CA2072883A1 - Cephalosporin compounds and processes for preparation thereof - Google Patents
Cephalosporin compounds and processes for preparation thereofInfo
- Publication number
- CA2072883A1 CA2072883A1 CA002072883A CA2072883A CA2072883A1 CA 2072883 A1 CA2072883 A1 CA 2072883A1 CA 002072883 A CA002072883 A CA 002072883A CA 2072883 A CA2072883 A CA 2072883A CA 2072883 A1 CA2072883 A1 CA 2072883A1
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- CA
- Canada
- Prior art keywords
- carboxylate
- cephem
- acetamido
- compound according
- thiomethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The present invention relates to new cephalosporin compounds of formula (I), pharmaceutically acceptable non-toxic salts thereof, and physiologically hydrolyzable esters and solvates thereof, which have potent and broad antibacterial activities. In formula (I), R1 is a C1-4 alkyl, C3-4 alkenyl, C3-4 alkynyl group, or -C(Ra)(Rb)CO2H, wherein Ra and Rb are the same or different, and each is a hydrogen atom or a C1-4 alkyl group, or Ra and Rb form a C3-7 cycloalkyl group with the carbon atom to which they are linked; R2 is a C1-4 alkyl, C3-4 alkenyl or C3-4 cycloalkyl group, a substituted or unsubstituted amino group, or a substituted or unsubstituted phenyl group; R3 is hydrogen or a C1-4 alkyl group; and Q is N or CH. The invention further relates to a process for preparing said compounds, and to pharmaceutical compositions containing said compounds.
Description
~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
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 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 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 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 :, ~ .
-- 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
..
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/
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 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
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 .. .... .. .
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 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 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 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 ~\ 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 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 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
~ ' ,.'' 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~
':
'~ ~
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 ~ 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 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 . . . _ . _ . _ .
,0~ ' ' .
H N~ O ~,SI~NH
co2 C~3 ~ ~
.: '-:. ' :
I- 50 : 7-1(Z)-2-(2-a~inothiazol-4-Yl)-2-(2-propen-i-oxyi~ino)aceta~ido1-3-(4,6-dia~ino-l-ethylpyriaidiniu~-2-yl)-3-cephe~-4-carboxylate N~C-C~ S~NH
- co2~ CH2CH3 , '' ~' :
. .
- : : .
. :
co~Paratiye co~Pound : Ceftazidi~e :
.:
N,O~CO2H . :
H,N--~S~ ~S~,N3 ::
:
: -, WO 92/08721 PCr/KP90/00018 2~2~83 ~ D D D ~ D ~ ~ ~ D 3 ~ ~ ~ ~ ~ ~
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C~ ~ C~7 C~ $ CT~ Cl~ _ C7 ~ 1~ ~ Q ~_ . :~
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~ ~_ ~
C ~ C CJ ~7 - ~ a~ 5~ - ~ ~ ~ ~ ~ U7 ~ ~ ~ ~
- - ---- - -- - c ooo ll ooll oooo o o - ;~
o o o ~ O O O O O O C
7 c~ - ~o c~ ~ a7 ~ ~ ~75~ cn ~7 ~ - ~ ~ c~n ~ ~ ~n ~ -------~
oo oooo oo o ~ ~ ~7 cn ~ ~ ~ ~ ~ ~ ~7 c~ ~7 ~ 5 ~ ~ ~7 ~ ~ ~ ~ a~ o7 o o o o ll o o ll o o o l o ~ l-o o o o o o o o o o o o o o - o o -c~ a~ 5~ c~ ~ ~ ~ ~ 5~ 5.7 ~7575~ 57 a~ C77 - ~ ~ ~ n cn ~ _7 ~ -- ~ ~
oooo oooooooo o -o o o o c~700 o co o o ~ ~7 - 5 a7 ~ - ~7 ~ ~ C~
--~ -o o o ll o o o o o o o o ~ ~ ~
oooo OOOOOOOC
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
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 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 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 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 :, ~ .
-- 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
..
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/
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 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
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 .. .... .. .
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 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 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 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 ~\ 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 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 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
~ ' ,.'' 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~
':
'~ ~
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 ~ 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 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 . . . _ . _ . _ .
,0~ ' ' .
H N~ O ~,SI~NH
co2 C~3 ~ ~
.: '-:. ' :
I- 50 : 7-1(Z)-2-(2-a~inothiazol-4-Yl)-2-(2-propen-i-oxyi~ino)aceta~ido1-3-(4,6-dia~ino-l-ethylpyriaidiniu~-2-yl)-3-cephe~-4-carboxylate N~C-C~ S~NH
- co2~ CH2CH3 , '' ~' :
. .
- : : .
. :
co~Paratiye co~Pound : Ceftazidi~e :
.:
N,O~CO2H . :
H,N--~S~ ~S~,N3 ::
:
: -, WO 92/08721 PCr/KP90/00018 2~2~83 ~ D D D ~ D ~ ~ ~ D 3 ~ ~ ~ ~ ~ ~
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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 .
~ .
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.
-'0 92/08721 PC~r7KR90/00018 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.
' ~ .
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cJ~ o~ ~ cn ~ ~' . ,' ; - : ~ , 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 - 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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.
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. ., w o 92/08721 pc~r/K R90/00018 2~2~3 :
~xanple 7 : Synthesis o~ 3-~l-allYl-4~6-diaDinopyri~idiniu~-2-yl)thiooetllyl ..
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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 .
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-'0 92/08721 PC~r7KR90/00018 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~
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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.
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cJ~ o~ ~ cn ~ ~' . ,' ; - : ~ , 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 - 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 :
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 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 ~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 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 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 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).
.
WO 9~iO872I PCr/KR90/00018 2~72~3 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 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~) :
, .
W O 92/08721 pc~r/KR9o/oool8 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 .
, WO 92/08721 pcr/KR9o/ûool8 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 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.
-, ~ . .
: .
.. ..
W O 92/08721 PC~r/KR9O/00018 2~72~3 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.
~ - , , "'~
WO 92/08721 PCr/KR90/0û018 2~72~3 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 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 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 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 ~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.
: .
~ ' -`: ~ :
'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.
.
: ~ :
:.
- 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 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 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 :
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 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 ~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 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 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 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).
.
WO 9~iO872I PCr/KR90/00018 2~72~3 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 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~) :
, .
W O 92/08721 pc~r/KR9o/oool8 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 .
, WO 92/08721 pcr/KR9o/ûool8 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 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.
-, ~ . .
: .
.. ..
W O 92/08721 PC~r/KR9O/00018 2~72~3 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.
~ - , , "'~
WO 92/08721 PCr/KR90/0û018 2~72~3 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 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 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 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 ~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.
: .
~ ' -`: ~ :
'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.
.
: ~ :
:.
Claims (60)
1. A cephalosporin compound of the formula (I) wherein R1 is a C1-4 alkyl, C3-4 alkenyl, C3-4 alkynyl group, or -C(Ra)(Rb)CO2H, wherein Ra and Rb are the same or different, and each is a hydrogen atom or a C1-4 alkyl group, or Ra and Rb form a C3-7 cycloalkyl group with the carbon atom to which they are linked ;
R2 is a C1-4 alkyl, C3-4 alkenyl or C3-4 cycloalkyl group, a substituted or unsubstituted amino group, or a substituted or unsubstituted phenyl group ;
R3 is hydrogen or a C1-4 alkyl group ; and Q is N or CH;
or a pharmacuetically acceptable non-toxic salt thereof, or a physiologically hydrolyzable ester or solvate thereof.
R2 is a C1-4 alkyl, C3-4 alkenyl or C3-4 cycloalkyl group, a substituted or unsubstituted amino group, or a substituted or unsubstituted phenyl group ;
R3 is hydrogen or a C1-4 alkyl group ; and Q is N or CH;
or a pharmacuetically acceptable non-toxic salt thereof, or a physiologically hydrolyzable ester or solvate thereof.
2. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxylprop-2-oxyimino)acetamido]-3-(4,6-diamino-1-methylpyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate.
3. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxylprop-2-oxyimino)acetamino]-3-(4,6-diamino-1-ethylpyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate.
4. The compound according to Claim 1 which is 3-(1-allyl-4,6-diaminopyrimidinium-2-yl)thiomethyl-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oxyimino)acetamido]-3-cephem-4-carboxylate.
5. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxyeth-1-oxyimino)acetamido[-3-(4,6-diamino-1-methylpyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate.
6. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxyeth-1-oxyimino)acetamido]-3-(4,6-diamino-1-ethylpyrimidinium-2-yl)thiomethy]-3-cephem-4-carboxylate.
7. The compound according to Claim 1 which is 3-(1-allyl-4,6-diaminopyrimidinium-2-yl)thiomethy1-7-](Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxyeth-1-oxyimino)acetamido]-3-cephem-4-carboxylate.
8. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(carboxymethoxyimino)acetamido]-9-(4,6-diamino-1-methylpyrimidinium-2-yl)thiomethy]-3-cephem-4-carboxylate.
9. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(carboxymethoxyimino)acetamido]-3-(4,6-diamino-1-ethylpyrimidinium-2-yl)thionmethyl-3-cephem-4-carboxylate.
10. The compound according to Claim 1 which is 3-(1-allyl-4,6-diaminopyrimidinium-2-yl)thiomethyl-7-[(Z)-2-aminothiazol-4-yl)-2-(carboxymethoxyimino)acetamido]-3-cephem-4-carboxylate.
11. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-(4,6-diamino-1-methylpyrimidinium-2-yl) thiomethyl-3-cephem-4-carboxylate.
12. The mompound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(ethoxyimino)acetamido]-3-(4,6-diamino-1-methylpyrimidinium-2-yl) thiomethyl-3-cephem-4-carboxylate.
13. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(ethoxyimino)acetamido]-3-(4,6-diamino-1-ethylpyrimidinium-2-yl) thiomethyl-3-cephem-4-carboxylate.
14. The compound according to Claim 1 which is 7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(2-carboxyprop-2-oxyimino)acetamido]-3-(1,4,6-triaminopyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate.
15. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxyeth-1-oxyimino)acetamido]-3-(1,4,6-triaminopyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate.
16. The compound according to Claim 1 which is 7-[(2)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oxyimino)acetamido]-3-(1,4,6-triaminopyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate.
17. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(ethoxyimino)acetamidol-3-(1,4,6-triaminopyrimidinium-2-yl) thiomethyl-3-cephem-4-carboxylate.
18. The compound according to Claim 1 which is 7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(ethoxyimino)acetamido]-3-(1,4,6-triaminopyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate.
19. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-propyn-1-oxyimino)acetamido]-3-(1,4,6-triaminopyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate.
20. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-3-(1,4,6-triaminopyrimidinium-2-yl) thiomethyl-3-cephem-4-carboxylate.
21. The compound according to Claim 1 which is 7-[(2)-2-(5-amino-1,2,4-thiadiazol-3 yl)-2-(ethoxyimino)acetamido]-3-(4,6-diamino-1-methylpyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate.
22. The compound according to Claim 1 which is 7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(ethoxyimino)acetamido]-3-(4,6-diamino-1-ethylpyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate.
23. The compound according to Claim 1 which is 7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(ethoxyimino)acetamido]-3-(4,6-diamino-1-propylpyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate.
24. The compound according to Claim 1 which is 3-(1-allyl-4,6-diaminopyrimidinium-2-yl)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(ethoxyimino)acetamido]-3-cephem-4-carboxylate.
25. The compound according to Claim 1 which is 7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetamido]-3-(4,6-diamino-1-methylpyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate.
26. The compound according to Claim 1 which is 7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetamido]-3-(4,6-diamino-1-ethylpyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate.
27. The compound according to Claim 1 which is 7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(2-carboxyprop-2-oxymino)acetamido]-3-(4,6-diamino-1-methylpyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate.
28. The compound according to Claim 1 which is 7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(2-carboxyprop-2-oxyimino)acetamido]-3-(4,6-diamino-1-ethylpyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate.
29. The compound according to Claim 1 which is 7-[(Z)-2-(5-anino-1.2,4-thiadiazol-3-yl)-2-(2-carboxyprop-2-oxyimino)acetamido]-3-(4,6-diamino-1-propylpyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate.
30. The compound according to Claim 1 which is 7-[(Z)-2-(5-amino-1.2,4-thiadiazol-3-yl)-2-(2-carboxyprop-2-oxyimino)acetamido]-3-(1-butyl-4,6-diaminopyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate.
31. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oxyimino)acetamido]-3-(4,6-diamino-1,5-dimethylpyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate.
32. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oxyimino)acetamido]-3-(4,6 diamino-5-ethy-1-methylpyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate.
33. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oxyimino)acetamido]-3-(4,6-diamino-1-ethyl-5-methylpyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate.
34. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oxyimino)acetamido]-3-(4,6-diamino-1,5-diethylpyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate.
35. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oxyimino)acetamino]-3-(5-methyl-1,4,6-triaminopyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate.
36. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oxyimino)acetamido]-3-(4,6-diamino-1-phenylpyrimidinium-2-yl)thiomethyl-3-cephem 4-carboxylate.
37. The compound according to Claim 1 which is 7-[(Z) 2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oxyimino)acetamido]-3-[1-(4-hydroxyphenyl)-4,6 diaminopyrimidinium-2-yl]-thiomethyl-3-cephem-4-carboxylate.
38. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(carboxymethoxyimino)acetamido]-3-(4,6-diamino-1-phenylpyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate.
39. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxyeth-1-oxyimino)acetamido]-3-(4,6-diamino-1-phenylpyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate.
40. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(ethoxyimino)acetamido]-3-(4,6-diamino-1-phenylpyrimidinium-2-yl) thiomethyl-3-cephem-4-carboxylate.
41. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(ethoxyimino)acetamido]-3-[1-(4-chlorophenyl)-4,6-diaminopyrimidinium-2-yl]thiomethyl-3-cephem-4-carboxylate.
42. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oxyimino)acetamido]-3-[4,6-diamino-1-(2,4-dimethylphenyl)-pyrimidinium-2-yl]thiomethyl-3-cephem-4-carboxylate.
43. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(ethoxyimino)acetamido]-3-(4,6-diamino-1-(2,4-dimethylphenyl)-pyrimidinium-2-yl]thiomethyl-3-cephem-4-carboxylate.
44. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oxyimino)acetamido]-3-[4,6-diamino-1-(2,6-dimethoxyphenyl)-pyrimidinium-2-yl]thiomethyl-3-cephem-4-carboxylate.
45. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oxyimino)acetamidol-3-[4,6-diamino-1-(4-chlorophenyl)-pyrimidinium-2-yl]thiomethyl-3-cephem-4-carboxylate.
46. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxyeth-1-oxyimino)acetamido]-3-[4,6-diamino-1-propylpyrimidinium-2-yl]thiomethyl-3-cephem-4-carboxylate.
47. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-propyn-1-oxyimino)acetamido]-3-(4,6-diamino-1-methylpyrimidinium-2-yl)thiomethy1-3-cephem-4-carboxylate.
48. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-propyn-1-oxyimino)acetamido]-3-(4,6-diamino-1-ethylpyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate.
49. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oxyimino)acetamido]-3-(1-cyclopropyl-4,6-diaminopyrimidinium-2-yl)-3-cephem-4-carboxylate.
50. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-propen-1-oxyimino)acetamido]-3-(4,6-diamino-1-methylpyrimidinium-2-yl)-3-cephem-4-carboxylate.
51. The compound according to Claim 1 which is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-propen-1-oxyimino)acetamido]-3-(4,6-diamino-1-ethylpyrimidinium-2-yl)-3-cephem-4-carboxylate.
52. A process for preparing the cephalosporin compounds of formula(I), pharmaceutically acceptable non-toxic salts thereof, or physiologically hydrolyzable esters or solvates thereof, which comprises reacting the compounds of the formula(II) with the compounds of the formula(III) in the presence of a solvent (I) (II) (III) wherein R1, R2, R3 and n are the same as defined in Claim 1 ;
n is an integer of 0 or 1 ;
R4 is a hydrogen atom or an amino protecting group ;
R5 is a C1-4 alkyl, C3-4 alkenyl. or C3-4 alkynyl group, or -C(Ra)(Rb)CO2(Rc), wherein Ra and Rb are the same or different, and each is a hydrogen atom or a C1-4 alkyl group, or Ra and Rb form a C3-7 cycloalkyl group with the carbon atom to which they are linked ; and Rc is a hydrogen atom or a carboxyl protecting group ;
Ra is a hydrogen or a carboxyl protecting group ; and L is a leaving group.
n is an integer of 0 or 1 ;
R4 is a hydrogen atom or an amino protecting group ;
R5 is a C1-4 alkyl, C3-4 alkenyl. or C3-4 alkynyl group, or -C(Ra)(Rb)CO2(Rc), wherein Ra and Rb are the same or different, and each is a hydrogen atom or a C1-4 alkyl group, or Ra and Rb form a C3-7 cycloalkyl group with the carbon atom to which they are linked ; and Rc is a hydrogen atom or a carboxyl protecting group ;
Ra is a hydrogen or a carboxyl protecting group ; and L is a leaving group.
53. The process according to Claim 52 wherein the solvent is water, or a mixed solvent of water and a water-mixable solvent.
54. The process according to Claim 53 wherein the water-mixable solvent is acetonitrile or acetone.
55. The process according to Claim 52 wherein the solvent has a pH
of from 5 to 8.
of from 5 to 8.
56. The process according to Claim 52 wherein the compounds(II) are used in an amount of from 1 to 2 equivalent(s) based on 1 equivalent of the compounds(III).
57. The process according to Claim 52 which is carried out in the presence of one or more stabilizing agents.
58. The process according to Claim 57 wherein the stabilizing agent is slected from the group consisting of sodium iodide, potassium iodide, sodium bromide, potassium bromide and potassium thiocyanate.
59. The process according to Claim 52 which further comprises removing the amino protecting group and/or the carboxyl protecting group and/
or reducing the S-oxide, before or after reacting the compounds(II) and the compounds(III).
or reducing the S-oxide, before or after reacting the compounds(II) and the compounds(III).
60. A pharmaceutical composition which comprises a therapeutically effective amount of one or more the cephalosporin compounds of formula(I) recited in Claim 1, pharmaceutically acceptable non-toxic slats thereof, or physiologically hydrolyzable esters or solvates thereof as active ingredients, in assoication with pharmaceutically acceptable carriers, excipients or other additives therefor.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU66315/90A AU656886B2 (en) | 1990-11-09 | 1990-11-09 | Novel cephalosporin compounds and processes for preparation thereof |
| PCT/KR1990/000018 WO1992008721A1 (en) | 1990-11-09 | 1990-11-09 | Novel cephalosporin compounds and processes for preparation thereof |
| CA002072883A CA2072883A1 (en) | 1990-11-09 | 1990-11-09 | Cephalosporin compounds and processes for preparation thereof |
| NO92922608A NO922608L (en) | 1990-11-09 | 1992-07-01 | NEW CEPHALOSPOR RELATIONS AND PROCEDURES FOR THEIR PREPARATION |
| FI923156A FI923156A (en) | 1990-11-09 | 1992-07-08 | NYA KEFALOSPORINFOERENINGAR OCH FOERFARANDEN FOER FRAMSTAELLNING AV DEM. |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/KR1990/000018 WO1992008721A1 (en) | 1990-11-09 | 1990-11-09 | Novel cephalosporin compounds and processes for preparation thereof |
| CA002072883A CA2072883A1 (en) | 1990-11-09 | 1990-11-09 | Cephalosporin compounds and processes for preparation thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2072883A1 true CA2072883A1 (en) | 1992-05-10 |
Family
ID=25675289
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002072883A Abandoned CA2072883A1 (en) | 1990-11-09 | 1990-11-09 | Cephalosporin compounds and processes for preparation thereof |
Country Status (5)
| Country | Link |
|---|---|
| AU (1) | AU656886B2 (en) |
| CA (1) | CA2072883A1 (en) |
| FI (1) | FI923156A (en) |
| NO (1) | NO922608L (en) |
| WO (1) | WO1992008721A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR930007264B1 (en) * | 1990-08-17 | 1993-08-04 | 주식회사 럭키 | Cephalosporin compounds and its process |
| KR970010069B1 (en) * | 1992-08-24 | 1997-06-20 | 주식회사 럭키 | Cephalosporn derivatives |
| KR970005896B1 (en) * | 1993-07-23 | 1997-04-21 | 주식회사 엘지화학 | Cephalsoporins derivatives |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR231986A1 (en) * | 1978-05-26 | 1985-04-30 | Glaxo Group Ltd | PROCEDURE FOR PREPARING CEPHALOSPORIN ANTIBIOTICS |
| DE3006888A1 (en) * | 1980-02-23 | 1981-09-10 | Hoechst Ag, 6000 Frankfurt | CEPHALOSPORINE DERIVATIVES AND METHOD FOR THEIR PRODUCTION |
| CA2005787A1 (en) * | 1988-12-29 | 1990-06-29 | Masao Wada | Cephalosporin compounds |
| KR930007264B1 (en) * | 1990-08-17 | 1993-08-04 | 주식회사 럭키 | Cephalosporin compounds and its process |
-
1990
- 1990-11-09 CA CA002072883A patent/CA2072883A1/en not_active Abandoned
- 1990-11-09 AU AU66315/90A patent/AU656886B2/en not_active Ceased
- 1990-11-09 WO PCT/KR1990/000018 patent/WO1992008721A1/en active Application Filing
-
1992
- 1992-07-01 NO NO92922608A patent/NO922608L/en unknown
- 1992-07-08 FI FI923156A patent/FI923156A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO1992008721A1 (en) | 1992-05-29 |
| NO922608L (en) | 1992-09-01 |
| FI923156A0 (en) | 1992-07-08 |
| FI923156A (en) | 1992-07-08 |
| NO922608D0 (en) | 1992-07-01 |
| AU6631590A (en) | 1992-06-11 |
| AU656886B2 (en) | 1995-02-23 |
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| Date | Code | Title | Description |
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| EEER | Examination request | ||
| FZDE | Discontinued |