3-HETEROCYCLIC THIOMETHYLCEPHALOSPORINS

THIOMETHYLCEPHALOSPORINES AVEC SUBSTITUTION EN 3 PAR UN COMPOSE HETEROCYCLIQUE

English Abstract

ABSTRACT OF THE DISCLOSURE
Cephalosporin compounds substituted at the
7-position with .alpha.-aminophenylacetamido and at the 3-position
with a triazolyl group are prepared by displacement of a
3-acetoxymethyl compound with the apprepriate mercapto-
heterocycle or 7-acylation of an appropriately-substituted
cephalosporin nucleus. The products are antibacterial agents.

Claims

The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:
1. A process for preparing a compound of the
formula
<IMG>
where R is 1, 2, 3-triazolyl, unsubstituted or
substituted with 1 or 2 groups selected from
the group consisting of lower alkyl of 1-4
carbon atoms,
comprising (1) reacting an acetoxymethyl cephalosporin
compound of the formula
<IMG>
where R1 is <IMG>, the NH2 group
being suitably protected as needed, or H,
with a heterocyclic thiol compound of the formula
HS-R, where R is as defined above;
(2) when R1 is H, acylating the resulting compound
with a p-hydroxyphenylacetic acid compound of
the formula
<IMG>
- 14 -

or an acylating or activated derivative thereof,
the NH2 group being suitably protected as
needed; and
(3) then removing any protective group.
2. A process as claimed in claim 1 for preparing
7-(.alpha.-amino-p-hydroxyphenylacetamido)-3-(1,2,3-triazol-4-
ylthiomethyl)-3-cephem-4-carboxylic acid comprising reacting
the N-t-butoxycarbonyl derivative of 7-(.alpha.-amino-p-hydroxy-
phenylacetamido)cephalosporanic acid with 4-mercapto-1,2,3-
triazole and then removing the protective group with tri-
fluoroacetic acid.
3. A process as claimed in claim 1 for preparing
a 7-(.alpha.-amino-p-hydroxyphenylacetamido)-3-(4-lower alkyl-1,2,3-
triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid comprising
reacting the N-t-butoxycarbonyl derivative of 7-(.alpha.-amino-p-
hydroxyphenylacetamido)cephalosporanic acid with a 4-lower
alkyl-5-mercapto-1,2,3-triazole and then removing the protective
group with trifluoroacetic acid, wherein said lower alkyl is
an alkyl of from 1 to 4 carbon atoms.
4. A process as claimed in claim 1, for preparing
7-(.alpha.-amino-p-hydroxyphenylacetamido)-3-(4-methyl-1,2,3-triazol-
5-ylthiomethyl)-3-cephem-4-carboxylic acid comprising reacting
the N-t-butoxycarbonyl derivative of 7-(.alpha.-amino-p-hydroxy-
phenylacetamido)cephalosporanic acid with 4-methyl-5-mercapto-
1,2,3-triazole and then removing the protective group with tri-
fluoroacetic acid.
5. A compound of the formula
<IMG>

where R is 1,2,3-triazolyl, unsubstituted or substituted
with 1 or 2 groups selected from the group
consisting of lower alkyl of 1-4 carbon atoms
when prepared by the process of claim 1 or its obvious chemical
equivalent.
6. 7-(.alpha.-Amino-p-hydroxyphenylacetamido)-3-(1,2,3-
triazol-4-ylthiomethyl)-3-cephem-4-carboxylic acid, when
prepared by the process of claim 2 or its obvious chemical
equivalent.
7. 7-(.alpha.-Amino-p-hydroxyphenylacetamido)-3-(4-
methyl-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic
acid, when prepared by the process of claim 4 or its obvious
chemical equivalent.
8. The process according to claim 1 for preparing
7-(.alpha.-amino p-hydroxyphenylacetamido)-3-(1-methyl-1,2,3-triazol-
5-ylthiomethyl)-3-cephem-4-carboxylic acid comprising reacting
the N-t-butoxycarbonyl derivative of 7-(.alpha.-amino-p-hydroxy-
phenylacetamido)cephalosporanic acid with 5-mercapto-1-methyl-
1,2,3-triazole and then removing the protective group with
trifluoroacetic acid.
9. 7-(.alpha.-Amino-p-hydroxyphenylacetamido)-3-(1-
methyl-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic
acid, when prepared by the process of claim 8 or its obvious
chemical equivalent.
10. The process according to claim 1 for preparing
7-(.alpha.-amino-p-hydroxyphenylacetamido)-3-(1,2,3-triazol-4-ylthio-
methyl)-3-cephem-4-carboxylic acid comprising acylating a
compound of the formula
16

<IMG>
wherein R is 1,2,3-triazol-4-yl, with a p-hydroxy-acetic acid
compound of the formula
<IMG>
or an acylating or activated derivative thereof,
the NH2 group being suitably protected as needed;
and then removing any protective group.
11. 7-(.alpha.-Amino-p-hydroxyphenylacetamido)-3-
(1,2,3-triazol-4-ylthiomethyl)-3-cephem-4-carboxylic acid,
when prepared by the process of claim 10 of its obvious
chemical equivalent.
12. The process according to claim 1 for preparing
7-(.alpha.-amino-p-hydroxyphenylacetamido)-3-(1H-1,2,3-triazol-5-
ylthiomethyl)-3-cephem-4-carboxylic acid which comprises reacting
7-(.alpha.-amino-p-hydroxyphenylacetamido)-3-acetoxymethyl-3-cephem-
4-carboxylic acid or a protected derivative thereof with 5-
mercapto-1H-1,2,3-triazole.
13. 7-(.alpha.-Amino-p-hydroxyphenylacetamido)-3-(1H-1,2,3-
triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid whenever
prepared by the process of claim 12.
14. The process according to claim 1 for preparing
7-(.alpha.-amino-p-hydroxyphenylacetamido)-3-(1H-1,2,3-triazol-5-
17

ylthiomethyl)-3-cephem-4-carboxylic acid which comprises re-
acting 7-amino-3-(1H-1,2,3-triazol-5-ylthiomethyl)-3-cephem-
4-carboxylic acid or a protected derivative thereof with an
acylating derivative of .alpha.-amino-p-hydroxyphenylacetic acid.
15. 7-(.alpha.-Amino-p-hydroxyphenylacetamido)-3-(1H-1,
2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid whenever
prepared by the process of claim 14.
18

Description

~ . ~ ~
This invention relates to ant'ibacterial
cephalosporin compounds. In particular the invention
relates to 7-p-hydroxyphenylacetamido-3-heterocyclic
thiomethylcephalosporins of the following formula
Ho~ cHcoNH~
\~CH2 S~R
COOH '-
wherein
R is l,233-triazolyl, unsubstituted or
with 1 Or 2 groups 6elected f
p ds of iornula I. In parti
invention relates to a process for preparing said compounds
ng an acetoxymethyl cephalosporin compound o~ the
R ~H ~ S ~ -
~L ~2ococH3 ~ " '
COOH
~5 in WhiCh Rl is H0 ~ CHCo
/ , the NH2 group being suitably
H2
protected as needed~ or H~ ~ith a heterocy~lic th~ol compound
HS-R
~ 2 _
~ 1-:
B
.

~L~76~ii6~
where R is as defined above; when R is H, acylating the
resulting compound with a p-hydroxyphenylacetic acid
compound of the formula
H ~ CHCOOH
NH2
IV
or an acylating or activated derivative thereof, the NH2
group being suitably protected as needed; and then removing
any protective group.
Among the preferred compounds of the invention
are:
7-(p-hydroxy-~-aminophenylacetamido)-3-(1,2,3-triazol-4-
ylthiomethyl)-3-cephem-4-carboxylic acid,
7-(p-hydroxy-~-aminophenylacetamido)-3-(4-methyl-1,2,3-
triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid.
The antibacterial compounds of this invention
unexpec-tedly have advantageous properties compared with
related compounds. For example, the compound 7-(a-amino-p-
hydroxyphenylacetamido)-3-(1,2,3-triazol--4-ylthiomethyl)-3-
cephem-4~carboxylic acid (compound 60771) is advantageous
over the compound 7-(~-aminophenylacetamido)-3-(1,2,3-
triazol-4-ylthiomethyl)-3-cephem-4-carboxylic acid
(compound 60222) in producing higher peak serum concentra-
tions in mice and particularly higher serum half-lives.
As a result, the activity observed upon on both oral and
subcutaneous administration to mice is significantly
improved as demonstrated by lower ED50's. Data obtained
are presented inZTables A ànd B.

.
~ 76~
TABLE A
Route of Peak Concen- Half-life
Compound Dose Administration tration (~g/ml.) (min.)
60771 20 mg/kg p.o. 52 62
60222 20 mg/kg p.o. 13 48
60771 20 mg/kg s.c. 54 71
60222 20 mg/kg s.c. 35 34
~ TABLE B
~ .
Mouse Protection Studies
Compound Test organism Route of Administration ED (mg/kg-)
~ 50
60771 E. coli 12140 s.c. ~0.8, 0.8
60222 ~. coli 12140 s.c. ~3, 3.6
60771 E. coli 12140 p.o. ~0.8, 1.2
60222 E. coli 12140 p.o. ~12.5, 4
60771 K. pneumoniae s.c. 0.6, 0.6 -
4200
60222 K. pneumoniae s.c. 4.8
4200
60771 K. pneumoniae p.o. 0.4, 0.5
4200
60222 K. pneumoniae p.o. 12.5
4200
Compound 60771 also is advantageous over
7~ amino-p-hydroxyphenylacetamido)-3-(5-methyl-1,2,4-
triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid (compound
61529) in having significantly lower ED50's in the mouse
protection test. Data obtained are presented in Table C.
-4-
:

61;~
TABLE C
Mouse Protection Studies
Com~ound Test organism Route of Adminis-tration ED50 (_~/kg.)
60771 E. coli 12140 s.c. ~0.8, 0.8
61529 E. coli 12140 s.c. 10.7
60771 E. coli 12140 p.o. (0.8, 1.2
61529 E. coli 12140 p.o. 7.5
60771 K. pneumoniae s.c. 0.6, 0.6
4200
61529 K. pneumoniae s.c. 8.6
4200
60771 K. pneumoniae p.o. 0.4, 0.5
4200
61529 K. pneumoniae p.o. 16.
4200
In addition9 the compound 7-(~-amino-p-hydroxy-
phenylacetamido)-3-(4-methyl-1,2,3 triazol-5-ylthiomethyl)-
3-cephem-4-carboxylic acid (61775) is advantageous over
7-(d-aminophenylacetamido)-3-(4-methyl-1,2,3-triazol-5-
ylthiomethyl)-3-cephem-4-carboxylic acid (61348) in having
lower ED50's in mouse protection studies. The data are
presented in Table D below.
TABLE D_
Mo_se Protection Studies
Compound Test organism Route of Administration ED50(mg/
61775 E. coli 12140 s.c. 1.8
61348 E. coli 12140 s.c. 42, 18.2
61775 E. coli 12140 p.o. 3.6, 3
61348 E. coli 12140 p.o. 50, 19
61775 K. pneumoniae s.c. 2.8
4200
61348 K. pneumoniae s.c. 20
4200
61775 K. pneumoniae p.o. 5.2
4200
61348 K. pneumoniae p.o. 146
4200

6~6~
Also, the compound 7-( a-amino-p~hydroxyphenyl_
acetamido)-3-(1-methyl-1~2~3~triazol-5-ylthiomethyl~-3-
cephem-4-carboxylic acid (60876) is advantageous over
8~(a -aminophenylacetamido)-3-(1-methyl-1~2,3-triazol~5-
ylthiomethyl)-3-cephem~4-carboxylic acid (60637) in having
lower ED50's and higher peak serum levels and half-lives,
as shown in Tables E and F, respectively.
TABLE E
Mouse Protection Studies
~ Test or~_nism Route of Administration ED5~ (mg/k~.)
60876 E. coli 12140 s.c. 5.2
60637 E. coli 12140 s~c~ 21.5
60876 E. coli 12140 p.o. 6.2
60637 E. coli 12140 p.o. 50
60876 K. pneumonlae s.c. 3.5
4200
60637 K. pneumoniae s.c. 40
4200
60876 K. pneumoniae p.o~ 6
60637 K. pneumoniae p.o. 200
TABLE F
Serum Concentrations in Mice
~ .
Route Peak Concen- Half-life
Comeound Dose Administration tration (ugLml.) (min.
60876 20 mg/kg. p.o. 14 48
60637 20 mg/kg. p.o. 1~8 *
60876 20 mg/kg. s.c. 44 48
60637 20 mg/~g. s.c. 21 12
* Too small to be meoningful.
Generally it can be said that the compounds of
this invention are superior in terms of lower protective
doses and/or high and prolonged serum levels.

~ 560
1 Th~ compounds of the invention may be prepared by
acylating the 7~amino group of the approprlate 7~amino 3-
heterQcyclic ~hiomethyl cephalosporin nucleus with a
p-hydroxyphenylglyclne. Prior ~c acylation9 it is de~irable
to protec~ ~he amino group on the glycine moiety with an
easily removable protective group such as t-butoxycarbonyl,
benzyl~xycarbonyl, tr~ chloroethoxycarbonyl 9 or simi:Lar
protective group co~only used in the synthexis of peptides.
For acyla~ion3 the carboxyl group of the ~cyla~ g agent can
io be ac~lva~ed by conver~ion to the acid chloride or to a mixed
anhydride with, ~or example~ a lower alk~l chloroformate.
The car~o~cyl group can al60 be aetivated by convar~ion to
~he 2,4; dini~rophenyl or N-hydroxysuccinimidoyl esters. I:E
an e~ter of the cephalo~porin n~cleu~, for example, the
15 benzhydryl~ t-butyl, trichloroethyl, or a benzyl est0r i8
used, ~che prot¢cted phenylglyclne can be coupled directly
to the 7-amino group by using a carbodiimide such a6
dicyclohe2ylcarbodiim$de. Alterna~ively9 the protected
phenylglycine can be activated :E0F cor~ensat~on with the
20 appropriaes cephalosporin ll~cleus b~ reacting it firs~ h
c~rbonyl diimidazole or its equival~nt.
The compound~ of the present invention are alYo
prepared by reaction of a compound differing from one of
formula I in ~hat the 3~ub~ cuen~ i~ acetoxymethyl ra~her
25 than R-'chiomethyl, with a mercaptoheterocycleO The reac~ion
i~ preferably conduct~d at a pH near neutrality~ The
solv~nt is preferably w~ter or ~ater-acetone. The reactio~
m~y be carried out at tempera~ures from about room tempera~ure
to 1:he boiling point of the solvent, ~he time o reaction
30 varying with ~he particul~r temperature, solven~ and r~ac~ants.

76560
1 Th~ reaction produc~ is isolated by careful acidification of
the reaction mixture and extrac~ion wi~h an appropriate
organic solvent. The aQamino gr~up on the phenylglycine
starting material should be protected with a readily
remov~ble group such as t~butoxycarbonyl9 carbobenzyLo~y or
trichloroethoxycarbonyl. The displacemen~ ~t the 3-positl.on
is then conducted, followed by removal of th~ prote~tive
group in the co~ventional manner.
The s~arting materials or use in the 3~displace-
ment of a 7-acylated cephalosporanic acid, are described in
the litera~ure or obtainable by known me~hods. The starting
materials for use în ~he 7-acyla~lon of a 3~he~erocyclic
thiomethyl nucleus are prepared by d:Lsplac~ng the 3-acetoxy
group of an alkali metal salt of 7-aminocephalosporanic acid
(7~-ACA~ with an alkali metal s~lt of lthe heterocyclic thiol
in9 for examp~, hot aqueou3 aceton~. . .
It is recognized that due to the asymmetrlc a-carbon
~n the 7-acetamîdo group optical isomers wlll e~ist, The
D is~mer is the preferred i~omer~ however, the L isomer and
2~ the racsm~c mixture are also within th~ ~cope of th~s
invention.
The compounds are formulated into injectable or
oral formulations in the same ma~ner as other cephalosporln
antlbiotics. They are administered by injec~ion or orally to
prevent and trea~ bacterial ln~ections in doses whlch will
vary with the n~ture and severity of the inventlon and the
age, welght, ~nd conditlon of the sub~ectc The co~pounds
where Y ls NH2 are generally administered either orally or
parenterally.
Due to the presence of both ~n amlne group and a
~ 8 ~

~7 ~ 56 ~
1 ca~boxylic acid group in certai~ of the cephalosporLn
compounds of this in~entiony it is possible~ by sta~dard
methods 9 to prepare ~oth acid and base salts of pharma~
ceutically acceptable nontoxic acids and bases as well as ~he
S zwitterionic forms of the compoundsO Salts9 when obtained9
are readily con~erted to the ~witterion~ by known methodsO
Salt~ of compounds that contain ~ly an acidic function are
also prepared using pharmaceutically acceptabLe nonto~ic
bases. It is to be understood that all ~hese sal~s ar~
included within the ~cop~ of this inven~ion.
The following examples are inte~ded to illu~trat~
the procasses and c~mpound~ of th~ in~ention9 but are not ~o
be construed as limiting the scope thereof.
~E
5 7-~a;~mino-p-hydroxyphenylacetamido)-3~(192~3-~riaæol~
c acid
To a stirred solution N-t~butoxyedrbonyl~p~
hydroxyphenylglycine (10.75 ~J 0.0375 mol) ln dry ~etrahydro-
uran (150 m~) was added triethylamine (5~2 mlg 0~0~75 mol~.
The mi~ture was cooled to -10 and then ~sobutyL chl~ro-
2~
formate ~4O92 ml, 000375 mol) was added dropwise over a lO
minute period. The reaction mixture was stirred at -10 for
70 minu~e~ and ~hen a cold solution of 7~ACA (10.1 g~
0.0375 mol) ln 5~O aqueous tetrahydrofi~ran (140 ml~ and
triethylamine (6.75 g, 0.0487 mol) wa~ added over a 15
minute period. The reaction wa~ stirred at ~5 ~:o 0~ for
one ho~r and at room ~emperature for 2 hours. The organic
solvents were evapora~ed and water (150 ml~ wa~ added to
the aqueous residueO The solution was extrac~ed wlth ~thyl
acetate and the aqueous phase was ~epara~cedg covered wi~h
_ g

1~76~
l fresh ethyl acetate9 acldiLied to pH 2.8, and fil~ered
The pha~es were separated and the acidic solu~ion reextracted
with ethyl acetate. The exLracts of the acidified aqueous
solutlon were combined, dried9 and evaporated to giv~ the
S N-butoxycarbonyl derivative of 7-(a-am~no~p~hydroxyphenyl~
acetamido)cephalosporanic acid.
A mixture of the above product (3.0 g9 0.00493 ~,ol)
in pH 6.4 phosphate buffer (30 ml~ was treated with NaHC03
(l.085 g9 0.0l233 mol~ and then 4-mercaptu-l92~3-triazole
(0.748 g, 0.0074 mol). The ~olution was warmed to 70 and
stirred at 70 + 3 for 2.75 hours. The solution was covled,
filtered, and acidlfied ~o pH 2.5, producing a residue. The
solvents were decanted and the residu~ washed with water.
The product was dissolved in ethyl acetate, washed with
water, dried, and evaporated to the N-protected product
which was reprecipltated from acetone-chloro~orm.
The proteoted product was s~irred at 0 ~o 5 wlth
a 9:1 trifluoroacet~c acid:anis~le solu~lon for 70 minutes
The solvents were evaporated and the residue was poured with
rapid s~irrin~ into ether (350 ml~. Tl-e solid was collected,
dissolved ln water9 and stirred with basîc lon-exchange
resin (Amberlite IR-45, a polystyrene amine anionlc resin)
until the pH rema~ned constant. The resin was ilt~red o~f
and the aqueous solution lyophilized to give th~ product~
Hl~N605S2n2 H20: C, 43.379 1-1~ 4~45; N 16 86~
Found. C, 43.67, ~19 4.14, N) 16062.
EX~MF~LE 2
7-(D-~-Amino-p-hydroxyphenylacetam~(1O)-3 (4~methYl~ 9 3-
triazo1-~y~thiomethy~ 3-c~phem-4-carbox~lic acld
5-~enzamido-4~methyl-l,2,3-thiadiaæole ~6~60 gmO,
0O03 mole, prepared as descrlbed In Berichte 99, 1629 (1966)]
* Trad~mark - lO
o.i~
, ....... .
- , . ' ,~ ~ .
, . , ' '

76~i6~
was oombined with 60 mlO oE 2 N NaOH and the ~olution heated
under ref~x overnightO After caO 25 h~urs of heatlngg the
reaction m~ ture was cooled in ice arld 120 mlO of 2N HCl
added with stlrringO Thc ~aixture was then refrlgerated ov~3r
5 ~:he weekend. The prec~p~ta~ed solid ~berl20lc acld~ wa~
then filtered off while the mlxtur~ was still c~ldo The
solid was washed with a little water arad t:he pH of the
filtrate adjusted to 30û WLt:h llD% NaOHO The aqueous solutlon
was extracted with ethyl acetate four timesO The ex~raets
were dried and f~teredO Sod~um 2-e~hylhexansate was added
until no more preeip~tat~on occ~rred. The so1id sodium salt
of 5-mercapto~4~methylw19293~riazole was i1tered of and then
dried under vacuum,
To a stirring susperlsion of 6.78 gm. ~0.013 mole)
of 7~(a-t-butoxycarbonylamino~p-hydroxypheny1acetamido)~
cephalosporanic acLd and 3.82 gmO (0.02 mo1e~ of the sodium
saLt of 5-mercapts~4-methyl~ 13293r-tr~azole in 100 ml. of pH
604 phosphate buffer was added 1.09 gmO (0~013 mole) of
NaHC03. The mi.xture wa~ heated at 70 ~or 4-1/2 hours9 ~he
Z0 reaetion being monitored by TLCo It w~s allowed to cool
arld the resulting gum stirred with water and any insoluble~
fil~ered o:Ef. The solutlorl was covered with ethyl acetate
and put in the re:Erigera~or overnight.
The layers were Jchen separated arld the aque~us
1ayer acidified to p~ 3.0 with 3N HC1. I~ was ~hen extrac~ed
several times W~ttl e~yl aceta~e and ~he extracts dr~ed and
evaporated. The resultlng gum was tr>it.urated with ether to
give 2.69 gm. of solid~ S~nall amo~nt~ were ~hen reprecipi~at-
ed tw~ce from methanol~ther9 and then the desired m~ter~al
~0 wa~ precipitated with petroleurn ether. ~he resulting solid

6~
1 (1.75 gmO) was chromatographed on 1~0 gmO of ~ilica gel
using 90:10:3 chloroformomethanol:formic acid. The co~umn
yielded 0o80 gmO of the t~bu~oxycarbonyl derivatlve of the
title compound.
The above derivative (0.80 gm., 0.00139 mole~ wa~
placed in a mall rou~bot~om flask with a drying tube and
immer~ed i~ an ice bath. ~bout 10 ml. of cold trifluoro~
acetic acid was added and the mi~ture stirred in the cold
for about 15 minutes~ ~hen evapora~ed over 15 minutes. The
residue was poured i~to approximately 100 ml. of e~her and
~he resulting soLid collected and digsolved in ~bou~ 25 ml.
o~ wa~er. t was then st~rred with IR 45 Amberlite res~n,
a basic ion-e~change polystyre~e re~ln (washed 3 tlmes),
unt~l t~e ~olution reached pH about 5O5~ The resin was
filtered off and the ~olution lyophilized over~ight to give
the title p~oduct.
Calc'd for ~lgH2oN605S2l2~3/4 H200 G,
Found- C, 43~75, H~ 4.80, ~, 15~27
E~AMPLE .3
When ~he t butoxycarbo~yl derivative of 7-(a-am~no-
p hydro~yphe~ylacetam~do)cephalospora~ic aci~ is reac~d
wi~h the appropriate mercaptoheterocycle according to the
procedure o Example 19 the foll~wing compounds are obtal~ed~
7-(a~amino~p~hydroxyphenylacetamido)~3 (l-methyl~l, 293
2S triazol 40ylthio~ethyl)-3~cephem- 4-carbo~i;ylic acid
7~ (a am~ r~o-p-hydro~phenylacetamido) ~3 (l-m~thyl-l, 2, 3-
tri~zol 5 ylthiolDethyl)~3~c~phem-4-car~ox~rlic acid .-
calc d ~ar Ç1~E~20~605S2-2~I20: C, 44-38; ~ 4-7~ 16-~Q
Found: C, 44.71; H, 4.42; N, 15.74.
7 (a-~mina-p~hydr~yphen~l~c~mido)-3-(2-m~thyl~ 3-
triazol-4-ylthloma~yl)-3-cephem-4-carboxyl~c acid
The compourlds described in examples 1-3 are also
prep~red by reacting ~he appropriate 7-amino-3rhet~rocyclic
thiomethyl-3~cephem54-carboxylic acid with the mixed
- 12
* Trademark

~6176~
anhydride formed from N-t-butoxycarbonyl-p-hydroxyphenyl-
glycine and isobutyl chloroformate or trichloroacetyl chloride.
The N-protective group is removed with trifluoroacetic acid
or glacial acetic acid-HCI.
EXANPLE 5
For parenteral administration a pharmaceutical
composition can be prepared by dissolving S00 mg. of sodium
7-( a-amino-p-hydroxyphenylacetamido)-3-(1,2,3-triazol-4-
ylthiomethyl)-3-cephem 4-carboxylate in 2 ml. of sterile
water or normal saline solutionO Any of the other
cephalosporins disclosed herein may be formulated in a similar
manner.
EXAMPLE 6
__
A capsule for oral administration can be prepared
by mixing 500 mg. of a cephalosporin disclosed herein,
250 mg. of lactose, and 75 mg~ of magnesium stearate. The
other hereindisclosed products are similarly formulated.
- 13 -
'' : ' , ' ,