nujol): 33507 3210, 1770~ 1670, 1620,
1520 cm 1
(61) 7- ~2-Methoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonyl-
amino)propyl}-ll-l-tetrazol-5-yl~thiomethyl-3-c~phem-
4-carboxyli~ acid (syn isomer~ mp. 175 ~o 180C ~de~.).
I.R. (Nujol): 3370g 3250, 1785, 1690, 1630,
1530 cm~l
(6~) 7- [~-Methoxyimino-2-(5-amino-1,2"4-
thiadiazol-3-yl)acetamido~-3-[1-{3~acetamido)propyl}-
lH-tetra~ol-5-yl]thiomethyl-3-cephem-4-carboxylic
acid ~syn isomer), n~ . 150 to 155C (dec.~.
I.R. ~Nujol): 3350, 3230, 1780, 1660, 1620,
1530 cm
(63) 7- ~2-Methoxyimino-2-(5-ami~o-1,2"4-
thiadiazol-3-yl) acetamido]-3- [1-{1 ~acetamidomethyl)-
ethyl}-lH-tetrazol-5-yl]thionethyl-3-cephem-4-
carboxylic acid ~syn isomer),, mp. 160 to 165C (dec.).
I.R. (Nujol): 3350, 3250, 1780, 1660, 1620,
1530 cm 1
(64) 7- ~2-Methoxyimino-2-~5-amino-1,2,4-
thiadiazol-3-yl)acetamido3-3- [l-{l-(~-t-butoxy-
carbonylaminomethyl)ethyl}-lH-tetrazol-5-yl3-
~ 75 -
thiometh~l-3-cephem-4-caTboxylic acid (syn isomer),
mp. lgO to 185~C (dec.).
I.R. (Nujol) : 3370, 32303 1780, 16'30, 163OJ
1530 cm~l
(65) 7-[2-Methox~imino-2-(5-amino-1,~,4-
thiadiazol-3-yl)acetamido]-3-[1-{3-~N,N-~imethylamino)-
propyl}-lH-tetrazol-5-yl]thiomethyl-3-cephem-4
carboxylic acid (syn isomer), mp. 165 to 170C (dec.).
I.R. ~Nujol) : 3350, 3200, 1770, 1670, 1610,
1530 cm~l
(66) 7-[2-Methoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3~ 2-carboxyethyl)-lH-
tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid
~syn isomer), mp. 150 to 1~5C ~dec.}.
I.R. (Nujol) : 3300, 3150, 1770, 1720, 1670,
1620, 1520 cm~l
N.M.R, (d6-DMSO, ~) : 2.93 (2H,~t, J=9Hz~,
3,70 ~2H, broad s), 3.92 ~3H, s)~
4.27 and 4.43 (2H, ABq, J=14H~,
4.45 (2H, t~ J=9Hz), 5.17 (lH, d, J=4Hz),
5,83 (lH, dd, J=4 and 8Hz),
8,18 ~2H, s), 9.67 ~lHy d, J=8~qz)
(67) 7-[2-Methoxyimino-2-(5-amino-1~2,4-
thiadi,zol-3-yl)acetamido~-3-(1-carboxymethyl-lH-
tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp. 123 to 125DC (dec.).
I.R. (Nujol) : 3300, 3200~ 1750, 1720, 1680,
1620, 1520 cm~l
(68) 7-[2-I'sopTopox~imino-2 t5-amin~ ,4-
thiadiazol-3-yl)acetamido~-3-(5-aminomethyl-1,3,4-
thiadiazol-2-yl)thiomethyl-3-cephem-4-ca~boxylic acid
(s}~ isomeT), mp. 210 to 215C (dec.).
I.R. (Nujol) : 3350, 3200J 1750, 1670, 1620,
1530 cm 1
(69) 7-[2-~isopropoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl) acetamido]-3- [1-~2-aminoethyl)-lH-
tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid
~syn isomer), mp. 195 to 200C ~dec.).
I.R. ~NUjO1): 3350~ 3250, 1775~ 1680, 16ZOJ
15 3Q Cm~1
( 70) 7- [2-Methoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl~acetamidol- 3- [ 1 - ( 3-aminopTopyl)-lH-
tetrazol-S-yl]thiomethyl-3-cephem-4-carboxylic acid
(syn isomer)~ n~p. 185 to 190C (dec.).
I.R.~Nujol) : 3300, 3200, 17709 16709 1610,
1530 cm
- ~71) 7-~2-Me~oxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3- ~ minomethy~ethyl}-
lH-tetra~ol-5~yl~thiomethy1-3-cephem-4-carboxylic
acid (syn isomer), mp. 190 to 195C (dec~).
I.R. (Nujol~: 3350, 3230~ 1770, ï670) 16207
1530 cm~l
(72) 7-~2-Isopropox~ Lnc~-2~(5-amino-1~2,4-
th~adiazol-3-yl) acetamido~-3-cephem-4-carboxylic acid
(syn isomer), mp. 208 to 213~C (dec.~.
I.R. (Nujol): 3400, 3350, 3250, 1770, 1660,
1630~ 1610, 1520 cm 1
(73) 7-~2-Ethoxyimino-2-(S-amino-1,294-
thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylic
acid (syn isomer)j mp. 190 to 195C ~dec.~.
I.R. ~Nujol): 3400, 3300, 3200, 1770, 1670,
1630, 1520 cm 1
E~le 12
To a cold solution of phosphorus pentachloride
~3.12 g) in methylene chloride (37 ml) W2S added
2-methoxyimino-2-~5-amino-1,2,4-thiadiazol-3-yl)-
acetic ~cid ~syn isomer) (1.01 g) at -15C and the
mixture ~as stirred for 25 minutes at -10 to -13C
and for 30 minutes at 0 to -3C. On ~he other hand,
'r ~ 6~
- 77 -
a mi~ture of 7-amino-3-~1,3,4-thiadiazol-2-yl)-
thiomethyl-3-cephem-4-carboxylic acid tl.82 g) and
trimethylsilylacetamide (5 g) in methylene chloride
(25 ml) was warmed to make a clear solution and then
cooled to -lO~C. The solutio~ was added to the above
activated mixture and the mixture was stirred for
0.5 hou~ at -5 to 0C. The reaction mixture was
filtered and to the filtra~e was added an aqueous
solution of sodium bicarbonate (80 mll. The mixture
was stirred at ambient temperature and methylene
chloride was distilled of~ The aqueous layer was
adjusted to p~ 1 wi~h 10% hydrochloric acid and
subjected to column chromatography on Diaion HP-20
resin (200 ml)tTrademark: prepared by Mitsubishi
Chemical Industries Ltd.) using successively water,
20% aqueous methanol t500 ml) and 40% aqueous methanol
t500 ml) and the eluate was lyophilized ~o gi~e
7 - ~2-methoxyimi~o-2 - ~5 -phosphonaamino- 1, 2 ~ 4-
thiadiazol - 3-y1) acetamido ~ - 3- (1, 3, 4 - thiadi azol -2 -
yl)thiomethyl-3-cephem-4-caTboxylic acid (syn isomer)
~440 mg), mp. 140 to 145C (dec.).
I.R. (Nujol) : 3180, 1765S 1670, 1515 cm 1
N.M.R. (d6-DMSO, ~3 : 3.72 (ZH, broad s),
3.93 (3H, s), 4.32 and 4.57 ~2H, ABq,
J=13Hz), 5.17 (lH, d, J=5H~3,
5.85 (lH, dd~ J=5 and 8H~ 58 (IH, s~,
9 63 ~lH, d, J=8~z)
Example 13
Preparation of 7-E2-methoxyimino-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylic
acid (syn isomer).
In a mixture of tetrahydrofuran (20 ml), methanol
(lD ml), acetic acid (0.25 ml) and water ~2.5 ml)
~as dissolved 4-nitrobenzyl 7-[2-methoxyimino-2-(5-
,
- 7~ ~
amino-1,2~4-thiadia~ol-3-yl)acetamido]-3-cephem-4-
carboxylate (syn isomer)(0 87 g) and thereto was added
5~ palladium-carbon (0.87 g~. The resulting mixture
was shaken under a hydrogen atmosphere at atmospheric
pressure and ambient tel~erature ~or 6 hours~ The
reaction mixture was filtered and the filtrate was
evaporated to dryness. The residue was dissolved in
a~ aqueous solution of sodium bicarbo~ate and the
solution was washed with ethyl acetate. The aqueous
layer was adjusted to pH 2 with 10% hydrochloric acid
and extracted with ethyl acetate. The extract was
dri~d over magnesium sulfate and evaporated to dryrless.
The residue was triturated with diethyl etner to gi.ve
the title compound (350 mg), mp. 190 to 195C ~dec~)
I.R. ~Nujol) : ~350, 1775, 1680, 1630~ 1530 c~L
N~ R- td6-DMSO~ 3.60 (~H~ broad s), 3~93 (3H,
s~, 5.10 (lH, d, J-4Hz), 5~85 (lH~ 2d,
J-4,8Hz), 6 50 (1}l, t, J-4Hz),
8.10 ~2H, s~, 9.57 (lH~ d, J=8Hz)
Example 14
A mixture of 4-nitroben~yl 7-[2-ethoxyimino-2-
(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-
4-carboxylate (syn isomer)(5~0 g) and 10% palladium
on carbon t2.5 g) in 70% aqueous tetrahydrofuran
(75 ml) was stirred under hydrogen atmosphere for 3
hours at ambient temperature. The catalyst was removed
by filtration and the filtrate was concentrated to
*hird volume. The residue ~as extracted with ethyl
acetate and transfeTred into an aqueous solution of
sodium bicarbonate. The aqueous layer was acidified
to pH 3 with 10~ hydrochloric acld and extracted with
ethyl acetate. The extract was dried over magnesium
sul~ate and concentrated to 10 ml under reduced pre-
~5 ssure. The resultant precipitates were collected,
t;,~
- 79 -
~ashed wi~h ethyl acetate and dried to give 7- ~2-
ethoxyimino-2-(5-amiIlo-132,4^thiadia~ol-3-yl)-
acetamido]-3-cephem-4-carboxylic acid (syn isomer)
(1.33 g), mp. 190 to 195C (dec.).
I.R (Nujol): 3400, 3300, 3200~ 1770, 1670,
1630, 1520 cm 1
N.M.R.(d6-DMSO, ~) : 1.23 ~3H, t, J=7Hz),
3.58 (2HJ broad s}, 4.17 (2H, q, .J=7Hz)
5.Q7 (lH, d, J=4Hz) 9 5.83 ~1H, dd,
lû J=4 and 8Hz) 7 6.45 ~lH, t, J=4Hz),
8rO5 ~2H, S~, 9~50 ~lH, d, J=8Hz)
Example 15
The following compounds were ob tained accord:;ng
to similar manners tG those of Examples 13 and 14.
(1) 7-[2 -Me~hoxyimino- 2 -(5-formamido-1,2,4-
thiadia~ol-3-yl) acetamido~-3- ~l-methyl-lH-tetra~ol-
5-ylthiomethyl)-3-cephem-4-carboxylic acid ~syn
isomer), mp. 170 to 175C.~ (dec.).
I.R. ~Nujol): 33009 1780, 1680 cm 1
(2) 7- [~-Methoxyimino-2-l~S-amino-1,,2,4-
thiadiazol-3-yl) acetamido]-3-~1-methyl-lH-tetrazol-
5-ylthiomethyl)-3-cephem-4-carboxylic acid ~syn
isomer), mp. 170 to 175C (dec.~.
I.R. (Nujol~: 3300, 1770, 166OJ 1610, 1520 cm
(3) 7- [2 -Me~hoxyimino -2 - (5 -amino-1,2 3 4-
thiad.iazol-3-yl) acetamido]cephalospoTanic acid ~syn
isomer~, mp. 180 to 185C (dec.).
I.R.:(Nujol): 3350, 1780, a730, 1680, 1620,
1530 cm~
(4) 7- [2-Methoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl) acetamido]-3-carbamoyloxymethyl-3-
cephem-4-carboxylic acid (syn isomer), mp. 185 to
1~0C (dec.). -1
I.R. (Nujol): 3350, 1780, 1720, 1680, 1620, 1530 cm
~0
(5) 7- [2-Methoxyimino-2 (5-amino-1,2,4~
thiadia.ol-3-yl)acetamido]-2-methyl-3-cephem-4-
carboxylic acid ~syn isomer), mp. 175 to 1~0C (dec,).
I.R. (Nujol): 33509 1775, 1675, 16309 1530 cm 1
~6) 7-[2-Methoxyimino-2-(5-amino-1~2,4-
thiad~ azol - 3-yl) acetamido3 - 3- (5-methyl-1,3,4-
thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid
~syn i~omer)" n~?. 175 to 180~C ~dec.).
I.R. ~Nujol~: 335û, 1780, 1680, 162~, 1530 cm 1
(7) 7- ~2-Methoxyimino-2-(5-~mino-lt2,4-thiadiazol-
3-yl)acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-
3-cephem-4-carboxylic acid ~syn isomer), mp. 172 tv
177C (dec.).
I.R. ~Nujol): 3350~ 1775, 1680, 1625" 1530 cm 1
t8) 7- [2-Methoxyimino-2-($-amino-1,2,4-
thiadiazol-3-yl) acetamido~3 (1-al:lyl-lH-tetrazol-5 _
ylthiomethyl)-3-cephem-4-carboxylic ~cid (syn isomer),
mp. 170 to 172C: (dec.).
I.R. ~Nujol): 3350, 1780, 1680~ 1625, 1530 cm 1
(9) 7-E2~isopropoxyimino-2-(5 amino-1,2~4-
thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylic
acid ~syn isomer~, mp. 208 to 213C (dec~).
I.R. (Nujol~: 3400, 33~0, 3250, 1770, 1660,
1630, 1610, 1520 cm~l
N.M.R. (d~-DMSO, ~): 1.27 ~6H, d, J=6~1z),
3.57 (2H~ d, J=4H~, 4.17-4.60 (lH, m),
5.07 ~lH" dJ J=4Hz)3 5.83 (lH, dd,
J=4 and 8Hz), 6.43 (lH, t, J=4Hz),
8.07 (2H9 s), 9.45 ~lH, d~ J=8Hz)
(10) 7- ~2-Isopropoxyimino-2-(5-amino-1,274-
thiadiazol-3-yl) acetamido]-3-~5-~N-t-butoxycaTbonyl-
amino)methyl-1,3,4-thiadiazol-2-yl]thiomethyl-3-
cephem-4-carboxylic acid (syn isomer), mp 140 to
145C (dec.).
I.R. (Nujol): 33003 1780~ 1670, 1620~ 1530 cm 1
~:17S8 ~3
81 -
~11) 7-[Z-Isopropoxyimino-2-(5-amino-1~2,4-
thiadiazol-3-yl~acetamido]-3~ carboxymethyl-lH-
~etrazol-5-yl)~hiomethyl-3 cephem-4-carboxylic acid
~syn isomer), mp. 175 to 180C (dec.).
I.R. ~Nujol) : 3300, 3200, 1770, 1720, 16~0,
1620, 1520 cm 1
~12) 7-[2-Me~hoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-(S-carboxymethylthio-
1,3~4-~hiadiazol-2-yl)thiome~hyl-3-cephem-4-carboxylic
acid (syn isomer), mp. 150 to 155C (dec.).
I.R. ~Nujol) : 3350, 3250, 1780, 1720, 1680,
1620~ 1530 cm~l
(13) 7-[2-Isopropoxyimino-2-(5-amino-1,2~4-
thiadiazol-3-yl)acetamido]-3-(1-methyl-lH-tetrazol-
5-yl)thiomethyl-3-cephem-4-carboxylic acid ~syn
isomer), mp. 170 to 175C (dec.).
I.R. ~Nujol): 3350, 3~50, 1780, 1680, 1620,
1530 cm~l
~14~ 7- [2-Isopropoxyimino-2- ~5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-~1-{2-(N-t-butoxy-
ca~bonylamino)ethyl}-lH-tetrazol-5-yl}~hiomethyl- 3-
cephem-4-carboxylic acid (syn isomer), mp. 142 to
147C ~dec.).
I.R. (Nujol) : 3350, 3250, 1780, 1690, 1630,
1530 cm 1
(15) 7-[2-IsopTopoxyimino-Z-(5-amino-1,2,4-
thiadiazol-3-yl)a etamido]-3-(tetrazolo~1,5-bJpyri-
dazin-6-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp. 165 to 170C tdec.).
I.R. (Nujol) : 3300, 3200, 1775, 1710, 1670,
1625, 1525 cm 1
(16) 7-[2-Isopropoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-
yl)thiomethyl-3-cephem-4-carboxylic acid ~syn isomer),
mp. 135 to 140C (dec.
' :..;
L~
I.R. ~uJol) : 3350, 3230, 1780, 1680, 1625,
1530 cm~l
(17) 7-[2-Methoxyimino-2-(5-amino-1~2,4-
thiadiazol-3-yl}acetamido]-3-(5-trifluoromethyl-
1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-fl-
carbox~lic aci.d (5yn isomer), mp. 150 to 155C (dec.).
I.R. ~Nujol) : 3300, 3200, 1770, 1670, 1620,
1520 cm~1
~18) 7-[2-Methoxyimino-2-~5-amino-1,2,4-
thiadiazol 3-yl)acetalLido~-3- r2-carboxymethy1-3-
oxo-2"3-dihydro-1,2,4-triazolo[4,3-b]pyTidazin-6-yl3-
thiomethyl-3-cephem-4-carboxylic acid ~syn isomeT~,
mp~ 205 to 210C ~dec.).
I.R. ~Nujol) : 3300, 1765~ 1710r 1~80~ 1620,
1550, 1520 cm 1
(19) 7-~2-Methoxyimino-2-(S-amino-1,?, 4-
th}adiazol-3-yl)acetamido]-3-(5-methylamino-1,314-
thîadia~ol-2-yl)thiomethyl-3-ceph~m-4-carboxyl:ic acid
tsyn isomer~, mp. 175 to 180C (dec~).
I.R. ~Nujol) : 3450~ 3370~ 3250, 1775~ 1710
1680, 1630, 1560 cm~l
t2o) 7- [2-Methoxyimino-2-(5-amino-1,294-thiadiazol-
3-yl)acetamido3-3-(5-amino-1,394-thiadiazol-2-yl)-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer),
mp. 165 to 170C tdec.).
I.R. ~Nujol) : 3350, 3210, 1770~ 1670, 1620
1520 cm
(21) 7-[2-Methoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido3-3-~1-{3-(N-t-butoxycaTbonyl-
amino)propyl}-lH-tetrazol-5~yl]thiomethyl-3-cephem-
4-caTboxylic acid ~syn isomer), mp. 175 to 180C
~dec.).
I.R. (Nujol) : 3370, 3250, 1785, 1690, 1630
1530 cm 1
~22) 7-~2-Methoxyimino-2-(5-amino-1,2,4-
w ~
-- 83 ~
thiadiazol-3-yl)acetamido]-3-~1-{ 3- (acetamido)propyl} -
lH-tetrazol-5-yl~thiomethyl-3-ceyhem-4-carboxylic
acid ~syn isomer), mp. 150 to 155C (dec.).
I.R. (Nujol): 3350, 3230, 1780, 1660, 1620,
1530 cm~l
(23) 7-[2-Methoxyimino-2-~5~amino-L,2,4-
thiadiazol-3-yl) acetamido]-3-[1-{1-(ac~tamidom~thyl)-
ethyl~-l}I-tetrazol-5-yl3thiomethyl-3-cephem-4-
carboxylic acid (syn isomer), mp. 160 ~o 165C (dec.~.
I.R. (Nujol): 3350, 3250, 1~80~ 1660, 16207
- 153Q cm 1
~24~ 7-~2-Methoxyimino-2-~5-amino-1,2 74-
thiadiazol-3-yl) acetamido]-3-[1-{1-~N-t-bu~oxy-
carbonylaminomethyl~ethyl~-lH-tetrazol-S-yl]~hiomet'hyl-
3-cephem-4-carboxylic acid (syn isomer), mp. 180 to
85C (dec.).
I.R. tNujol~: 3370, 3230" 1780, 1690, 1630,
1530 cm~l
~25) 7-[2-Methoxyimino-2-t5-amino-1,2"4-
20 thiadiazol-3-yl)acetamido]-3-~1-{3~tN,N-dimethylamino)-
propyl}-lH-tet~azol-S-yl]thiomethyl-3-cephem-4-
carboxylic acid ~syr isomer), mp. 165 to 170C ~dec.).
I.R. ~Nujol~: 3350, 3200, 17709 1670, 1610,
1530 cm~l
t~6) 7-[2-Methoxyimi~o-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-[1-(2-carb oxyethyl)-lH-
te~azol-5-yl3thiomethyl-3-cephem-4-carboxylic acid
(syn isomer~, mp. 150 to 155DC (dec.).
I.R. ~Nuj ol~ : 3300, 31509 1770, 1720, 1670,
1620, 1520 cm 1
(27) 7-~2-Methoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl) acetamido]-3-(1-caTboxymethyl-lH-
tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic- acid
(syn is~mer), mp 123 to 125C (dec.).
I.R.(Nuj ol) :33ûO, 3200, 1750, 1720, 1680, 1620,
1520 cm
s~
- 84 --
(~8) 7-[2-Isopropoxyimino-2-~5-amino-1,2,4
thiadiazol-3-yl)acetamido]-3-(S-aminomethyl-1,3,4-
thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer), mp. 210 to 215C (dec.)~
I.R. (Nujol) : 3350, 3200, 1750, 1670,
1670~ 1530 cm 1
t29) 7-~2-Isop~opoxyimino-~-~5-ami~o-:L,2,~-
thiadiazol~3-yl~acetamido]-3-[1-t~-aminoethyl~-lH-
tetra~ol-5-ylJthiomethyl-3-cephem-4-c:arboxylic acid
~10 ~syn isome~, mp~ 19~ to 200~C ~dec.).
.R. ~Nujol~ : 3350, 3250~ 1775~ 1680, 1620,
1530 cm~l
~30) 7-~2-Methoxyimino-2-~5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-[1-(3-a~ino~ropyl~-lH-
tetrazol-S-yl]thiomethyl-3-cephem-4-carboxyl~c ac:id
~syn isomeT)~ mp. 18S ~o 19~C (dec.).
I.R. ~Nujol~ : 3300~ 3200, 1770, 1670, 1610,
1530 cm~l
(31) 7-[2-Methoxyimino-2-~S-amino-1,2,4-
thiadia~ol-3-yl)acetamido]-3 [l-{l-~aminomethy~thyl~-
- lH- tet Ta z ol - 5 -y 1 ] thi omethyl - 3- cephem- 4-c arb ox:~lic
acid ~sy~ isomer), mp. 190 to 195~C ~dec~).
I.R. (Nujol) : 3350, 3230, 1770, 167Q,
1620, 1530 cm 1
(32) ?-~2-Methoxyimino-2-~S-phosphonoamino-
1,2,4-thiadiazol-3-yl~acetamido~-3-(1 ,3,4-thiadia;~ol-
2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isom~r)
n~ . 140 to 145 C ~dec .} .
I.R. ~Nujol~ : 3180, 1765, 1670, 1515 cm 1
(~3) 7-r2-~thoxyimi~o-2-~-amino-1~2~4-
thiadia_ol-a-yl)acetamido]-3-~1,3,4-thiadia~ol-2-yl)-
~hiometnyl-3-cephem-4-c~rboxylic acid ~syn isomer~
~p 150 ~o 155 C(~ec,).
I. R. ~Nujol) : a3~0, 32aO, 1775, 1680, 1620,
3~ 15;0 cm~l
- ~4) 7 E2--Iso~~o~o~im~o_2 ~5-- ~ no~1~2,4-
th;ad~æol-3-;yl)acet~;do]-,,-(1~3,4-thiadiazo7-2--
y~)t~io~ethyl~ ce~he~-d-cæ~bo~ylic acid (syn
iso~er), mp 145 to 150 C(dec~).
I.R. ~Nujol) : 3370, 32~0, 1780, 1~80, lfi25,
lS30 cm 1
t~)7-~2-Isopropo~yimino- 7- (5-ami~o~ 94-thiadia~ol-
3-yl)acetamido~cephalospor nic acid ~Sy:ll isomer)~
mp 150 to 155C. ~dec.)
I. R. ~Nujol): 3300, 17Bû, 1725, 1660, ~520 cm 1
t~6~ 7- ~2-Propoxyimi~o-2- ~5-amino~ ,4-
thiadiazol-3-yl)acetamido3-3-(1,3,4-~hi'adiazol-2-
yl) tniome~hyl -3-cephem-4 -carboxylic acid ~syn
isom~r)~ mp 130 to 133C ~dec.~
I. R. (Nu~nl): 3~gO, a230, 1780, 1680,
162~, 1530 cm 1
(37) ~- t2 -Me~hoxyimino- ~ - t5 -amino- 1, 2, 4 ~
thiadia~ol-3 yl) acetamidoJ -3- ~S- ~N-t-butoxycarbonyl-
amino)meth~ a~4~thiadiazol-2 yl~*hiome~hyl~3-
c~phem-4-carboxylic acid (syn isomer~, mp l~0 to
l~S~C (dec.)
I . ~. (Nuj ol~ : i35û, 3250, 1780, 16 70 cm
(3~ 7-~2-Methoxyimi~o-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamidQ3-3-(5-allylthio-1,3~4-
~hiadiazol-2~yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer). mp 160 ~o }65C ~dec~)
I. R. tNUjol) : 3350, 32503 17~0~ 16803
1620 cm 1
3o
_ ._ ... _ ... _._ _ .. __ _ _. . . ..... ...
. _ _ . _ .. . ... .. , . ._ , . . . . ,, _ .. . _ . .. .. . .
5 ~
- ~6 -
(39) 7-~2-Me~ho~yimino-2-(5-amino-192,4-
thiadia~ol^3-yl)acetamido]-3-acetylthiomethyl-3-
cephem-4-carboxylic acid tsyn isomer). mp 178 to
182C (dec.)
S I. ~. ~Nujol~ : 3350, 3250, 17B0, 1680, 1~20 cm 1
, ,
(40~ 7-[2-Me~hoxyimino-2-~-amino-1,2,4-
thiadiazol-3-yl~acetamido]-3-pyrazinylthiomethyl-3-
cephem-4-carboxylic acid (syn isomer). mp 170 to
174C ~dec.)
I. R, ~Nujol) : 3350~ 3250, 17B0, 1680, 1620"
1530 cm~l
~41) 7- ~-Methoxyimino-~- ~S-amino-1,294-
thiadiaz~l -3-yl~ acetamido3 - 3- (~ -thia~olLi~-2-yl)-
thiomethyl-3-cephem-4-carboxylic acid ~syn isomer~.
mp 175 ~o lB0 DC (dec.)
I. ~. (Nujol~ : 3350, 32~09 17B0~ 1680, 1620,
1530 cm~l
t42) 7-~2-Methoxymino-2-~5-~mino-1,2 9 4-thia-
diazol-3-yl)acetamido]-3-~e~azolo~1,5-blpyridazi.n-
6-yl)thiomethyl 3-cephem-4-ca~b~xylic acid (syn
isomer). mp 175 ~o 180C ~dec.)
I. R. ~Nujol) : 3400, 3250~ 1885~ 17257 1670,
1640, 1540 cm~l
~4~) 7-~2-Methoxyimino-2-~5-amino-1,2,4-
thiadiazol-3-yl~acetamido3-3-~1-{2-~N-t-butoxy-
carbonylamino)ethyl~lH-tetr~zol-5-yl]thiomethyl-3-.
cephem-4-carboxylic acid ~s~ isomer). mp 20G to
20a C (dec.)
I. R. (Nujol) : 3300, 1780, 17D0, 1680~ 16?0,
1520 cm 1
~7 -
t4~) 7-[2-Methoxyimino-2-~s-amino-l,2~4-
thiadia~ol~ l)acetamido]-3~ propyl-lH-tetrazol-
5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn
isomer). mp 155 to 160CC (dec.)
I. R. tNujD1) : 3350, 3250, 1780p 1680,
1630~; 1530 cm ~
(4~) 7-~2-~ethoxyimino-2-(5-amirLo-1,2,4-
thiadiazol-3-yl)acetamido~-3-~ 3-met:hoxypropyl)-
lH-*etrazol-5-yl]~hiomethyl-3-cephem-4-ca~boxylic
acid ~syn isomer). mp 165 to 167C (dec.)
Nujol~ : 33~0, 3250~ 1780~ 1680,
1$20 9 1530 cm 1
(46) 7-~2-Me~hoxyimino-2-~5-amino-1,2,4-
thiadia2O1-3-yl)acetamido]-3-~3-methyl-1,2,4~
thiadiazol-S-yl)thiomethyl-3-cephem-4 carboxylic
acid ~syn isomer~. mp 178 to 182C (dec.)
I, R. (Nujol~ : 3350~ 3250~ 1780, 1680,
1630~~ 1530 cm 1
~4~1 7-~2-Methoxyimino-2-~5-ami~o-1,2~4-
thiadia2O~-3-y1)acetamidoJ-3-(S-me~hoxymethy~-193,4-
~hiadiazol-2-yl)thiome~hyl-3 cephem-4-carboxylic
acid`(syn isomer). mp 170 to 174DC (dec~3
I. R~ (Nujol) : 3350, 3250, 1780~ lS80
1630~. 1530 cm 1
2a ~8 ) 7-[2-Methoxyi~ino-2-~5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-~S-methylthiomethyl-
1,3a4-thiadiazol-2-yl)~hiomethyl-3-cephem-4-
carboxylic acid ~syn isomer). mp 173 to 175C dec.
T.R. (NU3O1) : 3350, 3250, 1780, 1680,
1630, 1530 cm 1
~9 ) 7-[2-Me~hoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido] -3- (4-propyl-4H-1,2,4-
t~iazol-3-yl3thiomethyl-3-cephem-4-carboxylic acid
(syn isomer). mp 182 ~o 184C ~dec.)
3; I. R. (Nujol) : 3350, 3250, 1780, 1680, 1620,
1530 cm-l
38 -
~ 50) 7- [2-Methoxyimino-2- (5-amino-7 ,~,4-
thi~diazol^3-yl3ace~amido~-3~ methylt~iomethyl-
lH-te~ra~ol-5-yl3thiomethyl-3-cephem-4-carboxylic
acid ~syn isomer). mæ 175 to 178C ~dec.)
I. R. ~Nujol): 3350, 3250J 1780, 1680, 1620,
1530 cm~1
(51) 7- ~2-Me$hoxyimino-2- (5-amino-1,2,4-
~hiadia2O1-3-y1) acetamid~} -3- (1-isopropy1-1H-
tetrazol-5-yl~thiomethyt-3-cephem-4-c,arboxyli~ acid
~syn isom~r~. mp 180 ~o 182C ~dec~)
I. R. (Nujol3 : 3350, 3250, 17~0, 168V~
1630, 1530 cm 1
(52) 7-~2-Methoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-[1-~2-hydroxyethyl)-lH-
tetrazol-~-yl]thiomethyl-3-cephem-4-carboxylic acid
~syn isomer), mp 170 to 175C ~dec.}
I, R. ~Nujol) : 3350, 3250, 1780, 1680t
16~5, 1530 cm~l
~5~) 7~ Methoxyimino-~-~5-~mino-1 J 2j4-
thiadia~ol-3-yl)acetamido]-3-[5-~2-hydroxyethyl)-
1,3,4-thiadiazol-2-yl3thiomethyl-3-cephem-4-
carboxylic acid (syn isomeI). mp 175 to 180~C ~dec.)
I. R. (Nujol) : 3~50~ 3250, 1780, 1680, 1630,
! 1530 cm~l
(54) 7-[2-Methoxyimino-2-(5-amino~ ,4-
thiadiazol-3-yl)ace~amido]-3-(5-propyl-1,3,4-
thiadiazol-2-yl~thiomethyl-3-cephem-4-carboxylic
- acid (syn isomer). mp 177 to 180C (dec.)
I. R. ~Nu~ol) : 3350, 3250, 1780, 1680
1630, 15-30 cm~l
~53 7-~2-~lethoxyimi~o-2-(5-amino-1,2,4-
thiadia-ol-3-yl)ace~amido]-3-(5-hydroxymethyl-1,3~4-
thiadia~ol-2-yl3~hiom~thyl-3-cephem-4-ca~boxylic
acid (syn isomer). mp 165 to 170C (dec.)
~5 I. R. ~Nujo1): 3350, 3250, 1780, 1680, 1620,
1530 c~-l
fl ~
-89 -
(56) 7-[2-Methoxyimino-2-~5-amino-1,2 ,4-
thi~dia~ol-3^yl)acet~mido]-a-~5-methanesu:Lonamido-
meLhyl-1,3,4-thiadiazol-2-yl)th.iomethyl 3-cephem-
4-carboxylic acid (syn isomer), mp 17D to 175C
~dec . )
I. R. ~Nujol) : a350 J 3250, 1780, 16~0,
1620, 1530 cm 1
~57) 7-[~-Methoxyimino-2-(5-amino-1,2,4-
thiadiazol - 3 -yl) acetamido3-3-(3-allylthio-1,2,4-
thiadiazol 5-yl)thiome~hyl-3-cephem-4-carboxylic
acid ~syn isomer~. mp 170 to 173C (dec,)
. R, ~Nujol) : 3350, 3250, 1780, 1680,
1620, 1530 cm~l
t58) 7-[2-Methoxyimino-2-~5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-~5-mesylmethyl-1,3,4-
thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer). mp 175 to 180C ~dec.)
I. R. ~Nujo~) : 3350, 3250~ 1780, 1680,
lfi20, 1530 cm~l
(59) Sodium 7-~2,~hoxyimino-2-(5-amino-
1,2~4-thiadia201-3-yl)acetamido3-3~ sulfona~omethyl-
lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer). mp 205 to 210C (dec.)
I, ~. (Nujol) : 3350, 3250, 17B0, 1~80,
1530 cm~l
(~) 7-~-Methoxyimino-2-~5-amino-1,2,4-
thiadia~ol-3-yl)acetamido~-3-(4-methyl-4H-1,2,4~
triazol-3-yl)*hiomethyl-3-cephem-4-carb~xylic aci a
~syn isomer). mp 180 to 185C (dec.)
I. R. (Nujol) : 3350, 3250-, 1780, 1680,
1620, 1530 cm~l
~l ) 7-[2-Methoxyimino-2-(5-amino-1,2,4-
thiadi2zol-3-yl)acetamidGI-a-~1-{2-(N,N-dimethylamino)-
e.hyl~lH-~etra~ol-5-yl~thiomethyl-3-cephem-4-
a5 carboxylic acid (syn isomer). mp 185 to 190C ~dec.)
-90 -
I. R, (Nujol) : ~507 3250, 1780, 16S0,
1620, 1530 cm ~
~62) 7-~2-Methox~imino-2-(5-2mino-1,2,4w
thiadia_ol-3-yl)aceta~.ido]-a-~4-~3-methoxypropyl~-
4H-1,2,4-triazol-3-yl]thiomethyl-3-cephem 4-
casboxylic acid (syn isomer~. mp 175 to 180C (dec.)
1, R. ~Nujol) : 3350; a250J 1780, 1680,
1620, 1530 cm 1
(6~) 7-~2-Methoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl).~cetamidoJ-3-~5-(2-aminoethyl)-1,3,4-
thiadia~ol-2-yl~thiomethyl-3~cephem-4-carboxylic
acid (syn isomer). mp 205 to 210C (dec.)
I, R. (Nujol) : 3200, 1770, 1670, 1620,
1530 cJn 1
(64`) 7^[2-Metho~yimino-2-~S-amino-1,2,4-
thiadia~ol-a-yl)acetamido]-3-(S-aminomethyl-1,3,4-
thiadia~ol-2-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer). mp 210 ~o 21SC (dec,~
I~ R. ~Nujol~ : 3350, 3Z00, 1770~ 1680, 1620 cm 1
(65) 7-~2-Methoxyimino-2-~5-amino-1~2,4
thiadîa~ol-3-yl)acetamido~-3-~1-(2-aminoethyl)-lH-
tet~a701-S-yl]thiomethyl-3-cephem-4-carboxylic acid
(syn isomer). mp 200 to 205C (dec.
I. R. ~Nujol) : 3350, 3?00, 1775, 1670
~ 1620, 1530 c~ 1
(6~ 7-~2-Ethoxyimino-2-~5-amino-1,2,4-
- thiadia_ol-~-yl)acetamido3ceph~10sporanic ~id
(syn iscmer}. mp 140 to 156C (dec.)
I. R. ~Nujol) : 3370, 3250, 1780, 1730, 1680,
1620, 1530, 1380, 1240, 1040 cm~
,
'o
1~
~67, 7-~2 Ethoxyimino~2-tS-amino-1,2,4-
thiadia~ol-3-yl)acetamido~-3-~1-{3-~N-t-butoxy-
carbonylamino)propyl}~ te~razol-~-yl]~hiomethyl-
3-cephem-4-carboxylic acid ~syn isomer~ mp 183
to 188 C (dec.~
I.R~ (Nujol) : 3370, 3240, 1780, 1690, 1630,
15;0, 1380, 1260, 1170, 104a cm~
~8~ 7-~2-Ethoxyimino-2-~5-amino-1,2,4-
~ 25 thiadia2O1-3-yl)acetamido]-3~[1-{2-~N-t-butoxy-
ca~bonylami~o)ethyl}~lH-tetrazol-S-yl~thiomethyl-
3 cephem-4-carboxylic acid (syn isomer3D
Nujol~ : 3360, 3240, 1780, 1690, 1630,
1530, 1375, 1250D 1170~ 1040 cm 1
~9 ) 7-~2-~.hoxyimino-2-(5-amino-1,2,4-
~hiadia-ol-3-yl)acetamido]-3-(1-methyl-lH-te;ra~ol-
;-yl)~h_ome-hyl-3-ce?~em-4-car~oxylic acid (syn
isomer). mp 156 tO 159C (dec.)
~.R. (Nujol) : 3360, ;250, 1780, 1~80,
3~ 1625, 1~80, 1080, }040 c~ ~
:,
5 ~
- 92 -
~O~ 7-LZ-Ethoxyimino-2-(5-amino-1,2,4-
thiadia~ol-3-yl)acetamido]-3- fi-{2- ~N,N-dimethylamino)~
ethyl}-lH-~etra~ol-5-yl~thiomethyl-3-cephem-4-
- carboxylic acid ~syn isomer). mp 177 to 180C ~dec.)
I,R. ~Nujol) : 3380, 3250, 1775, lG70, 1620,
1535, 1380, 1040 cm 1
c7l) 7-~?-E~hoxyimino-2-~s-amino-~2J4-
thiadiazol-3~yl)acetamido~-3-(1-allyl-lH-tetraY-ol-5-
yl~thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
mp 160 to 155C (dec.)
I.R. ~Nujol) : 3380, 3250, 1780, 1680 9 16aO,
1530, 1380, 1040 cm l
~) 7-~2-Ethoxyimino-2-(5-amino-1,2,4
thiadia~ol-;-yl)ace~amido]-3-~etrazolo[l,S-b~pyr:idazin~
6-yl)thiome~hyl-3~cephem-4-carboxylic acid (syn
isomer). mp 180 to 185C (dec.~
I.R. ~Nujol) : ~350J 3240~ 1780~ 1680f 16?0,
1530, 1380, 1040 cm~l
~3 ~ 7-~2-Ethoxyimina~2~ amino-1,2,4-
thiadiazol-~-yl)acetamido]-3-(5-aminome~hyl-1,3,4-
thiadiazol 2-yl)thiomethyl-3~cephem-4-carboxylic
acid (syn isomer}. mp 198 ~o 205~C ~dec.~
I.R. ~Nujol) : 3a50, 3250, 1775, 1680, 1620,
1535, 1380, 1040 cm 1
t743 7-~2-Ethoxyimino-2-(5lramino-1,2~4-
thiadiazol-3-yl)acetamido]-3-[1-~2-hydro~yethyl~-lH-
tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid
tsyn isomer?. mp 170 to 173C ~dec.)
I.R. (Nujol) : 3350/ 3240J 1780, 1675, 1~25,
1530, 1380-j 1040, 720 cm 1
~75~ 7-~2 -Methoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-;-~4-allyl-4H-1,2,4-
t,iazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer). mp 185 to lgO~C ~dec.)
3; I.R. (Nujol) : 3350, 3210, 1780, 1680, 1625,
1530 cm~
~ 3
c ~
(7~ 7~ e~no~yimi~.o~ amino-lt2,~-
thiadia~ol-3-yl)acet?~ido3-3-~-~etho~ycar~onyl-
1, ~ 94 -thiadia-cl-5-yl~hiomethyl-~-cephem-4-
carbo~ylic acid tsyn isome~). mp 180 to 18SC ~dec.)
I.R. tNUjol~ : 3~50, 3250, 178OJ 17403 1680,
16~0, 1530 cm~l
(77) 7-~2-Methoxyimino-~-~5-amino~1,2,4-
~hiadia~ol-3-yl~acetamidoJ-3-(;-carbc)xy-:L,2,4-
thiadiazol-~-yl~thiomethyl-3-cephem-4-carboxylic
acid (sy~ isomer). mp 175 ~o ~80C ~dec.)
I.R.-(Nujol~ : 3350~ 3250, 1780, 1730, 1680,
1620, lS~0 cm~
~783 7- ~2-L:thoxyimino-2~ amino-1,2,4-
thiadia?ol - 3-yl) acetamido ] ~ o - ~1- t 3- aminopropyl) -
2S lH-tetrazol-S-yl]thiomethyl-3-cephem-4 carboxylic:
acid ~syn isomer). mp 182 to 185C ~dec.).
I.R. .tNujol) : 33509 3200, 1770, 1670, 1620,
1530, 1380, 1040 cm 1
~9~ 7-~2-Ethoxyimino-2-CS-amino~ ,4-
~0 thiadia-ol-3-yl)ace~amido]-~.-[1-(2-aminoethyl)-lH-
te-ra~ol-;-yl3tniome~hyl-3-cephem-4-carboxylic acid
~syn isome~ ..p lg5 to 710 ~ ~dec.).
I.R. ~Nujol) : 33~0, 3210, '770, 167i, 16Z0,
1;30, 1380, 10~0 cm 15
~ 5~
_ 9~
E~ample 1~
A mixture o~ 7-[2-methoxyimino-2-~S-amino-1,2,4-
thiadiazol-3-yl)acetamido]cephalosporanic acid ~syn
isomer)~3.5 g), pyrazinethiol ~1.1 g) and sodium
~icarbonate ~1.3 g) in pH 6.86 phosphate buffer
solution (lS0 ml) was stirred for 2 hours at 70C.
The mixture was cooled in an ice bath, acidified
with 10% hydrochloric acid and extracted with ethyl
. acetate. ~he extrac~ was dried over maanesium
sulfate and concentIa~ed to 15 ml in ~acuo.
A resul~ing precipitate was collected by filtration,
~ashed with ethyl acetate and dried to give crude
7-[2-methoxyimino-2-(S-amino-1,2,4-thiadiazol-3-yl)-
acetamido]-3-pyrazinylthiomethyl-3-cephem-4-
carboxylic a~id (syn isomer)~l.8 g). The crudeproduct was dissolved ~n acetone, ~reated with
activated charcoal powder and eraporated t~ dryness.
The residue was dissolved in an aqueous solu~ion
of sodium bicarbonate and reprecipitated with an
addition of 10~ hydrochloTic acid to give pure
ob~ect compound ~1.1 g~. mp 170 to 174~C ~dec.)
I.R. ~Nujol) : 33S0, 32S0, 1780, 1680, 1620,
1530 cm
N.M.R. (d6-DMSO, ~ : 3.52 and 3.70 (2.I, ABq,
J=18Hz), 3.97 ~3H~ s), 4.05 and 4.57
~2H, ABq, J=13H~), 5.13 ~lH, d, J=4H7~,
5080 tlH, dd, J=4 and 8Hz3, 8.12 ~2H,
s~, 8.3-8.6 (3H, m), 9.SS ~lH, d, J=8Hz)
Exam~le 17
~ . .
A mi~ture of 7-l2-methoxyimino-2-~S-amino-
1,2,~-thiadiazol-3-yl)acetamido]cephalosporanic acld
~syn isomer)~3.0 g), tetrazolo~l,S-b]pyrida-ine-6-
thiol ~1.3 g~ and sodium bicarbonate (1.1 g) in pH
6.86 phosphate buffer solution ~130 ml) was stirred
for ~ hours at 70C. The mi~ture was cooled i~ an
,
9~
ice bath~ acidified to pH 2 with 10% hydrochloric
acid and extracted ~i~h e~hyl acetate. The extract
was dried over magnesium sul~ate and concentrated
to 15 ml in vacuo. A resulting precipita~e was
S collected ~y iltration, washed with ethyl acetate
and dried to give crude 7-~2 methoxyimino-2-~5-
amino-1,2,4-~hiadiazol-3 yl)acetamido~-3-(tetrazolo-
~1,5-~3pyridazin-6-yl)thiomethyl-3-cephem~4-
oa~o.Yylic acid ~syn isome~)(Z.5 g). The crude
10 product was dissolved in aqueous acetone, treated
with ac~iva~ed charcoal powder and evapora~ed to
dryness, The residue was dissolved in an aqueous
solution of sodium bicarbonate and reprecipitated
with an addition o lO~o hydrochloric acid to gi~e
pure object compound ~1.15 g). mp 175 ~o 180C (dec.)
I .R. (Nu jal) : 3400, 3250, 1885, 1725, 1670,
1640 ,1540 cm 1
N.M.~, (d6-DMSO, ~): 3.62 and 3,82 ~2H, A~q,
J-18Hz), 3.92 ~3H, s), 4, 20 and 4 .~
(2H, ABq, J=14Hz), 5.14 tlH, d, J-4Hz),
5.80 (lH, dd, J-4 and ~H7), 7.72 (~H,
d, J-8Hz), 8.10 ~2H9 s), 8.5~ ~lH, d,
J-8Hz), 9.56 (lH, d, J=8Hz)
Exam~le 18
A mi~ture of 7-~2-methoxyimino-2-~5-amino-
1,2,4-thiadiazol-3-yl)acetamido~cephalosporanic
acid (syn isomeT)(3.5 g~, 1-[2-(N-t-butoxycarbonyl-
amino)ethyl]-lH-~etrazole-5-thiol ~2.45 g) and
sodium bicarbonate ~ g) in pH 6.86 phosphate
buffer solution ~150 ml) was stirred for 3 hours
at 70C. The mixture was cooled in an ice bath,
washed with ethyl acetate, acidified to pH ~ with
10% hydrochloric acid and e~tracted with ethyl
acetate. The extract wac dried over magnesium
sulfate and concentrated to 10 ml in vacuo.
~ 96 -
.4 resulting precipitate was collected by filtration,
washed wi~h ethyl acetate and die~yl ether and dried
to give 7-[2 met~oxyimino-2-(5-amino-l,Z,4-
thiadia~ol-3-yl)acetamido3-3-[1-{2-(N-t-~utoxy-
carbonylamino)ethyl~lH-te~razol-5-yl]thiomethyl-3-
cephem-4-carboxylic acid ~syn isomer)~2,0 g). mp 200
to ~05C ~dec.)
I.R. ~Nujol) 3300, 1780, 1700, 1680, 1620,
15~0 c~ 1
N.M.R. ~d6-DMSOg ~) : 1.27 (9H, s) 9 3.28 ~2~, m),
3.63 ~2H~ broad s~, 3.87 t3H, s), 4-27
(4H, broad s), 5.07 (lH~ d, J=4Hz3, 5.75
~lH, dd~ J=4 and 8H~), 8.10 ~2~, s),
9.50 ~lH,d, Ja8Hq)
A mix~ure o 7-~Z-methoxyimino-2-~5-amino-
1,2,4-thiadiazol~3-yl)acetamido~cephalosporanic acid
~syn isomer)~3.5 g), sodium (5-mercapto-lH te~razol-
l-yl)me~hanesulfonate (2.18 g) and sodium bicarbona~e
~1.3 g) in pH 6.86 phosphate bu~er solution tl50 ml)
w~s stirred for 3 hours at 70~C. The mixtuTe was
cooled in an ice bath, adjusted to pH 3 wi*h 10%
hyd~ochloric acid and washed ~ith ethyl acetate. The
a~ueous solution was subjected to column ch~omato-
graphy on non ion adsorption resin ~Diaion HP 20)
(Trademark: prepared by Mitsubishi Chemical Industries~.
The column was washed with wa~er and eluted with
30~ aqueous methanal. The eluate was evaporated to
remove methanol and then lyophilized ~o gi~e sodium
7-~2-methoxyimino-2-~5-amino-1,2,4-thiadiazol-3-yl)-
acetamido]-3~ sulfonatomethyl-lH-tetra~ol-S-yl)-
thiomethyl-3-cephem-4-carboxylic acid ~syn iscmer)
(0.67 g). mp 205 to 210C (dec,~ --
I.R. ~Nujol) : 3350, 32S0, 1780, 1680, 1530 cm l
~5 N.M.R. (d6-DMSO, ~) : 3.63 (2H~ broad s),
3~ srl~ s) ~ 7 and 4.33 ~ZH, ABq,
J~14Hz), 4.98 ~2H, s), 5.07 (lH, d~
J-4~z), 5 77 ~lH, dd, J~4 and 8Hz)
9.55 ~lH, d~ JY~HZ)
S Ex~mple_2Q
A mîxture of 7-~2-methoxyimino-2-(5-a~ino-
1~2,4-~hi~dia~ol-3-yl)acetamldo]cephalosporanic acid
~syn isomer)~3.5 g) 9 disodium (S-sulfido-l~-tetrazol-
l-yl)acetate (2.0 g~ and sodi~m bica~bonate ~1.3 g)
in pH 6.8 phosphate buffer solution ~:IS~ ml) was
stirred for 3.5 hours at 70C. The reaction mix~ure
was ~ooled in ~n ice bath, mixed with ethyl acetate
and ~djusted to pH 3 with lOg~ h~drochloric acid.
Th~ ~ueous layer was sep~ra~ed, mixed wi~h ethyl
acetate and the mixture was adjusted to p~I 1 wi~h 10~
hydrochlori.c acid. Th~ ~thyl acetate layer was dried
over magnes~um sul~ate and evaporated ~o dryness.
The r~sidue was triturated with diethyl ether to give
7-~2 methoxyimino-2-~5-amino-1 J 2,4-thiadiazol-;-yl)-
~ 20 acetamido~-3~ carboxymethyl-lH-tet~azol-5-yl~-
thiomethyl-3-cephem-4-carboxylic ac~d (syn isome~)
(1.68 g), mp. 123 ~ 125C (dec.).
I.R. ~Nujol) : 33QQ, 3200, 1750, 172~,
1~80~ 162Q, 1520 cm 1
N.M.R. (d6-DMSO, ~) : 3.72 (2H, broad s~,
3.97 ~3H, s), 4.27 and 4.50 ~2H, ABq,
J=13Hz), 5.13 (lH, d~ J=4H7), 5.33
~2H, s~, 5.83 ~lH, dd, J=4 a~d 8~-),
8.13 (2H, s), 9.60 (lH, d~ J=8Hz)
.-
~'~,t~S~
_ ~8 -
Example 21
~he following compounds were obtained accord-
ing to similar manners to ~hose of E~amples 16 to 200
~1) 7-~2-Methoxyimino-2-,'5-amino-1,2,4-
thiadia~ol-3-yl)acetamido~-3-~2-~hia~olin-2-yl~thio_
me~hyl-3-c~phem-4-carbo~ylic acid (syn isomer). mp
17~ tc 1~0C ~dec,).
I.R, tNUjol) : 3350, 3250l 1780, 1680, 16209
lSaQ cm
N.M.R. ~d6~DMS0, ~) : 3.43 ~2Ht m), 3.S7 ~H9
broad s), 3.9~ (3H, s)~ 4.0-4.5 ~4H, m),
5.10 ~lH, d, J~4H,.), S.~0 ~lH, dd, J~4
and 8H~), 8.10 ~2H, 5), 9.50 ~lH, d,
J~8HZ)
~2~ 7-12~Me~hoxyimino-2-~5-amino-l,Z,4-
~hiadia701-3-yl)zcet2mido]~ propyl-l~-tetra~ol-
5-yl)thiomethyl-3-cephem-4-ca~boxylic acid (syn
isomer). mp 1$5 ~o 160C (dec.)
I.R, (~uJol) : 3350, 3250, 1780, 16809 1~30,
1530 cm~l .
N.~.R. ~d6-D~S0, ~) : 0.83 ~3H, t, J~7Hz),
1.80 ~2H, sextet~ J=7Hz), 3,67 (2H9
bIoad s~, 3,92 (3H, s), 4.23 (2H, t,
J=7Hz~, 4.;5 ~2H, broad s), 5.08 (lH,
d9 J=~H~, 5,78 ~1~, dd, J=~ and 8H,~,
8,08 ~2H, s~, 9.52 (lH, d, J=8H )
3o (3) 7-~Z-.~etho~yimino-2-(S-amino-1,2,~-
.hlacia-ot-;-yl)ace.amido~-3-,ri-~a-methoxy~ropyl)-
iH-tet~a-ol-S-yll.hiomethyl-a-cephem-~-carbo.Yylic
acid (syn isome~ p 165 to 167C ~dec.)
I.R. (~ujol~ : 33;0~ 3250, 1~80, 1680~ 1670
1530 cm~1
. .
~ ~ ~t~ 3
_ 9g
N.M.R. (d6-DMSO, ~) : 2.02 (2H, quin,et,
J-7Hz)~ 3.17 ~3H, s), 3.30 (2H,
t, J-7Hz), 3.67 ~2H, ~road s),
3O90 ~3H, s), 4.32 (2H, t, J=7Hz),
S 4.35 ~2~, broad s), S.~.0 (lR~ d,
J=4H~), 5.80 (lH, dd, J~4 and 8Hz)~
8.13 (2H, s) ) 9.57 ~lH, d, ~=8Hz)
~4) 7-~2-Me~hoxyimino 2-tS-amino-1~2 3 4 -
thiadiazol^3-y~)acetamido3-3-~3-me~hy1-1,2,4-thia~
diazol-5-yl)thiom~thyl-3-cephem 4-carboxylic acid
~syn }somer). mp 178 to 182C (dec. ~
I.R. (Nujol) : 3350, 3250~ 17~0, 1680, 1630,
1530 cm 1
N.M.R. (d6-DMS0, ~ .S8 ~3H, s}, 3,60 and
3.?7 ~2H, ABq, J=17Hz), 3.97 ~3H~ s),
4.30 and 4~63 ~2~, ABq, J~14Hz~, 5.17
~lH~ d, J~Hz), 5.85 (lH, dd, J~4 and
8H~), 8.13 (2H, s), 9.57 ~lH, d, J~Hz~
~5) 7-~2-Methoxyimina-2-(5-~mino-1,2J4~
thiadiazol-3-yl~acetamido]-3-~5-me~hoxymethyl-1,3,4-
thiadiazol-2~yl)thiomethyl-3-cephem-4-carboxylic
acid ~syn isomer). mp 17Q to 174C ~dec,)
I.R. ~Nujol) : 3350, 3250, 1780, 1680, 1630,
1530 cm }
N.M.R. ~d6-DMSO, ~ : 3.40 (3H, s~, 3.70 (2H;
broad s), 3.93 (3H~ s), 4.27 and 4.70
~2H, ABq, J=13Hz), 4.83 ~2H, s),
5.17 tlH, d, J=4Hz), 5.83 (1~, dd,
J=4 and 8Hz), 8.12 ~2H, s~, 9.57 ~lH,
-o d, J=8H~) ~~
(6) 7 [2-~ethoxyimino- 2- ~5- amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-(;-methy1thiomethyl-
1,3,4-thiadiazol-2-yl)thiomethyl-;-cephem 4-
carboxylic acid ~syn isomer~. mp 173 to 175C ~dec.)
I.R. ~Nujol) : 3350, 3250, 1780, 1680, 1630,
1530 cm~l
S~ 3
100--
N.M~R. (d6-DMSO~ o) : ~.13 ~3H, 5), 3.70 t2H7
broad s), 3.97 ~3H, s), 4.17 ~2H, s),
4.27 and ~.57 ~2H, ABq, J~14Hz), 5.17
~lH, d, J=4~7), 5.85 ~lH, dd, J=4 and
8Hz), 8.la ~2H, s)~ 9.58 ~lH, d, J-8}{z
~7) 7-~2-Methoxyimino-2-~S-amino-1~2,4-
thiadia~ol-3-yl)acetamido~-3-(4-propyl-4H 1~2,4~
~riazol-3-yl)thiomethyl-3-cephem^4-calboxylic acid
~syn isomer). mp la2 to 184C ~dec,)
I.R. ~Nujol) : 3350, 3250, 178~, 1680, 1~20,
1530 cm 1
N.M.~. (d6-DMSO9 ~) : 0.83 (3H, t, J=7Hz),
1.7~ (2H1 m), 3.67 (2H, broad s~, 3.90
(2~, t, J~7Hz), 3.93 ~3H~ s~, 4.~0 (2H,
broad s), S.lO (lH, d, J-4H~), 5,80 ~lH,
dd, ~-4 and 8Hz)) 8.12 (2~, s), 8,63
~lH, s), 9.57 ~lH; d, J~8Hz)
~ 8~ 7-~2-Methoxyimlno-2-~S-amin~-~,2,4-
thiadiazol-3-yl)a~etamido}-3-(1-methyl~hiomethyl-
lH-tetrazol-S-yl)thiomethyl-3 cephem-4-carboxylic
acid (syn isomer~. mp 175 to 178C ~dec.)
I.R. ~Nujol) : 3350, 3250, 1780, 1680, 1620,
1530 cm~l
N.M.R. (d6-DMSO, ~ : 2.17 t3H, s), 3. 72 (2H,
broad s), 3.93 (3HJ S), 4.30 and 4.50
(2H, ABq, J-13Hz), 5.13 ~lH, d, J=4Hz),
5.53 (2H, s), 5.83 (lH, dd, J=4 and
8Hz), 8.1~ (2H~ s), 9.57 ~lH, d, J=8Hz)
(9) 7-~2-Methoxyimino-2-(S-amino-1,2,4-
30 thiadiazol-3-yl)acetamido~-3-(1--isopropyl-lH-
tetrazol-5-yl)thiomethyl-~-cephem-4-carboxylic ~cid
(syn isomer). mp 180 to 182C ~dec.
I.R. (Nujol) : 3350, 32aO~ 1780, 1680, i630,
1530 cm 1
N.~S.R. (d6-DMSO, ~) : 1.48 (6H, d, J=6Hz),
101--
.
3.70 ~2H, broad s), 3.93 (3H~ s),
4.43 t2H, ~road, s), 4.75 ~lH, m),
5.13 ~lH, d, Ja4Hz), 5.82 ~lH, dd,
J~4 and 8HZ)I 8,1~ ~2H, s) J 9.57 ~lH,
d, ~8Hz)
~10~ 7~ Methoxyimino-2-~5-amino-1,2~4-
thiadiazol~3-yl)acetamido~-3-~ 2-hydroxyethyl~-lH-
tetrazol-5-yl3thiomethyl-3-cephem-4-carboxylic
acid ~syn isomer). mp 170 to 175~C ~dec.)
I.R. (~ujol~ : 3350, 3250, 178~, 1680, 1625,
1530 cm~l
N.M,R. ~d6-DMS0, ~ : 3.67 ~2H, broad s),
3.73 (2H, broad s), 3.90 (3H, s),
4~27 ~2H, broad s), 4.33 (2H, broad s),
lS 5.. 10 ~lH, d~ J=4Hz~, 5,80 ~lH, dd,
~4 and 8~z), 8.07 (2H, s), 9~S3 (lH, d,
J~8HZ)
~11) 7-~2-M~thoxyimino-2-~5-ami~o~ ,4-
thiadiazol-3-yl)acetamido]-3-[5-(2-hydroxyethyl)-
1,3,4-thiadiazol-2-yl]thiomethyl~3-cephem-4-
ca~boxylic acid ~syn isomer). mp. 175 to 180C ~dec.)
I.R. (Nujol) : 3350, ~250, 1780, 1680, 1630,
1530 cm
~ N.M.R. ~d6-DMS0, ~ : 3.20 ~2H, t, J=5Hz),
3.67 ~2H) ~road s), 3.73 ~2H, t, J=SHz),
3.95 (3Hg s~, 4.27 and 4.57 (2H, ABq,
J=13Hz), 5.17 (lH, d, J=4Hz), 5.83 ~lH,
dd5 J=4 and 8Hz), 8.13 ~2H, s), ~.58
(lH, d, J=8Hz)
(12) 7-[2-Methoxyimino--2-~5-amino-1,2,4-
thiadiazol-;-yl)acetamido}-3-(S-propyl-1,;,4-
tniadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer~. mp 177 to 180C (dec.)
I.R. (Nujol) : 3350, 3250, 1780, 1680, 1630,
;5 1530 cm 1
;~ ~7~ 9
-- 102 -
N.~.R. ~d6-DMS0, ~) : 0.97 ~3H, t, J~7Hz),
1. 73 ~2H, m) 9 3.07 (2H, ~, J-7Hz),
3.70 tZH, broad s), 3.97 ~3~[, s) J
4~37 and 4.57 ~2H, ABq, ~13Hz),
5.17 (lH, d~ J~4H2), 5.8:3 (lH, ddJ
J-4 and 8H~), 8.13 (2H, ~s), 9.S7 ~lH,
d, J-8H2)
(13) 7- ~2-Methoxyimino-2- ~5-amino-1, 2, 4-
thiadiazol- 3-yl) acetamidQ ] - 3- ~S -hydroxymethyl -
101"3,4-thiadiazol-?-yl3thiam~thyl-3 cephem-4-
carboxylic acid (syn isomer) . mp 165 to 170C (dec. )
I.R. ~Nujol): 3350, 3250, 1780, 1680, 1620,
1530 cm 1
N.M.R. ~d~j-DMS0, ~) : 3. 67 ~2H, broad s),
3.92 ~3H, s), 4.27 and 4.57 ~2H, ABq,
J~13Hz) ~ 4.8~ ~ZH, s), 5.13 (lH, d,
J~4~I~), 5 . 83 ~lH, dd, J~ and 8Hz},
8,17 ~2H, s), 9.60 ~lHl d, Ja8Hz~
~14~ 7- ~2-Methoxyimino- 2- (5-amino-1, 2 ,4 -
20 thiadiazol-3-yl)acetamido~-3- ~5-methanesulfonamido-
methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem^
4-carboxylic acid (syn isomer). mp 170 to 175C
~dec.).
I.R. ~Nujol) : 3;50, 3250, 1780, 1680, 16Z0,
1530 cm 1
N.M.R. (d6-DMSO, ~) : 3.00 (3H, s), 3.67 (2H,
broad s), 3.93 (3H, s), 4.27 and 4.53
(2H, ABq, J=14Hz), 4.55 (2H, d, J=6Hz),
S.13 (lH, d, J-4Hz), 5,80 (lH, ddJ
J=4 and 8Hz), 8.0;-(lH, t, ~=6Hz),
8.10 (ZH, s~, 9.53 (lH, dg J=8Hz~
~15) 7-[2-Methoxyimino-2-(5-amino-1,~
thiadiazol-3-yl)acetamido]-3-(3-allylthio-1,2,4-
thiadiazol-5-yl~thiomethyl-3-cephem-4-carboxylic
;5a id (syn isomer). mp 170 to 173C (dec.)
7~
- 103 -
I.R. ~Nujol) ; 3350, 3Z50, 1780g 168Q, 162QJ
1530 cm 1
N~.R. ~d6-DMS0, ~) : 3.58 and ~l.74 (2H~ ABq,
J-17Hz), 3.90 (~H, d, J=6H~), 3.92
(3H, s), 4.32 and 4.54 (2H, ABq, J=}4Hz),
5.15 (lH, d, J34Hz), 5.0-.i.4 (2H~ m),
5.7-~.l (lH, m), 5.84 (lH, dd, J=4 and
8Hz), 8.12 ~2H9 s), 9.58 ~lH, d, J=8H2)
~16~ 7-~2-M~thoxyimino-2-(5-am:ino-1,2,4-
10 thiadiazol-3-yl)acetamido]-3-~5-mesylme~hyl-1,3,4-
thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer)~ ~p 175 to 180C (dec.)
I,R. ~Nujol) : 3350, 3~50, 1780, 1680, 16Z0,
1530 cm 1
N.hl.R. ~d~-DMS0, ~) : 3.13 (3H, s), 3.70 ~2H,
broad s), 3.93 (~H, s), 4.lS and 4.63
~2H, ABq, J~13H~), 5 ol7 ~2H9 s), 5,13
(lH, d, J~4Hz), 5.83 ~lH, dd, J-4 and
8Hz) 3 8,08 ~H, s), 9.~3 (lH, d~ J~8Hz)
~173 7-~2-Me~hoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido~-3-~4-methyl-4H-192,4-
tria~ol-3-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer). mp 18~ to 185C (dec.)
IoR~ (Nujol) : 3350, 3250, 1780, 1680) 16209
1530 cm l
N.~l.R. ~d6-D~S0, ~) : 3.53 ~3H, s), 3.62 (2H,
broad s), 3.87 (3H, 5), 4.08 t2H, broa~
s), 5.07 ~1~, d, J=4Hz), 5.75 ~lH, dd,
J=4 and 8Hz), 8.08 ~2H, s), 8.52 ~lH, s~,
9.50 ~lH, d, J=8Hz)-
~18) 7-~2-Methoxyimino-2-(5-amino-192,4-
thiadiazol-3 yl)a~etamido]-3~ 2-~N,N-dimethyl-
amino)ethyl}-lH-tetrazol-5-yl]thiomethyl-~-cephem-
4-carboxylic acid ~syn isomer). mp 185 ~o l9QC ~dec.}
I.R. (Nujol) : 3350, 3250, 1780, 1680, 16207
- 1530 cm~l
.. _ _ _ _ _ _ _ _ .. . _ , . _ . . _ , . , . . . . . . . . . . . . .. . , . . ~ . ~ . .
.
}~
~ 104 ~
N.~l~R. ~d6-DMS0? ~) . 2~47 (6H, s), ~.0-3.3
~H, m), 3.67 ~2H, broad s~ 3.90
~3H, s), 4 28 (2H, broad s~, 4.4-4;7
{2H, m), 5.08 (lH, d, J~4H~), 5.77 ~lH~
dd, J=4 and 8Hz)~ 8.12 (2H, s),
9.55 ~lH, d, J~8H~)
~19~ 7-~2-Methoxyimino-2-~5-amino-1,2,4-
thiadiazol~3-yl~acetamido~-3-~4-(3-me~hoxrpropyl~-
4H~1 ,2,4-triazol-3-yl]thiomethyl-3-cephem-4-
10 carboxylic acid (syn isomer). mp 175 to lBO~C ~dec.)
I.R. ~Nujol): 3350, 3250, 1780, 1680l 1620,
1530 cm 1
N.M.R. (d~-DMS0, ~) : 1.97 ~2~, m), 3.28 ~3H,
s} ~ 3.35 (2H~ t, J~8H~), 3. ~3 ~2H~ broad
s~, 3.97 (3H, s), 4.03 t2H~ t, J~8H~),
4,23 ~2H, broad s), 5.17 ~lH, d, Ji4H~),
S A 83 ~lH~ dd, J~4 and 8Hz), 8 . 15 ~2H,
s)~ 8.67 tlH" s), 9.57 ~lHJ ~, J38Hz)
t20) 7-~2-Methoxyimino-2-(S-amino-l,Z,4
~0 thiadia 201- 3 -yl ) ace~amidoJ-3-~5-~2-aminoe~hyl~-
1,3,4-thiadiazal-2-yl3thiomethyl-3-cephem-4~
carboxylic acid ~syn isomer). mp 205 to 210C ~dec.)
I.R. ~Nujol) : 3200, 1770, 1670, 1620, 1530 c:m 1
N.M.R. ~d6-DMS0, ~) : 3,10-3,70 (6H~ m), 3.92
2~ ~3H, s), 4.50 ~2H, broad s), 5.06 ~lH,
d, J~4Hz~, 5.72 (lH, dd, J=4 and 8Hz),
8.18 ~2H, s), 9.50 tlH, d, J~8Hz)
~ 21) 7-~2-~ethoxyimino-2-~5-amino-1,234-
thiadiazol-3-yl)acetamido]-3-~5-aminomethyl-1,3,4-
; thiadiazol-2-yl)thiomethyl-3-c~phem-4-carboxylic
acid (syn isomer). mp 210 to 215QC (dec.)
I.R~ ~Nujol3 : 33S0, 3200, 1770, 1680, 1620 cm 1
(22) 7-[2-Methoxyimino-2-~5-amino-1J2,4-
thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-lH-
tetrazol-5-yl]thiomethyl-;-cephem-4-carboxylic acid
`-,.~A
tiJS~'~3
- 705 ~
C~ 5Qmer~. ~? ~ LO 2~5C ~dec~)
I.R. ~Nujol): 3aSO,32~0,1775,1~70,16?0,15~Q cm
( 2~3 7 - ~ 2 -Ethoxyimino - 2 - ~S - ami~o ~1, 2, 4 -
thiadia:ol-3-yl)ace~amido~-3~(1,a,~-thiadia_ol-2^
S yl)thiomeLhyl-3-c~phem-4-carbo.~ylic acid ~syn isomer).
mp 150 to lS5~C (dec.)
I,R. (Nujol) : 3iaO,32;0,1775,1680,1620,1530 cm
~ 24) 7-~2-Isopropoxyimino-2-(S-amino-1,~,4-
~iad azol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl~-
10 ~hiome~hyi-3-cephem-4-ca~buxylic acid (syn isomer).
mp 145 o 150~ (dec.)
I~R. (Nujol): 3a70, 3230, 1780, 1680, 1625,
1530 cm 1
~5 ) 7~ Propo~imino~ 5-amlno-1,2,4-
15 thiadia~ol-;-yl)ace~amido] -~- (l,a,4-thiadiaol-2~yl) -
thiomethyl-3-cephem-4-carboxylic acid ~syn isomer).
mp 130 to 133~C ~dec.)
I,R~ ~Nuj~ 3380, 3230J 1780, 1680, 16?5,
1530 cm l
~ ) 7-[~-~ethoxyimino-2^(5-ami~o~ 4-
thiadiazol-3-yl~acetamido]-3-~S-(N-t-butoxycaTbonyl-
amino)methyl-7, 7,4-thiadia.,ol-2-ylJthiome~hyl-3-
cPphem-4-caTboxylic acid (syn isomer~. mp 150 to
15 5 C ~dec . )
I~R. ~Nujol): 3350, 3250, 1780, 1670 cm 1
( 27) 7- ~2-Methoxyimino-2- (5-amino-1,2 ,4-
thiadia~ol-3-yl)2cetamido]-3- ~5-allyl~nio-1,i,4-
thiadi a o l - 2 ~ yl ) thiom~thyl-3-cephem-4-carboYylic
acid (syn isomer~. mp 160 ta 165C ~dec.)
aO I.R. ~ujol~: 3350, 3250~ 1780, 1680, 162Q c~ 1
- 06
C~8) 7-~2~ethoYyimlno-2-~5-amina-1,2,4-
t~iadia~ol-i~ acetamido]-3-acet~lt~iomethyl~a-
ce~ 4^c r~oxylic acid (syn isomer). mp 178 to
182~ (dec. ~ .
I.R. ~Nuj~ 3350~ 3250, 1780, 1680, 1620 cm
(2g3 7-~2~E~hoxyimino-Z-~5-amino-1 t 2,4-
th;adia~ol-3-yl)acetamido~-3~ {a-(N-t-
butoxycarbonylamino)psopyl}-lH-~tr~zol~5-yl~-
thiome~hyl-3-cephem-4-carboxylic acid (syn isomer~. -
mp 183 to }83C ~dec.)
I.R. ~Nujol) : 3a70, 3240, 1780, 1690, 16;0,
, 1530, 1380, 1260) 1170) 1040 cm~
N.M.R. ~d6-DMSO, ~) : 1.27 ~;H, t, J=7H~),
1.38 ~9H, s), 2.0 ~2H~ m), 2.98 ~2H, m),
3.7 ~2H~ m)~ 4.0-4.42 ~6H, m), $~17 ~lH,
d~ J~4.5Hz), 5.8~a ~lH, dd, J~4.5 and
8.0Hz), 6.83 ~lH, m~, ~.13 t2H1 b~oad s),
9-53 tlH, d, J~8.0H~)
0) 7-~2-Etho~yimino-2-~5-amino-1,2,4-
thiadiazol-3-yl)acetamidol-3~ {2-(N-t-
butoxyca~honylamino)ethyl}-lH-te~a~ol-5-yl]-
thiomeLhyl-3-cephem-4-ca~oxylic acid (syn isomer).
I.R. ~Nujol) : 3360, 3240~ 1780, 16gO, 1630
153Q, 137~, 1250, 1170, 1040 c~-
N.M.R~ (d6- D~SO, ~) : 1.27 ~3H, t, J-7Hz),
1.33 tgH~ s),.3.17-4.0 (6H, ~), 4,01-
405 (4H, m), 5.17 ~1~, d, J=4.5H~),
aO 5.87 (lH, dd, J=~.5~and 8~0H-), 7.0 (lH,
m), 8.16 ~2H, b~oad s), 9.5t ~lH, d,
J=8.0H:)
~1~ 7-[2-~thoxyimino-2-(5-amino-1,2,4-
thiadia:ol-;-yl~acetamido]-a^(l-me;hyl-lH-te~r~_ol- ~5 5-vl)th-amethyl-a-cephem-~-ca~bo~yllc ~cic ~syn isomer).
~ ~7 -
mp. 156 to 159C (dec.)
I~R. (Nujol) : 3360, 3~5a, 1730, 1680~
~625, 13gO, 1080~ 1040 cm
N.M.R~ ~d~-~MS0, ~ .27 (3H, t, J=7H?~
3.7 ~ H, broad s), 3,95 ~3H~ s), 4.0-
4.56 ~4H, m), SolS ~lH, d, 3~4.5Hz),
5.83 ~lH, dd, J~4.5 and ~z), 8.12
~ZH9 broad s), 9.53 ~lH, d, J=8.0Hz)
~2) 7-~2-Ethoxyimino-2-~5~amino-1,2,4-
thiadia~ol-3-yl~acetamido3-3-~1-{2-~N,N-dimethyl-
amino)ethyl}-lH-tetrazol 5-yl]thiome~hyl-3-cephem
4-carboxylic acid (syn isomsr). mp 177 to 180C
(dec.)
I,R. ~Nujol) : 3380~ 3250, 1775, 1670~ 1620,
1535, 1380l 1040 cm 1
N~M.R~ ~d6-DMS0, ~) : 1.27 (3~, t, J~7H~),
- 2.S0 ~6H, s), 3.17 t2H, m), 3.67 ~2H,
m), 4,22 (2H, q, J-7H~)9 4.~-4,7 (4H~
m~, 5.13 (lH, d, J~4.5Hz), 5.83 tlH,
. 20 dd, J-4.5 and 8~0H~), 8.17 (2H, broad
s~, 9.58 (lH, d, J~8.0Hz)
(3~) 7-[ 7 - Ethoxyimino-2-~5-amino-1,2,4-
thiadia~ol-3-yl)acetamido]-3-(1-allyl-lH-tetrazol-
S-yl)thiomethyl-3-cephem-4-carboxylic acid ~syn
isomer). mp 160 to 165C ~dec.)
I.R. (Nujol) : 3380, 3250, 1780, 1680, 1630,
1530, 13809 1040 cm 1
N~M,R. (d6-DMSO, ~) : 1.25 ~3H, t, J=7Hz3,
3.7 (2H, m~, 4.0-6.0 (13H, m)j 8.13
t2H, broad s)j 9.57 (lH9 d, J=8.0Hz)
(34) 7-~2-Ethoxyimino-2-(5-amino~ ,4
thiadia7O1-3-yl)acetamido]-3-~tetrazolo[1,5-b]-
pyrida~in-6-yl)thiomethyl-;-cephem-4-carboxylic
acid ~syn isome~3. mp 18Q to 185C (dec.)
I.R. ~Nujol~ : 3350, 3Z40, 1780, 1610, 1620,
15~0, 1~80, 1040 c~~
~08 ~
N.M.R. (d6~DMSO, ~) : 1.27 ~3H, t, J=7Hz),
3.77 (2H, m), 4.20 ~2H, q, J~7~z),
4.20 and 4.67 ~2H, ABq, J~12Hz), 5.20
~lH, d, J~4.5Hz), S.83 (lII, dd, J~4.5
and ~Hz), 7.73 ~lH, d, J~9~z), 8.12 ~2H,
broad s), 8.56 ~lH, d, J39Hz), 9,53 tlH,
d, J=8Hz)
~5 ) 7-C2-Ethoxyimino-2-(5-amino-1,2,4-
~hiadiazol~3-yl)acetamido~-3-~5-aminomethyl~1,3,4-
10 thladiazol-2-yl) ~hiomet~yl-3-cepheD3-4-ca~boxy~lic
acid ~syn isomer). mp lg8 to 2~5C (dec.~
I.R. ~Nujol} : 3350, 3250, 1775, 1680~ 1620,
1535~ 1380, 1040 cm
N~.R. ~d6-DhlSO~D2O, ~) : 1.27 ~3H, t~ J~7Hz),
3.6 (2H, broad s) ) 4. 23 (2H) q, J~7Hx),
4,0-4.83 ~4H~ m), S~13 ~lH~ d, J~4.5H
5.80 ~lH, d J J~4,$H~)
~ 6) 7-~2-Ethoxyimino-2-(S-amino-1 J ~ ~ 4-
thiadiazol-3~yl)ac~tamido3~3-~ 2-hydroxyethyl)-
lH-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic
acid ~syn isomer)~ mp 170 to 173C (dec.)
I.R. tNujol~ : 33S0, 3240, 1780, 1675, 1625,
1530, 1380, 1040, 720 tm-l
N.h~.R. (d6-DMSO, ~) : 1.27 (3H, t, J=7Hz),
~5 3.67-4.4 ~lOH, m), 5.15 (lH, d, J-4.5Hz),
5 . 83 ~lH, dd, ~=4 . 5 and 8Hz), 8013 ~2H,
broad s), 9.57 (lH, d, J=8.0Hz)
~7) 7-~2-Methoxyimino-2-(5-amino-1,2,4-
thiadiazol-~-yl)acetamido]-3-(4-allyl-4H-l~2~4-
triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid
(Sy3l isomer) . mp 185 to 190 C ~dec . )
I.R. ~Nujol) : 3350, 3250, 1780, 1680,
1625, 1530 cm 1
N.M.~. (d6-DMSO, ~) : 3.67 (2H, broad s~, 3.9;
~3H, s), 4.20 (2H, b~oad 5)1 4.43-4.66
- 10~ _
~, m~, 4.88-5.4Q ~3H, m), 5.60-6.06
(2H, m), 8.18 ~2H~ s), 8.63 (lK, s),
~.57 (lH, d, J~8Hz~
(38) 7-~2~Methoxyimino-Z~(5-aminq-1,2,4-
thiadi~ol-;~yl~acetamido3-~-t3-methox~carb~nyl-
1~2,4~thiadia~ol-S-yl) thiomethyl-3-cephem-4-carboxylic
acid ~syn isomer). mp 180 to 1854C (de~c.)
I.R~ ~Nujol) : 3~50~ ~250, 1180 D 1740, 1680,
1620, ~530 cm~l
io N.M.~. ~d6-DMS0, ~ : 3~70 (2H, broad s),
3.93 ~6H, s), 4~7 (2H, bToad s)~ 5.17
~lH, d, J~4Hz~ 9 5.83 ~lH# dd~ J~4 and
8H~), 8.10 t2H? s), 9~57 ~lH7 d, J~8H~)
~9) 7-~2-hlethoxyimino-2-~5-amino~ ,4-
thiadiazol-3-yl)ace~amido]-3-~3-carbo~y-1,2,~-
thiadia~ol-S-yl)thiomethyl-3-cephem-4^carboxylic
acid ~sy~ isamer). mp 175 to laOC ~d~c.)
I.R. (~u}ol) : 3350, 3250, 17~0, 1730, 1680,
16~0, 1530 cm~l
N.M.~. ~d6-~MS0, ~) : 3.73 ~2H, broad s~, 3.93
(3H, s), 4.47 ~2H, b~oad s) 9 5.17 (lH,
d~ J~4Hz), 5.83 (lH, d~, J=4 and 8Hz),
8.10 ~2H, s), 9.57 (lH, d, J=8Hz~
C40~ . 7-~2-Ethoxyimino-2-~5-amino~1,2~4
thiadiazol-3-yl)acetamido]-3-tl-~3-aminopropyl)-
lH-tetra2O1-5-yl~thiomethyl-3-cephem-4-carboxylic
acid ~syn isomer), mp 182 ~o 185C (dec.)
I.R. ~Nujol) : ;350, 3200, 1770; 1670, 1670,
- 1530, 13~0, 1040 c~-l
(47 ) 7-~2-Ethoxyimino-2-~5-amino-1,2,4-
thiadiazol-;-yl)acetamido3~3~ 2-amir.oe.hyl)-lH-
~e~r~_ol-5-yl]thiomethyl-;-cephem-4-car~o~yl~r acid
~syn isomer). mp 195 ~o 2104C ~dec.)
I.R. ~ujol) : ;3~0, 3210, 1770~ 1675, 16~0,
1550, 1380, 1040 cm 1
~>7~
-- 110 --
(42) 7-[2-Isopropoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-~1-carboxymethyl-lH-
tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp. 17S to 180C (dec.).
I.R. ~Nujol) : 3300, 3~00J 177Q, 17~,0,
1680, 1620,1$2Q cm 1
N.M.R. ~d6-D~SO, ~ 7 (6~, d, J=6H~),
,i 3.67 (2H, broad s), 4~23 and 4.47
~2H~ ABq7 J=14Hz), 4.20-4.50 (lH, m) 9
5.10 ~lH, d, J=4~z), 5.30 (2H, s),
5.80 ~lH, dd, J=4 and 8Hz~, 8.10 ~2H, s),
9.47 ~lH, d, J=8Hz)
(43) 7-[2-Methoxyimino-~-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-(5-carboxymethylthio-
lS 1j3~4-thiadiazol-2-yl)thiomethyl-3-cephem-4-c~rboxylic
acid tsyn lsomer), mp~ 150 to 155C (dec.).
I.R. (Nujol) : 3350, 3~50, 1780, 1720,
1680, 1620, 1530 cm~l
N.M.R. (d6-DMSO, ~ : 3.60 and 3~72 (2H, ABq,
J=18Hz), 3.~Z ~3H, s), 4.14 ~2~, s)~
4.22 and 4.48 (2HJ ABq, J-14HZ),
5.12 ~lH, d, J=4H7.)9 5,8~ (lH, dd,
J=4 and 8Hz), 8.50 (2H, s), 9.50 ~lH,
d, J=8Hz)
(44) 7-[2-~isopropoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl)acet~mado]-3-(1-methyl-lH-tetrazol-
5-yl)thiomethyl-3-cephem-4-carboxylic acid ~syn isomer),
mp. 17Q to 175C (dec.~.
I.R. (Nujol) : 3350 9 325Q, 1780,
16 sa ~ 1620, 15~0 cm 1
N.M.R. (d6-DMS0, ~) : 1.27 ~6H9 d, J=6H2), 3.73
~2H, broad s), 4.00 (3H, s), 4.33 (2H3
broad s), 4.27-4.67 ~lH, m~, 5.17 ~lH,
d, J=4Hz)~ 5.87 ~lH7 dd, J=4 and 8Hz),
a5 8.15 ~2H, s), 9.53 (lH, d, J=8H~).
3~ 3
~45) 7-~2-Isopropoxyimino-2-(5-amino-1,2,~-
thiadiazol-3-yl)acetamido]-3-[1-{2-~N-t-
butoxycarbonylamino)ethyl} lH-tetrazol-5-yl~thiomethyl-
3-cephem-4-carboxylic acid (syn isomer), mp. 142 to
S 147C (dec )~
I.R. ~Nujol) : 3350, 3~50, 1780, 1690, 16 3n ,
1530 cm 1
N.M.R. (d6-DMSO, ~) : 1.22 ~6H, d, J=6Hz),
1.30 (9H, s), 3.17-3.50 (2H, m),
. 3.70 ~2H, broad s), 4.17-4.57 ~Sh, m),
5.13 ~lH, d, J=4Hz), 5.83 ~lH, dd,
J=4 and 8Hz), 8.17 ~2H, s), 9.55 (lH,
d, J=8Hz)
t46) 7-[Z Isopropoxyimino-2-(5-amino-1~2,4-
15 thiadiazol-3-yl)acetamido]-3-~tetrazolo~l,5-b]pyri-
d~zin-6-yl)thiomethyl-3^cephem-4-carboxylic acicl
~syn isomer), mp. 165 to 170C ~dec.).
I.R. (Nujol) : 3300~ 3~00, 1775, 17103 1670
1625, lS25 cm 1
N.M.R. ~d6-DMSO~ 1.23 ~6H, d, J=6Hz~,
3.73 ~2H, broad s), 4.20-4.50 ~lH, m),
4.25 and 4.62 ~2~, ABq, J-l~Hz),
5.18 (lH, d, J=5Hz), 5.87 (lH, dd,
J=5 and 8Hz), 7.78 ~lH, d, 3=lOHz),
8.18 ~2H, broad s), 8.63 (lH~ d,
J=lOHz), 9.63 (lH, d, J=8Hz)
~47) 7-[2-Isopropoxyimino-2-~5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-~1-allyl-l~-tetrazol-5-
yl)thiomethyl-3-cephem-4-c~rboxylic acid (syn isomer),
mp. 135 to 140C (dec.).
I.R. ~Nujol) : 3350~ 3230, 1780, 1680, 1625,
1530 cm 1
N.~l.R. (d6-DMSO, ~) : l.Z7 ~6H, d, J=6Hz),
3.68 ~2H, broad s), 4.25 and ~.45
(2H, ABq, J=13Hz~, 4.20-4.50 (lH, m),
- 112-
4.85-5.08 (2H, m), 5.13 (1H, d, J=SHz),
5.18-5.45 (2H, m), 5.82 (1H, dd,
J=5 and 8Hz), 5.60-6.20 (1H, m),
8.12 (2H, broad s), 9.48 (1H d, J=8Hz)
(48) 7-[2-Methoxyimino-2-(5-amino-1,2,4-
thiadizol-3-yl)acetamido]-3-(5-trifluoromethyl-1,3,4-
thiadizol-2-yl)thiomethyl-3-cephem-4-carboxlic acid
(syn isomer), mp. 150 to 155°C (dec.).
I.R. (Nujol) : 3300, 3200, 1770, 1670, 1620,
1520 cm-1
N.M.R. (d6DMSO, .delta.) : 3.70 (2H, broad s), 3.93
(3H, s), 4.37 and 4.65 (2H, ABq, J=13Hz),
5.17 (1H, d, J=5Hz), 5.85 (1H, dd,
J=5 and 8Hz), 8.17 (2H, broas s),
9.57 (1H, d, J=8Hz)
(49) 7-[2-Methoxyimino-2-(5-amino-1,2,4-
thiadizol-3-yl)acetamido]-3-[2-carboxymethyl-3-oxo-
2,3-dihydro-1,2,4-triazolo[4,3-b]pyridazin-6-yl]-
thiomethyl-3-cephem-4-carboxlic acid (syn isomer),
mp. 205 to 210°C (dec.).
I.R. (Nujol) : 3300, 1765, 1710, 1680, 1620,
1550, 1520 cm-1
N.M.R. (d6DMSO, .delta.) : 3.67 (2H, broad s), 3.93
(3H, s), 4.27 (2H, broad s), 4.63,
(2H, s), 5.10 (1H, d, J=5Hz),
5.75 (1H, dd, J=5 and 8Hz), 7.05
(1H, d, J=10Hz), 7.67 (1H, d, J=8Hz)
(50) 7-[2-Methoxyimino-2-(5-amino-1,2,4-
thiadizol-3-yl)acetamido]-3-(5-methylamino-1,3,4-
thiadiazol-2-yl)thiomethyl-3cephem-4-carboxylic
acid (syn isomer), mp. 175 to 180°C (dec.)
I.R. (Nujol) : 3450, 3370, 3250, 1775, 1710,
1680, 1630,1560 cm-1
~L 31 t~ 3;~3
N,~l.R. (d6-D~IS0, ~) : 2.90 (3H, s), 3.68
(~H, broad s), 3.95 (3E-l, s),
4.10 and 4.21 (2H, ABq, J-13Hz),
5 ~13 ~lH~ d~ J=5Hz), S . 83 ~lH) dd,
J=5 and 8HZ), 7 . 83 ~ , broad s),
8.17 ~2H, broad s), 9.60 (lH, d,
J=8HZ)
~51) 7- [2-MethoxyinLino-2-~5-an~ino-1~2,4-
thiadiazol-3-yl)acetamido]-3- ~5-amino-1~3,4-
thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid
tSY11 15Omer) ~ mP. 165 to 170C (dec.).
I.R. (Nujol) : 3350" 3210, 1770J 1670, 1620,
15~0 C~l 1
N.M.R, ~d6-DMSO, ~) : 3.67 ~2}l~ broad s), 3.95
~3H, s), 4.0~ and 4.25 ~2H, A~q,
J=13Hz~, 5.12 ~lH, d, J~SHz), 5.8CI
~:LH, dd, J~S and 8H~), 7. 33 (~HJ bTOad
S)3 8.15 (2H, broad s), 9.S7 (ZH, d,
J= 8HZ)
~52) 7-[2 Methoxyimino-2-~5-amino-1,2,4-
thia~iazol-3-yl)acetamido]-3-~1-{3-~N-$-butoxycarbonyl-
amino~propyl}-lH-tetrazol-5-yl]thiomethyl-3-cephem-
4-caTbo.Yylic acid ~syn isomer), mp. 175 to 180C (dec.).
I,R. ~Nujol): 3370, 3250, 1785, 1690, 16309
1530 cm~l
N.M.R. (d6-D~iSO, ô): 1.37 ~9H, S~, 1.73-2.17
t2H, m), 2.73-3.17 t2H, m), 3.68
(2H, broad s), 3.90 ~3H, s), 4.25 ~2H,
t, J=7Hz), 4.27 ~2H, broad s),
5.12 ~1~, d~ J=5H~), 5 . 80 (lH, dd,
J=5 and 8HZ) ~ 6.70-7.02 (lH, m),
8.13 (2H, b~oad s~, 9.55 ~lH, d, J=8H )
(53) 7~ E2-~IethOXYiminO-2- (5-aminO-1,2,4-
thiadia~ol- 3-yl) acetamido3- 3- [1- { 3-(acetamido)propyl}-
lH-tetTazol-5-yl~thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp. 150 to 155C (dec.).
I.R. (Nujol) : 3350, 3230, 1780, 1660, 1620,
1530 cm~l
N.M.R. (d6-DMS0, ~} : 1.80 (3H, s), 1.87-2.17
(2H9 m), 2 .90-a. 30 (2H, ~), 3.70
~2H, broad s), 3.93 ~3H, s) ~ 4.28
(2H, ~, J~7Hz), 4~30 ~2~, b~oad s),
5.13 ~lH, d, J~SHz), 5.82 ~lH~ dd,
J=5 and 8Hz), 7. 77-8.03 ~lH, m),
8.10 (~H, b~oad s), 9.57 ~lH, d, J=8Hz)
t54) 7-E2-Methoxyimino-2-(5-amino-l~2~4
thiadiazol-3-yl)acetamido~-3-~1-{l~acetamidomethyl)-
ethyl~-lH-te~razol-5-yllthiomethyl-3-cephem-4-
carboxylic acid (syn isomer), mp. 160 to 165~C (dec4).
r.3~. (Nujol): 3350, 3250, 1780, 1660, 16~0,
1530 cm ~
N M R ~d6-DMS0, ~) : 1.52 t3H, d) J=6Hz),
1.75 (3H, s), 3.13-3.80 ~2H, m~,
3,72 (2H, broad 5), 3.93 ~3H~ s),
4.33 (2H, br~ad s~, 4.50-4.83 ~lH, m),
5.12 ~lH, d, J=SHz) ~ S. 80 (lH, dd,
J-5 alld 8Hz), 8.00 tlEl" t, J=6Hz),
8.10 t2H, broad s), ~ 53 ~lH, d, J=8Hz)
t55) 7-~2-Methoxyimino-2-~5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-~1-{1-(N-t-butoxycarbonyl-
aminomethyl)ethyl}-lH-tetrazol-5-yl]thiomethyl-3-
cephem-4-carboxylic aaid (syn isom~r), mp. 180 to
1&5 C (dec . ) .
I.R. ~Nujol): 3370, 3Z30, 1780, 1690, 1630"
15 30 cm
N.M.R. ~d6-DMS0, ~) : 1.33- (9H, s), 1.50 ~3H, d,.
J=6Hz), 3.17-3.60 ~2H, m), 3.73 ~2H,
broad s), 3.93 ~3H, S), 4.35 (ZH,
broad s~, 4. 33-4.83 ~lH, m), 5.17 ~lH,
d, J=SHz~, 5.87 tIH, dd, J=S ~nd 8HP),
.. . . _ _ _ . _ _ _ . _ , .. . .. . . . . . . . . .
~ 115 -
6.93 - 7.23 (lH, m), 8 ZQ (2H, broad
s), 9.72 (1~-l, d, J-RH~)
~563 7-12-Methoxyimino-2-(5-amino-1>2~4-
thiadia ol-3-yl)acetamido]-3-[1-{3-~N~N-dimethylamino)-
p~opyl~-lH-tetrazol-5-yl~thiometh~1-3-cephem-4-
ca~boxylic acid (syn isomer~, mp~ 165 to :L70~C ~dec.).
I.R. (Nujol) : 33507 32Q0, 1770, 1670, 1610,
1530 cm 1
N.~.R. ~d6-DMSO) ~ : Z~03-2.57 ~2H~ m),
2.67 (6H5 s)y ~.73-3.27 ~2H, m),
3.67 ~2H~ b~oad s), 3.93 ~3H s) 7
4.33 (2H, broad s), 4.10-4.77 (2H, m),
5.05 ~lH~ d, J-5Hz), 5.70 ~lH, dd,
J=5 and 8~1~), 7.~3-8.43 ~3H, m),
9.53 (lH, d, J=XH~
~5;7,) 7-[2-Isopropoxyimino-~-(5-amino-1,2,4-
thiadiazol- 3-yl) acetamido~ 3- [5- ~N-t-bu~oxycarbonyl-
amino)methyl-l ,3,4-thiadiazol-2-yl]thiomethyl-3-
20 cephem-4-carbo~cylic acid (syn isomer), mp~ 140 to
145C ~dec~
IAR. (Nujol) : 3300, 1780, 1670, 16Z0,
1530 cm~l
~58) 7-~2-Methoxyimino-2-t5- amino- 1, 2, 4 -
thiadiazol-3-yl)acetamido]-3-~ 2 -carbo~ ethyl) - ].H-
tet~azol-5-yl]thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp. 150 to 155~ ~dec.).
I.R. (Nujol) : 3300~ 3150, 1770, 1720,
1670, 1620, 1520 cm 1
~5g) 7-E2-Methoxyimino-2-~5 -phosphonoamino-1, 2,4-
thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)-
thiom~thyl-3-cephem-4-caTboxylic acid ~syn isome~),
mp. 140 to 145G (dec.),
I.R. t~jol) : 3180~ 1765, 1670; 1515 cm 1
(60) 7-l2-~lethoxyimino-2-(5-amino-1,2,4-
- 116 -
thiadiazol-3-yl)acetamido]-3~ 3-aminopropyl~-
lH-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic
acid (syn isomer), mp. 185 to 190C ~dec.).
I.R. ~Nujol) : 3300) 3200, 1770, 1670, 1610,
1530 c~ 1
(61) 7-~2-Isopropoxyimino-2-~5-amino-1,2,4
thiadiazol-3-yl~acetamido3-3-~5-aminomethyl-1,3,4-
thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer), mp. 210 to ~15C tdec.).
I.R. ~Nujol) : 3350, 3200, 1750, 1670,
1620, 1530 cm~l
~62~ 7-l2-Isopropo.~yimino-2-tS-amino-1,2,4-
thiadia~ol-3-yl)acetamido]-3-[1-(2-amino~thyl)-la-
tetrazol-S-yl]thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp. 195 to 20n~c (dec.).
I.R. (Nujol) : 3350, 3250, 1775, 1680~ 16~0,
1530 cm~
(63) 7-~2-Me~hoxyimino-2-(5-amino-1,2,4~
thiadiazol 3-yl)acetamido]-3-~1-[1-~aminomethyl~thyl}- :
lH-tetrazol-5-yl~thiomethyl-3-cephem-4-carboXylic
acid (syn isomer~ J mp. 190 ~o 195C (dec.).
I.R. ~Nujol) : 3350, 3~30~ 1770, 1670, 16209
1530 cm~l
(64) 7-[2-Methoxyimino-2-(5-formamido-1,2,4-
thiadiazol-3-yl)acetamido~-3-~1-methyl-lH-tetrazol-
~-ylthiomethyl)-3-cephem-4-caTboxylic acid ~syn
isomer), mp. 170 to 175C (dec.).
I.R. (Nujol) : 3300~ 1780, 1680 cm 1
(S5~ 7-~2-Methoxyimino-2-~5-amino-19294-
thiadiazol-3-yl)acetamido]-3-(1-methyl-lH-tetrazol-
5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn
isomer), mp. 170 to 175C ~dec.~.
I.R. (Nujol) : 3300, 1770, 1660, 1610, 1520 cm 1
(66) 7-[2-Methoxyimino-2-~5-amino-1,2,4-
thiadiazol-3-yl)acetamidoJ-3-(5-methyl-1,3,4-
117 -
thiadiaæol-2-ylthiomethyl)-3-cephem-4-carboxylic
acid ~syn isomer), mp. 175 to 180C ~dec.)~
I.R. ~Nujol) : 3350, 1780l 1680, 1625,
1530 cm~l
(67~ 7-~2-Methoxyimino-2-(5-amino-1,2~4-
thiadlazol- 3-yl) acetamido~-3- (1, 3, 4-thiadia~ol-2-
ylthiomethyl}3-cephem-4-carboxylic acid (syn isomer),
m~. 172 to 177C (dec.)~
I.R. tNujol) : 3350, 17759 1680, 1626, 1530 cm 1
~68) 7-~2-Methoxyimino-2-e5-amino-1,2~4-
thiadia~ol-3-yl)acetamido]-3-tl-allyl-1~-tetrazol-
5-ylthiomethyl~-:3-cephem-4-carboxylic acid (syn
isomer), mp. 170 to 172C ~dec.).
I.R. (Nujol~ : 3350, 1780, 1680~ 1625, 1530 c:m
118
~amile 22
_
A solu~ion o~ 7-~2~methoYyimino-Z-~5-amino-
1,?,4-thiadia~ol-a-yl)ace~amido3~ -{2~(N-t-
butvxycarbonylamino)ethyl}-lH-te~ra-ol-5~yl~-
S thiomethyl-3-cephem-~-carbo~ylic acld tsyn isomer)
~.0 g) in g9~ fo~mic acid t20 ml3 wa:s s~irred or
2. S hours at am~ient temperatuTe. The mixture was
evaporated to dryness and the residue was dissolved
in an aqueous solution of sodium ~icarbonate and
adjusted to'pH 3 ~ith 10% hydrochloric acid. A
resulting precipitate was filtered off and the
fil~ra~e ~-as subjected ~o column chroma~ography OIL
non ion ads~rp~ion resin (Diaion HP 20)(TrademarX:
prepared by ~itsubishi Chemical Industries). The
column was washed with water and elu~ed with S0
aqueous methanol. The eluate was eYaporated to
remove methanol and ~h~n lyoph~lized ta give 7-~Z~
methoxyimino-Z-~5-amino-1,2j4-~hiadiazol-3-yl)-
acetamida]-3~ 2-aminoethyl)-lH-te~razol-S-yl~-
thiomethyl-3-cephem-4-carboxylic acid (syn isome
~250 mg)~ mp 2~0 to 205C ~ec.)
I.R. (NU3O1) ~ 3350, 3200, 1775, 1670, 1620 3
1530 cm 1
N.~.R. ~d6-DMS0, ~) : 3.47 (2H, bro~d s),
3.60 ~2~, b~oad s), 3.93 (3Hg s)~
4.2 ~2~, b~oad s~, 4.37 ~2H, broad s~
4.78 ~2H, broad s) 9 5 .03 ~lH, d, ~=4H~),
5.70 (lH, dd, J=4 and 8H~) 3 ~.10 (2H,s)
9.50 (lH, d, J=8Hz)
_5
.. . . . . .. _ _
-L 1'~ 3
-- 1~9 --
E~m~le 23
~ solutio~ o~ 7-[2-methox~imino-2-~5-ami~o-
1~2,4-~hiadia~ol-3-yl)acetamido]-a [1-{3-(~-t-
buto.xycarbonylamino)propyl}-lH-tet~a_ol-S-yl3-
thiome~hyl-3-cephem-4-carboxylic acid (sy~ isomer)
(2.22 g) in formic acid ~2Z ml) ~as stirred for
2.~ hours a~ ambient temperature. T~.e reactio~
mixtu~e was post-treated in a can~entional manner
t~ give 7-~2-me~hsxyimino-2 (5~ 1,2~4-
thiadiazo~-3-yl3acetamido]-3-rl-~3-an~nopropyl)-LH-
tetrazol-5-yl~thiomethyl-3-cephem-4-ca~oxylic acid
(syn isomer)~0.875 g), mp. 185 to 190C (dec.).
I.R. ~Nujol) : 3300, 3200~ 1770, 16707 1610,
1530 cm~l
l; N.M.R, (d6-D~ISO~D~0, ~ -Z~33 (2H, m),
Z~67-3.0 ~2H, m), 3.40-3.70 (ZH, m),
3.93 (3H, s), 4.10-4.67 (4~, M),
5.03 ~lH~ d, J-5Hz)~ 5~75 ~lH, d,
J~5~z~
~o E am~le 24x
The following compounds weTe obtained according
to ~mi~ar m~nners to those o~ Ez2mple~. 22 2~d 2~.
(1) 7 ~2-~ethoxylmino-2~ amino-1,2,~-
thiadia~ol-3-yl~ace.amido]-3-~5-aminamethyl-1,3,4-
2~ thiadia7ol-2-yl)thiom~thyl-;-ce~hem-4-caTboxylic acid
~syn ssomer~ p 21~215C ~d~c.~
I.R. ~Nujol) : i350, 320a, 1770, 1680, 162~ cm
N.M.R. ~d6-DMS0, ~ : a.60 ~2H, broad s)~ 3.93
(3~, s), 4.33 and 4.57 (2H, A3q9 J=13~
~ ~.43 ~H, s), 5.10 ~lH, d, J~4H-), 5.77
~lH, dd, J-4 and 8Hz~, 8.17 ~2H, s)~
9.50 (lH, d, J=8H-~
~ 3~ ~
_ ~0- -
~) 7-~2-~e~ha~yiml~o- 7 ~ amino-1, 7, 4 ~
thiadia~ol-3-yl)acetamido]-3-~5-t2-aminoe~hyl)-1,3,4-
thiadiazol-2-yllthi~methyl-3-cephem-4-carbo~xylic acid
~syn i~omer). mp 205 to 210~C ~dec.)
I.R. ~Nujol) : 3200, 1770, 1~70, 1620, lS30 cm
~3) 7-~2 Ethoxyimina-2-~5-amirlo-lv2,4-
thiadiazol~3-yl)acetamido3-;-~5-aminomethyl-1,3,4-
~iadiazol-2-yl)~hiom~hyl-3-cephem-4-carbo.YylYc acid
tsY~ isomer~. mp 198 ~o 205C (dec.)
I.R. (~ujol~ : 33S0, ;~50 3 1775~ 1680, 16~,
153S, 1380~ 1040 c~ 1
~.4) 7-~2-Etho~yimino-2-~5-amino-1,2,4-
- thiadiazol-3-yl)acetamidQ}~ aminopropyl)-lH-
te~ra~ol-5-yllthiomethyl-3-cephem-~-c~rbo.Yyllc acid
lS ~syn isomer). mp 182 ~o 185~C ~dec.)
X.R~ ~Nujol) : 33SO, 3200, 1770~ 1670~ 1~2D,
1530, t380, 1040 cm l
N.M.~. ~d6-DMSO, ~ : l.Z7 (3H, t, J-7H~,
2.17 ~2H, m), ~.83 ~ZH~ m), 4.17 ~
20 ~ ~ J-7Hz), 3~7-4.7 ~6H, m~j 5.00 (lH,
d, J~4.5~3, 5.70 (lH, dd, J-4.5 and
S.OHz), 8.17 ~2H, broad s), 9.3a ~lH, d,
J=8,0Hz~
~5) 7~ Ethoxyimino-2-~5-amir.o-1,2,4~
thiadiazol-3-yl)acetamido~-3~ 2-amino~thyl) lH-
tetrazol~5-yllthiomethyl-3-cephem-4-carboxylic acid
~5yn isomer). mp l9i to 210C (dec.)
I.R. ~Nujol) : 33409 3210, 1770, 1675, 1620,
15309 1~80, 1040 cm 1
3 N~M~Ro (d6-DMSO+D20, ~ 1.26 (3H, t, 3-7Hz),
3 0-3-7 t4X, m), 4.0-4.5 (4H, m),
4.66 t~H, m~, 5.03 tlH, d, J~4.~Hz),
5.~0 tlH, d, J=4.S~z)
~ 3
- 121
~6) 7-[2-Isopropoxyimino-2-(5-amino-1,2,4-
thiadia~ol-3-yl)acetamido]-3-~5-aminomet}lyl-1"3,4-
thladiazol-2-yl) thiomethyl- 3-cephem 4-carboxylic
acid ~syn i~omel), mp~ 210 to 215C (dec~)~
I .R . ~Nu; ol) ; 3350, 3Z00 J 1750, 16 70, 1620,
1530 cm
N.. M.R. ~d6-~ISO, ~ 30 (6H, d, J-6Hz) )
3.67 ~2H, broad s), 4 .20-4. 83 (5H, m),
5.13 (lH, d~ J=4Hz) 9 5.80 ~lH, dd,
J=4 and 8Hz~ " 8.13 (2H, s), 9.43 (lH,
d, J=8HZ)
~7) 7- ~2-~s opTopoxyimino- 2 - (5- amino- 1, 2, 4-
thiadiazol-3-yl) acetamido] -3- [~- (2-aminoethyl) -lH-
tetrazol-5-y:l~thiomethyl-3 cephem-4-carboxyl:ic aci.(l
~syn isomer) ~ mp. 195 ~o 200'1C tdec.) .
I.R. ~Nujol): 3350t 3250l 1775, 1680, 16Z0,
15 30 cm~
.M.R. (d6-DMSO, ~ : 1.27 ~6~1 d, J-6~Iz) 7
3.47 (2H, broad ~), 3 . 6 7 ~2H~ broad s),
4,27 t2H, broad s~, 4.33-4.57
(lH~ m), 4.67 (2H~ broad s), 5.10 tlH,
d, J=4Hz), 5.83 (lH) dd, J=4 and 8Hz),
8.17 (2H~ s), 9.47 (lH, d, J=8Hz)
~8) 7-[2-Methoxyimino-2-(S-amino-1,2,4-
~hiadiazol-i-yl~a~etamido~-3-El-{l-(aminometh ~ ethyl}-
lH-tetrazol-S-yl]thiomethyl-3-cephem-4-carboxylic
acid ~syn lsomer), mp 190 to 195C (dec.).
I.R. ~Nujol): 3350, 3230, 1770, 1670, 1620,
1530 c~
N-M-R- (d6-D~SO~D20, ~ : 1.23-1.70 t3H~ m),
3.10-3.80 ~4H,~m)) 3.92 ~3H, s),
4 ,0-4. 5 ~3H, m), 5. 05 ~lH7 d, J=5Hz),
5.73 (lH, d, J=5Hz)
~9~ 7~ Methoxyimino-2- (S-amino-1,2 ,4-
thiadiazol-3-yl)acetamido~-3-(5-amino-1,3,4-
. _ _ _ _, .. , . _ _ . ., . , . . _ .. _ _ _ . _ . . _ _ . _ _ _ _ _ _ _ . . .. _ _ . _ . .... . .. .
.
-- 122
thiadia~ol-2-yl) thiomethyl-3-cephem-4-
carboxylic acid (syn isomer), mp. 165 to 170C
~d~c . ) .
I.R. ~ujol): 3350, 321n, 1770, 1670, 1620
1520 cm
In this specification the expression "such
as" is intended to mean l'for examplel', and is not
intended to restrict the scope of the invention.
a
.
~5
