Note: Descriptions are shown in the official language in which they were submitted.
~VO 92/08721 PCI/KP~90/00018
2072~83 ~
NOVEL CEP~ALOSPORIH COHPOUNDS AND
PROCESS~S FOR PREPARATION T~IEREOP
Field o~ the InventiQn
The present inventioo relates to novel cephalosporin co~pounds,
pharnaceutically acceptable non-toxic salts thereof, and phYsiologicallY
hydrolyzable esters, hydrates and solvates thereof, which possess
poteot and broad antibacterial activities. The ioveotion also
relates to processes for preparing the saoe, and to Pharoaceutical
compositions containing the saoe as active ingredients.
Back~round ~ ith~_lnQention
Antibiotics of cephalosporin series are widely used in therapy
for treat~ent of diseases uhich are caused by general pathogenic
bacteria in hu~an beings and ani~als. It has been known that
.: .
~ such antibiotics are useful for the treat~ent of diseases c~used -
.
by bacteria exhibiting the resistance to other aotibiotics, e.g.
penicillin - resi6tant bacteria, and for treatnent of penicillin -
sensitive patients.
In most circuastances it is desirable to eoploy antibiotics
~hoving broad antibacterial activities against both Grao-positive and
GraD-negative bacteria. In this regard. there have been nade oaoY
studirs in developing a variety of cephalosporin antibiotics with
broad-spectrum antibiotic activities.
:: ~ : . :
For exa~ple, in GB patent No. 1.399.086 there are disclosed ~aoy
cephalosporin derivatives which are sho~n bY the ~or~ula
::: :
w o 92/08721 pc~rlK R90/000l8
20728~3 - 2 -
H
- C - C - N
(A)
0~ ~ P
CO2H
S ~herein
R is hYdrogen or an organic group ;
R~ is an etherifying uonovalent organic group linked to the
oxygen atom through a carbon atom ;
B is -S- or , S -~ 0 ; and
P is an or~anic group.
After the invention of these compounds, there ~ere manY attempts
to develop antibiotic conpounds having more ioproved properties,
to certain bacteriuus, especially to 6ra~-negative bacteria.
GB patent No. 1,522,140 discloses cephalosporin antibiotic
co~pounds of the formula(B) Nhich exist as syn isoDers, or as a ~ixture
of syn and anti isomers ~herein the syn isooers are present in at least
90 %,
o
CO2
herein . : .
R' is a furyl or thienyl grouP;
1 : R'' is a Cl-~ alXyl, C9~7 cYcloalkYl, furylnethYl or thienyl-
;` 2S oethyl group ; and
R " ' is hydrogen or a carba~oYl, carboxymethyl, sulfonyl or
oethyl group.
' -:
,: .
w O 92/087~1 PC~r/KR90/00018
- 3 -
2~72~83
The foregoing cephalosporin co~pounds have high antibacterial
activi-ties against a range of Gra~-positive snd Gra~-negative bacteria,
and particularly high st~bilitY to ~-lactaDases produced bY various
Gram-negative bacteria. ~oreover, they are very stable in ViYo.
Recently, there have been efforts to Prepare ne~ antibiotics having
improved and broadened antibiotic spectru~s ~hile showing potent
antibiotic activities, especialIy against Gra~-negstive bacteria.
Consequently a large nu~ber of cephalosporin antibiotics with analogous
structures, to those above, have been developed.
As a part of said efforts, an acylamido group has been introduced
into the 7-position of the cephen nucleus as shown in the foregoing
for~ula(0) and certain groups have been introduced into the 3-position
thereo~. ~
.
For exa~ple, in BE patent No. ~52,427 there are reported a nu~ber
of cephalosporin compounds having antibiotic activities which are sho~n
by the foregoing for~ula(A) ~herein the R is substituted ~ith various
organic groups including 2-aninothiazol, the oxygen ato~ of the
oxyiuino grouP is directly bonded to an aliphatic hYdrocarbon group,
~hlch aliphatic hydrocarbon group ~ay itself be substituted ~ith
a carboxy group. The substituent in 3-position of such co~pounds
-.
is an acetoxYmethyl, hYdroxYDethYl~ for~Yl group, or an optionally
substituted hetero cYcllc thio~ethyl group.
~ ~ Also, in US patent No. 4,390,534 to Psuto~u Terachi et al, there
are reproted new cephe~ co~pounds of the for~ula
~' ~ ` ,
:
W O 92/08721 pc~r/KR9o/oool8
2~72883 o
,N 11 ~S R3 . .
~ R4 (C3
~herein
Rl is a~ino or a protected aDino group:
RZ is hydrogen, acYl, substituted or unsubstituted arYI, substituted
alkyl, alkenyl, alkynyl, substituted or unsubstituted cycloalkYl,
cycloalkenyl, or a 0- or S-containing S-eenbered hetero cYclic
grouP ;
Ra is hydrogen or alkyl ;
R~ is an acyloxyalkyl, acylthioalkyl, substituted or unsubstituted
pyridiniuualkyl, substituted or unsubstituted heterocYclic
thioalkyl, alkYl~ hydroxy, or a substituted or unsubstitued
thiazoliu~alkyl grouP. or halogen ;
R~ is carboxy or a protected carboxY group, ~herein R5 is C00~ ~hen
: R~ is a substituted or unsubstituted pyridiniuoalkyl grouP or
a substituted or unsubstituted thiazoliuDalkYl group ; and
the dotted line "------" represents a single bond or a double bond.
While th~ P o~ the aforesaid GB Patent No. 1,399,0B6 or the R~ of the
aforesaid US patent No. 4,390,534 are defined very broadly as an organic
group or a ~ubstituted or unsubstituted heterocyclic thioalkyl gronP~~ :
respectively,~ there is not~therein sentioned the heRrt of the present
~ ~ 25 : Invention, that IS a co~pound having (l-substituted-4,6-diauinopyrisidinius-
:~; : 2-yl~thiomethyl group introduced into 3-position of the cephe~ nucleus.- .
;:
w O 92/08721 pc~r/KR9o/ooo18
s - 2~72~83
Also, European patent application No. 62,321 discloses cephe~
co~pounds of the foroula(D) and pharoacelIticallY acceptable salts :~
thereof, and their inter~ediates of the ~or~ulalD')
R~ C - C - N ~ S
oR2 N ~ ~ (D)
C O ,,- ' `
~herein
R~ is a~ino ar a protected a~ino group ;
RZ is a substituted or unsubstituted lo~er aliphatic IIYdrocarbon group,
or a cycloalkenYl group ; and .
- N 3 is a substituted or unsubstituted heterocYclic cation group
containing one or eore nitroBen atons :
O ~
N~ 11 H .
N 11 ~ ~S ~
oR2 ~LN ~ ~J (D ' ) ~ :
R'~ X-
~herein
R1 a~d RZ are the sare as de~ined in the ~oruula(D), respectivelY ;
Rt is a protected carbo%yl group ; and
X~ is sn scid residue. ~:
''..
: In European patent application N0. 74,563, the cephe~ coBpounds of
. the for~ula~) and their salts are proposed as antibiotic coDpounds
. . .
N ~ 11 H
~N 11 ` ~S~ /=,`,R (E)
OFIZ ~N~ ~, R~
CoZ-
w o 92/08721 pc~r/KR9o/oool8
- 6 -
2~72883
wherein
Rl is amino or a protected amino group ;
RZ is a protected or unprotected lower aliphatic hydrocarbon group,
cyclo(lower)alkyl, or cYclo(lower)alkenYl grouP ; :~ .
R~ is (lower)alkylamino, N-protected~lo~er)alkYla3ino, di(lo~er) .
alkylamino, sulfo(lower)alkyla~ino, hYdroxY(lowerlalkyla~ino,
N-protected hydroxy(lo~er)alkyla~ino, acyloxy(lo~er)alkyl,
(lower)alkoxy(lo~er)alkoxy(lower)alkyl, di(lo~er)alkYla~ino
(lower)alkyl, (lo~er)alXylthio(lower)alkyl, (lower)alkYlthio, -
(lower)alkoxy(lo~er)alkoxy, (lo~er)alkoxy, hYdroxy(lober)alkoxY,
acyl(lower)alkyl, hydroxy(lower)alkYlthio~ di(lower)alkylaoino..
(lower)alkylthio, N-containing unsaturated 5-~e~bered heterocyclic
grouP~ N-containing unsaturated 5-oeLbered heterocyclic thio
group, or N-containing unsaturated 5- or 6-~eubered heterocyclic
lS (louer)alkyl group which may be optionaily substituted with
: suitable substituent(s) ; and ~ :
R~ is hydrogen or a (lower)alkYl group.
There are disclosed cephem compounds of the for~ula(F) and their ~ a
salts in European patent application No.47,977
(O)n
Il H ~ :
A m--T--C--C--N ~n~ S
`oR2 ~---N ~CH2R,
- wherein~ CO2-
~n is an integer o~ 0 or 1 ;
~ . , ,
Ao is amino:or B substituted aaino group ;
: T is a thladlazoly ooiety, ~here one carbon ato~ i8 bonded to A~ ~nd
:, ~ .
-
WO 92/08721 PCI/KR90/00018
- 7 2~72883 :
the other carbon atoo is bonded to the group oi -C(=N-0-R2)- ; :
RZ is hYdrogen, a substituted or unsubstituted carba~oyl group, a
cycloalkyl grouP, or a substituted or unsubstituted carba~oyl
group ; and .
Rl is a substituted or unsubstituted thiazoliuo group, a substituted
or unsubstituted pyrazoliu~ grouP, a tri(lo~er)alkyl a~oniuu ~ :
group or a pyridiniu~ group of the ~'ollowing for~ula :
R'
N- ~
R' Rb
[~herein .
R~ is (lower)alkyl [which is substituted vith a substituent selected
froo the group consisting of cycloalkyl, nethyl, hYdroxy~ -
alkoxy, halogen, cYano, carbaooyl, carboxYl and sulfonYll,
(lower)alkenyl or carboxy-substituted (lo~er)alkenyl, (lower)
alkylthio or carboxy-substltuted (lo~er)alkYlthio, a~ino or
ono-substituted anino [wherein the substituent is selected
from the group consisting of~(lower) alkYl~ (lo~er)alkanoYl or
auinobenzene~ulfonyl], di(lower)albla~ino, carba~oyl l~hich is
substituted by (lower)alkYl, hydroxy~lower)alkYl~ (lo~er)alkoxy,
hydroxy ar CYanol~ di(lo~er)slkYlcarba30Yl, thiocarbssoyl,
cycloalkyl, phenyl, hydroxY, (lower)alkoxY~ halogen, (lower)
alkoxycarbonyl, (lo~er)alkanoyloxy, ~(lo~er)alkanoYl, carboxy,
sulfocyano, nitro, or a hydroxYsul~o(lower)alkYl group : .
~ Rb is ~hydrogen, a carba~oyl group, or a group selected fro~ the
groups deflned for R~ ; and ~ :
R is hYdrogen or a~group selected~ froD:the groups as de~lned in:the R~.
~ : :
~: : .
w o 9~/08721 Pc~r/~ ~90/000~8
2o~2883
As described above, there are a variety of cePhe~ cooPounds ~hose 7-
positions are substituted by a substituted aoinothiadiazole ring.
~o~ever, there are no reports about the ~ost ioportant characteristic
of the present invention that is a (1-substituted-4,6-dia~inoPYri~idiniu~
-2-yl)thio~ethyl group introduced into the ~-position of the cephe~
nucleus.
Su~aa~X of the Invention
An obiective of the Present invention is to Provide new antibiotic
cephalosporin coopounds of the for~ula(I ), phsroaceuticallY acceptable
non-toxic salts thereof, and uetabolically labile esters and solvates
thereof
N~C--C--N~a , N~
CO~- R2
~herein
R' is a C~ alkyl (preferablY oethyl or ethyl), C9~~ alhenYl
(pre~erably allyl), C~-~ alkynyl (perierably prop~rgyl) group,
or -C(R~)tRb)C0~, whereln R~ and Rb, sa~e or di~ferent, are
a hydrogen ato~ or a C,~~ alkyl grouP~ or R~ and R~ for~ a
Ca-~ cYcloalkyl group with the carbon ato~ to whlch they are
linked ;
R~ is a Cl~~ alkyl (per~erably a strai~ht alkyl group such as Dethyl,
ethyl, n-propyl or n-butYl)~ Ca~4 alkenyl (preferably allyl),
Ca-7 cYcloalkYl~ substituted or unsubstituted a~ino or A
..
WO 92/08721 PCI/KR90/00018
g _ . ;
2072~3
substituted or unsub~tituted phenyl (pre~erablY Phenyl, 4-
hydroxyphenyl, 4-chlorophenYl, 3,4-di~ethylphenyl, 2,4-
di~ethylphenyl or 2,~-dioethyoxyphenyl) group ;
R9 is hYdrogen or a C,-~ alkYl group(preferably ~ethYl or ethyl) :
and Q is N or C~.
. . .
Another objective of the present invention is to provide processes
for preparing the cephalosporin conpounds of foroula(I).
: .
1~ A further objective of the present invention is to provide
pharoaceutical coepositions co~prising one or more of the cephalosporin
coapounds o~ foruula(I) as act~ve ingredients.
, . .. . .
Description of the Proferred Eshodu~nts
The ne~ cephalosporin co~pounds of the present invention are either
syn isooers or oixtures of syn and anti isoners ~hich contain at least
90% of the sYn isomer and not nore than 10% of the anti i60mer. Also,
when the R1 group of formula(I) co~pounds is -C(R~)(Rb)C~H, ~herein R~
and Rb are diffierent, the carbon atom to which R~ and Rb are linked
20 becomes an nsYo~etrical center, these co~pounds being diastereoisooers.
Therefore, the present invention also includes such diastereoisomers of
cephalosporin conpounds of formula (I), and mixtures thereof.
Also, the solvates including hYdrates of the compoundstI) are
- included within the scope of the invention. In addltion, the co~pounds
25 of the ~or~ulatI) according to the present invention naY exist in
tautomeric forms and such tauto~ers are also included ~ithin the ficope of
~ .
~ the invention. Naoe1Y~ when ~ of the fornula (I) is a carbon ato~,
.
WO 9~/08721 PCl/KR90/00018
2~ 2883 - lo
the a~inothiazolyl group undergoes tauto~eris~ to for~ a i~inothiazolinYI
grouP~ its tautomer, as follows :
5_~ HNI ~
When the q of the forDula (I) is a nitrogen ato~, the
aminothiadiazolyl group ~orms ininothiadiszolinyl grouPs, its tautcmers
by tautomeris~ as ~ollows :
H
N~ ~ HN~ ~ - HN1~ ,Nil
~ he co~pounds o~ the for~ula (I ) also include the ~ollowing
resonance structures (I') and (I '') :
on~
11 r~ 2
~C-C~ R~
CO~. R
/
,ORI 11111 .ORI rlll2
C - C--l ~ ~ o O~ ~ ~ S--I [ ~ ~ " "
CO,~ CO2~
( 1' ~ ( 1" ) ''-': '
"' .
. ~
.; : . .
W O 9~/08721 pc~r/KRso/oools
- 11 - 2~72883
Suitable pharnsceuticallY acceptable ~alts o~ the object co~pound~
(I) are conventional non-toxic salts snd maY include an inorganic salt,
for example, a ~etal salt such as an alkali ~etal salt(e.g., sodiu~
salt, potassiu~ salt, etc.) and an alkaline earth ~etal saltle.g., calciu~
salt, nagnesiu~ salt, etc.), anmoniu~ salt,' etc.; an organic salt, ~or
exa~ple, an organic a~ine salt~e.g., tri~ethyla~ine salt, triethYla~ine
salt, pYridine salt, procaine salt, Picoline salt, dicYclohexYla~ine salt,
N,N'-dibenzylethylene-diamine salt, N-~ethYlgluca~ine salt, diethanola~ine
salt, triethanola~ine salt, tris(hydroxymethylaaino) ~ethane salt,
phenYlethYlbenzylanine salt : dibenzYlethylenedia~ine salt, etc.) etc.;
organic carboxylic or sulfonic acid salt(e.g., forcate, acetate, aaleate,
tartrate, nethanesul~onate, benzenesulfonate,'toluenesulfonate etc.): an
inorganic acid salt(e.g., hydrochloride, hydrobro~ide, sul~ate, Pho~phste,
etc.) ; a salt with a basic or acidic a~ino acid(e.g., arginino, ~spartic
acid, glutanic acid, lYsine. etc.) and the like.
The Physiologicall hYdrolYzable esters o~ the co~pounds (I) ~aY
include, for e~a~ple, indanYl, phthalidYl, nethoxy~ethyl. pivaloYloxy~eth
glycyloxy~ethyl, phenYlglycyloxY~ethyl or 6-eethyl-2-oxo-1,3-dioxolan-4-Y
esters, and other phYsiologicallY hydrolYzable esters which have been
20 ~ ~idely used in the technlcal fields of penicillin a~d cephalosporinantibiotics. These esters can be prepared in accordance vith known
: .
nethods. :
; The cephalosporin co~pounds of the ~or-~ la~I) exhibit hi8h ' -
antibacterial activities against both Gra~-positiv~ and Grao - negative ''
bacteria, and are especiallY useful in the thefapheutic and prophylactic ;~
trFat~ent of bacterial infections in hu~an beings and aninals.
WO 9~/08721 PCl/KR90/00018
2~372~83 - 12 -
The present invention also includes ~ithin its scope pharmaceutical
compositions cooprising one or ~ore of the conpounds (I) according
to the present invention as active ingredients, in association ~ith
phar~aceutically acceptable carriers, excipients or other additives.
The antibiotic compoundstI) of the invention Lay be for~ulated
for adoinistration, which may be presented in unit dose form or in
multidose containers. The conpositions ~ay take vsrious forcs such
as solutions, suspensions or emulsions in oilY or aqueous vehicles,
vhich can contain conventional additives such as disPersing agents,
suspending agents, stabilizing agents, and the li~e. AlternativelY~
the active ingredient may be ~or~ed into a dried powder that can be
normally dissolved in an aqueous solution of sterile, PYrogen-free
water, before use. The co~pounds(I) Day be also ~ornulated into
suppositories containing conventional suppository bases such as cocoa
butter or other glycerides.
The pharmaceutical compositions in unit dose forn, preferably
co~prise about fro~ 50 to 1,500 ~g of the active ingredient, dependlng
on the age and body ~eight of the patient, the nature and the severitY
of the illness, and so on. In general it hafi Proved advantageous
to adoiniater the ac~ive coupounds in an amount of about 500 to
5,000 ~g per day in order to achieve the desired results, depending
on the routes and frequencY of ad~inistration. In tase of intra-
~uscular or intravenous ad~inistrations for adult human treatment,
the dose of about 150 to 3,000 ~g per day is thought suf~icient, but
it may be increased in case of treatment for specific Lnfection6
caused by some strains.
. . , .. . .. ... . .. , " . . ... . . . . . . . . . . . ............. . . . . .
.- . .. : .:~ .:, . . . : . :,:, . . . . . .. , . . .. . .: ,
~'0 92/08721 pc~r/KR9o/
- 13
2~72~33
If desired, the co~pounds(I) can be ad~inistered in co~bination
with other antibiotics such as penicillins or other cephalosporins.
The coDpounds o~ the present invention as described above, exhibit
potent and broad antibscterial activities against Gra~-positive bacteria
and a variety of Grau-negatiYe bacteria as well, particularY against
Pseudo~n3~. Also, these coopounds have high stabilitY to ~-lacta~ases
produced by a nu~ber of Grao-ne~ative bcteria.
Exa~ples of especially preferred coopounds (I) are the coopoun~s
(I-1) and (I -15) of the foroula(I) ~herein Rl is -C(C~1~)2C0zll, R2
is uethyl or aoino, RD is hydrogen, and n ls Cll, snd their Phar~a-
ceutically acceptable non-toxic salts. These co~pounds (1-1) and
(I -15) posseses excellent antibacterial activities, especiallY agalnst
Psel~do~onas.
N~O \ / C2l~ Nll2
H2N~ ~) o ~
CO" ,CI 1,
.:
z o N ~--/ CO"I~ N I 1
H2N~ o ~L~ " N~ ~
CO,Nl 12 .:
2~ -
', ':
; ~ ~
,, . , ,. . . ~ .. , - -
.. .~ ~ , :.. , , .;, . . ... .. . . . . .. . . . .. . . .
w o 92/08721 pc~r/KR9o/oool8
2 ~ 7 2 8 8 3 - 14
Further exa~ples of preferred coapoundslI ) of the present invention
are as f~llo~s :
, . . _
R1 RZ Ri~ Q
_
-C(CHs)zCOzH ~Cna H Cll
-C(C8~)yC02H ~C8zCHa H Cll
-C(CH3)~C02H -NHz R CH
-C (CHa ) zCOzH -Cl~3 ~CHa CH
~CH(CHa)COzH -CHa ~ CN
-CH(C83)COzM -CHzClla H CH
-CH(C8~)COzH -CHzClL CH3 R Cll
-C(CH~)C02H -NH2 H CH
-CH;:C--CH -CH3 8 CH
` -C82C_ C8 -CH2CH3 H CH
-CL C_ CH -NH2 H CH ::
-cnz CHa -NHz H CH
~C8zCHa -Cllz
-C8~C83 -NHz N N ~.
-:
-CH2COzH -Cll~ H cn ;:
~ ~ -CHzCOzH ~CHzCHs H CH
:
~ ~ :
~ 25
~. . . .
:
. . ~ .~ : . i,, ,: . . . . ...... . .. .. . .. . . . ..
w o 92/08721 P ~ /KR90/0~01~
- 15 - 2 3 7 2 g ~ 3
The cephalosPorin co~pounds (I), pharDaceuticallY acceptable non-
toxic salts thereof, or phYsiologicallY hYdrolyzable esters or solvates
(including hydrates) thereof ~ay be prepared bY reacting the co~PouDds .
of the formula (Il) with the compounds of the for~ula(m) in the presence
of a solvent, and then, if necessary, re~ovi~g the aaino protecting group
and/or the carboxyl protecting group and/or reducing the S-oxide ~that is,
S~~(O)n] by a kno~n ~ethod, before or a~ter said reaction. This process
also eonstitutes a further aspect of the inYention. ::
R N11--~5,Q o? ~ ?~, N'~
CO2FI6 r~2
(Il) I (111) ~:'
'. .
ORI ::
N ' NH2 . .
~ NIl2
CO,- R2 `:
20Nherein :
R1, R', R~ and ~ are the saoe a~ defined above ;
n is an integer of 0 or l ; :. :
R4 is hydrogen~or an aoino protecting grouP ; - .
~: ; R is a C1~4 slkyl, C3~4 alkenyl or C~4 alkYnl group, or
:~ 25 -C(R~)(Rb)C02(R), ~herein R~ and Rb, sa~e or different, are
a hydrogen ato~ or a Cl~ alkYl group, or R~ and Rb ~aY for~
~'O 9~/08721 pc~r/~R9o/ooo18
16
2~333
a C~~7 cycloalkyl group with the carbon atou to which theY
are linked ; and R is hYdrogen or 8 carboxyl protecting
group ;
R~ is a hYdrogen aton or a carboxyl protecting group ; and
L is a leaving group.
The aaino protecting group ~ay include acyl, subst~tuted or
unsubstituted aryl(lower)alkyl(e.g. benzyl, diphsnyl~ethYl, triphenYl~ethYI
and 4-~ethoxybenzyll, halo(lo~er~alkYl(e.g. trichloro~ethYl and
trichloroethyl), tetrahydropyranyl, substituted phenylthio, substituted
alkylidene, substituted aralkylidene or substituted cyelolidene. The
acyl group as an a~ino protecting group ~ay include, for exs~ple, Cl-a
~lower) alkanoyl ( e.g. fornyl ard acetyl), C~0 alkoxycarbonyl(e.g.
~ethoxycarbonyl and ethoxycarbonyl), (lover)alkanesul~onyl ( e.g.
uethanesulfonyl and ethanesulfonyl), or arYl(lower)alkoxycarbonyl(e.g.
benzyloxycarbon~l), where the acyl group can be sub6tituted by 1~ 3
substituent(s) such as halogen, hYdroxY, cyano or nitro. In addition,
the auino protecting group maY include reaction products obtained fro~ -
aeino groups and silane, boron or phosphorus co~pounds.
The carboxyl protecting group as R o~ R~ or R ~ay include for
e~aDple, (lower) alkYlesters (e.g. uethYlester and t-butylester), (lower)
.
alkenylesters (e.g. vinylester and allylester), (lo~er) alkoxy (lower)
alkylesters (e.g. ~ethoxynethylester), (lower) alkylthio (lower) alkyl
esters~(e.g. ~ethylthio~ethylester), ~ halo~lower)alkYlesters (e.g. 2,2.2-
trichloroethYles~er)~ substituted or unsubstituted aralkylesters (e.g.
benzylester and p-nitrobenzYlester) or silYlester~ ~hich can be selecte~ -~a~ter consideration of the chenicsl propertY of the desired co~pounds(I).
.
W O 92/08721 pc~r/~R9o/ooolx
- 17 - 2~72383
It is desired that the afore~entioned a~ino or carboxyl protecting
groups oay be readilY re~oved under ~ild reaction conditions by
a known oethod.
~he leaving group L may include, for exa~ples, halogen ~uch as
chlorine or fluorine, an (lower)alkanoyloxy group such as acetoxy, a
(lower)aIkanesulfonyloxy group such as ~ethanesulfonyloxy, an
arenesulfonyloxy group such as p-toluenesulfonYloxy~ an alkoxycarbonyl-
oxy groups and the like.
The starting naterials of the co~pounds~ll) are kno~n as ~;
inter~ediates conventionally e~ployed for the preparation o~ cephalosporin
compounds. The dotted line of the fornula(ll) represents A sjngle
bond or a double bond, and therefore, the coapound~ o~ the for~ula(ll)
may be the coDpounds of the formula(ll-a), or co~pound~ of the foreula
(n-b)~ or oixtures thereo~ :
N,ORs ()n
Il H
R4NH Y~ \ ,, N ~ S ~ .
SN ~ L
CO2R
2n N,ORsH ()n
N~C-C--N S
R NH~S,b o ~L ~ II-b )
: CO2F~
;
wherein
n, R4, R~, R5, q and L are the ~sme as defined above.
WO 92/08721 PCl`/KR90/00018
2a7~33 - 18
The co~pounds of the for~ula(ll) can be prepared by activating tt~
compounds o~ the formula(rV) or their salts ~ith an scYlatin~ ~gent,
and reacting ~ith the co~pounds of the for~ula(V), as follows :
()n
~OR; H~N ~r~S
C--C--CO,.H(Na) . . I ~ L
CO F~
(IV) (V)
¦ ACY~ o~
N,ORs ()n
Il H 4
R NH~
~herein . (II) CO~R6
n, R~, R~, R~, Q and L are the sa~e as defined above , and
the dotted line of the formula(V) presents a single bond
or a double bond, so that the co~pounds of th~ ~ormula(V)
m8y be the conpounds of the formula(V-a), or conPounds of the
formuls(V -b), or mixtures thereof
()n ()n
H2N ~T--~ S ~ H2N ~ S
O~ ~ L o~ N ~ L
CO2R6 CO.,R
( V-a) ( V-b)
~herein n, R~ and L snd the sa~e as defined ebo~e.
: , .
w o 92/08721 P(~r/KR90/00018
19 - 2~7~3 :
In the preparation of the objective co~pounds(I), the co~pounds of
the forsula(l1) are used preferablY in an aoo~mt of fron ] to 2
equivalent(s) based on 1 equivalent of the compounds of the for~ula(~).
Aoino or acid protecting grouPs can be readily reDoved by a
conventional deprotection methods which are well kno~n in the field
of cephalosporin antibiotics. For example, acid- or base-hYdrolYsis
or reduction are generally applicable. For further e~aeple, ~hen the
protecting group is an amido group, it is feasible to subject such
co~pounds to imino-halogenation and imino-etherification, and then,
~ollo~ by hYdrolYsis~ Acid hydrolysis is preferable applicable to
renoval of such groups as tri(di)phenYloethYl or a~koxYcarbonyl, and is
carried out in the presence of an organic acid such as formic acid,
tri~luoroacetic acid, or p-tolueneacetic acid or an inorganic acid such
as hYdrochloric acid or the like.
The reaction for introducin8 the compounds(m) into the 3-Position
of co~pounds(ll) to prepare comPounds(I) is carried out in the presence
of a solvent such as water, or a mixed aqueous solvent o~ ~ater and a
water-sixable solvent. In the reaction, the pl~ o~ the solvent should
range from 5 to 8, but preferably frn~ 6 to 7.5. An appropriate
water-oixable solvent is ~cetonitrile or acetone.
Also, the reaction oay be carried out at 40 to lOO-C, preferab~Y
60 to 80-C.
To stabilize reaction products and their interDediates, one or oore
salts selected fron the group con~isting of sodiuo iodide, potassius
iodide, sodiun bro~ide, potassium brocide and potassiu~ thiocyanate can
be used as stabilizing agents.
:. ~ . - . .. .. . : . . .
w o 92/08721 PC~r/K R90/00018
20728~3 - 20
On the other hand, the separation and puri~ication of the co~pounds(I
can be carried out using a known method such as recrystalliz~tion, colu~n
chrooatography over silica gel or ion-exchange chrooatographY.
The cephalosporin compounds(I) of the present invention, and their
non-toxic salts, preferably alkali metal salts, alkaline earth retal
salts, inorganic acid salts or a~ino acid salts, show potent antibacterial
activities again6t a variety of general pathogenic bacteria including
Gra~-negative and Gra~-positive bacteria, there~ore, they are especiQllY
use~ul in theraphy for treatuent of bacterial infections in huoan
beings and anioals.
In order to illustrate the usefulness of the invent0d coapounds,
the oininal inhibitory concentrations(HIC) thereof against standard
strains and against clinicallY isolated-strains, were deternined and
conpared with Ceftazidioe of a kno~n coopound.
Also, the Ln vitro antibacterial activity was detersiDed by a two-
fold dilution ~ethod as descrlbed below :
That is, the t~o-fold serial dilutions of the coopound ~ere ~ade and
dispersed in Huller-Hinton agar uediuo. 2 ~ of standard test strain
~hich had the 107 C~U per mQ was inoculated on the oediun, and Ha
incubated at 37-C ~or 20 hours. The results of the ~IC test~ are sho~n
in ~
The results of the HIC tests against clinically sepsrated-strains
are sho~n in Tahle 2.
Specific exa~ples of the coDpounds of foroula(I ) provided by th~s
invention a~e shown below :
:
, .
`~o 92/08721 pc~r/KRsolooo18
- 21 - 2~72~83 ~
7-[(Z)-2-(2-aoinothiazol-4-Yl)-2-(2-carbo~ylproP-2-oxYioino)
acetaoido]-3-(4,B-diamino-1-~ethylpyri~idiniuD-2-yl)thiooethyl-3-
cephe~-4-carboxylate
- : .
\/ :.:
,0 C02H ~H2
N ;~ C - C--" ~ S ~l NH 2 .
co2 CH3
- 10 I - 2 : 7-[tZ~-2-(2-aoinothiazol-4-yl)-2-(2-carboxylprop-2-oxYi~ino)
aceta~ino]-3-(4,6-dia~ino-1-ethylpyri~idiniu~-2-yl)thiomethYI-3-
cephe~-4-carbo~ylate
... - - ------ ,
~o~CO2H NH2
0~5~-- ~ NH2
Ci CH.,CH,
- 3 : 3-(1-allyl-4,6-disrinopyri~idiniuu-2-yl)thiorethyl-7-~(2)-2-(2-
aoinothiszol-4-yl)-2-(2-carbo~yprop-2-oxyiuino)acetaoido]-3-cepheD-
4-carboxylate
N~O~COzH NH
N~C-C--N 5~ N~NH2
C02- CH2cHc~l2
~;: ~: . ,' '
w 79~ 22 - pc~r/K R9O/OOOlX
I - 4 : 7-[(Z)-2-(2-a~inothiazol-4-yl)-2-(l-carboxyeth-l-o~Yiuino)
acetamido]-3-(4,6-dia~ino-1-sethylpyri~idiniuu-2-yl)thlomethyl-3-
cephe~-4-carboxylate
,0 CO~H NH2
N ~ C - C - N ~ ` N H2
CO2- CH,
I - 5 : 7-~(Z~-2-(2-a~inothiazol-4-yl)-2 (1-carboxYeth-l-oxYi~ino)
acets~ido]-3-(4,6-dia~ino-1-ethylpyri~i.diniuo-2-yl)thiollethyl-3-
cepheo-4-carboxylate
'''.
:~ ,0 CO2H NH2
0~ N H2
co2- CH2CH, : :-
.
l - 6 : 3-(1-allYl-4,6-dia~inopYri~idiniu~-2-yl)thio~ethyl-7-~(z)-2-(2
aYinothiszol-4-yl)-2-(1-carbo~yeth-1-oxyi~ino)aceta~ido]-3-cephe~
-4-carboxylate
:. . :.
~ -
,0 ~ CO2H NH2
N~C-C--N ,5~ NJ~
~: 25 ~ H2N~ ~ O ~ ~ ~1NH2
CO2- C~CHCH2
.
: ~ ;
~vo 9~Jo8721 pc~r/KRso/
- 23 - 2 ~ 7 2 ~ 8 3
1- 7 : 7-E(Z)-2-(2-a~inothiazol-4-yl) 2-(carbo~y~ethoxyimino)acetanidol-
3-(4,6-dia~ino-1-~ethylpyri~idiniu~ yl)thioDethyl-3-cephe~
carbo~ylate
.. .... .. .
O CO2H NH7
N~C-C-N , S~ NJ~
2 S o ~ N ~ ~1NH2 :
co2- CHI
.
I- 8 : 7-~(Z)-2-(2-a~inothiazol-4-yl)-2-(carboxYoethoxYinino)aceta~ido]-
3-(4,6-diamino-l-ethylpyrioidinium-2-yl)thio~ethyl-3-cepheo-4-
carboxylate .
-- :
; ~ N,o_CO"H NH7 ~:
N--c -C--N ~ ` NH,
CO"- Cl~,~C~,
~:
. .
1 - 9 : 3-(1-allyl-4,6-diaDinopyri~idinium-2-yl)thio~ethyl-7-1(Z)-2-
aoinothiazol-4-yl)-2-(carboxyoethoxyioino)acetaDido]-3-cepheo-4-
; carboxylate
N, H N~
~ H2N~
CO~- CH2CI~CH~
wo 9~/08721 Pcr/KRso/00018
- 24
2~72~83
I - lO: 7-~ (Z)-2-(2-a~inothiazol-4-yl)-2-(~ethoxyi~tino)aceta~ido]-3-(4,6-
diaDino-l-oethylpyriDidinium-2-yl)thio~ethyl-3-cephe~ carboxylat
OCH3
N H ~NH2
co2~ CH,
I- 11 :7-l(Z)-2-(2-aminothiazol-4-yl)-2-(ethoxyioino)acetaoido]-3-(4,6-
diamino-l-~ethylpyri~idiniuo-2-yl)thioDtethyl-3-ceplte~-4-carbo~late
, ,
,OCff2CH~
N H NH~
HaN ~ o ~ ` NH,
co2~ C~
: -
:: ,
1- l2: 7-~(Z)-2-(2-acinothiazol-4-yl)-2-(ethoxYltino)acetaoido]-3-(4,~-
20dia tino-1-ethylpyri~idiniu~t-2-yl~ thio~ethyl-3-cepheltt-4-carboxylate
J~
,OC~I CHI NH2
S ~S~s J~NH2
co~ c~2c~
. .
~ ~ ; ; ~ ,: "`
: ; :
w o 92/0~72l PC~r/K R90/00018
- 25 - 2~72~3
I - 13 : 7-[(~)-2-(5-a~ino-1,2,4-thiadiazol-3-yl)-2-(2-carboxyprop-2-
oxyi~ino)scetamido]-3-(1,4,6-triaminopyri~idiniu~-2-yl)thiomethyl-
3-cephe~-4-carboxylate . .
S o\/CO H NH2
H2N~ N O ~
co2- NH2
I - 14 : 7-E~Z)-2-(2-a~inothiazol-4-Yl)-2-(l-carboxyeth-l-oxyi~ino)
aceta~ido]-3-(1,4,B-triaoinopyri~idiniuc-2-yl)thiooethyl-3-cephe~-
4-carboxylate
.
N~O CO2H NH2 :-
H2N~ ~K~ `NH2
co2~ NH2 .
: ' '
I - 15 : 7-[(2)-2-~2-aoinothiazol-4-yl)-2-(2-carboxYprop-2-oxyl~ino)
aceta~idol-3-(1,4,6-tria~i~oPYrioidiniuy-2-yl)thio~ethyl-3-cephe~
-4-carboxylate
o\ /CO~H NH2
H2~ ~ S ~
CO, NH2
,'
.. ... ... . . .. : .. . .. ~ .. . ` .
w o g /08721 pc~rlK R90/00018
2~72~3 2~ -
I - 16 7-~(Z)-2-(2-a~inothiazol-4-yl)-2-(ethoxyi~ino)ac~ta~ido]-3-(1,4,
6-tria~inopyri~idiniu~-2-yl)thiomethyl-3-ceph0D-4-carboxylate
. .... v .. _ ~
,OCH2c~l, NH2
0~ ~NH2 ;
CO.- NH2 :
., ~
I - 17 7-1(Z)-2-(5-a~ino-1,2,4-thiadiagol-3-YI)-2-(ethoxYislno)
aceta~idol-3-(1,4,6-tria~inopyri~idiniu~-2-yl)thio~ethyl-3-cephe~
-4-carboxylate
N~c-C-N S N~
S ~, S ~ ~ N ~ :
co2~ NH2 . .
I - 18 ~-[~Z)-2-(2-arinothiazol 4-yl)-2-(2-propyn-1-o~ylDlno)aceta~ido]-
3-(1,4,6-triazinopyri~idiniun-2-yl)thionethyl-3-cepheo-4-
carboxylate
N--~ O ~
COz- NH"
~o 92/08721 pc~r/KR9o/oool8
- 27 - 2~728~3
I- 19 : 7-~(Z)-2-(2-aoinothiazD1-4-y1)-2-t~etboxYlDino)acetaoidoJ-3-(1,~,
6-tria~inopyri~idiniu~-2-yl)thio~ethYl--3-cephe~-4-carbo~ylate
. . . _ . _ _ _ . . . _ . .
N ~ c - C--N ~ N ~ ~
co2- ~IH2
I- 20 : 7-[(Z)-~-(5-aoino-1,2,4-thiadiazol-3-yl)-2-(etho~Yiaino)
aceta~idoJ-3-(4,6-dia~ino-1,-methylpyrieidiniu~-2-yl)thioDethyl-3- ,. '
ce~he~-4-carboxylate
... -- . _ :
~OCHzCH3
N~C-C--N~ 'S ~ NH
CO2~ CH3
-:
I - 21 : 7-[(Z)-2-(5-aoino-1,2,4-thiadiazol-3-yl)-2-(ethoxyi~ino)
aceta~idol-3-(4,6-dia~ino-l-ethYlpYrixidiniu~-2-yl)thio3ethyl-3
cephe~-4-carboxylate
: :
: ~ ~ ,OCH2CH3
rJ H NH2
; 25 ~ H2N~ N o N~
CO2-CH.CH3
w o 92t08721 pc~r/K R90/00018
- 28
2~rl 2883
I - 22 : 7-[(Z)-2-(5-a~ino-1,2,4-thiadiazol-3-Yl)-2-(ethoxyi~iao)aceta~idol-
3-(4,6-diaoino-1-propyl~yri~idiniu~-2-yl)thio~ethyl-3-cephe~-4-
- carboxylate
. .
,OCH2CHI NH2
N~C-C--N _~S~ NJ~
H2N~S'N ~LN~ ~lNH
co2~ CH~CH2CH
10I - 23 : 3-(1-allyl-4,6-diaDinopyri~idiniu~-2-Yl)-7-[(Z)-2-(5-a~ino-1.2.4-
thiadiazol-3-yl)-2-~ethoxyiolno)aceta~idol-3-cephe~-4-carboxyla~e ' '~ '
.
,OCH2CHI NH2
. H2N~ ,N O ~,5~
CO2- CH2C~CH2
I - 24 : 7-[(Z)-2-(5-acino-1,2,4-thiadiazol-3-Yl)-2-(~ethoxyi~ino)aceta~ido~- ..
203-(4,6-dia~ino-1-oethylpyri~idiniu~-2-yl)thiooethyl-3-ceptlec-4-
carboxylate
: . '
N, H NH2
N ~ C - C ~ S ~ N J~
~ H2N--~S,N ~LN~f~S~ NH2
CO2 ~ CH~
w o 92/OX721 pc~r/KR9o/oool8
- 29 - 2~72~83
I - 25 : 7-[(Z)-2-(5-aDino-1,2,4-thiadiazol-3-Yl)-2-(~etho~Yicino~a~etaoidol-
3-(4t6-dia~ino-l-ethylpyri~idiniuD-2-yl)thio~ethyl-3-cephera-4- ',
carbo~ylate
,OCH, NH,
N ~ C & N ~ S ~ ;
CO2 CH.,CH~
I- 26 i 7-[(Z)-2-(S-a~ino-1,2,4-thiadiazol-3-yl)-2-~2-carboxyprop-2-
oxyDino)aceta~ido]-3-(4,B-dia~ino-1-~ethyl~yri~idiniu~-2-yl)
thio~ethyl-3-cephe~-4-carboxylate :
_ _ -
.
,0 /COzH NH2
H2N~S NO ~5~ NH2
CO2- CH,
.
I- 27 : 7-[(Z)-2-(5-a~ino-1,2,4-thiadiazol-3-yl~-2-(2-carboxyprop-2-
oxyL~ino)aceta~idol-3-(4,6-dia~ino-1-ethylpYri~idiniu~-2-yl)
thio~ethyl-3-cephes-4-carboxylate
-- -- -
o\ /
N H NH2
"
::: N ~\ C-C--N~ S~N~q
s o ~ N ~ ~Nt'L`NH
:~ . C02- CH2CH~, .
.
: .
. .
:
W O 92/08721 pc~r/KR9o/ooo18
2072~83 - 30
I - 2R : 7-~(Z)-2-(5-a~ino-1,2,4-thiadiazol-3-yl)-2-(2-carboxyprop-2-
oxyillino)aceta~ido]-3-(4,6-dia~ino-1-propylpyri~idiniuD-2-Yl)
thionethyl-3-cepheo-4-carboxylate
,a C02H NH .
N ~ C - C - N ~ S ~i~` N H 2
co~- CH~CH2CH3 ~ -
I- 29 : 7-1(Z)-2-(5-aoino-1,2,4-thiadiazol-3-Yl)-2-(2-carboxYprop-2- ::
oxYioino)acetaoidol-3~ hutyl-4 ,B-dia~inopyri~idiniuL-2-yl) ',
thio~ethyl-3-cepheo-4-carboxylate
H,N~5,N d--n~,~ SI~NH,
CO~,~ CY2C~-.C~.,C~3
I - 90 : 7-~(Z)-2-(2-a~inothiazol-4-Yl)-2-(2-carbo~yprop-2-o~yioino)
acetanido]-3-(4,6-diaNino-1,5-di~ethYlpYrinidiniu~-2-Yl~thiooeth
-3-cepheo-4-carboxylate
.. . . .
.
. .
,o\ ~ co.. lt NH~
: N C-C--N S~ N~C11, .
Z5 ~ H2N ~ ~ ~ ~ S ~ N~ ~ ~JIt2
~ ~ C02- C~3
.
w o 92/08721 pc~r/KRso/oool8
- 31
207,?3~3
I- 31 : 7-ltZ)-2-(2-a~inothiazol 4-yl)-2-(2-carbo~yprop-2-oxyi~ino)
aceta~idol-3-(4,6-dia~ino-5-ethYl-l-methYlpyrimidiniu~-2-Yl) :
thiosethyl-3-cephe~-4-carboxylate
,N, H NH2
N ;~ C - C - N ~, t`l ~ C H~CH,
co2~ C~
I- 32 : 7-[(Z)-2-(2-a~inothiazol-4-Yl)-2-(2-carboxYProP-2-oxyi~ino)
aceta~ido]-3-(4,6-dia~ino-1-ethyl-5-~ethylpyri~idiniu~-2-yl)
.
N, H NH"
N~C -C--N ~ NH.
co2- CH2CHI '
.
I- 33 : 7-[(Z)-2-(2-aoinothiazo]-4-yl)-2-(2-carboxYprop-2-oxyi~ino)
aceta~ido~-3-(4,B-diacino-l,S-diethylpYri-idiniu~-2-yl)thio~ethyl
-3-cephe~-4-carboxylate
~,0 CO,.H NH2 : .
tt2N~5 ~ ~ N~CH"CH3 ~ .
C2 ~2C~
' ;~
. ~ ' : ' .
W O 92/08721 pc~r/KR9o/oool8
- 32
2 883
I- 34 : 7-[(Z)-2-t2-aoinothiazol-4-yl)-2-(2-carbo~yprop-2-oxYimino)
ac~taoino~-3-(5-methyl-1,4,6-triaminopyrimidiniuD-2-yl)thio~ethyl ~.
-3-cephe~-4-carboxylate . -
O\/CO H NH~ .
N "- C - C -N ~, S ~ N~ CH~ . .
H2N~S~ ~L I ~ ~N~ ~H2
CO.. - NH2 ..... ,.. -
I- 35 : 7-[(Z)-2-(2-aminothiaæol-4-yl)-2-(2-carboxyproP-2-olylmino)
aceta~ido]-3-(4,6-diamino-l-phenylpyrinidinium-2-Yl)thiomethyl-3
cephem-4-carboxylate
.
N~O\ /CQ2H
~ H2N ~S~ ~;~ S
C02
~ ' ,.''
I- 36 : 7-[(Z)-2-(2-aminothiazol-4-Yl)-2-(2-carboxYprop-2-oxYi~ino)
acetamido]-3-[1-(4-hydro2yphenyl)-4~6-diaoinopyri~idinium-2-yl]-
thio~ethyl-3-cepheo-4-carboxylate
.
: N~O CO2H NH2 .:
; H2N~S~ O ~;~_SI~NH : :~
2 ~ :
OH
,'; ' ~ ,,:'
W o 92/08721 pc~r/KRso/oool8
- 33 - 2~7~3
I - 37 : 7-~(Z)-2-(2-a~inothiazol-4-Yl)-2-(carboxywethoxyimino)acet~aido~
-3-(4,6-dia~ino-1-phenylpyri~idiniu~-2-yl)thio~ethyl-3-cephem-4-
carboxylate
Il H NH2
N C-C--t~ S~ N
2 ;;~ o~ ~ S--N- ~H~
CO~- 0
lOI - 38 : 7-[(Z)-2-(2-aDinothiazol-4-Yl)-2-~l-carboxyeth-l-oxyioin
acetaDido]-3-(4,6-diamino-1-phenylpYri~idiniu~-2-yl)thio~ethyl-3-
cephem-4-carboxylate
.
N~O--CO2H NH2
15N~C-C-N ~S~ N~q
H2N~S~ ~N~s--N~ NH,
CO2~
~ : ~,:'
I- 39 : 7-[(Z)-2-(2-aDinothiazol-4-yl)-2-(ethoxyiDino)aceta~ido~-3-14,6- :~.
20diamino-l-phenYlPYrimidinium-2-yl)thioDethyl-3-cephe~-4-carboxylate
-- :
~ ~ N~OC2~s NH2
H N~ Q ~ s~
2 5 2 0
':
'~ ~
WO 92/08721 PCI`/KR90/00018
- 34 - :
20~2~3
I - 40 : 7-[(Z)-2-(2-a~inothiazol-4-Yl)-2-(ethoxYi~ino)aceta~idol-3-[1-(4-
chlorophenyl)-4,6-dia~inopyrimidiniu3-2-yl~thiooethyl-3-cephe~-4-
carbo~ylate
,OC2Hs NH2
H2N~S~ o ~s~ H ;
CO~
I- 41 : 7-[(Z)-2-(2-a~inothiazol-4-Yl)-2-(2-carboxYprop-2-oxyiDino) :
acetamidol-3-14,6-diamino-l-[2,9-dimethylphenyl)-pyri~idiniu~-2-
yl]thiomethyl-3-cephso-4-carboxylate
N, H NH2
H2N~ o ~
CO,.- ~3,CII, ~
Cl~
I- 42 . 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(ethoxyi~ino)aceta~ido]-3-(4,~- -
dia~ino-l-t2,4-di~ethylphenyl)-pyri~idiniu~-2-Yll-thio~ethyl-3
cephe~-4-carboxylate
. .
N~OC~lts NH2 :
H2N~5~ o ~--'S~I~NH
CO~ ,CH,
.
.
W O 92/08721 PC~r/KR90/00018
- 35 - 2~72~83
1- 43 : 7-[(Z)-2-(2-a~inothiazol-4-yl)-2-(2-carboxYproP-2-oxYi~ino)
acetaoido]-3-[4,6-dia~ino-1-(2,6-dimethoxyphenyl)-pyri~idiniu~-2-
yllthiomethyl-3-cephem-4-carboxylate
.
o\/ co H NH2
H2N--~ ~,5~ '
CO2- ~ ,OCH,
CHJO ~ I ~ -
10 I- 44 : 7-[(Z)-2-t2-a~inothiazol-4-yl)-2-(2-carboxyprop-2-oxyi~ino)
acetamido]-3-[9,6-dianino-1-(4-chlorophenYl)-pYri~idiniu~-2-Yll . . '
thionethyl-3-cephem-4-carboxylate ::
:.
,O~C02H NH2
N~C -C--N~, S
CO2 ~ .,
~jJ ,,
I- 45 : 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(l-carboxYeth-l-oxYi~ino)
aceta~ido]-3-[4,6-diamino-l-propylpyrimidiniu~-2-yl]thio~ethyl-3-
cephem-4-carboxylate
::
N'O~co2H NH2
H2N~ ~ /~S~lNH
CO2CH ,CH ~CH,
W O 92/08721 PC~r/K R90/00018
2a~2883 - 36
1 - 46 : 7-[(Z)-2-(2-a~inothiazol-4-yl)-2-(2-propyn-1-oxYimino)acetamido1-
: 3-(4,6-diamino-1-methylpyrimidiniu~-2-yl)thio~ethyl-3-cephem-4- :
carboxylate
o/~
N H 1 2
N ~ C - C--11 ~ S ~ N~l2
co2~ CHI '
'
I - 47 : 7-[(2)-2-(2-sninot iazol-4-Yl)-2-(2-ProPYn-l-oxyimino)acetaoido]
-3-(4,6-diaoino-1-ethylpyrimidiniu~-2-yl)thiomethyl-3-cephe~-4-
carboxylate
o~ :
N, H NH2
H2N~ O ~,_~SJ~NH2 ~;.
C02- C~2C~ ,
~.
, .
48 : 7-[(Z)-2-(2-sminothiazol-4-Yl)-2-(2-carboxYprop-2-oxyioino) ~:
acetamidol-3-(1-cyclopropyl-4,6-diaDinopyri~idinium-2-yl)-3-
cepheo-4-carboxylate .~:
. - . .. ~__ _
.
N C-C--N S N~
25~ H2N~ O ~ ~N- NH~
C07- ,~
:~
:~
.
,, : .
w o 92/087~1 Pc~r/~R90/00018
- 37
2~2~3
I- 49 : 7-1(Z)-2-~2-a~inothiazol-4-yl)-2-(2-ProPen-l oxYi~ino)aceta~ido1
-3-(4,6-diaoino-l-~ethylpyri~idiniu3-2-yl)-3-cephe~-4-carboxylaLe
. . . _ . _ . _ .
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I- 50 : 7-1(Z)-2-(2-a~inothiazol-4-Yl)-2-(2-propen-i-oxyi~ino)aceta~ido1-
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WO 92/08721 PCr/KP90/00018
- 38
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- 39
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2072~3~3
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-- 42
2a72~83
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- ~3 ~ ~72~83 : ~
Tnl)le 2: Antibilcterinl ActivilY n~in~t Cli
.:
~IIC(mcg/mQ)
Co~pound Str~ins(No. teste~l)
llange 50 % ~0 %
Eschericllia coli(38) 0.016^~0.25 0.063 0.13
A~lebsiella pnell~olli~7e(10) O.OG3^~0.25 O.OG3 U.13
St~,uhylococclls sureus
~ethicillin suscepti~lef~2) 2^~4 2 2
St~ lYlococcus Alll~ells
3etbicillin resistant(7) 32~>12B >128 >128
Pseu(lo~on~s aerl/~inos~ (5~) O .13^~ G4 1 4
_
I -2 ~scherichia coli f38) 0.016^~0.25 0.063 O.13
~lebsiella pneu~oniaeflO) O .031^~ 0.25 O .13 O .13
St~phylococclls aureus
~ethicillin suscePtible(42) 1~4 2 2
Stal)hylococcus allreus
3ethicillin resistdnt(7) 32^~>128 >128 >IZ8
Psell~o~ollfls derugillosfl (5~) O .13^~ 64 2 .
_
1-4 Escllerichia coli(38) -0.008~v0.25 0.031 0.063
hlellsiellA pneu~oniaeflO) 0.031^~G.13 0.031 0.13
S~fl~hYlococclls flll~eus
~ethicilIiA suscePtibIe(~2) 2~4 4 4
S~flphylococcus flurells ., .
Inetbicillin resistnnt(7) >32 j32 >32
Pseudo~onns flel~u~inos~ (54) I,v > 128 __ _ _
I -5 &chel~ichifl coli (38~<=0.008~ 0.50.0~3 0.13
Klel)siella pneu~onifleflo)O.OG3^~0.25 0.063 0.25
Sldphylococcus flureus
~ethicillin susceptible (42J 2^~ 8 4 4
St.n~-llylococclls aureus . . ,.
3ethicillin resistflnt(7) G4^~?128 >12B >128
Pseudo~onfls fleruginosfl (5~)Q,25,v 64
I-l Escherichia coli(38)0.008~vO.OIGO.OIG 0.063
fiJebsiellfl pnewonide(10)0.016^~0.0G30~016 0.031
Stn~hylococcus dUl~ells ::
~ethicillin susceptible(42) 2^~4 4 4
Staphylococcus flureus
ethicillin resistdnt(7) >32 >32 >3~
~seu~0~011fls derllgi/losfl(5~)0.5~ 128 4 IG
_
1-14 Escherictlid coli(38)-0.008^~0.250.031 O.OG3
Ale~sielld pneu~onide(10)0.016^~0.063 0.031 O.OG3
Stnpllylococcus flurells
~ethicillin susceptible(g2~O .5^~ 4 4 4
. StflphyJococclls aurells
:~ : Inethicillin resistnnt(7) 4^~>128 >128 >128
Pseudooonfls fleruginos~ (5~)0 i 25^J 64_ 1 4
<No~e> $ Orotll ~icrodilution test
'.~
' ' '
,. , . ..... .. . .. , .. I . .... " ~ ... .. , . .. ~ ... .. . . . . . . . ... ..
WO ~/08721 PCT/KR90/00018
- 4~ -
2~28~3
Table 2(continue~)
_ . . ___ __
~IIC(~cg/mQ)~
Compound Strains(No. tested) _ __
Rnn~e 50 % 90 %
_
1 1~ ~scllcricllis coli(38)0.016^~0.25 O.OG3 n. 13
h'lel)siells pneu~oni.?e(10) 0.031^~0.2$ 0.13 0.13
Stfll~bylococclls Aureus
~cthicillill suscepti~le(~2) 2^~a 2 4
Staphylococcus aurells
methicillill resistantf7)32^~)128 >128 )128
Pseudo~onss aerugillos-~f51) 0.25^~ 32 2 8
_ _ .
1-16 Escherichia coli(38J0.031^~0.5 0.13 0.25
h'lebsiellA pneu~oniae(10)O.OG3^~0.250.13 0.13
StaplJylococcus flureus
~ethicillin susceptil)le(~2) 0.25^~0.5 0.25 0.25
Staphylococcus aul~eus
laethicillin resistant (7) 8^~>32 >32 >32
Pseudo30nfls Aer(lgil10sa ~5~) 0.5^~64
1-17 Eschellchia coli(38) O.OG3^~10.13 0.25
hlebsiellfl ~neu~onide(10) 0.13~0.250.25 0.25
Stnph,~lococclls allrells
~ethicillin susceptil~le (~J2) ' O . 5~ 1 O.5 I :
Stn~hylococcus fl(lreus
IDetllicillin resistsnt(7) 2~vl28 16 G4
_ Pseu(l~ollAs nerllginosfl (54) o, 6,v 128 8
1-l~, Escherichia coli(38) G,031~vl0.13 0.25
h'lebsiella pllelmol3iae(10) 0.13 0.13 0.13
St~lll/ylococcus nurells
loethicillin susceptible(~2J 0.13~0.25 0.25 0.25 3
Stsl~llylococcus flureus .,
~ethicillin resistant(7) G^~>128 128 >128
Pseudo~ooas serllgillos-7 (5~1) 0.5^~1G ~1 8
.. __
1-20 Escllerichis coli(38J O.OIG^~0.50.063 0.25
l'lel)siell.7 pneu~olliae(10)O.OG3^~0.25 0.13 0.13
St.7phylococcus sureus
i~ethicillin susce~tible(g2) 0.25^~0.5 0.5 0.5
St.7~Jhylococcus ~7ul~eus
oletllicillill resistsllt (7) 1^~128 16 32
rselldooonfls Aerll6inoss (5g) 1~ 64 4 IG
.... ____ _ _
1-30 &cbel1chia coli(38)0.031^~0.5 0.13 G.25
Klel)siells pneu~onise(lO)0.063~0.250.13 0.25
Stsphylococcus aurells
Inethicillin s~lsce~ti~le(~2) 2^~8 2 4
St.7phylococcùs 8lmells
oetllicillin resistal1t (7~ 32^~>128 )128 ~128
Psell~looon.1s flerllgillos-7 (5~)0.13^~ 32 2
<Nole> ~ llroLll microdilution lest
.
~ .
'~ :
.
-'0 92/08721 PC~r7KR90/00018
- 45
2072~3
Table 2(contin~
_ _ I
HIC (~cg/mQ)~
Co~-ound Strains(No. ~este(l)
Range 50 % 90 %
~ _ . .
1-45 Eschericllia coli(38) 0.031~0.250.13 0.13
hlebsielld pncu3ollifle(lo) O.OG3~0.25 O.13 0.13
Stflphylococcus aunells
~e~hicillin susce~tible(42) 2~4 2 2
Staphylococcus ~7w~eus
oethicillin resistAIl~(7) 64~>128 )128 >128
Pseudo~onas aerugilJosa(5~) 0.5~128 4 16
_ ~
1-4G ~scherichia coli(3R) 0.013~0.50.13 O.Z5
hlebsielld pneumonise(10) O.OG3v0.25 0.13 0.13
StAPhylococclls Allrells
~ethicillin susce~1tible(~2) 0.13~1 0.25 0.25
St~7hylococcus flurells
~ethicillin l~esistsnt(7) 4~)32 >32 >32
Pseudonoll~s aerugi1los~ f5~) O .5~ 32 4 8
.
1-47 Escherichia colif38) O.OIB~0.50.063 0 25
~lebsiella pneu~oniaeflû) 0.063~0.250.25 O 25
Stfll~hy]ococcus flurells .
oethicillin susceptible(42~ ~.13~0.25 0.25 0.25
Std~ ylococclls Alll'ellS
nethicillin resistflnt(7) 4~128 ~4 64
Pseudo~onAs aerllginosfl (54) 0.5~ 16 4 16
. . _... __ --
Ceftazidice Escherichia coli(3810.063~4 0.13 0.13 :
~lebsiell~ pneuoolliAe(lo)O.OG3~0.50.0~3 0.5
StAphylococcus aurells
nethicillin suscePtible(42) 2^~1~ 8 8
Stflphylococcus aurells
~ethicillin resistAnt(7)64~>128 128 >128
. Pseudo~on~s ~erugillosd (54) 0.5~128 __
<NoLe> ~ eroth ~iorodilution tes~
, ' ,:
.
: '
.
w O 9~/08721 pc~r/K R90/00018
2~7 ~3 - 46
In-vivo absorbencY of the invented compounds(l ) ~as studied in SD
rat(~ ) weighing 220~ 3gOg, as follows : The test compound ~as
intravenously administered in a dose of 20~g/kg respectively to 2~ 5 . .
rats. The blood samples from the femoral vein of the rats ~ere taken
5 every hour after administration, and analyzed by bio-assay(agar well
method). The results were shown in Tahle.3.
' ~ .
' '
WO 92/08721 PCr/l~R90/00018
- 47 - 2~72~3
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- 48
2072~83
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w o 92/08721 P ~ /KR90/000]8
,,9 20723~3
The Present invention i9 described in detail by the following
Preparations and Examples :
Preparation 1 : Preparation of 4,6-diamino~ ethyl-2(1H)-pyri~idinethione
- _
Sodium metal (4.6g) was added to dried ethyl alcohol (1~0mQ), and
re~luxed for an hour. After N-oethylthiourea (9g) and ~alononitrile
(6.6g) ~ere added thereto, the reaction ~ixture WA8 refluxed for 2~ hours. ;~
The reaction ~ixture was cooled to roo~ teoperature and neutralized with
conc. hydrochloric scid. The PreciPitates were filtered, washed
~ith wster (20mQ) and ethYI alcohol (50m~) and dried in vacuo to give
the above~indicated compound (8.~g) in pale Yellow solid.
el: 185DC~ (decoup.)
~ (D20 + acetone-dO)
3.80(s, 3~), 5.39(s, lH),
~LEIl : 15~(H'), 126 -
IR(KCI. c~ 3441, 3335(N-H), lB82(C=N~, 1095(C=S)
",.. "',.
Preparation 2 : Prepsration of 4,6-diaminD-1-ethYl-2(lM)-pyriuidinethione
-- -
Sodiun Eetal (4.6g) was added to dried ethyl alcohol (l00mQ~, and
re~luxed for an hour. A~ter N ethylthiourea (10.4g) and oalononitrile
(6.6g) ~ere added thereto, the obtained reaction mi~ture ~as refluxed
~or 48 hours. The reaction mixture ~as cooled to rcon teDperature
and neutralized with conc. hYdrochloric acid. The precipitates
~ere ~11tered, ~ashed with ethyl alcohol (50mQ), and the filtrate was
concentrated under reduced pressure. The residue was chroeatographed
: ~ '
WO 92/08721 pcr/KR~o/oool8
2~72883 50
over silica gel to give the above-indicated co~pound (6.2g) in yellow
solid.
m~: 197C^~ (deco~p.)
~: ~ (D20 + acetone-dO)
1.32(t, 3H), 4.61(~, 2H), 5.68(s, 1~)
~11: 170(H~), 142
~R(KCI~ 348D, 32D0(N-H), 1665(C=N). 1130(C=S)
Preparation 3: Preparstion of 4,6-dia~ino-1-propyl-2(1H)-pyriaidinethione
1 0 . .. .. . ._ . __ __
SodiuD aetal (4.6g) ~as added to dried ethyl alcohol ~100m~), and
re~llLsed for an hour. After N-propylthiourea (11.8g) and ralononitrile
(~,Bg) ~ere added thereto, the reaction oixture was refluxed ~or 72
hours, cool~d to roo~ temperature, and neutralized ~lith conc.
l~rdrochloric acid. The precipitates were filtered, ~ashed with ethyl
alcohol (5DmQ), and the filtrate was concentrated under reduced Pressure.
The residue ~as chromatographed over silica gel to give the
above-indicated co~pound (5.7g) in yello~ish brown ~olid.
~: 195-C^~ tdecoop.)
1~: ~ tD20 t acetone-d~)
0.96(t, 3H), 1.~ , 2H), 4.51(t. 2H), 5.46(s, lN)
~L~ll: 184(H'-), 142
IR(~Cl. cr~~1): 3310, 3200(N-H), 1634(C=N), 1150(C=S)
,~.
Preparstiols 4: Preparation of l-butYl-4,6-dialliDo-2(1H)-Pyrioidinethione
: ~ ,: '
Sodiu~ ~etal (4.6g) was added to dried ethYl alcohol (lOl)m~), and
.' ' ,:
.. . ~ .. - , . .. .. . . . . .. . . .
w o 92/08721 PC~F/KR90/0~018
- 51
- 207~3
refluxed for an hour. After ~-butylthiourea (13.2~) and malononitrile
(6.6g) were added thereto, the reaction mixture was re~luxed for 72 hours,
cooled to roo~ te~perature and neutralized with conc. hYdrochloric acid.
The precipitates were filtered, washed ~ith-ethyl alcohol (50mQ), and
the filtrate was concentrated under reduced pressure~ The residue ~as
chro~atographed over silica gel to give the above-indicated co3pound
(4.8g) in hro~n solid.
: 195~C ~ (decomp.)
~ DzO ~-acetone-d~)
0.88(t, 3H), 1.36(~, 211), 1.69(m, 2H), ~.59tt, 2H), 5.41(s, 1l1)
IL : 198(~), 142
IR(KCl. c~ 3320, 3200(N-N), 164~(C=N), lllO(C-S)
Preparation 5 : Preparation of 1-allyl-4,6-diaoino-2(111)-pyrimidinethione
- - -
Sodiun Detal (4.6g) was added to dried ethyl alcohol (lOOm~), and
refluxed for an hour. A~ter N-allYlthiourea (11.6g) and malononitrile
(6.Bg) vere added thereto, the reaction oixture was refluxed for 72
hours, cooled to room te~Perature and neutralized with conc
hydrochloric acid. The precipitates were filtered, ~ashed vith ethYl
alcohol (50mQ~, and the filtrate was concentrated under reduced pressure
The residue ~as chromatographed over silica gel to ~ive the
above-indicated campound (~.2g) in yellowish bro~n solid.
. .
193-C^J(deconp.)
~ (CD~OD)
5.42(s, lH), 5.16~ 6.11(m, 5H)
HS(E~) : 182(H'), 142
w o 92/08721 P ~ /KR9~/00018
2 ~ 52 -
IR(Kcll-clL~ 3310, 3260(N-H), 1645(C=N), 1012(C-S)
Preparation 6 : Preparation of 1,~,6-tria~ino-2(111)-PYriuidinethione
Sodiun ~etal (4.6g) ~as added to dried ethYl alcohol ~lOOmQ), and
re~luxed bY heating ~or an hour. After oalononitrile (8.6g)
and thioseuicarbazide~9.lg) ~ere sdded thereto, the reaction aixture
was refluxed for 24 hours, cooled to roo~ temperature. The
precipitates were filtered, ~ashed with ethYl alcohol (5~nQ), and dried
under reduced pressure to give the above-indicated compound (8.3g) in
~hite solid.
: 225'C ~ ~decoup.)
E~R : ~ (D20 + acetone-d~)
5.42(s, lH)
~LEIl : 157(H~), 126
IRtRCl._cn~') : 3440, 3420~N-NH~),-3310, 3260(N-11), 1645(C=N), 1138(C=S)
Preparation 7 : Preparation of 4,6-diaoino-1,5-d}uethYl-2(1H~-
pyriDidinethione
A. PreParation o~ ~ethYl (+)-2-cYanoProPiQnate
To ()-2-bro~opropionic acid (81.08g) was added water (~OmQ).
Sodiuo carbonate (28.62g) was added slouly over an hour and dissolved
therein. A solution of potassiuo cyanide(37.77g) dissolved in water
, .
25; (75mQj ~as addded, and heated to about 50C. Accordingly as the
reaction pro&ressed, the teoperature of the reaction ~olution rose
to 90CC. The reaction solution ~as stirred at 90 a lOO~C for
: '
w O 92/08721 PC~r/K~R9O/000l8
- 53 ~
an hour. cooled to roo~ temperature, and neutralized ~ith conc
hydrochloric acid (BOnQ). A~terwards, the thus neutralized solution
uas concentrated under reduced pressure, ethyl alcohol(300nQ) ~as
added to the concentrated solution. The ethanolic solution was
concentrated under reduced pressure again. To the residue was added
ethyl alcohol (700mQ), followed by filtration. After conc. sulfuric
acid(1~ 5m~) ~as addPd to the filtrate, the solution was refluxed
for 5 hours and distilled to re~ove about 300mQ of ethylalcohol. The
solution was concentrated under reduced pressure, and residue ~as added
to sodium carbonate saturated solution (200mQ). Af~er extraction with
ether(400mQ), the separated organic layer ~as washed with a 10
saline solution (50DmQ) and a saturated saline solution (200mQ), and
dried over anhydrous uagnesiun sul~ate, filtered and then concentrated
The residue was distilled under reduced pressure to give the colorless
above-indicated compound(44.74g).
YiQl~ : 70 %
b.P. : 87~ 90C/12 torr
L~ (CDCl~)
1.33(t, 3H), 1.60(d, 3H), 3.55(q, lH)~ 4.28(q, 2H).
B. PrePara~ion ~o~ (*)-2-cYanoProPiona~ide
To ethyl (+)-2-cyanoproPionate (44.74g) ~as added conc. aqueous
a~nonia solution ~200mQ). The reaction mixture ~as stirred at roou
te~perature for an hour and concentrated under reduced pressure. After
addition of ethyl alcohol (200mQ), the ethanolic solution ~as
concentrated again. The residue ~as dried in a Yacuu~ oven to give
the green above-indicated compound (33.00g).
:
.
WO 92/08721 pcr/KR9o/oool8
- 54
2 ~ 3
96%
~: ~ (DllSO-d~)
1.40(d, 3H), 3.74(q, lH), 7.39(bs, lH), 7.82(bs, IH).
C. PreParation of~-~e~hyl~alononitrile
( + )-2-CyanopropionaDide (33.00g), and phosphorus pentachloride
(28.07g) ground oinutely in a ~ortar were added to a flask equipped
with a distillation apparatus. While producing a vaccu~ using a ~ater
pu~p, the ~ixture ~as stirred at 90^~100C for 20 ~inutes to re~ove
hydrogen chloride gas and phosphorus oxychloride, and distil}ed under
reduced pressure in a bath heated to 180-C to give the above-indicated
coopound(15.678~. This compound ~as solidified to a ~hite solid state
at rooD teoperature.
58%
b.P.: 86~89DC~12torr
~: ~ (DHSO-do)
1.63(d, 3H), 4.76(q, 1~)
~ ' . '
D. PreParatioLof 4.6-dia~ino-1.5-dimethvl-2(1Hl-PYri~idinethione
A~ter sodiun ~etal (9.Olg) ~as dissolved in dried ethyl alcohol
(150mQ) under nitrogen strea~, N-~ethylthiourea(17.67g) ~as added
thereto and refluxed for an hour. 2-Hethyloalononitrile (17.67g) was
added to the solution and then refluxed for 15 hours. The reaction
ni~ture was cooled to 40C and filtered. The filtered solid ~as washed
with cold ethYl alcohol ~lOOmQ) and dried to gi~e the pale yellow above-
indicated cospound(25.20g).
L~.: 230-C~v (decomp.)
~: '
:
W O 92/08721 PC~r/KR9OtOOO18
- 5~ -
2~72~3
Y1Q1~ : 76%
~L~ : Rf 0.2(HeOH/CH2Clz = 1/5)
.. . . .
DMSO~da)
1.6(s, lH), 3.60(s, 3H), 4.92(bs, 4H)
~lEll : 170(H~), 156
IR(RCI. cn~~l : 3480, 3360(N-H), 1623(C=N), 1090(C-S)
Preparation 8 : Preparation of 4,6-dia~ino-1-ethYl-5-~ethYl-2~111)- -
pyri~idinethione
1 0
A~ter Sodiun ~etal (2.30g) ~as dissolved in dried ethyl alcohol
(50mQ), H-ethylthiourea (5.20g) ~as added and refluxed ~or a~ hour.
2-Methylaslononitrile (4.0~) ~as added to the solution and then refluxed
~or 15 hours. The reaction oixture ~as cooled to rooc teDPerature,
neutralized vith conc. hydrochloric acid, and filtered. After water
(20mQ) was added to the filtered solid, the oixture was stirred for 10
minutes, and ~iltered. The filtered solid was dried to give the pale
yellow above-indicated co~pound(3.57g).
~he~ : 281-C ~ (decoop.)
Yield : 39~
E~a : ~ (DMSO-do)
1.15(t, 3H), 1.75(s, 3H), 4.57(bs, 2H), 6.24(bs, 2H), 6.68(bs, 2H),
HS(EI~ : 184(H~), 156
~ L ~ : 3418, 3300(N-H), 1620(C=N), 1105(C=S)
: ,
',
W O 9 /08721 PC~r/KR90/00018
- S6
2 ~ 3
Preparation 9 : PreParation of 5-methyl-1,4,6-triaoino-2(111)-
pyrimidinethione
After sodium Metal (~.30g) was dissolvcd in dried ethyl alcohol
(50m~), thiosemicarbazide (4.55g) was added thereto and refluxed for
an hour. 2-Methylmalononitrile (4.0g) ~as added to the ~ixture
and then refluxed for 15 hours. The reaction mixture was cooled to
40C, and filtered, washed with ethyl alcohol(50r~), and dried to ~ive
the pale Yellow above-indicated compound~3.78g).
~ 215-C ~ (deco~p.)
YiQl~ : 44 %
a~ (D~S0-d~)
1.68(s, 3B), 3.48(bs, 2H), 5.20(bs, 2H), 5.95(bs, 2
~LELL : 171(M'), 156
IR(RCI. c~~~) : 3470, 3340tN-H), 1622(C=N), lDBO~C-~)
.
Preparstion 10 : Preparation of 4,6-diaoino-5-ethyl-l-methyl-2(1H)-
pyrinidinethione
.. .
1. PreParati~n of ~ethYl (* )-2-&~anobutYrate
To (+)-2-brouobutyric acid(167.01g) ~as added ~ater(150mQ).
Sodiuo carbonate (54.05g) was added slo~ly over an hour and dissolved
therein. A solution of Potassiu~ cyanide (68.55g) dissolved in
water (150nQ) was added, and heated to about 50C. Accordingly as the
reaction pro~ressed, the temperature of the reaction solution rose to 80C.
The reaction solution was stirred at 80~90C for an hour, cooled to
rooo teoperature, and neutralized with conc. hydrochlolic acid
,
w o 92/08721 P ~ /~R90/00018
- 57
2~12~3
(120m~). A~terwards, the thus neutralized solution was concentrated
under reduced pressure, and ethYl alcohol (500mQ) was added to the
residue. The obtained ethanolic solution was concentrated under
reduced pressure again. To the residue ~as added ethYl alcohol
(700mQ), follo~ed ~y filtration. After conc. sul~uric acid (3mQ) ~as
added to the ~iltrate, the solution ~as refluxed for 5 houre and
distilled to re~ove about 300m~ of ethYl alcohol. The solution
was concentrated under reduced prrssure, and the residue ~as added to
sodiu~ carbonste saturated solution(400mQ). After extraction ~ith
ether (50ûmQ), the separated organic layer was ~ashed ~ith a 10%
saline solution (500mQ) and a saturated saline solution(300mQ), dried
over anhydrous ~agnesiun sulfate, filtered and then concentrated. The
residue solution vas distilled under reduced pressure to give the
colorless above-indicated comPound(49.90g).
YiQl~ : 35%
e~ : 93~ 96-C/12torr
-(CDCl~) ~
1.14(t, 3~), 1.34(t, 3H), 2.01(~, 2~), 3.47(t, lH), 4.28(q, 211)
B. Pr~eparation o~ 2-cYanobutYra~ide
~o ethyl (~)-2-cyanobutyrate (49.90g) ~as added ethYI a}cohol
(40m~). A~ter conc. aqueous anaonia solution(200mQ) ~as added thereto
.
over 10 ~inutes, the ~olution vas stirred at 30~ 40C ~or 30 ninutes.
Ether(500mQ) ~as added to the solution and stirred for 10 ~inutes.
The precipitates ~ere filtered, and dried to give the colorless above-
indicated coopound(31.9~g).
YiQl~ : 81%
.
W O 92~08721 PC~r/K R90/00018
- 58
29~2~83
~M~ : ~ (DNS0-d~)
0.98(t, 3H), 1.83(~, 2H), 3.63lt, lH), 7.43~bs, 1~), 7.7~(bs, lH)
C. PrePa~ ion of 2-ethYl~alononitrile
(+ )-2-Cyanobutyraoide (31.g6g), and pbosphorus pentachloride
(23.85g) ground in a ~ortar ~ere added to a flask equipped ~ith a
difitillation apparatu~. While producing a vaccuu using a water pump.
the ni~ture was stirred at 90~ 100C for 20 ~inutes to reoove hydrogen
chloride gas and phosphorus oxychloride, and distilled under reduced
pressure in a bath heated to 180~C to give the above-indicated coopound
(l9.g5g).
~iQl~ : 73 ~
tDMS0-d~)
1.2~(t, 3H), 2.1~t~, 2H), 3.73(t, lH)
-
D. PreParation of 4.6-dia~ino-5-ethYl-l-~ethY1-2Ll~)-DYrimidinetbione
After sodiu~ metal (2.30g) w~s dissolved in dried ethyl alcohol
(50mQ), N-methYlthlourea(4.50g) was added thereto and refluxed for an
hour. 2-Ethylralononitrile (4.70g) was added to the solution and then
refluxed for 18 hours. The reaction lixture ~as cooled to 40'C,
neutralized ~ith conc. hydrochloric acid, and filtered. To the
filtered solid vas added ~atert50mQ). The ~ixture was stirred for 10
inutes, filtered, and dried to give the ~hite aboYe-indicated coupound
(4.15g).
~e~ : 259C ~ (decomP~)
YiQl~ : 45 %
(D~SO-do)
' ", ",.
w O 92/08721 PC~r/KR9O/00018
- 59
2072~3
0.92(t, 311), 2.34(q, 2}1), 3.82(s, 3H), 6.78(bs, 211), 7.06(bs, 2H)
~lEIl : 184~M'), 169, 156
IR(KCll c~~') : 3410, 3280(N-H), 1645(C=N), 108S(C=S)
Preparation 11 : Preparation of 4,6-diaoino-1,5-diethyl-2(1H)-
pyri~idinethione
A~ter sodiu~ ~etal (2.30g) ~as dissolved in dried ethyl alcohol
(50nQ), N-ethylthiourea (5.20g) was added thereto and refluxed for an
hour. 2-EthYl~alononitrile (4.70g) was added to the reflux ~ixture
and then refluxed for 18 hours. The reaction nixture was cooled
to 40C, and adjusted pH to 5 with a 28% solution of hYdrogen chloride
dissolved in isopropyl alcohol. The reaction oixture was ~iltered,
~nd then water(50mQ) ~as added to the ~iltered solid. After the
solution was stirred for lD niDutes and filtered again, the residue
was dried to give the pale Yellow above-indicated compound(2.79g).
: 269C ~ (decomP.)
Yiçl~ : 28%
~ (DHSO-du)
O.91(t, 3H), 1.16~t, 3H),2.28(q, 2M), 4.57(bs, 2M), 6.45(bs, 2H),
6.70(bs, 2H)
~Ell : 198(H~), 170
TR(KCI. c~-~l : 3380, 3320(N-H), 1646~C=N~, llOl(C=9)
- .
..
.
W O 92/08721 pc~r/KR9o/oool8
- 60
2972~3
Pre~aration 12 : Yreparation of 4,6-dia~ino~1-phenYl-2(11l1-
pyrioidinethione
Sodiuo ~etal (B.6g) was added to dried ethYl alcohol~l00mQ), and
re~luxed ~or an hour. After N-phenylthiourea ~9g) and malononitrile (6.6g~
~ere added thereto, the reaction 3ixture ~as re~luxed for 72 hours. The
reaction olxture was cooled to roo~ te~perature and neutralized with
conc. hYdrochloric acid. The precipitates were filtered, ~ashed ~ith
water(20m~) and ethYl alcohol (50m~), and dried in vacuo to give the
above-indicated co~pound (4.7g~ in a pale yello~ color.
: 281~C ~ (deco~p.)
(acetone-dO)
5.48(s, ln), 5.90(bs, 2H), 6.52~bs, 2H), B.80~ 7.70(D9 5H)
~ 21~H~)
1~I3~-J3L:~L : 34~4, 34005N~H), 1830(C=N), 1182(C=S)
Preparatlon 13 : Preparation of 1-(4-chloroPhenYl)-4~6-dia~ino-2(lN)
pyri~idinethione
N-(4-Chlorophenyl)-thiourea (llg) and ~alononitrile (6.6g) were reacted
in the s~e ~ethod as described in Prepar~tion 12 to giYe the
above-indicated co~Pound (5.3g~.
: 275C~v(deco~p.)
(DtlSO-do )
5.31(s, lH), 6.38(bs, 2H), 6.81(bs, 2H), 7.18(d, 2H), 7.55(d, lH)
~EI~ : 252(~)
IR~C1. ~ : 34~0, 3400(N-H), 1630(C=N), 1095(C-S)
~.
~'0 92/08721 pc~r/KR9o/ooo18
- 61
2~72883
Preparation 14 : Preparation of 4,6-diaoino-1-~2,4-di~ethylphenyl)-2(1H)-
pyri~idinethione
~-(2,4-Dioethylphenyl)-thiourea (10.8g) ~nd raloDonitrile (6.6g)
were reacted in the sa~e ~ethod as described in Preparation 12 to give
the above-indicated co~Pound (5.7g).
aLR~ : 212-C ~ (decoep.)
(acetone-d~)
2.D8(s, 3H), 2,30(s, 3H), 5.58~s, lH), 5.91(bs, 2H), B.80~'1.2D
(a, 5H)
~lEI~ : 24~
IR(KC L c~ 3440, 3300(N-H), 1632(C=N), lO90(C=S)
Preparation 15 : Preparation o~ 4,6-di~ino-1-l2,6-diDetho~yphenyl)-
2(1N)-pyrividinethlDne
._ : ._ . - . - -
N-t2,6-Di~ethoxyphenyl)-thiourea (11.5g) and calononitrile (6.6g)
~ere reacted in the sa~e nethod as described in Preparation 12 to give
the above-indicated coDpound (6.2g).
2D ~le~ : Z07-C ~ (deconp.)
8~ (acetone-d~)
3.84(s, ~H), 5.44(s, lN), 5.B9(bs, 2H), 6.48(bs, 2H), 6.40~ 7.01
` ~ ID, 3H)
~11: 278(~
TR(~CI. ~ 3438, 3310~N-H), 1631(C-N), 1043(C=S)
.: :
: ` ' ' '"
'.
w o 9~/08721 PC~r/KR90/~0018
- B2
2~2~83
Preparation 16 : Preparation of 4,6-dia~ino-1-(4--hydroxyphenyl)-2(1H)-
pyri~idinethione
. . . _ _ _
N-(4-hydro~yphenyl)-thiourea (9.3g) and Dalononitrile (6.6g) were
reacted in the sa~e nethod as described in Preparation 12 to give the
above-indicated conPound (4.1g).
P. : 282-C ~ ~
(DHSO-d~) -
5.30(8, lH), B.l~(bs, 2H), 6.76(bi3, 2H), 6.84(s, 411), 9.78(bs, 111)
~ 234(H~)
IR(KC~. c~~) : 3480, 3470(N-H), 1640(C=N), 1038(C=S)
Preparation 17 : Preparation of l-cyclopropyl-4~6-di~3ino-2(11l)-
w ri~idinethione
N-cyclopropylthiourea (6.2g) snd malononitrile~6.6g) were reacted
in the sane nethod as described in PreParation 12 to give the pale yello~
above-indicated coDpound(3.7g).
~e~ : 242-C ~ (decomp.)
a~ (DHSO-d~)
0.88~ 1.52(m, 4~), 2.80~ 3.16(~, lH), 5.48(s, lH)
~ : 182(H~)
IR(KCl, c~ : 1580(C=N), 1015(C=S)
~ ' .
::
~,'
wo 92/0872~ PCr/KR9O/I)0018
- 63
2~2$~3`
Preparation 18: Preparation of 3-acethoxyDIethyl-7-l(Z)-2-(2-
aninothiazol-4-yl)-2-(~ethoxyi~ino)aceta~ido]-3-
cephell-4-carboxylic acid
~, .
A. PreParation of ethYl (Z)-2-(~etho~Yimino)-2-12-(triphenYloethyl)
a~inQth~æol-4-Yllacetate
~o ethyl (Z)-2-(hydroxyi~ino)-2-[2-(triphenylsethyl)aeinothiazol-4-Yl~
acetate(46g) were added iodo ~ethane(28.4g), potassiua carbonate (27.6g)
and dimethylsul~oxide(500nQ), and the ~ixture s~as stirred ~'or S hours st
room te-perature. After ethYl ether(2Q ) was added to the reaction
aixture, the nixture was washed S ti~es with distilled water(500mQ).
The separated organic layer ~as dehydrated with anhydrous na8nesiuo
sul~ate, ~iltered, and then concentr~ted. The residue vas
chroDatographed over silica gel to ~ive the above-indicated compound
(35.2g) as a pale yellow solid.
. .
B. Preparation of (Z)-2-(sethoxYiuino)-2-12-(triphenYlcethYl)
aoinothiazol-4-Yllacetic acid
A~ter the conpound(23.6g) prepared in (A) was dissolved in a ~ixed
solvent of ethYl alcohol(lOOnQ) and tetrahydrofuran(50mQ), aqueous
5N-sodiun hYdroxide solution (20n~ as added thereto. The reaction
~ixture ~as stirred for 2 hours and neutralized with 5N-hydrochrolic
acid (20me). After the organic solvent was reuoved under reduced
pressure, ethyl acetate (lQ ) was added to the residue, and then the
reaction nixture was washed twice with distilled ~ater(500mQ).
The separated organic layer was dehydrated, and concentrated to give
.
the above-indicated compound(20.7g) as a white solid.
~: .. ..
:~ .,", ' '
.
W O 92/08721 PC~r/K R9O/00018
2~72~83 - 6~ -
C. Preparation o~ 3-acethoxy~ethyl-7-[(Z)-2-(2-a~inothiazol-4-yl)-2-
l~etho~Yi~in~)a~eta~i~n~ sP~ -c~r~n~lic~
The co~pound(4.4g) prepared in (B) ~as di~solved in N.N-disethYl
aceta~ide(30mQ). To the solution ~ere added triethylasine (3.5m~) and
mesithylene sulfonyl chloride(2.3g) at O~C, and stirred for 20 ninutes.
After adding 7-a~inocephalosporanic acid ~2.9g), the reaction ~Ixture
was stirred again for 2 hours. To the Dixture ~as added ethYl acetate
(300m2), and lt ~as washed with 1 % -hydrochloric acid (lOOm~), sodiu~
chloride solution(lOOm~) and distilled ~ater(200m~ he separated
organic layer ~as dehydrsted, and concentrated. Foraic acid (4DmQ)
~as added to the residue. After the solution ~as stirre~ for 2
hours ~t rooa temperature, the recipitates ~ere filtered off.
The ~iltrate ~as concentrated under reduced pressure, triturated ~ith
ethyl ether(lOOmQ). The solid ~as filtered, ~ashed, and dried tD
Bive the aboYe-indicated compound(4.17g) as a pale yell w solid.
~E~ : ~ (DzO ~ Na~C0~
2.08(s, 3H), 3.52(ABq, 2H), 3.99(s, 31l), 4.41(~Bg, 211), 5.23
(d, lN), 5.84(d, lH), 7.01(s, lH)
':
Preparation 19 : Preparation of 3-acetho~YnethYl-7-l(z)-2-(2-a~inothiazol- ;
4-YI)-2-(ethoxyimino)acetauido]-3-cepbe~-4-carboxYlic
acid -
~ .
A. PreParation of ethyl (Z)-2-(ethoxYi~ino)-2-l2-~triPhenYl~ethYl)
~ aminothiazol-4-Yllacetate _ ;
To ethyl (Z)-2-(hYdroxyimino)-2-[2-(triphen~YleethYl)aYinollliazol-4
acetate(46g) ~ere added broDoethane(21.8g), potaS5iUD carbonate (27.6g~
,,'
wo 92/08721 pcr/}cR9o/oool8
- 65 - 2D7~3 ` ~
and di~ethylsulfoxide(500m~), and the solution s~as stirred for 7 hours
at roo~ te~perature. After ethyl ether t2Q ) ~as added thereto, the
~ixture ~as ~ashed 5 ti~e~ ~ith distilled water (500mQ).
The separated organic layer was dehYdrated, and concentrated to give
the above-indicated coDpound(41.4g) as a pale yellow solid.
B. Preparation of (Z)-2-(etho~Yi~ino)-2-l2-(triPhenYl~ethYl)
acinothiazol-~-yllacetic acid __ __
The cocpound (24.3g) Prepared io (A) was dissolved in a ~ixed
solvent of ethyl alcohol(lOOmQ) and tetrahydrofuran (50m~). After
aqueous 5N-sodiu~ hydroxide solution(20n~Q) was added thereto, the
reaction Lixture was stirred for 2 hours at roon terperature. The
reaction nixture ~as neutralized ~ith 5N-hydrochloric acid, and the
organic solvent was re~oved under reduced pressure. To the residue
~as added ethyl acetate(lQ ), and it was washed t~ice with distilled
~ater(500nQ). The separated organic layer was dehydrated, and
concentrated to give the above-indicated co~pound(19.8g) in white solid
C. Preparation of 3-acethoxy1~ethyl-7-l~Z)-2-(2-aDinothiazol-4-yl)-
2-(ethoxYi~ino)acetaoidol-~-~ePhe~-~-carboxYlic acid
(Z)-2-(ethoxyinino)-2-~2-(triphenYll~ethyl)a~inothiazol-4-yll acetic
acid (4.6g) was reacted in the sane ~ethod as deqcribed in (C) of
Preparation 18 to give the above-indicated coDpound(3.98g) in ~hite solid
~(D~O-~ NaHCO~)
1.31(t, 3N), 2.02(s, 3H), 3.57(A~q. 2H), 4.07(q, 2ll), 4.52(ABq, 2l5
5.20(d, lH), 5.81(d, lH), 7.00~s, la)
" . ' ,' ' ' '
, ' ' ~. ~ .
w O 92/08721 p~r/KRso/oool8
- 66
2~72~3
Preparation 20 : Preparation of 3-acethoxy~ethyl-7-[tZ)-2-(2-~ninotlliazol-
4-yl?-2-(2-carbo%yprop-2-oxyi~ino)ecet~oido]-3-cephe~-4-
c~rboxylic acid dihYdrochloride
..... . _ _
A. Preparation of ethyl (Z)-2-(2-tert-butoxYcarbonYlProp-2-oxYi~ino)
-~2-l2-(triPh-enyl~ethyl)a~lnothi~z-ol-~-vllacetate
To ethYI (Z)-2-(hYdroxYi~ino)-2-12-(triphenYl~ethYl)a~inothi~zol-4-
yllacetate(~Bg) were added potassium carbonate(27.6g), tert-butYl-2-bro~o-
2-methylpropionate(24.1g) and di~ethYlsulfoxide(300mQ), and then the ;-~
solution was stirred for 6 hours at roo~ te~perature. After~ards,
distilled water (lOOm~) ~as added therein, the solution was stirred again
~or an hour. The precipitates wqre filtered, washed with distilled
~ater(500m~), and dried under reduced pressure to give the above-indicated
co~pound(45.1g) as a Nhite solid.
-
B. Preparation of IZ)-2-(2-tert-butoxycarbonYlprop-2-oxyi~ino)-2-12-
(triPhen.YI~eth~l~A~inothi~znl-4-Yll~retic acid _
The co~pound(30g) Prepared in (A) was reacted in the sa~e sethod as
described in (B) of Preparation 19. ~he resultant solid was recrystalized
with Dethyl alcohol(lOOmQ) to ~ive the above-indicated co~pound(21g) as
a ~hite solid.
C. Preparation of 3-acethoxymethY1-7-1(2)-2-(2-aDinothiazol-4-Yl)-2
(2-carbo~yprop-2-oxyimino)aceta~ido-3-cephec-4-carboxYlic acid
25 ~ ~ d~ ~rochloride
(Z)-2-(2-tert-butoxYcarbonylprop-2-oxyi~ino)-2-12-ttriPhenYl~ethYl)
; ~ a~inothlazol-4-yl~acetic acid (5.7g) ~as dissolved in N,N-di~ethYlforoa~ide ~ :
~:
w O 92/08721 - 67 - pc~r/KRso/oool8
2~72g33
(30m~). Triethyla~ine (3.5m~) and ~esithylenesulfonyl chloride~2.3~)
were added thereto at to O~C, and the obtained solution ~as stirred for
10 ~inutes. After 7-a~inocephalosporanic acid (2.9g) ~as added to
the solution, the ~ixture was further stirred for 2 hours.
~o the reaction mixture was added ethYl acetate(300mQ), and it ~as
then vashed ~ith 1% -hYdrochloric acid (lOOmQ), ~aline fiolution (lOOm~),
and distilled water (200nQ). The separated organic laYer was
dehydrated, and concentrated. To the residue ~ere added formic
acid (40me) and conc. hYdrochloric acid(3mQ) at O'C. After stirrin~
for 2 hours, the solid was filtered off. The ~iltrate ~as
concentrated under reduced pressure, and triturated ~ith ethy] ether.
The solid ~as ~iltered, washed, and dried to giYe the above-indicated
coupound (3.87g) in a yello~ solid.
~ (Acetone-d~)
1.50ts, ~), 2.05(s, 3H), 3.53(ABq, 2H), 4.38(A~q, 2~), 5.12(d, lH),
5.98(q, 1~), 7.05(s, lH), 7.32(bs, 2~).
Preparation 21 : PreParation of 3-acethoxYmethYl-7-[(Z)-2-(2-a~inothiazol-
~-yl)-2-(1-carboxYeth-1-oxYioino)aceta~ido]-3-cephea-
4-carboxylic acid
_. _
A. Preparation of ethyl ~Z)-2-(1-tert-butoxYcarbonYleth-l-o~Yisino)-
2-~2-(triDhenYl~eth~l~amino~hiazol-4-~llacetate
After potassium carbonate (27.6g), tert-butYl-2-bro~opiopyonate
(23g) and dimethylsulfo%ide(300mQ) ~ere added to ethyl (2)-2-
(hydroxyi~ino)-2-12-(trlphenYlm2thyl)a2inothiazol-4-Yllacetate(46g)l the
mlxture ~as stlrred for 5 hours at room te~perature. Ethyl ether (2Q ~
'
.
,: ~ : . ;:: .. ., : , . . . . . . .. . . .
w O 9~/08721 ~8 PC~r/KR90tOO018
2 ~ ~ 2 ~ 8 was added thereto, and the mixture waslled 5 times ~ith distilled
water(500m~). The separated organic layer ~as del~drated, and ~ ;
concentrated to give the above-indicated coupound (51g) in a Pale yello~
solid.
B. Preparation of (Z)-2-(1-carboxYeth-l-oxYi~ino-2-l2-(triphenYl~ethYl)
a~inothiazol-4-Yllacetic acid ~ _
The coEpound(27~9g) prepared in ~A) ~as dissolved in a nixed solvent
o~ ethyl alcohol(100m~) and tetrahydrofuran(S0nQ). After~ards, a SN-
sodiu~ hYdroxide aqueous solution (4~n~) ~as added thereto, and the
solution ~as stirred for 2 hours at room te~perature. ~he reactio
mixture was neutralized ~ith 5N-hydrochioric acid (4Dm~), and the
organic solvent ~as removed under reduced pressure. To the residue
~as added ethyl acetate(lQ ), and it ~as Nashed t~ice ~ith distilled ; :
I5 ~ater (500n~). The separated organic layer was dehydrated und dried
to give the above indicated compound(23.1g) in a pale yellow solid.
'' ~
C. Preparation of 3-acethoxyoethyl-7-~(Z)-2-(2-aainothiazol-4-yl~-
~-(l-carboxyeth-l-oxyi~ino)acetamido]-3-cephea-4-carboxylic
acid _ _
To a solution of (Z)-2~ carboxyeth-1-oxyinino)-2-~2-(triphenyl
methyl)aminothiszol-4-yl]acetic acid(5.6g) dissolved in N,N-diuethyl
aceta~ide(30m~) were added triethylsmine (~.4m~) and ~esithylene
sulfonylchloride ~2.3g) at -10C. After stirred for 50 ninutes,
triethylamine(2.8mQ) snd 7-aminocePhalosporanic acid (2.9g) ~as added
thereto. The reaction uixture was stirred again for 2 hours.
After raising the temperature of the reaction mixture to roo~
WO 92/08721 PCrt~CR90/00018
- 69
2 ~ 8 3
te~perature, ethyl acetate (500m~) was added thereto. The reaction
~ixture ~as washed twice vith 1 % hYdrochloric acid (200mQ), saline
solution (200m~) and distilled water (200m~). The separated organic
layer was dehydrated, and concentrated. To the residue was added for~ic
acid (50m~). The solution ~as stirred for 2 hours, and the obtained
solid ~as ~iltered of~. The filtrate ~as concentrated udnder reduced
pressure, and powder-solidified by addition of ethYI ether. The solid
was filtered, uashed, and dried to give the above-indicated co3pound
(~ . 65B) .
lD ~ (DzO t NaHcoa)
1.45(d, 3H), 2.U7(s, 3R), 3.54~ABq, 2H), 4.64(q, 111), 4.91(ABq,
2H), 5.24(d, lH), 5.8B(dd, lH), 7.03(s, lH)
Preparation 22 : Preparation of 3-ncetho~y~ethyl-7-~(2)-Z-(2-auinothiazol-
4-yl)-Z-(1-carboxYmethYDxYiDino)acetaoido~-3-cepheo-4
carb~xylic acid
A. Preparation of ethyl (Z)-2-(butoxycarbonylnetho~Yioino)-2-12-
(triPhen!viHe~hAyl)aminothiazol-4~yllacetate
To ethyl (Z)-2-thydro~Yi~ino)-2~2-(triphenyl~eth~vl)a~inothiazol-4-
yl]acetate(4BB) ~ere added potassium carbonate~27.B~), tert-butyl-2-
brooopropionate(20g) and diuethYlsulfoxidet300m~ he reaction rixture
was stirred for 5 hours at room te~perature, follo~ed by addition of
ethyl ether (2~ ). After the reaction mixture ~as ~ashed 5 ti~es
with distilled ~ater(500mQ), the separated organic layer ~as dehydrated
and concentrated to give the above-indicated conpound(47.2g) in a Ye
soiid.
W o 92/08721 70 pc~r/KR9o/oool8
2~2~3
B. PreparAtion of (Z)-2-(carboxyuethoxyi~ino)-2-[2-(triphenyl~ethyl)
n~inn~hinzQl 4-Y~l~Getate
The conpound(27.2g) prePared in (A) bas reacted in the sa~e
~ethod as described in (a) of Preparation 21 to give the above-indicated
co~pound (21.3g) in a pale Yellow solid.
.
C. Preparation of 3-acethoxyxethYl-7-~(Z)-2-(2-aainothiazo]-4-YI)-2-
(I-çsrbo~oethoxv-1-oxYl~lno)aceta~idol-3-cePhe~-~-carboxy ~c acid
To a solution of (Z)-2-~1-carboxYuethoxY-]-oxYi~ino)-2-~2-(triphenY
aethyl~aminothiazol-4-Yl]acetic acid (5.4g) dissolved in N,N-disethYlacet-
a~ide (30n~) were added triethylamine (1.4mQ) and mesithylene sulfonYI
chloride (2.3g) at -20~C. After stirrine for an hour, trie~hYlaoine
(2.8nQ) and 7-~minocephalosporanic acid (2.9g) were added thereto. The
soluSion uas stirred again for 2 hours. After slowlY raising the
te~perature of the reaction ni~ture to roo~ te~perature, ethYl acetate
(500m~) was added thereto. The reaction mixture ~as ~ashed twice with -
1% hydrochloric acid(2DOmQ), saline solution(200m~) and distilled ~ater
(200n~). The separated organic laYer ~as dehydrated, and concentrated.
To the residue was added for~ic acid (50mQ). The solution ~as stirred
for 2 hours at roo~ teoperature and the formed solid was filtered off.
The filtrate ~as concentrated under reduced pressure, and then triturated
wi~h ethYl ether. The solid was filtered, ~ashed, and dried to give
the above-indicated comPound (3.32g) in a Yellow solid.
: ~ (D20 t Na~3C09)
2.06(s, 3H), 3.52(ABq, 213), 4.73(ABq, 2H), 4.82(s, 2H), 5.21
(d, lN~, 5.84(d, lH), 7.07(s, lH)
.
W O 92/08721 - 71 - PC~r/KR90/000l8
2~72$83 :
Preparation 23 : Preparation of 3-~cethoxy~ethyl-7-1(Z)-2-(2-
a~inothiazol-4-yl)-2-t2-propen-1-oxyi~ino)acetaaido]-
3-cephe~-4-carboxylic acid
A. Preparation of ethyl (Z)-2-(2-propen-1-oxYi~ino)-2-[2-
(tri~henyl~thYl)~Din~hiazol-4-YIlacetate
The above-indicated co~pound(39.1g) ~as prepared in the sa~e ~ethod
as described in (A) of Preparation 19, except that 3-rooopropyne(24.2g)
~as used in place o~ bro~oethane.
B. Preparation of (Z)-2-(2-propen-l-oxyiRino)-2-[2-(triphenYlaethyl)
a~inQ~hLazQl-4-~1lacetic acid
The coopound (24.9g) obtsined in (A) ~as reacted in the sase ~ethod
as described in (B) of PreParation 18 to give the abov~indicat~d co~pound
(21.lg).
.
C. Preparation o~ 3-acethoxY~ethyl-7-~(2)-2-(2-a~inothiazol-4-
yl)-2-(2-propen-1-o%yi~aino)acetaDIidol-3-cephe~-4-carboxylic
~c1d - -
(Z)-2-(2-Propen-l-oxYi~ino)-2-~2-(triphenYl~ethyl)aainothiazol-4-yl)
acetic acid(4.7g) was reacted in the sa~e ~ethod as described in (C) of
Preparation 18 to give the above-indicated conpound ~4.05g) in a pale
yello~ solid.
tD20 + ~aHC0~)
~ .
2.07(s, 3~, 3.52(ABq, 2H), 4.81(s, 2H), 4.80(ABq, 2H),
5.23(d, 1~). 5.84(d, 111), S.15~ 6.24(~, 3H), 6.99(s, 111)
: : ~ , ~ ' , ' .'
w o 92/08721 - 72 - pc~r/KR9o/oool8
Preparation 24 : Preparation of 3-acethoxyl~ethyl-1-[(Z)-2-~2-a~ino-
thiazol-4-yl)-2-(2-propen-l~o~yioino)aceta~ido]-3-cephe~-
4-carboxylic acid
... . _ . .. _ . . .
-
A. Preparation of ethyl (Z)-2-(2-propYn-1-oxYi~ino)-2-l2-
. l tl~iPhen~ p~ inolthLazQl-4-yllacetate-
The above-indicated coopound(30.7g) was prepared in the sace ~ethod
as described in (A) of Preparation 19, except that 3-brooopropyne(14.9g)
~as used in place of bro~oethane.
.'"' -. '
B. Preparation of (z)-2-(2-propYn l-oxyimino)-2-[2-~triphenYl~ethyl)
a~iLQ~kulu~iL L~Yll~ççtic acid
The coDpound(24.8g) prePared in (A~ ~as reacted in the sa~e ~ethod
as described in (B) of Preparation 19 to give the above-indicated co~Pound
~21.1g).
.~
C. Preparation of 3-acethoxy~ethyl-7-[(Z)-2-(2-aninothiazol-4-yl)-
2-(2-ProP~n-l-ox.Yi~inQ)-a~taDi~Ql-3-oçphe~-4-rarhQx~lic acid
(Z)-2-(2-propyn-l-oxYi~ino)-2-[2-(triphenYloethyl)a~inothiazol-9-yl)
acetic acid (4.7g) was reacted in the sa~e nethod as described in ~C) of
Preparation 17 to give the above-indicated cocpound(~.95g) in a yellow
solid.
a~ (DzO ~ NaHC0~)
2.0B(s, 3H), 2.96(s, 111), 3.56(ABq, 2}1), 4.15~ABq, 211), 4.8
(s, 2H), 5.11(d, 111), 5.84(d, 111), 1.05(s, lH)
- . ..
,
, ,~ . "
w o 92/08721 73 pc~r/KRso/ooo18
2~7~3
Preparation 25 : Preparation of 3-acethoxy~ethyl-7-[(Z)-2-(5-aoino-
1,2,4-thiadiazol-4-yl)-2-(2-~ethoxyimino)ace~aoido]-
3-cephe~-4-carboxylic acid
A, PreParation of 2-~hydroxyimino)~a!ononitrile
To a sol~tion of malononitrile(66~1g) dissolved in ~ater(SOmQ) and
acetic acidt50m~ as added slowlY sodiu~ nitrite(69g) dissolved in
water(lOOm~) at 4C. and then, stirred for 3 hours at roo~ temperature.
~he reaction mixture was extracted 3 ti~es with ethyl acetate (respectivelY,
500mQ, 250n~ and 250n~), dried with anhydrous magnesiuo sulfate, and
concentrated in vacuo. The residue was triturated uith ethyl ether to
give the above-indicated co~pound (92.5g) in a uhite solid.
~. PreParatiQ Lo~ 2~ ethoxyi~inQ~a~on~nitrile
To a solution of 2-(hYdroxYimino)malononitrile (95g) dissolved in
di~ethylsulfoxide(200m~) ~ere added potassiuD carbonate(l40g) and
di~ethYlsulfate(126.1g). The reaction mixture ~as stirred for an hour
at roou temperature and ethyl ether (700mQ) uas added thereto.
A~ter the ~ixture was washed 5 times with distilled water (IQ i, the
separated organic laYer ~as dehydrated, concentrated, and then,
distilled under reduced pressure to give the above-indicated compound(gOg)
in a pale yello~ liquid.
b.P. : 60~ 65aC/20torr
~ tCDCl~)
3.90(s, 3H).
.
:
.
.. . .: .. ,, .. : . , ;,.. .... , . - : . ., ~, . .
W O 92/08721 74 pc~r/KR9~/oool8
2~72~3 ' '
C. ~rePar~ion Qf 2-c~ano-2-l~ethoxYimino~acetamidiniu~ acet~te
To a Dixed solution of aDmonium chloride(14.2g) dissolved in ethanol
(9OmQ) and conc. a~onium hydroxide aqueous solution (178mQ) was adde(l
2-(~ethoxyinino)~alononitrile(29g) at -5~ 0~C, and the mix~ure was
stirred for 10 hours at these temperatures. Tile reaction ~i~ture was
extracted 3 times with methylene chlori(Je (respectivelY, ~50mQ, lOOmQ
and lOOmQ), dehydrated, filtere(l, and concentrated. The resi(lllc was
dissolved in ethyl acetate, and crystalized with acetic acid to give
the above-indicated compound ~20.5g) in pale ~rown.
IO ~ (DHS0-d~)
l.90(s, 3H), l.90(s, 3H), 4.18(s, 3H), 7.88(s, 111)
D, Preparation of 2-(5-amino-1,2,4-thiadiazol-3-Yl~-2-~etlloxyiuino)
acetonitrile
To a solution of 2-cYano-2-~methoxYimino)acetamidiniu~ acetate (12.5g)
dissolved in ~ethanol(lOOn~) ~as added triethyla~ine(23.4n2).
Thereafter, broDine (12.9g) was added slowly in small psrtions at -15'C,
and the mixture was stirred for 5 minutes at -15~ -lO~C. Potassiu~
thiocyanate(3.7g) dissolved in methanol(55n~) ~as then added dro~wise : -
to the mixture at teoperatures of -10 to -5~C, and the ~ixture was
stirred for 2 hours at O'C. The reaction mixture was poured into
ice water (1.2Q ), and stirred for 30 minutes. The precipitates were
filtered and dired to give the above-indicated compound (12.2g)
in pale brown.
~ (DHS0-d~) -
3.90~s, 3H), 8.37(s, 2H).
.
'.' ' ' '
W O 92/08721 pc~r/KR9o/oool~
~ 75 ~ 2~72~83
E. PreParation of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(~ethoxYi~ino)
~cetic acid
A solution of 2-(5-a~ino-1,2,4-thiadiazol-3-yl)-2-(~etho~yi~inD)
acetonitrile(l2.2g) dissolved in 4N- sodium hYdroxide aqueous solution
(250m~) vas stirred for D hours at te~peratures of 50 to 55C. The
reaction ~ixture was cooled to room temperature and the pH adiusted to
~ith Phosphoric acid, followed by extraction with a 3 : 1 (v/v) ~ixed
solvent of ethYl acetate and tetrahydrofuran. A~ter the separated
organic layer was dried, filtered and concentrated the residue was
triturated ~ith ethyl ether, and the solid ~as filtered to give the
above-indicated compound(ll.2g) in pale bro~n.
E~ (DHSO-d~)
3.91(s, 3H), 8.2û(s, 211).
F. PreParation of 3-acethoxymethyl-7-[(Z)-2-(5-a~ino-1,2,4-thiadiazol-
3-Yl~-2-(~-DethoxYi~ino)ac~a~idol-3-cePhe~-4-carboxylic acid
2-(5-anino-1,2,4-thiadiazol-3-yl)-2-(~ethoxyinino)acetic acid (2.Dg)
was dissolved in dried di~ethylaceta~ide(20mQ), and then cooled to -lO-C.
Triethyla~ine(1.5m~) and oesithYlene sulfonYl chloride(2.3g) was added
therein, and the ~ixture was stirred for an hour st -lO~C. A~er
addition of 7-amino-cephalosporanic acid(3.26g) and triethylaoine (~mQ),
the uixture was stirred for 2 hours at rooo teePeratUre. ~ater (lDOmQ)
~as added to the reaction ~ixture. The ~ixture ~as adjusted pH to 1 with
phosphoric acid, and extracted with a 3 : l(v/v) mixed solvent of
ethyl acetate and tetrahydrofuran. The reaction uixture was dried,
filtered, and concentrated. The residue was triturated ~ith isopropyl
ether, and the solid ~as filtered to give the above-indicated
.
W o 92/08721 ~ 76 - p(~r~K R9O/00018
2 ~ ~ 2 ~ 3 3 co~pound(3.05g) in a clear brown solid.
(DHS0-d~)
2.05(s, 3H), 3.2~ 3.6(ABq, 2H), 3.95(s, 311), 4.42~ 5.45(A~q,
2~), 5.18(d, 1~l), 5.80(q, lH), 8.20(s, 2H).
Preparation 26 : Preparation of 3-acethoxYmethyl-7-[(Z)-2-(5-a~ino- -
1,2,4,-thiadiazol-3-yl)-2-(2-carboxyprop-2-oxyiDino) . : .'
acetaDido]-3-cephe~- 4-carboxylic acid
. . _ . . _ . . ~ _
A. ~reDaration of ~ hn~yl~inn~alnn~nitrile
2-(hydroxyimino)malononitrile (95g) and diethYlsulfate (230mQ) were
reacted in the saoe aethod as described in (B) of Preparation 25 to give
the above-indicated conpound (97g).
b.D. : 65^J67C/13torr
~ (CDCl~) -
1.20(t, 3H), 4.20(q, 2H)
B. PreParation pf 2-cxano-2-(ethQ~lpino~aceta~idlni~ aceta~e
2-(ethoxYinino)~alononitrile (15.9g) was reacted in the saxe aethod
as described in (C) of Preparation 25 to give the above-indicated coopound
(22.4g).
(D~SO-d~)
1.2D(t, 3~), l.9D(s, 3B), 4.10(q, 2~), 7O90(s, 4~)~
~: .
;~ 25 C. Preparation of 2-(5-a~ino-1,2,4-thiadiazol-3-yl)-~-(ethoxyi~ino)
acetoni~rile
2-cyano-2-(ethoxYi~ino)aceta~idiniu~ acetate (13.1g) was reacted in
.
.
~ ' ' "
W O 92/08721 pc~r/KRso/oool8
- 77
2~72~83
the same method as described in (D) of Preparation 25 to give the aBove-
indicated cocpound (12.1g).
a~ (DHS0-d~)
1.37(t, 3H). 4.50 (q, 2~), 8.37 (s, 2H).
D. Preparation of 2-(5-asino-1,2,4-thiadiazol-3-yl)-2-(ethoxyi~ino)
acetic acid
2 (5-a~ino-1.2,4-thiadiazol-3-yl)-2-(ethoxYi~ino)acetonitrile (12.Ig)
~as reacted in the same ~ethod as described in (E) of Preparation 25
to give the above-indicated conpound (10.8g).
: ~ (D~lSO-do )
1.20(t, 3H), 4.2~(q, 2H), 8.21(s, 211).
-: .
E. Preparstion of 3-acethoxY~ethyl-7-~(Z)-2-(5-anino-1.2,4-thiadiszol-
_3-Yl)-2-(2-çthoxviminn)~çPt~mi~nl-~-re~he~-4-~ar~bnY~ c aci~
2-(5-aoino-1,2,4-thiadiazol-3-yl)-2-(ethoxyiDino)acetic acid (2.14~)
was reacted in the sane ~ethod as described in (F) of Preparation 25
to give the above-indicated coopound (3.31g).
~ (DNS0-d~)
1.25(t, 3H), 2.05(s, 3H), 3.40~ 3.80(ABq, 2H), 4.22(q, 2~),
4.60~ 5.48(q, lH), 8.28(s, 2H)
' ' '.
Preparation 27 : Preparation of 3-acethoxY~ethYl-7 l(Z)-2-(5-amino-
1,2,4-thiadiazo]-3-yl)-2-(2-carboxYprOP-2-oXYimino)
acetaMido~-3-cephem-4-carboxYlic acid
-- -
~: . .
w o 92/08721 - 78 - pc~r/K R90/00018
2 ~ 3
A. Pr~ParatiQn_Qf~ ert-b~thoxYcarbony-le~oe~Q~imirlo)~lonQnilLll~
2-(hydroxyimino)malononitrile (95g) and tert-butyl-2-brooo-2-methYI
propionate (240g) ~ere reacted in the same laethod as described in
(B) of Preparation 25 to give the above-indicated co~pound ~17Bg).
b.P. : 115~ 120C/13 torr
a~ (CDCl~)
1.48(s, 9H), 1.63(s, 611)
'': .
3. Preparation of 2-(tert-butnxycarbonylprop-2-oxYi~ino)-2-cYano-
ac~ta~idinium acetate _
To an~onium acetate (18.5g) dissolved in ~ethanol (lOOmQ) was added
2-(tert-butoxycarbonylprop-2-oxyimino)oalononitrile (19g~.
After stirring for 2 hours, the mixture was alloued to st~nd overnight
at room temperature. The reaction mixture was concentrated, and
water (5DOm~) was added thereto. The obtained 7ixture ~as extracted
~ith ethylacetate ~500m~). After the extract was dehydrated, filtered,
and concentrated, ethyl ether was added thereto, and the ~ixture stirred
for 30 minutes.
The precipitates were filtered to give the above-indicated compound (15~)
in pale yellow.
~: ~ (DHSO-do ~
1.40(s, 9H), 1.60(s, 6H), 1.98(s, 3H), 7.38(bs, 3H).
C. PreParation of 2-(5-a~ino-1,2,4-thiadiazol-3-Yl)-2-(tert-
b~tQx~carboo~lproP-2-o~yi~ino~acet~nitrile
2-(tert-butoxycarbonYlprop-2-oxyimino)-2-cyanoacetamdiniu~ acetate
(24.1g) was reacted in the same ~ethod as described in (D) of Preparation
::
W O 92/08721 pc~r/KR9o/ooo]8 - 79
2072~3
25 to give the above-indicated co~pound (13.7g).
(DHS0-d~)
1.40(s, 9~1), 1.5~(s, BH), 8.43(s, 2H).
D. Preparation of 2-(5-a~ino-1,2,4,-thiadiazol-3-yl)-2-(2-
c~E~nxyDrop-2-o~yisino)aoetlc acid~
2-(5-a~ino-1,2,4-thiadiazol-3-Yl)-2-(2-butoxycarbonylprop-2-oxyi~ino)
acetonitrile (13.7g) was reacted in the sa~e ~ethod as described in (E)
of Preparation 25 to give the above-indicated coopound (10.1
~ (DNS0-d~
1.42(s, B~), 8.22(s, 211). ~
' ' .
E. Preparation of 3-acethoxYoethYl-7-l(z)-2-(5-aoino-l~2~4-
thiadiazol-3-yl)-2-(2-carboxyprop-2-oxYioino)aceta~ido]-3-
cePhe~-4-carbo~lic acid
2-(5-a~ino-1,2,4-thiadiazol-3-Yl)-2-(2-carboxYProP-2-oxyi~ino~acetic
acid (2.93g) ~as reacted in the sa~e nethod as d~scribed in (F) o~
Preparation 25 to give the above-indicated ~oaPound (9.42g).
~ lDzO + NaHC0~)
1.58(e, 6H), 2.05(s, 3H), 3.10~ 3.72(ABq, 2H), 4.B0~ 4.95
(ABq, 2H), 5.14(d, lH), S.70(d, lH).
E~ample 1 : Synthesis of 7-1(Z)-2-(2-a~inothiazol-4-Yl)-2-(Dethoxyimino)
acetaoido]-3-~g.6-diaoino-1-methYlPYri~idiniu~-2-Yl)thio~eth
2i -3-eepheo-4-carboxylate
. .
:
To a solution of 3-acetoxY~ethY1-7-[(Z)-2-(2-aEinothiazol-4-yl)-
:: :
,
.:.
wo 92/0~721 pcr~KRso/oool8
- 80
207~8~3
2-~ethoxyinino) acetamidD]-3-cepheo-4-carboxylic acid(500~g) suspended
in distilled water(5mQ) ~ere added 4,B-diamino-l-~ethyl-2(1H)- :
pyrioidinethi~n&(200~g) and potassiuu iodide(800Og). While adiusting
the pH of the ~aixture to 7.1^~7.2 ~ith a sodiu~ bicarbonaLe solution,
the reaction ~ixture ~as heated to 7D-C. After stirred for 4 hours,
the Dixture ~as cooled to roo~ te~perature. The pH ~as adjusted to
3^~3.5 ~ith 2N hydrochloric acid, and the PreciPitates ~ere filtered,
washed ~ith distilled water(5nLQ), and chro~atographed over silica gel.
Elution ~ith a 5: 1 (v/v) ~ixture of acetonitrile/distilled ~ater gaYe
the above-indicated compound(320~g) in a pale ~hite solid.
.: 157C~ (deconp.)
~: ~ (DzO t NaHC0:,) -
3.54 (~, 3~), 3.6} (ABq, 2H), 3.98 (s, 3H), 5.17 (d, ltl), 5.65 (s,
l~t), 5.78 (d, 1~), 7.03 (s, 1
HS(PAB~ H + 1): 552
IR(~c~ 17B5 (~-lactao), 1660, 1630, 1550.
example 2: Synthesis of 7-l(Z)-2-(2-aminothiazol-4-Yl)-2-(ethoxYiDino)
acetaDido]-3-(4,6-diamino-1-methyl-pyrillidinium-2-yl)thiooethyl
-3-cephem-4-tarboxylate
.
3-Acetox~ethyl-7-[(Z)-2-(2-Aminothiazol-4-Yl)-2-(ethoxYi~ o)
acetamido]-3-cephem-4-carboxylic acid (500Rg) ltas reacted in the saDe
~anner as described in Exa~Ple I to give the above-indicated co~pound
2b (310ug) in a white solid.
: 163C^J (decomp.)
~: ~ (D20 + NallCû9)
' '; :
:
: ~: ~ - : .. . . : , ., - . .. : ,
- . . . . . . , :
.. ..
w O 92/08721 P ~ /~R9O/00018
- 81
2~7~3 :
l.09 (t, 3H), 3.48 (s, 311), 3.56 (A3q, 2H), 4.l4 (q, 211), 5.11
(d, lH), 5.5B (s, lH), 5.78 (d, lH), 6.94 (~, lH).
HS(~AB. ~ t l) : 566
IRl~Br. c~ 1760 (~-lacta~), 1660, l590.
Exaople 3 : Synthesis of 7-[(Z)-2-(2-a~inothiszol-9-yl)-2-(ethoxyi2ino)
aceta~ido]-3-(4,6-diaoino-l-ethYlpyrioidiniu~-2-yl)thio~ethYI
-3-cephe~~4-carboxylate
To a solution of 3-acetoxY~ethYl-7-[tZ)-2-(2-aninothiazol-4-yl)
-2~(etho~yioino)aceta~idol-3-cephe~-4-carboxylic acid (500Eg) suspended
in distilled ~ater (5m~) ~ere added 4,6-dia~ino-1-ethyl-2(1H)-
pyrimidinethione (2~0~g) and potassiu~ iodide (lg). ~ith adjusting
pl1 of the 0ixture to pH 7.1~ 7.2 ~ith a sodium bicarbonate solution,
the reaction ~ixture vas heated to 70'C. A~ter stirred for 5 hours,
the ~ixture was cooled to roo~ tenperature. The pH ~as adiusted to 3~
3.5 with 2N hYdrochloric acid, and the PreciPitates were ~iltered, ~ashed
~ith distilled water (5mQ), and chromatographed over silica gel.
Elution with a 5 : 1 (v/v) oixture of acetonitrile/distilled ~ater gave
the above-indicated co~pound(290~g) in a pale white solid.
e~ : 161'C ~ (deco~p,)
(D~0 t NaHCO~)
1.31 (~, 6H), 3.60 (ABq, 2H), 4.19 (~, 411), 4.43 (A~q, 2H), 5.~9
(d, lH), 5.66 (s, l11), 5.84 (d, ll1), 6.92 (s, IH).
KS(~AB~ H t 1~ : 580
IIIII _ ~ ') : 1768 (~-3acta~), 1680, 1620, 1560.
;~
w O 92/08721 pc~r/K~9o/oool8
- 82
2072~3
Exa~ple 4 : Synthesis of 3-(1-allyl-4,6-dia~inopyri~idiniue-2-yl)-
thio~ethyl-7-l(Z)-2-(2-a~inothia2O1-4-yl)-2-(ethoxyioino)
aceta~ido~-3-cepheo-4-carboxylate
To a solution of 3-acetoxYDethY1-7-~(Z)-2-~2-aYinothiazol-4-yl)-
2-(ethoxyi~ino3aceta~ido)-3-cephe~-4-carboxylic acid t500~g) susPended
in distilled water (5mQ) were added l-all~1-4,6-diacino-2(1H)-
pyrimidinethione (200Ig) and potassium iodide (lg). The plJ o~ the ~-
mlxture ~as adjusted to 7.1~ 7.2 ~ith a sodiu~ carbonate solution, and
acetonitrile (li~) ~as added thereto. After stirring for 4 hours at
75-C, the ~ixture ~as cooled to roo~ te~perature. The Pll ~as adjusted
to 3~ 3.5 ~ith 2N hydrochloric acid, and the precipitates were filtered,
~ashed ~ith di~tilled water (5mQ), and chrooatographed over silica gel.
Elution ~ith a 5 : 1 (v/v) ~ixture of acetonitrile/distilled water gave
the above-indicated co~Pound(300~g) in a ~hite solid.
e~ : 165-C ~ (deconp.)
~e : ~ (DzO t NanCOa)
1.29 (t, 3~), 3.57 (ABq, 2H), 4.17 (q, 2H), 5.16 (d, 11l), 5.66 (s,
lH), 5.82 (d, lH), 5.09~ 6.56 (m, 5H), 8.96 (s, 111).
HSt~AB. H t Il : 592
IR(K~r. c~~~) : 1765 (~-lactao), 1680, 1630, 1550.
; Exa~ple 5 : Synthesis of 7-1(Z)-2-(2-a~inothiazol-4-Yl)-2-(2-ProPe~
: o~yi~ino)acetanido~-3-(4,6-dia~ino-1-~ethylpyri~idiniu~-2-yl)
thiooethYl-3-cePhe~-q-carboxYlate
A solution of 3-acetoxy~ethYl-7-1(Z)-2-(2-aoinothiazol-4-yl)-2-
:: . .
:
W O 92/08721 PC~r/KR9O/~0018
- 83
2~72~3
(2-propen-1-oxyimino)aceta~idoI-3-cephem-4-carboxylic acid (500~g)
suspended in distilled water (5n~) was reacted in the saQe nanner as
described in ExamPle 1 to give the above-indicated co~pound (260~g)
in a pale ~hite solid.
S mLe~ : 169-C ~ ~deco~P.)
NHR : ~ (DzO t acetone-d~)
3.60 (ABq, 2H), 3.61 (s, 3H), 4.40 (ABq, 2H), 5.16 (d, IH), 5.68 (s,
lH), 5.84 (d, 18), 5.11~ 6.25 (~, 58), 6.96 (s, lH).
HS~PAB. ~ 578
IRL~B~. c~ 1760 (~-lacta~), 1670, 1618, 1522.
Exanple 6 : Synthesis of 7-1(~)-2-(2-a~inothiazol-4-Yl)-2-(2-proPen
oxyi~ino)aceta~lido]-3-(4,6-dia~ino-1-ethylpyriLidinium-2-yl)
thio~ethyl-3-cephes-4-carboxylate
_ _
3-Acetoxy~ethyl-7-[(Z)-2-(2-aninothiazol-4-Yl)-2-(2-propen-1-oxyimino)
aceta~idol-3-cephe~-4-carboxylic acid (500~g) and 4,6-dia~ino-1-ethyl-
2(1H)-pyri~idinethione (200~g) were reacted in the sa~e oanner as
described in Exa~ple 1 to give the above-indicated coopound (290mg).
2D ~.P. : 165'C~ (deco~p.)
ER_: ~ (D20 t acetone-d~)
1.41 (t, 38), 3.57 (ABq, 2H), 4.14 (q, 2H), 4.41 (ABq, 211), 5.16 (d,
111), 5.67 (s, lH), 5.84 (d, lH), 5.05~ 6.12 (I, 5H), 6.96 (s, lH).
HS I PAB . M t 1 ) : 592
I~O 1~ 1764 (~-lncta~), 1765, 1615, 1522.
' ~
. .,
w o 92/08721 pc~r/K R90/00018
- 84
2~2~3 :
~xanple 7 : Synthesis o~ 3-~l-allYl-4~6-diaDinopyri~idiniu~-2-yl)thiooetllyl ..
-7-[(2)-2-(2-arinothiazol-4-yl)-2-(propen-l-oxyi~ino)acetami~ol
-3-cephec-4-carboxylate :~
- 5 3-AcetoxYDethyl-l-l(Z)-2-(2-aminothiazol-4-yl)-2-(2-propene-1-oxyioino)
acetamidol-3-cephe~-4-carboxylic acid (500~g) and 1-allyl-4,6-diamino-
2(1~)-pyrimidinethione (200~g) were reacted in the sa~e nanner as
described in ExaDple 1 to give the above-indicated coDpound (31D~g).
N~R : ~ (DzO + acetone-d~)
~.56 ~ABq, 2H~, 4.39 (ABq, 2H), 5.16 (d, lH), 5.62 (s, lH), 5.79 (d,
lR), 5,08rV6.21 ~, lOH), 7.01 (s, 1~).
HSl~AB. ~ 604
IBI~}h~_~aL~ 1770 ( ~ -lacta~), 166~, 1620, 1531.
~xanple 8: SYnthesis of 7-l(z)-2-~2-aoinothiazol-4-yl)-2-t2-propyn-l-
oxyimino)acetsmidoJ-3-(4,6-diamino-1-methYlP~Yri~idiniuo-2-Yl)
.
thiomethyl-3-cephe~-4-carboxylRte `
To a solution of 3-acetoxymethyl-7-1(Z)-2-(2-aminothiazol-4-yl)-2-
(2-propyn-1-oxyiuino)acetaaido]-3-cephem-4-carboxylic acid (500m~) suspended
in distilled ~ater ~5m~) were added 4,6-diamino-1-~ethyl-2(1H)-
pyrimidinethione (200m~) and potassium iodide (lg). While adiusting the .. ~.
- pR of the ~ixture to 7.1~ 7.2 ~ith a sodiu~ bicarbonate solution, the
reactio~ mixture was heated to 70C. After stirring for.4 hours, the
ixture ~as cooled to room teDperature. The p}l ~as adjusted to
3^v3.5 with 2N hydrochloric acid, and the precipitntes Nere filtered,
washed with distilled ~ater (5~), and chro~atographed over silica gel.
:.;' .'
. . .: . . .: ~ .. - . , .. i, . .. . . . .
w o 92tO8721 PC~r/KR9OtOO018
- 85 - ~072~3
Elution Hith a 5 : 1 (v/v) aixture of acetonitrile/distilled ~ater gave
the sbove-indicated compound (300~g) in a pale white solid.
DlE~ I67DC~ (deco~p.)
NMR: ~ (DzO t acetone-dO)
3.01 (s, lH), 3.58 (s, 3H), 3.62 (ABq, 2H), 4.76 (5~ 2H), 5.12 (d,
lH), 5.B5 (s, 1~), 5.79 (d, lH), 6.96 (s, lH).
~SfF~, H +1~ : 576
IR(KBr~_c~L : 1766 (~-lactam), 1685, 1632, 1525.
E~anple 9 : SYnthesis of 7-1(Z)-2-(2-aoinothiazol-4-Yl)-2-(2-proPYn-l-
oxyiRino)acetaoldo]-3-(4,6-dia~ino-1-ethylpyri~idinium-2-yl)
thio~ethyl-3-cephe~-4-carboxylate
:
3-Acetoxy~ethyl-7-[(Z)-2-(2-a~inothiazol-4-Yl)-2-t2-propyn-1-oxyi~ino)
aceta~ido]-3-cephe~-4-carboxylic acid (500Eg) and 4,6-diacino-1-ethyl-
2(1H)-pyrioidinethione(200~g) ~ere reacted in the saoe manner as
described in Exa~Ple 1 to give the above-indicated co~pound (280~g).
D .p.: 165'C ~ (decoop.)
NHR : ~ (D20 + acetone-d~) ~
1.41 (t, 3H), 3.03 (s, lH), 3.56 (ABq, 2H), 4.16 (q, 21I), 4.39 (AB~. ;
2H), 4.81 (s, 2H), 5.16 (d, 111), 5.66 (s, 111), 5.84 (d, 111), 7.00 (s,
lH).
~Sf~AB. H t 1) : 590
IRiKBr. c~~') : 1769 (~-lacta~), I781, I630, 1525.
.
'
WO 92/08721 PCr/KR90/00018
2~)72~83 - 86 -
Example 10: Synthe~is of 3-(1-allYl-4,6-diaoinopyriuidiniuu-2-Yl)
thiooethyl- 7-[(Z)-2-(2-aoinothiazol-4-yl)-2-(2-propyn-1-
oxYi~ino)acetauido1-3-cePhe~-4-carboxylate
3-AcetoxY;~ethYl-7-[(Z)-2-(2-a~inothiazol-4-yl)-2-(2-propyn-1-oxyioino)
aceta~ido]-3-cepheo-4-carboxylic acid (500~g) and 1-allyl-4,6-dia~ino-
2(1H)-pyrioidinethione (200ng) were reacted in the fiaue oanner as
described in Exa~ple 1 to give -the above-indicated co~pound (270mg).
~ : 171-C^~ (decoop.)
NMR ~ z0 t acetone-dO)
3.02 (s, lH), 3.57 tA8q. 2N), 4.43 (A~q, 21!), 4.79 (s, 2~1), 5.18 (d,
1~3), 5.63 (s, 1~), 5.79 (d, lH), 5.12^~6.31 (u, 5~1), 6.97 (s, 111).
HS(~A~. M ~ 602
IR~K13r cm~'): }765 (,~-lacta~ 60, 1620, 1530.
Exaople 11: Synthesis of 7-~(Z)-2-(2-aninothia~ol-4-yl)-2-(2-carboxyprop- -
2-oxyioino)acetanlidol-3-(4,6-diaaino-l-~ethylPyri~idiniu~-2-yl)
thiomethyl-3-cephen-4-carboxylate
To a solution of 3-scetoxY~ethYl-7-E(Z)-2-(2-aminothi2zol-4-Yl)-2-
(csrboxyprop-2-oxyinino)aceta~ido~-3-cepheo-4-carboxylic acid (500ng)
suspended in distilled Hater (5mQ) ~ere added 4,6-diauino-1-uethyl-2(1H)-
pyrioidinethione (200mg~ and potassium iodide (1.2g). ~hile adiusting ~;
the pH of the ~ixture to 7.3^~7.5 with a sodium bicarbonate solution,
the reaction ~ixture ~as heated to 7ûC. After stirring for 4 hours.
the ~ixture ~as cooled to rooo te~perature. Insoluble naterials
were removed bY filtration, and the PH of the filtrate ~as adjusted
::
.
- , .
, . ~ ' ' . , . ' ~
w o 92/08721 pc~r/KR9otooo18
- 87
2~72~83 -
to 4 with 2~-hYdrochloric acid. The Precipitates ~ere filtercd,
washed ~ith distilled water (5m~), and chro~atographed over silica
gel. Elution with a 5 : l (v/v) mixture of acetonitrile/distille~
uater gave the above-indicated co~pound ~2B0~g) in a pale ~hite s~lid.
~ : 151'C ~ (deco~p.)
NHR : ~ (Dz0 + Na~CO9)
1.50 (s, 6H), 3.50 ~s, 3H), 3.59 (A~q, 2H), 4.29 ~ABq, 2H), 5.17
(d, lH), 5.58 (s, lH), 5.79 (d, 111), 6.95 (s, IH).
~S(~A~ + 1) : 624 ~ ;
~R(KBr. cm~1) : 1761 (~-lacta~), 1660, 1580, 1550.
Exa~ple 12 : SYnthesis of 7-[(Z)-2-(2-aDinothiazol-4-YI)-2-(2-carboxyprop
-2-o~yi~ino)aceta~ido~-3-(4,6-dia~ino-l-ethylpyri~idiniu~-2-
yl~thio~ethyl-3-cephe~-4-carboxylate
..
3-AcetoxYmethYl-7-~ (Z)-2-(2-aminothiazol-4-Yl)-2-(2-carboxyprop-2
; oxYioino)acetamido]-3-cephe~-4-carboxYlic acid dihYdrochloride (500mg)
and 4,6-dia~ino-1-ethyl-2(1H)-pyri~idinethione (200ig) ~ere reacted in
the sa~e ~anner as described in Exa~ple 11 to give the above-indicated
coDpound (310~g) in a pale ~hite solid.
~hEl : 153C~ (decoop,)
~2_: ~ (Dz0 + NaHC03)
1.32 (t, 3H), 1.48 ts, 6H), 3.56 (ABq, 2H), 4.04 (q, 2H), 4.31 (A~q,
211), 5.12 (d, lH), 5~53 (s, lH), 5.73 (d, lU), 6.92 (s, 11l~.
,
~S(~B, ~ + lL : 638
IR(K~r~ c~~~) : 1770 (~-lacta~), 1680, 1590, 1530. ~ -
,..... ..
WO 92/08721 PCI/KR90/D110]8
- 88
2~72~ Example 13 : Synthesis of 7-j(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop
-2~oxyi~ino)sceta~ido~-3-(4,6-diamino-1-propylpyrioidiniu~-2-
yl)thio~ethyl-3-cephem-9-carboxylate
... . , _ .
To a solution of 3-acetoxy:ethyl-7-~(Z)-2-(2-a~inothiazol-4-Yl)-
2-(2-carboxyprop-2-oxyi~ino)acetamido~-3-cephe~-4-carboxylic acid
dihydrochloride (500~g) dissolved in distilled ~ater (lOm~) ~ere a~ded
4,6-diaoino-1-propyl-2(1H)-pyrimidinethione (200~g) and potassium iodide
(1.2g). The pH of the mi~ture was adjusted to 7,3rv7 4 with a
1~ sodium bicarbonate solution, and acetonirile (3m~) was added thereto.
After stirring for 5 hours at 73C, the mixture ~as cooled to roo~
te~perature, and the acetonitrile was removed under reduced pressure.
Insoluble materials were ~iltered of~i and pll of the fil~rate was
adjusted to 4.5 ~ith 2N-hydrochloric acid. After being concentrated
under reduced pressure, the residue wàs chrooatographed over silica
gel. Elution with a 5 : 1(V/Y) mixture of acetonitrile/distilled
water gave the above-indicated co~Pound (210~g) in a pale yel~lo~ solid. :
m. P, : 156Crv(decomp.)
~ (D20 t NaHCO9)
0.93 (t, 3H), 1.49 (s, 6H), 1.77 (m, 2H), 3.61 (ABq, 2H), 3.91 (t,
2H)I 5.14 (d, lH), 5.54 (s, 11l), 5.77 (d, 1ll), 6.92 (s, 111~.
MS(F~. M ~ 11 : 652
IR~K6r. c~~') : 1765 ( ~ -lactam), 1650l 1596, 1530.
~: .
': ~ ' ;
~0 92/08721 PCI/KR90/0~)018 :
- 89
2~72~3
exa~ple 14 : Synthesis of 7-1(Z)-2-(2-a~inothiazol-4-yl)-2-(2-carboxYprop
-2-oxyi~ino)aceta~idol-3-(1-butyl-4,B-dinviDopyrillidiniu~-2- , ,'
yl)thio~ethyl-3-cephem-4-carboxYlate
___ _ __
3-Acetoxy~ethyl-7-[(Z)-2-(2-a~inothiazol-4-yl)-2-(2-carboxyprop-2-
oxyi~ino)aceta~ido]-3-cephe~-4-carboxylic acid dihydrochloride (500~g)
and 1-butyl-4,6-dia~ino-1-2(1N)-PYrimidinethione (20Q~g) ~ere reacted in ~ ~ -
the same ~anner as described in Exa~ple 13 to give the above indicated-
co~pound (23D~g).
ID ~E~ : 161'C ~ (decomp.)
(D~0 t acetone-d~)
0.92 (t, 3~), 1.36 (~, 211), 1.4~ (s, 611), 1.71 (D, 211), 3.52 ~A~q,
2H), 3.99 (t, 2H), 4.35 tABq, 211), 5.14 (d, lH), 5.58 (s, 111), 5.7
(d, 1~), 6.95 (s, lH).
~S~FA~ t 1) : 666
IR(KBr~ CIL:~l : 1768 (~-lactao), 1671, 1625, 1528.
Example 15 : Synthesis o~ 3-(l-allYl-4~6-diaminopyrimidiniun-2-yl)thioneth
-7-[(2)-2-(2-aninothiazol-4-yl)-2-(2-carboxyprop-2-oxyioino)
acetanido]-3-cephe~-4-carboxYlate
.. . .'
3-Acetoxy~ethyl-7-[(Z)-2-(2-aminothiazol-4-Yl)-2-(2-carbo~yprop-2-
oxYimino)acetamido]-3-cePhem-4-carboxYlic acid dih~drochloride (500~g)
and l-allYl-4,6-dia~ino-2(1H)-pYrimidinethione (200~g) were reacted in
, .. .. .
the same ~anner as described in Exa~ple 13 to give the above-indicated
;co~pound (310~g).
e~ : 160'C ~ (deco~p.)
, , ,
WO 92/08721 PCl/KR90/00018
- 90
2~2~3
NHR_: ~ (D~0 + acetone-dD)
1.4B (s, 6R), 3.56 (ABq, 2H), 5.16 (d, lH), 5.61 (s, lH), 5.79 (~.
lH), 5.05^~6.51 (e, 5H), 6.96 ~" lH).
~IS(~A~, ~ + 1): 650
IR(X~r~ c~l~: 1765 (~'-lactam), 1670, 1620, 1530.
E~aeple 16: Synthesis of 7-1(2)-2-(2-aainothiazol-4-Yl)-2-(~-carboxyeth
-l-o~yiDino)aceta~idol-3-(9,6-dia~in~ ethYlpYrimidiniu~-2-
yl)thio~ethyl-3-cephe~-4-carboxylste
1 0
~o a solution of 3-acetoxYmethYI-7-[(2)-2-(2-a~inothiazol-4-Yl)-2-
(2-carbo~yeth-2-oxyimino)aceta~idol-3-cephe~-4-carboxylic acid (50û~g~
suspended in distilled water (lûn~Q) were added 4,6-diacino-l-uethYl-2(lN)
pyrimidinethione (200m~,) and potassium iodide (1.2g). ~Ihile ad,iusting
the pH o~ the mixture to 7.1^~7.2 ~ith a sodiu~ bicarbonate solution,
the reaction ~ixture ~as heated to 70-C. After stirring for 5 hours,
the ~ixture was cooled to room te~Perature. The Pl! ~as adjusted
to 4.1 ~ith 2N-hYdrochloric acid, and the precipitates were filtered,
~ashed ~ith distilled water (5mQ), and chroDatographed over silica
gel. ~lution with a 5: 1 (v/v) ~ixture of scetonitrile/distilled water
gave the above-indicated compound (200mg) in a pale ~hite solid.
: 153-C~v (decomp.)
~: ~ (D20~+ Nal~Cû~)
1.48 (d, ~R), 3.53 (s, 3n), 3.59 (ABq. 2H), 4.36 (ABq, 2Hi, 5.~7 (d.
lH), 5.60 (s, lH), 5.79 (d, 1~), 7.01 (s, lH).
H9(EA~. H + Ll: 610
IR(~r, c~'): 1766 (B-lacta~). 1765, 1595. 1525.
~ ~ .
. " ,.. . .. ~ . , , . . . - . . . .
w ~ 92/08721 - 91 - pc~r/KR9o/oool8
2~72~3
Exaaple 17 : Synthesis of 7-[(Z)-2-(2-aoinothiazol-4-yl)~2-~2-carboxyeth
-1-oxyinino)aceta~ido]-3-(1-ethy}-4,~-dia~inopyri~idiniu~-2-
yl)thio~ethyl-3-cepheo-4-carboxYlate
.. . .. . __ ............................................. . .
3-AcetoxY~ethyl-7-[lz)-2-(2-aminothiazol-4-yl)-2-(2-carboxyeth-l-
oxyi~ino)acetamido]-3-cephe~-4-carbo~ylic acid ~500~g) and 4,6-diamino-
1-ethyl-2(1H~-pyri~idinethione (200~g) ~ere reacted in the saDe oanner
- as described in ~xa~Ple 16 to give the above-indicated coopound(2lORg).
~ 155-C ~ (deco~p.)
~ (DzO t acetone-d~)
1.34 (t, 3H), 1.48 (d, 31i), 3.59 (A~q, 2H), 4.04 (q, 2~), 5.15 (d,
lH), 5.52 (s, 1~), 5.78 (d, lH), 6.96 (s, 1~).
MS(~AB. ~ t 1) : B24
IRtK~r. CD~ 1785 (~-lacta~), 1765, 1590, 1530.
;
aople 18 ~ SYnthesis oi 7-[(Z)-2-(2-aminothiazol-~-yl)-2-(2-carboxyeth
-l-o~yioino)acetaDidol-3-(4 ,6-diamino-l-ProPylpyri~idiniu~-2- ' , .
yl)thiomethyl-3-cepheo-4-carboxylate
.....
3-AcetoxY~ethyl-7-i(Z)-2-(2-aminothiazol-4-Yl)-2-(2-carboxyeth-1-
oxyinino)acetamidol-3-ceph~o-4-carboxylic acid (500~g) and 4,~-dia~ino-
I-propyl-2~1~)-pyri~idinethione (200Dg) were rèacted in the saoe
anner as described in ExaDple 16 to give the above-indicated compound
(170~g).
~ke~ : 154-C ~ (deco~p.)
E~e_: ~ (D20 + Na~COa)
WO 92/08721 pclrlKR9o/ooûls
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2~72~3
0.95 (t, 3H), 1.46 (d, 3i1), 1.65 (m, 211), 3.56 (ABq, 211), 3.91 (L, 211),
5.17 (d, lH), 5.56 (s, 111), 5.77 (d, lH), 6.96 (s, 111).
HS(~AB~ H +Il: 638
IR(X~r. c~l : 176D ( ~-lactan), 1671, 1690, 1525.
Exallple 19: SYnthesis of 3-(l-allyl-4,6-diaminopyrimidiniull-2-yl)thiomethYI
-7-[ (Z)-2-(2-a~inothiazol-4-yl)-2-(carboxYeth-2-oxyi~ino)
aceta~ido]-3-cephem-4-carboxylate
.~
3-Acetoxymethyl-7-1(Z)-2-(2-a~inothiazol-4-Yl)-2-(2-carboxyeth-l-
oxyioino)aceta~ido]-3-cephem-4-carboxylic acid (500mg) and 1-allyl-4,6-
diaDino-2(11~)-pyri~idinethione (200 mg) were reacted in the saoe manner
as described in ~xanple 16 to give the above-indicated cooPound(290~g).
m.PI: l55-C~V ~decomP~)
NMR: ~ (D20 t acetone-dO)
1.44 (d, 3N), 3.52 (ABq, 2~), 5.16 (d, lH), 5~59 (s, lH), 5.76 (d,
lH), 5.07^~6.51 (~, 51~), 6.99 (s, lH).
HS~AB. ~ + 1): 636
IR(KBr. C~ 1765 (~-lactam), 1680, 1600, 1530.
Exauple 20 : SYnthesis o~ 7-f(Z)-2-(2-a~inothiazol-4-yl)-2-(1-carboxymeth-
oxyimino)acetamido]-3-(4,6 diamino-1-methYlpyrioidiniu~-2-yl)
thio~ethyl-3-cephe~-4-carboxylate
~,
To a solutiDn of 3-acetoxY~ethYI-7-[(Z~-2-(2-a~inothiazol-4-YI)-2-
(2-carbo~yDethoxyi~ino)acetamido]-3-cephem-4-carboxYlic acià (500mg)
suspended in distilled water (l(lmQ) were added 4,6-dia~ino-1-oethyl-2(111)-
',:'
WO 9~/08721 pcr/KR9o/ooo18
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2~72~3
pyri3idinethione (200mg) and potassiu~ iodide (1.2g). blith the adjusting
of the pll of the mixture to 7.2 with a sodiu~ bicar~onate solution,
the reaction oixture ~as stirred for 5 hours at 70~C. A~ter the
uixture cooled to room te~perature, insoluble materials ~ere filtered off,
and the pll of the filtrate was adjusted to 4.1 with 2N-hYdrochloric
acid. After being concentrated under reduced pressure, the residue
~as chroeato~raphed over silica gel. Elution with a 4: 1 (v/v) oixture
of acetonitrile/distilled water gaYe aboYe-indicated co~pound(350mg) in a
~hite solid.
aL,~: 167C^~ (decomp,)
NHR: ~ (DzO t NaHC09)
3.49 (s, 3~), 3.52 (A3q, 211), 4.34 (A8q, 211), 4.60 (s, 211), 5.1G
(d, lN), 5.56 (s, 113), 5.78 (d, lH), 6.98 (s, lH).
HS(~AB,~L t I) 598
~: 1760 (,B-lactam), 1670, 1600, 1550.
Exa~ple 21: Synthesis of 7-1(Z)-2-(2-allinothiazol-4-Yl)-2-(carboxY~eth-
oxYi~ino)acetamido]-3-(4.6-dianino-1-ethYlPYrioidiniuu-2
yl)thiomethyl-3-cephe~-4-carboxylate
- -- -
3-Acetoxymethyl-7-[(Z)-2-(2-aminothiazol-4-Yl)-2-(2-carbo~YoethoxYioino)
acetanido]-3-cephem-4.carboxylic acid (500 ~g) and 4,6-dianino-1-ethy]-
2(1H)-pyriDidinethione (200 mg) ~ere reacted in tlle saDe ranner as
described in Exa~ple 2û to give the above-indicated co~Pound(280~g).
~,~,: 165-C^~ (deco~p.)
N~ (Dzû ~ NaHCûa)
1.32 (t, 3H), 3.62 (ABq, 211), 3.98 (q, 2H), 4.60 (s, 211)j 5.17 (ù,
W o 92/08721 pc~r/KR9o/oool8
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2 ~ 7 2 8 8 3 111), 5.58 (s, lH), 5.80 (d, 111), 7.01 (s, lH).
HS(FAB. H + Ll : 610
IR(K~r~ c~ 1765 ( ~ -lacta~), 1670, 1600, 1520.
Exaople 22 : Synthesis of 7-[(Z)-2-(2-aDinothiazol-4-yl)-2-(c~rboxYceth-
oxyimiDo)aceta~ido]-3-(4,6-dia~ino-1-propylpyrimidinium-2-
yl)thiomethyl-3-cephem-4-carboxylate
...A . _ . _ ..~
3-Acetoxy~ethyl-7-l(Z)-2-(2-aminothiazo~-4-yl)-2-(2-carboxymethoxyicino)
acetamidol-3-cephem-4-carboxylic acid (SOO~g) and 4,6-diamino-1-propYI-
2(1H)-pyrimidinethione (200~g) were reacted in the same mnnner as
described in Exawple 20 to give the above-indicated co~pound(210m~).
m~e~ : 169-C^J(decoop,)
~ (DzO + NaHCOa)
0.93 (t, 3H), 1.73 (m, 211), 3.56 (ABq, 211), 3.92 (t, 211), 4.5~ (s,
2H), 5.15 (d, 1~3), 5.56 (s, lH), 5.78 (d, lH), 6.98 ~s, lll).
HStPA~. H t 1) : 624
IR(K~r. c~-l) : 1763 (~ -lacta~), 1670, 1610, 1525.
E~aople 23 : Synthesis of 7-1(Z)-2-(2-a~inothiazol-4-yl)-2-(carboxyLeth-
oxYi~ino)acetamidol-3-(l-butyl-4,6-dia~inopyrimidiniu~- 2-
yl~thiomethyl-3-cephem-4-carboxylate
3-AcetoxYmethyl-7-[(z)-2-(2-a~inothiazol-4-yl)-2-(2-carboxy~ethoxyimino)
acetamidoI-3-cephem-4-carboxYlic acid (500Dg) and l-but~1-4,6-diacino-
2(lH)-pyrimidinethione (200~g) ~ere reacted in the sa~e oanner as
described in Exa~ple 20 to ~ive the above-indicated coopound~240~g).
.
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11,~.: 167-C^~ (decomp.)
NHR: ~ (D20 t NaHcoa)
0.92 ~t, 3H), 1.32 (~, 2H), 1.6B (m, 2H), 3.60 (A~q, 211~, 3.9G ~t, 2H),
4.57 ~s, 2H), 5.15 (d, 1~), 5.58 (s, l}i), 5.78~d, llI), 7.01 (s, IH).
~S(PA~ H t 1): 638
IR(K~r. ~ ): 1765 (,~-lacta~), 1670, 1610, l53D.
~xa~ple 24: SYnthesis of 3-(l-allY1-4,6-dia~inopyriDidiniu~-2-Yl)thiouethyl
-7-[(Z)-2-(2-a~inothiazol-4-yl)-2-(2-carboxynethoxyi~ino)aceta-
Dido]-3-cepheo-4-carboxylate
3-Aceto~Y~ethyl-7-1(Z)-2-(2-aoinothiazol-4-yl)-2-(2-carboxy~ethoxyi~ino)
acetaDidol-3-cephe~-4-carboxylic acid (500ng) and 1-allyl-4,6-diaoino-
2(111)-pyri~idinethione (2000g) were reacted in the ~aue Danner as
described in Example 20 to give the above-indicated co~pound~220sg~.
IIL,EL : 165-C~ tdeco~p.)
NMR: ~ (Dz0 t NallC09)
3.56 (Aaq, 2H), 4.56 (s, 2H), 5.12 (d, IH), 5.63 (s, 111), 5.79 (d,
IH), 5.07^~6.51 (n, 5H), 7.0û (s, 1~1).
2û HS(~AB. tl ~ 1): 622
IR(KBr. c~ : 1770 (,B-lactau), 1660, 1600, 1535. ' :' '.
~sa-Ple 25: ~ynthesis of 7-~Z)-2-(2-allinothiazol-4-Yl)-2-(oethoxYi~ino)
aceta~ido]-3-(1,4,6-triaminopYri~idiniu~-2-yl~thio~ethyl-3-
cephe~-4-carboxYIate
'~ :
To a solution o~ 3-acetoxy~ethyl-7-l~2)-2-(2-aoinothiazol-4-yl)-2-
'
. -
wo 92/08721 PCr/KR90/00018
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2~2~3
~oethoxyimino)acetamido]-3-cephe~-4-carboxylic acid (500mg) susPended in
distilled ~ater (5m~) were added 1,4,6-triamino-2(1~)-pYri~idinethione
(200Dg) and potassium iodide (800mg). With adjusting of the pll o~
the mixture to 7.1^~7.2 ~ith a sodium bicarbonate solution, the reaction
Dixture ~as heated to 70C. After stirring fnr 4 hours, the ~ixture
was cooled to roo~ teoperature. The pH was adjusted to 3^~3.5
with 2N-hydrochloric acid, and the precipitates Kere filtered, washed
with distilled water (5mQ), and chro~atographed over silica gel
Elution with a 5: l~v/v) mixture of acetonitrile/distilled water gave
the above-indicated compound (300~g) in a pale vhite solid.
~: 156-C^~ ~deco~p. )
(DzO + acetone-dO)
3.58 (A~q, 2H), 3.81 ~s, 31i), 4.33 (A3q, 2H), 5.12 (d, 1ll), 5.GI
ln), 5.83 (d, lH), 6.91 (s, lR).
HS(FAB, tLtll: 553
IR(R~r. ~ ): 1765 (,~-lactam), 1670, 1620, 1560.
', " .
Example 26: Synthesis of 7-[(Z)-2-(2-aoinothiazol-4-Yl)-2-(etlloxYi~ino)
aceta~idol-3-(1,4,6-triaminopyri~idinium-2-yl)thiocQthY1-3- ;
cephem-4-carboxYlate
.~ .
3-Aceto~ethyl-~-l(Z)-2-(2-aminothiazol-4-YI)-2-(ethoxYimino)
acetamido]-3-cepheo-4-carboxylic acid ~5000g) was reacted in the same
. .
manner as described in Exam~le 25 to give the above-indicated com~ound
(290~g) in a pale white solid.
.: 165-C^~ (decomp.)
(D~0 t acetone-d~)
:
, .
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2~ 72~3
1.29 ~t, 2N), 3.57 (ABq, 211), 4.24 (q, 211), 4.35 (ABq, 2H), 5.16 (d,
1~), 5.62 (s, lH), 6.91 (s, lH).
HS~FAB~ H t 1) : 5~7
IR(K~r. c~ 17B5 (~-lacta~), 1680, 1590.
S
~xa~ple 27 : Synthe~is of 7-~(Z)-2-(2-a~inothiaYol-4-yl)-2-(2-propyn
-l-oxyioino)acetamidol-3-(1,4,6-tr:La:~inopyri~lidiniu~-2-yl)
thiometh~l-3-cephem-4-carboxylate
3-Acetox ~ ethYl-7-1(Z)-2-(2-aainothiazol-4-yl)-2-(2-propyn-1-oxYimino)
acetamido]-3-cephem-4-carboxylic acid (500mg) was reacted in the same manner
as described in Example 25 to ~ive the above-indicated coopound (350mg)
in a pale yellow solid.
~e~ : 167-C ~ (decomp,)
~Me_: ~ (DzO + acetone-d~)
3.06 (t, 1~), 3.56 (A~q, 2H), 4.41 (ABq, 2~), 4.80 (d, 211), 5.12
(d, lH), 5.62 (s, lH), 5.80 (d, lH), 6.96 (s, lH).
MS(~AB. H t 1) : 577
: ' :
IR(~rl cm~l) : 1765 (~-lactam), 1690, 1580.
~xample 28 : Synthesis of 7-[(Z)-2-(5-amino-1,2.4-thiadiazol-3-yl)-2-
(etho~yimino)aceta~ido]-3-(1,4,6-trianinopyrioeidiniuo-2-yl)
thiomethyl-3-cephem-4-carboxylate
~ ' ':
3-AcetoxYmethYl-7-[(Z)-2-(5-amino-1,2,4-thiadiazol~3-yl)-2-(ethoxyi~ino)
acetamidol-3-cephem-4-carboxylic acid (50Q~g) was reacted in the sa~e
~anner as described in Example 25 to give the above-indicated compound
.
,
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2~2~33
(280~g) in a Yellow solid.
m.P. : 169DC^~ (decomp.)
N~IR_: ~ (D20 t ~cetone-d~)
1.52 (t, 3H), 3.57 (ABq, 2H), 4.26 (A6q, 2H), 4.36 (q, 211), 5.1~ (d,
lII), 5.58 (s, lH), 5.84 (d, lH).
IR(KBr. c~ 1769 ( ~-lacta~, 169û, 1630.
example 29: Synthesis of 7-l(Z)-2-(2-a~inothiazol-4-yl)-2-(carboxypr
2-oxyi~ino)aceta~ido~-3-(1,4,~-tria~inopyri~idiniu~-2-yl)
thio~ethyl-3-cePhe~-4-carboxYlate
~o a solution of 3-acetoxy~ethYl-7-1(Z)-(2-acinothiazol-4-yl)-2-(2- ~ -
carboxyprop-2-oxyimino)acetamido~-3-cephem-4-carboxylic acid (50Dmg) in
distilled water (lOmQ) ~ere added 1,4,6-tria~ino-2-(lH)-pyri~idinethione
(200mg) and potassium iodide (1.2g). The pH of the reaction mixture was
adjusted to 7.1^~7.3 ~ith a sodium bicarbonate 601ution, and the reaction
mixture ~as heated for 4 hours to 70-C. After cooling to roo~ te~Perature,
insoluble lDaterials were filtered o~f, and the pH of the filtrate was :~
adjusted to 4. After being concentrated under reduced pressure, the
residue ~as chromatographed over silica gel. ~lution with a 4:1 (v/v)
mixture of acetonitrile/distilled water gave the above-indicated compound
(310mg) in a pale white solid.
m~ : 155~C~V (decomp.)
~ D20 + NaHC09)
:::
1.49 (s, 6R), 3.58 (ABq, 211), 4.22 (ABq, 211), 5.16 (d, 111), 5.56 (s,
IH~, 5.77 (d, lH), 6.94 (s, llI).
H~(IAB~ H ~ 1): 625
: ,
wo 92/08721 99 pcrJKR9o/oool8
2~7~3
IR(Ker~ c~ 1770 (,~-lactam), }690t 1610, 1570.
Exa~ple 3D: Synthesis o~ 7-11~)-2-(2-a~inothiazol-4-Y1)-2-(1-carboxYeth
l-oxyiDino)aceta~ido}-3-(1,4,6-tria~inopyri~idiniuD-2-yl)
thio~ethyl-3-cepheo-4-carboxylate
.
3-Acetoxymethyl-7-[(2)-2-(2-aoinothiazol-4-yl)-2-(1-carboxyeth-1-
ox~imino)acetaDido~-3-cepheo-4-carboxylic acid (500~ as reacted in
the sa~e llanner as described in Example 29 to give the above-indicated
co~Pound (230~g) in a pale yellow solid.
167'C^~ tdeco~p.)
~_: ~ (Di~0 t acetone-dO)
1.44 (d, 31~), 3.55 (A~qI 2II), 4.21 (ABq, 2H), S.17 ~d, III), 5.54
(s, l~I), 5.76 (d, 1~), 6.97 (s, lH).
~IS(FAB. H t 1): 611
(K~r. c~ ): 1765 (,B-lacta~), 166û, 1590, 1540.
Example 31: Synthesis of 7-[(Z)-2-(5-amino-1,2,4-thiadiszol-3-yl)-2-(2-
carboxyprop-2-oxyiaino)acetamidoI-3-(l,q,8-triaminopyrimidiDium
-2-yl)thiomethyl 3-cephem-4-carbo~ylate
'" ~.
3-Acetox~ethyl-7-i(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(2- ~
:
carboxyprop-2-oxyi~ino)acetamido}-3-cephem-4-carboxylic acid (50ûmg) ~as
reacted in the same oanner as described in Example 29 to give the above-
Indicated co~pound (280~g) in a pale ~hite solid.
~: 173-C^~ (de,,omp.)
(D~0 t Na~lC0~,)
w O 92/08721 PC~rJKR90/00018
- 100 - --
29~ 3 3.62 (s, 311), 3.66 (ABq, 211), 4.05 (s, 311), 4.45 (A~q, 211), 5.15
(s, lH), 5.81 (d, 111).
IR(K~r. c~ 1760 (~-lacta~), 1690, 1610, 1570.
Exa~ple 32 : SYnthesis of 7-[(Z)-2-(5-a~ino-1,2,4-thiadiazol-3-yl)-2-
(~ethoxyimino)aceta~ido]-3-(4,6-dia~ino-l-methylpyri~idiniu3
-2-Yl)thio~ethYl-3-cephem-4-carboxylste -~
Io a solution of 3-acetoxYmethY1-7-((Z)-(5-aDino-1,2,4-thiadi~zol
-3-yl)-2-(~ethoxyimino)~cetamido]-3-cephem-4-carboxylic acid (50i~mg~
suspended in distilled water (5m~) were added 4,6-dial~ino-1-metHYI-
2(1H)-pyrimidinethione (2DOm~) and Potassium iodide (800~g). With
adjusting of the pll of the mixture to 7.1~ 7.2 with a sndiuo
bicarbonate solution, the renction mixture was heated to 70~C.
A~ter stirring for 9 hours, the uixture ~as cooled to room te~perature.
The pH ~as adjusted to 3~ 3.5 with 2~-hydrochloric acid, and the
resultant precipitates were filtered, washed with distilled ~ater
t5mQ), and chro~atographed over silica gel. Elution with a 5 : I(v/v)
mixt~re of acetonitrile/distilled water gave the above-indicated
compound(300~g) in a Pale ~hite solid.
m.P. : 161C ~ (decomp.)
(DzO t acetone-dO)
3.62 (s, 3H), 3.66 (A~q, 211), 4.05 (s, 3H), 4.45 (ADq, 211), 5.15
(d, lH), 5.62 (s, lH), 5.81 (d, IH).
IR(RBr. cm~1) : 1765 (~-lsctam), 1680, 163G. 157D.
-
, ~ . .
: .
.. ..
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Exa~ple 33 : Synthesis of 7-1(2)-2-(5-amino-1.2,4-thiadiazol-3-YI)-2-
~methoxyioino)acetamido]-3-(4,6-dia~ino-1-ethylpyrimidiniu~
-2-yl)thiomethyl-3-cePhem-4-carboxylate
' .
3-AcetoxYmethYl-7-~(Z)-2-15-a~ino-1,2,4-thiadiazol-3-yl)-2-(methoxyiDino)
aceta~ido]-3-cephem-4-carboxylic acid (500mg) and 4,6-dia~ino-1-ethYI-
2(1H)-pyri~idinethione (200mg) ~ere reacted in the sa~e manner as
described in Example 32 to give the above-indicated co~pound (230~g).
m~e~ : 169C ~ (decomp.)
N~R: ~ (DzO + acetone-d~
3.60 (q, 2H), 3.60 (A~q, 2H), 4.05 (s, 38), 4.55 (ABq, 211), 5.11
(d, 111), 5.68 (s, IH), 5.82 (d, IH).
IR(KBrl_c~ 1770 (~-lactan), IB90, 1630, 1580.
Exaople 34 : Synthesis of 7-l(Z)-2-(5-a~ino-1,2,4-thiadiazol-3-Yl)-2-
(~ethoxyi~ino)acetamido]-3-(4,6-diamino-1-propylpyri~idiniu~
-2-yl)thio~ethyl-3-cephem-4-carboxylate
3-Acetoxy~ethyl-7-~(Z)-2-(5-amino-1,2,4-thiadiazol-3-YI)-2-(oethoxYi~ino)
acetamidoJ-3-cePhem-4-carboxylic acid (500m~) and 4,6-dia~ino-1-propyl-
2(18)-pyri~idinethione (200mg) were reacted in the same manner as
described in ~xample 32 to give the above-indicated co~pound (250mg).
.P. : 67C ~ (decomp.)
E~ (D20 t acetone-dO,
- 25 1.05 (t, 38), 1.80 (~, 2H), 3.52 (ABq, 28), 3.80 (t, 211), 4.05
~ (s, 3N). 4.55 (ABq, 2H), 5.16 (d, 111), 6.65 (s, lH), 5.84 (d, 111).
: IR(R~r. c~L : 1765 (~-lactam), 1695, 1640, 1580.
~ - , , "'~
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Exa3ple 35: SYnthesis of 7-l(Z)-2-(5 a~ino-1,2,4-thiadiazal-3-YI)-2-
(~ethoxyi~ino)acetamido~-3-(1-allyl-4,6-dia~inopyri~idiniu~
-2-yl)thio~ethY~-3-cephem-4-carboxylate
3-Acetoxy~ethyl-7-~(Z)-2-(5-amino-1,2,4-thiadia201-3-yl)-2-
(methoxyimino)acetaoido]-3-cephe~-q-carboxylic acid (500ng) ~nd 1-allYi-4,
6-diaminD-2(1H)-pyri~idinethione (20D~g) were reacted in the same ~anner
as described in Exaople 32 to giYe the above-indicated compound(l70mg).
~.P.: 158-C^~ (decomp.)
NMR: ô (D~O t acetone-d~)
3.56 (ABq, 2H), 4.05 (s, 3H), 4.42 (ABg, 2H), 5.16 (d, 111), 5.70
ts, lH), 5.85 (d, lII), 5.05^~6.51 (m, 511).
IR(K~r, c~ 1760 ~,6-lactam), 1700, 1650, 1590.
Exao[~le 36 : Synthesis of 7-[(Z)-2-(5-amino-1,2,4-thiadiazol-~-Y])-2
..
(ethoxyimino)acetamido]-3-(4,6-diamino~ ethylpyrimidinillm ~ : '
-2-yl)thio~ethYI-3-cePhem-4-carboxylate
.. . . ~
3-Acetoxymethyl-7-[(Z)-2-(5-a~ino-1,2,4-thiadiazol-3-yl)-2-(ethoxyiminn)
acetamido~-3-cepheo-4-carboxylic acid (5DOmg) and 4,6-diamino-1-metilyl-
2(1H)-pyri~idinethione (200~g) were reac-ted in the same maIlner as
described in Example 32 to give the above-indicated co~pound (280nlg).
~ : 163-C^~(decomp.)
jNMR: ~ (DzO ~ acetone-dr)
.
1.30 (t, 311), 3.60 (s, 3ii), 3.5G (ABq, 21i), 4.30 (q, 2II), 4.10
(ABq, 2H), 5.13 (d, ~lH), 5.G2 (s, 111), 5.84 (d, III).
IR~R~r~ CT~ : 1768 (,~-lactam), lB90, 1630, 1580.
:. '
Wo 92/08721 PCr/KR9O/OOOls
- 103
2~7.~3 :
Example 37: Synthesis of 7-~(Z)-2-(5-amino-1,2,4-thiadiazol-3-yI)-2-
(ethoxyimino)acetamido]-3-(4,6-diamino-1-ethylpyrimidinillm
-2-yl)thio~ethYI-3-cephem-4-carboxylate
3-AcetoxyDethyl-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(ethoxyinino)
acetamido~-3-cephe~-4-carboxylic acid (500m) and 4,6-diamino-1-ethYI-
2(1H)-pyri~idinetbione (20Qmg) Nere reacted in the sa~e manner as
described im Example 32 to give the above-indicated co~pound(27ûmg).
DL.E~: 165'C~v (decomP.)
~: ô (DzO t acetone-da)
1.18 (t, 3H), 1.30 (t, 313), 3.60 (q, 211), 3.58 (A~q, 211), i.3n (tl,
2H), 4.40 (ABq, 211), 5.18 (d, lll), 5.71 (s, lII), 5.84 (d,
IR(K~r~, clD~'): 1765 (l~-lactam), 1695, 1630, I570.
~xa~ple 38: Synthesis o~ 7-~(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-
(ethoxyimino)acetamido]-3-(4,6-diamino-1-propy~pyrimidinium
- -2-yl)thiomethyl-3-cephem-4-carboxylate
. _ . _ _ . . .
3-Acetoxymethyl-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-~-yl)-2-(ethoxyi~ino)
2û acetamidol-3-cephem-4-carboxylic acid (500mg) and 4,6-dia~ino-1-pro~2~1H)-pyrimidinethione (2DOmg) ~ere reacted in the sa~e manner as
described in ExamPle 32 to give the above-indicated compound(230mg).
.: 158C~v (decomp.)
NMR : ~ (DzQ t acetone-dt;)
1.05 ~t, 3H), 1.30 (t, 311), 1.80 (m, 2H), 3.54 (ABs, 2H), 4.0 (l,
2H), 4.32 (q, 2H), 4.58 (ABq, 2H), 5.18 (d, 111), 5.69 (s, 111),
5.84 (d, IH).
;~ ~ ' . '' '
WO 92/08721 pcr/KR9o/ooo18
- 104
2 ~ 3
IR(K~r~ c~1770 (,~-lactam), 1690, 1640, 15~0.
Example 39: SYnthesis of 7-[(Z)-2-(5-anino-1,2,4-thiadiazol-3-yl)-2-
' (ethoxyimino)acetamido]-3-(1-allyl-4,6-dia~inopyrimidinillm
-2-yl)thiomethyl-3-cephem-4-carboxylate
- -
3-Acetoxymethyl-7-[(Z)-2-(5-amino-1~2,4-thiadiazol-3-yl)-2-(ethoxYiuino)
acetamido]-3-cephem-4-carboxylic acid (5DOmg) and l-allYI-4,6-diA~ino-
2~1H)-pyrimidinethione (200~ ere reacted in the same Danner as
described in Exa~ple 32 to give the above-indicated co~pound(210mg).
E~.: 159-C~V (decomp.)
(D~O ~ scetone-d~)
1~31 (t~ r~ 3.60 (A~q, 2H), 4.32 (q, 2H), 4.42 (A~l, 2ll~, 5.16 (d,
lH), 5.6B (s, lll), 5.82 (d, lH), 5.05^~6.51 (m, 51~).
IRIK,Br. c~ : 1769(,~-lactam), 1695, 1630, 1570.
Example 40: SYnthesis of 7-~(Z~-2-(5-amino-1,2,4-thiadiazol-3-YI)-2-
(2-carboxyprop-2-oxyimino)acetamido]-3-(4,6-diamino-1-
methylpyrimidinium-2-yl)thiomethYl-3-cepllem-4-carboxylate -~
_ _ _ _ _
Tn a solution of 3-acetoxYmethYl-7-l(~)-2-(5-amino-l~2r4-thiadiazo]
-3-yl)-2-~2-carboxyprop-2-oxyimino)acetamidn]-3-cephem-4-carboxYlic acid :
(500m~) suspended in distilled ~ater (lOmQ) ~ere added 4,6-diamino-l-
methyl-2(1H)-pYri~idinethione (200mg) and potsssium iodide (1.26).
After adiusting the pH of tbe reaction mlXtUre to 7.3^~7~5 ~ith a
sodium bicarbonate solution, the reaction ~ixture ~as stirred for
hours ~t 70C. The mixture s~as cooled to room temperature, and
w~ 92/08721 PCr/KR90/00018
- 105 ~ 2~72~3
insoluble ~aterials ~ere Eiltered off, and pli of the filtrate was
adjusted to 4. After concentr~tion under reduced pressllre. ~He
residue was chro~atographed over silica gel. Elution ~itll a ~: 1
(v/v) ~ixture of acetonitrile/distilled water gave the above-indicated
conpound (200mg) in a pale white solid.
.P,: 154'C^~(decomp.) ~ ~
NHR: ~ (Dz0 t scetone-dO) - -
1.52 (s, 6H), 3.51 (s, 3H), 3.58 (A~q, 2H), 4.40 (ABq, 2H), 5.18
(d, lH), 5.60 (s, la), 5.81 (d, lH).
10 IR(R2r c~ 1769 ( ~-lactam), 1700, lB50, 1590.
Exa~ple 41: Synthesis of 7-~(Z)-2-(5-a~lino-l,2,4-thiadiazol-3-yl)-2-
(carboxyprop-2-oxyimino)aceta~ido~-3-(9,6-diaoino-1-
ethylpyri~idinium-2-yl)thiooethyl-3-cephem-4-carboxylate
~_ _ __
3-Acetoxy~ethyl-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(2-
carboxyprop-2-o~yimino)acetamidol-3-cePhem-4-carboxYlic acid (500mg) an~l
9,6-diamino-i-ethyl-2(1H)-pyri~idinethione (200 ~ ere reacted in the
sa~e manner as described in Exa~ple 40 to give the above-indicated
comPound(2502g).
m.P~: 161'C~ (decomp.)
NHR: ~ (Dz0 t acetone-d~
1.32 (t, 3H), 1.58 (s, 6H), 3.56 (A~q, 2H), 4.02 (q, 211), 4.43 ~A~q,
2H), 5.18 (d, lH), 5.58 (s, 111), 5.81 (d, lH).
~ 25IR(K~r. c~ 1767 (~-lactam), 1695, 164û, 1580.
:
'
~ ~ , .
Wo 92/08721 pcr/KRso/ûool8
- 106
29~ 2~3
Exa~ple 42: Synthesis of 7-l(Z)-2-(5-amino-1.2,4-thiadiazol-3-Yl)-2
(2-carboxyProp-2-oxyimiw)acetaoidol-3-~4~6-dia~ino-l-
propylpyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate
3-Acetoxymethyl-7-~(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(2-
carboxyprop-2-oxyinino)acetaoido]-3-cephem-4-carboxylic acid(500~g)
and 4,6-diamino-1-propyl-2(1H)-pyri~idinethione (200~g) were reacted in
the saoe ~anner as described in Exa~ple 40 to give the above-indicated
compound(l9Qmg).
m P. : 159~C^~deco~p.)
RMR: ~ (Dz0 + acetone-dO)
1.02 (t, 3H), 1.52 (s, 611), 1.53 (m, 2H), 3.G0 (A~q, 2H), 3.98 ~t,
2H), 4.45 lA~q, 2~), 5.18 (d, 11l), 5.58 (s, 111). 5.81 (d, 111).
IR(l~r.l._çr~~'): 1755 (,6-lactam), 1690, 1630, 1570.
Example 43: Synthesis of 7-1(Z)-2-(5-amino-1,2,4-thiadiazol-3-Yl)-2-
(2-carboxyprop-2-oxYiDino)acetamidol-3-(l-butyl-4~6-dia~ino
pyrimidinium-2-yl) thiomethYl-3-cephem-4-carboxYlate ;
3-acetoxYmethYl-7-l (Z)-2-(5-amino-1 ,2,4-thiadiazol-3-yl)-2-(2
carboxyprop-2-oxYimino)acetamido)-3-cePhem 4-carboxylic acid(500ng) and
l-butyl-4,6-dia~ino-2(111)-pyrimidinethione (200~) ~ere reacted in the
same manner as described in Example 40 to give the above-indicated
co~pound(l60mg).
m.P~ : 163 C~v (decomp.)
. ~ : ;
~_ ~ (Dz0 t acetone-dO)
0.98 (t, 3H), 1.50 (m, 4H), 1.54 (s, 611), 3.60 (A~q, 211), 3.95 (t,
~- '
~vo 92/0872~ - 107 - P ~ /KR90/00018
2~72~3
2H), 4.46 (A~q, 2H), 5.18 (d, 111), 5.58(s, 1!1), 5.81 (d, 111).
IR(KBr. c~-'L : 1770 (~-lacta~), 1690, 1620, 1550.
~xa~ple 44 : Synthesis of 7-~(Z)-2-(5-auino-1,2,4-thiadiazol-3-y~)-2-
(2-carboxyprop-2-oxyimino)aceta~ido]-3-(1-allyl-4,6-dia~ino-
pyr iDi diniuo-2-yl)thiomethYl-3-cephe~-4-carboxylate
.. _ . _ .. .. . _
3-Acetoxyoethyl-l-[(Z)-2-(5-auino-1,2,4-thiadiazol-3-yl)-2-(2-carb-
oxyprop-2-oxyi~ino)aceta~ido]-3-cephem-4-carboxylic acid (500Dg) and
1-allyl-4,6-dia~ino-2(1H)-pyri~idinethione (200mg) ~ere reacted in the
sane manner as described in Exaople 40 to give the above-indicated
coopound (210~g).
.P. : 156-C ~ (deconp.)
NHR : ~ (D~0 ~ acetone-dO)
1.58 (s, BR), 3.B0 (ABq, 2H), 3.71 (d, 211), 4.45 ~A3q, 211), 5.18 (d,
lH), 5.60 (s, lH), 5.81 (d, 1~), 5.01~ 6.51 (~, 3
I~(R~r. ~ 17~0 (~-lactau), 1680, 1620, 1570.
exa~ple 45 : Synthesis of 7-l(Z)-2-(2-a~inothiazol-4-Yl)-2-(2-carboxyprop
-2-oxyiDino)acetamido~-3-(9,6-dia~ino-1,5-dinethylpyri~idiniun
-2-yl~thio~ethyl-3-cepheu-4-carboxYlate
~o 3-acetoxymethyl-7-[(Z)-2-(2-aminothiazol-4-Yl)-2-(2-carboxyprop-
1-oxyimino)aceta~ido]-3-cephem-4-carboxylic acid (500~g) ~ere added 4,6- .
dianino-1,5-dimethyl-2(1H)-pyriDidinethione (200~g) obtained in Preparation
1, potassiu~ iodide t800~g) and distilled ~ater (30mQ). With adjusting
~: of the p~l of the mixture to 7.0~ 7.5 with a saturated aqueous sodiu~
.
.
wo 92/08721 PCr/KR90~00018
- 108 -
~rlæ~3
bicarbonate solution, the reaction mixture ~as stirred for 4 hours
at 70^~15C. After the ~i~ture ~as cooled to roon teoperature, the
pll Or the nixture was adjusted to 4.5^~5.0 with 211-hydrochloric acid.
The precipitates were collected by filteration and chro~atographed over
silica gel. Elution with a 7: 1 (v/v) ~ixture of a~etonitrile/
distilled water gave the above-indicated compound (126Mg) in a pale
yellow solid.
.: 174 C~v (decomp.)
NHR: ~ (DzO t NallCO~
1.48 (s, 6H), 2.21 (s, 3H), 3.33 and 3.73 (ABq, 2H), 3.49 (s, 3H),
3.89 and 4.72 (ABq, 21~), 5.18 (d, 1~), 5.78 (d, lH), 6.92 (s, lH).
~S~E~3. ~1 + 1) : 638
r C~ 1770 ~-lactal), 1761, 1590, 1527.
Exaople 46: SYnthesis of 7-1(Z)-2-(2-a~inothiazol-4-Yl)-2-l2-csrbo~Yprop
-2-o~yimino)aceta~ido]-3-(4,6-diarino-5-eth~Yl-l-~ethylpyriLid-
iniu~-2-yl)thiooethyl-3-cephe~-4-carbo~ylate
The abosve-indicated co~Pound tl30mg) in a pa}e s~hite solid was
prepared in the same nethod as described in E~a~ple 45 e~cept for using
4,6-dia~ino-l-ethYl-5-methyl-2(111)-pYri~idinethione ~2DOag) obtained in
Preparation 10 in place of 4,6-dia~ino-1,5-di~eth,Yl-2(1H)-pYriridinethione
m P.: 178C^~(decomP~
NLIR: ~ (DMS0-d~
0.93 (t, 311), 1.42 (d, 6N), 2.~38 (q, 2H)9 3.I9 and 3.54 ~ABq. 2H),
3.49 (s, 3l1), 3.85 and 4.80 (ABq, 2n), 4.96 (d, 111), 5.68 (dd, lH),
6.75 (s, lH), 7~20 (s, 2H), 7.71 (bs, 4H), 11.42 (bs, lH).
:' - . ',.
: . , .
~ :: ': :
~vo 92/08721 109 pc~r/KR9o/oool8
2~2~3
~FAB~. H ~ 652
IR(K~r. c~L : 1769 ~-lactam), 1685, 1632, 158Q.
Exa~ple 47 : Synthesis of 7~ )-2-(2-aminothia2O1-4-yl)-2-(2-carboxyprop
-2-oxyioino)aceta~idol-3-(4,6-dia~ino-1-ethyl-6-methylpyrim-
idiniu~-2-Yl)thio~ethYI-3-cephe~-4-carboxylate
The above-indicated co~pound (150mg) in a yellow solid was prepared
in the same method as described in ExamPle 45 except for using 4,6-dia~ino-
1-ethyl-5-oethyl-2~1H)-pyri~idinethione (200mg) obtained in PreParation 8
in place of 4,6-diamino-1,5-dimethyl-2(1H)-pyrimidinethione~
n ~ Pl: 180C ~ (decomp.)
(DHSO-do )
1.22 (t, 3H), 1.42 (d, 6N), 1.90 ~s. 3H), 3.20 and 3.55 (ABq, 211),
3.~9 and 4.78 ~ABq. 2H), 4.10 (q, 2~), 4.98 (d, lH), 5.70 (dd, lll).
6.79 (s, IH), 7.22 (s, 211), 7.78 (bs, 4H), 11.24 (bs, 111).
HS~FAB. ~ 852
IRlK~r. c~~') : 1765 (~-lacta~), 1685, 1630, 1580.
:, ,'
exauple 48 : SYnthesis of 7-l(Z)-2-(2-Aminothiazol-4-Yl)-2-(2-carboxYProp
-2-oxYimino)acetamido~-3-(4,6-diamino-1,5-dieth~lpyri~idinium
-2-Yl)thiomethyl-3-cephem-4-carboxylate
- - --- --- . .
; The aùove-indicated coDpound 1140mg) in a Pale Yello~ solid ~as
;25 prePared in the same method as described in ExamPle 45 except for ~ -
using 4,6-dia~ino-1,5-diethYI-2(111)-PYrimidinethione (2~0 mg) obtained in
PreParation 11 in Place of 4,6-diamino-1,5-dimethYl-2(111)-pYrisidinethione
i
'
w o 92/08721 - 110 - P cr/KR9o/oool8
2372~3
168-C ~ (decomp.)
~B_: ~ tDHS0-do)
0.97 (t, 3H), 1.22 (t, 311), 1.43 (d, 6Zl), 2.40 (9, 211), 3.2U and 3.56
(ABq, 2H), 3.84 and 4.81 (ABq, 211), 4.08 (q, 211), 4.g8 (d, 111), 5.70
6 (dd, lli), 6.74 (s, lH), 7.20 (s, 2H), 7.71 (bs, aiH), 11.45 (bs, 111).
NS(FAB. ~ t Ll : 666
IR(K~r. ~ ) : 1766 (~ -lactam), 1640, 1600.
; ' '
Exa~ple 49 : Synthesis of 7-~(Z)-2-(2-aminothiazol-4-yl)-2-(2-car~loxy~ro~
-2-oxyimino)aceta~ido]-3-(5-methyl-1,4,G-triaminopyrimidi~ m-
-2-yl)thiomethyl-3-cephe~-4-carboxylate
The above-indicated componnd (170mg) in a Pale yellDw solid was
prepared in the same method as described in Example 45 except for usin~
5-methyl-1,4,6-triamino-2(1}i)-Pyrimidinethione (200mg) obtained in
Preparation 9 in place of 4,6-diamino-1,5-dinethyl-2(1il)-pyrimldinethione.
.P. : 178nC ~ ~deco~p.)
(DMS0-d~)
1.43 (d, 61i), 1.82 (s, 3H), 3.19 and 3.48 (ABq, 21i), 3.~2 and ~.52
(A3q, 2ii), 4.99 (d, lH), 5.68 (dd, lH), 6.11 (s, 211), 6.73 (s, lH),
7.22 (s, 2H), 7.70 (bs, 4H), 11.31 (bs, lH).
~S(FAB. H + 1) : 639
,
IR(KBr. c~ 1765 ( ~ -lactam), 1628. 1590.
:
: ~ ... . ':
~vo 9 /08721 - 111 - pc~r/KR9o/oool8
2972g~3
Example 50 : SYnthesis of 7-1(Z)-2-(2-aminothiazol-4-Yl)-2-(2-carboxyprop
-2-oxyimino)acetamido~-3-(1-cyclopropyl-4,6-diaminopyrimidinium
-2-yl)thiomethYI-3-cephem-4-carboxylate
. _ . - --- :
To a solution of 3-acetoxYmethyl-7-[(Z)-2-(2-a~inothiazol-4-yl)-2
(carboxyprop-2-oxyimino)acetamido]-3-cephem-4-carboxylic acid dihYdro-
chloride (500mg) suspended in distilled ~ater (lOm~) ~ere added 1- ~ -
cyclopropyl-4,6-diamino-2(111)-pyrimidinethione (200mg) and potassiu~
iodide ~1.2g). With adjustin~ of the p~l of the reaction ~ixture to
7.3~ 7.5 with a sodium bicarbonate solution, the reaction mix~ure
was stirred for 4 hours at 70C. After the mixture ~as cooled ~o
room temperature, insoluble materials were filtered off, and the
pH of the filtrate was adjusted to 4. A~ter being conccntratc~l
under reduced pressure, the residue was chromato~raphcd over silica
gel. Elution with a 4 : 1 (v/v) ~ixture of acetonitrile/distilled~
~ater gave the above-indicated compound (150mg) in a pa~e yello~ solid.
~ -
e : 194'C ~ (decomp.)
(DzO t NaNC03)
1.18~m, 2H), 1.44 (s, 6H), 1.50(m, 2H~, 3.00(m, lN), 3.41 (A~q,
2H), 4.32 (A~q, 2H), 5.11 (d, lN), 5.66(s, lN), 5.71 (d, IH),
6.92 (s, lH).
~S(FAB. u t 1) : 650
leL~r. c~~'L : 1766 (~-lactam), 1645, 1600.
: .
~ ' -
`: ~ :
WO 92/08721 - 112 - PCI/KR90/00018
'2~28~J3
Exa~ple 51: Synthesis of 7-~(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxYprop
-2-oxyinino)acetamidol-3-~1-(4-chlorophenyl)-4,6-diaminopyrimi-
dinium-2-yl)thiomethYl-3-cephe~-4-carùoxylate
. ~
3-Acetoxymethyl-7-1(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxYprop-2-oxy-
inino)~ceta~ido~-3-cephem-4-carboxylic acid (500ng) and 1-(4-chloroPhenYl)
-4,6-dia~ino-2(1H)-pyrimidinethione (200mg) were reacted in the same manner
as described in Exa~ple 50 to give the above-indicated co~pound (170mg).
o.P.: 182C~V (deco~p.)
NMR: ~ (DzO t NaHC0~)
1.43 (s, 6H), 3.42 (ABq, 211), 4.35 (ABq, 2H), 5.a8 (d, 111), 5.64 (s,
lH), 5.66 (d, lH), 6.84 (s, lH), 7.26~V7.62 (m, 4H).
HS(I~A~. H + 11: 720
IR(K~r. c~ : 1768 (,B-lactan), 1643, 1600.
Exaople 52: Synthesis of 7-1(~)-2-(2-aoinothiazol-4-Yl)-2-(2-carboxYmet-
hoxyi~ino)acetauidol-3-(4,6-dia~ino-1-phenylpYrinidinillm-2- '.
yl)thiomethyl-3-cephem-4-carboxylate
3-Acetnx~ethyl-7-1(Z)-2-(2-aminothiazol-4-Yl)-2-(2-carboxYmethoxYi~ino)
acetamido~-3-cephem-4-carboxylic acid (500mg) and 4,6-diamino-1-phenyl-2(1H)
-pyrimidinethione (200~g) were reacted in the same manner as describcd in
Example 50 to give the above-indicated compound (19Or~g).
: 187-C^~ (decomp.)
I~R: ~ (D20 + NaHCOa)
3.48 (ABq, 2H), 4.42 (ABq. 2H), 4.59 (s, 2H), 5.08 (d, lH), 5.69
(s, lH), 5.71 (d, IH), 6.96 (s, lH), 7.41^~7.82 (~, 511).
~:
: . ; .. '
.
~0 92/0872] _ 113 - pcr/KR9o/ooo18
2~72~3
MS(FA~. H t 1~: ~5B
IR(K~r~ c~~l): 17~6 (~-lscta~), 1655, 160û, 1538.
ExaDple 53: Synthesis of 7-~(2)-2-(2-aminothiazol-4-yl)-2-(1-carboxYetll
-l~oxyi~ino)aceta~ido~-3-(4,6-diaui.no-]-phenylpyri~idinium-2
-yl)thio~ethyl-3-cer)hem-4-carboxylate
3-Acetoxymethyl-7-1tZ)-2-(2-a~inothiazol-4-yl)-2-(2-carboxyeth-1-oxyi-
mino)aceta~idol-3-cephem-4-carboxylic acid (500ng) and 4,6-diamino-1-PhenYl
-2(1~)-pYrinidinethione (200mg) were reacted in the sa~e manner
as described in ExaDple 50 to give the above-indicated cocpound ~210mg).
,: 156'C~ (decomP~)
(DzO t NaHCQ9)
1.48 (d, 3H~, 3.48 (ABq, 2H), 4.49 (ABq, 2H), 5.16 (d, lH), 5.76 (s,
lH~, 5.79 (d, lH), 6.97 (s, 1~), 7.48~7.~3 (m, 611).
US~PAB. H ~ B72
IR(RBr. cm~'): 1765 (~-lacta~), 1655, 1598, 1515.
~xaDple S4: Synthesis of 7-l(Z)-2-(2-a~inothiazol-4-Yl)-2-~ethoxyimino)
aceta~ido]-3-t4,6-diamino-1-phenylpyriuidiniu~-2-yl)thio~ethyl
-3-cephec-4-carboxylate
3-lcetox~metlul-7-~(Z)-2-(aminothiazol-4-yl)-2-(~thoxyimino)acetamido
-3-cephem-4-car~oxYlic acid (500~g) and 4,6-diamino-1-phenyl-2(111)-pyri~-
idinethione ~200mg) were reacted in the same eanner as described in
E~a~ple 5D to give the above-indicated compound (13D~).
~: 182~C^~ (decomp.)
W O 92/08721 - 114 - pc~r/K R9O/00018
%~ 20~83
NMR : ~ (DzD + Na~C09)
1.28 (t, 3H), 3.52 (A~q, 2H), 4.20 (q, 2H), 4.31 lABq, 2il), 5.16
(d, lH), 5.76 (s, lH), 5.81 (d, lll), 6.88 (s, 111), 7.48~ 7.82 (~, 511).
HS(FAB. H + 1) : 628
IR(~Br. c~ ') : 1788 ( ~ -lactam), 1643, 1612, 1600, 1515.
Exacple 5S : Synthesis of 7-1(Z)-2-(2-aoinothiazol-4-Yl)-2-(ethoxYiDino)
acetamido]-3-11-(4-chloraphenyl)-4,6-diamino-1-phenylpyri~-
idinium-2-yl~thioDethyl-3-cephe~-4-carboxylate
:.
3-AcetoxYmethyl-7-l(Z)-2-(2-aminothiazol-4-Yl)-2-(ethoxyimino)aceta~ido) : .
-3-cephem-4-carboxylic acid (500mg) and 1-(4-chlorophenyl-4,6-dianino-
2(1H)-pyrioidinethione (200mg) ~ere reacted in the same ranner as
described in Example 50 to give the ahove-indicated compound (170~g).
~e~ : 177~C~v(decomp.)
~E~ (DzO + scetone-dO)
1.28 (t, 3H), 3.48 (ABq, 2H), 4.21 ~q, 2H), 4.32 (ABq, 2H), 5.12
(d, lll), 5.73 (s, lH), 5.80 (d, 111), 6.87 (s, 111), 7.52~ 7.79 (m, 411).
~ AB~ H + 1) : 662
IR(K~r. CR-I): 1635 (~ -1actam), 1643, lB10, 1530.
Exaople 56 : Synthesis of 7-[(Z)-2-(2-aDinothi~zo1-4-Yl)-2-(2-carboxyprop-
2-oxyieino)acetamido]-3-14,6-diamino-1-~2,4-dimethYlphenYI)- :.
pyrimidinium-2-yllthiomethYI-3-cephem-4-carboxylate
3-acetoxYmethY1-7-[(Z)-2-t2-aoinothiazDl-4-Yl)-2-(2-carboxyprop-2-ox-
yimino)aceta~ido]-3-cephem-4-carboxYlic acid (500~g) and 4,B-dia~ino-l- ~ -
.
.
`~0 92/08721 - 115 - pc~r/KR9o/ooo18
2 ~ 3
(2,4-di~ethylphenyl)-2(1H)-pyri~idinethione (200~g) were reacted in the
saoe ~anner as described in Example 50 to giYe the above-indicated
cospound (180~g).
~E~ : 189~C ~ (deco~p.)
~a ~ (D20 t NaHC03)
1.44 (s, 6H), 2.02 (s, 3H), 2.34 (s, 311), 3.36 (ABq, 211), 4.27 (Aaq,
2H), 5.06 ~d, lH), 5.68 (s, lH), 5.11 ~d, lH), 6.~8 (s, lH), 7.08
7.35 (~, 3~).
H~(~AB. ~ t 1) : 714
IR(KBr~ ) : 1768 (~-lactam), 1641, 1600, 1552.
Example 57 : Synthesis of 7-1(Z)-2-(2-a~inothiazol-4-yl)-2-(ethoxYi~ino)
acetamido]-3-~(4,6-diamino-1-(2,4-dimethylphenYl)-pyri~idiniu~
-2-yl]thioDethyl-3-cephem-4-carboxylate
3-AcetoxY~ethyl-7-~(Z)-2-(2-aminothiazol-4-Yl)-2-~ethoxyhino)acetamid
-3-cephem-4-carboxylic acid (500mg) and 4,6-dia~in~-1-(2,4-dimethYlphenYI)
-2(1H)-pyri~idinethione (2001g) were reacted in the sa~e ~anaer
as described in FxaDple 50 to give the above-indicated compound (130mg).
~he~ : 176C ~ (deco~p.)
NMR : ~ (DzO t acetone-d~)
1.29 (t, 3H), 2.12 (s, 3H), 2.40 (s, 3H), 3.51 (ABq, 2H), 4.21(q, 2H),
4.36 (ABq, 2H), 5.09 (d, lH), 5.76 (s, lH), 5.81 ~d, 111), 6.90 (s, 111),
7,23~ 7.41 (~, 3H).
MS(FA8~ ~ t 1) : B56
IR(K~r. c~-1) : 1770 ~-lactam), 1643, 1610, 1540.
:
' . ; ' ~ . : '
WO 92/08721 - 116 - pcr/KR9o/ooo18 --
2~2 Exa~ple 58: Synthesis of 7-ltZ)-2-~2-a~inothiazol-4-YI)~2-(2-carboxYProp
-2-oxyinino)aceta~ido]-3-[4,6-dia~ino-1-(2,6-di~ethoxyphenyl)
-pYrimidiniu~-2-yl~thio~ethYl-3-cephem-4-carboxylate
. . . _ . . .
3-Acetox~ethYl-7- [ (Z) -2- (2-a~inothiazol -4-Yl ) -2- (2-carboxvproT~-2-oxY-
imino)acetamido~-3-cephem-4-carboxYlic acid (SOOm~) and ~1,6-diamino-1-(2,
6-diDethoxyphenyl)-2(1H)-pyrimidinethione (2()Omg) were reacted in the
sa~e manner as described in Example 50 to give the above-indicate(l
co~pound (21 Omg ) .
~.P : 16~C~V (decomp.)
NMR .: ~ (DzO + NaHCO9)
1.4~ (s, 611), 3.40 (ABq, 211), 3.79 (s, 611), ~.29 (ABg, 211), 5,12 (d,
IH), 5.67 (s, llJ), 5.76 (d, 111), 6.95 (s, lll), 7.04^~7.28 (m, 311).
HS(PA~, M + li: 746
I~(KBr. cm~1): 1766 (I~-lactam), 1641, 1600, 1550.
- :
Exa~ple 59: SYnthesis of 7-l(Z)-2-(2-aminothiazol-4-Yl)-2-(2-carboxYProp
-2-oxyimino)acetamidol-3-[ (4,6-diamino-1-(4-hYdroxYphenYI)-
pyri~idiniu~-2-yl ] thiomethy]-3-cephem-4-carboxYlate ;
3-AcetoxymethYl-7- ~ (Z) -2- (2-aminothiazol-4-YI ) -2- (2-carboxYprop-2-oxy-
imino)aceta~idol-3-cephe~-4-carboxYlic acid (50Qmg) and 416-diamino-1-(4-
hydroxyphenyl)-2(111)-pyrimidinetllione (200~g) vere reacted in the same
~anner as described in ~xample 50 to ~ive the above-indicated comPonnd
(230mg).
~: 171C~ (decomp. )
Dz3 + NaHCO9)
~; , , .
WO 92/08721 - 117 - PCl/~SR90/û0018
2~72833
1.47 (s, 6H), 3.39 (ABq, 211), 4.27 (ABq, 2H), 5.06 (d, lH),
5.64 (s. lH), 5.74 (d, 111), 6.91 ts, lH), 6.90^~7.32 (m, 411).
HS (FA~ 702
I~Br. cTq~ll: 1768 (B-lactam~, 1641, 1600, 1525.
.
: ~ :
:.
