~6Z70~L
~e In on~
(1) ~ , - The cephal-
osporins of the present invention possesg the
u~ual ~ttr~butes o~ such compounds and ~re . .
particularly useful in the treatment of bacterial
infections by oral adminl~ration.
(2) Description of the_prior art.
A. Ce ~ in~ in Gener~l
Cephalothin and cephalorldine are well-known
~ntibacterial agent~; see U.S. patents 3~218,318;
3~449,338 and 3l498,979. The litersture ~lso
coneain~ considerable d~a on the activlty of
~ephaloglycin and cephalexin; ~ee U.S. patents
3,303~193~ 3,507,861 and 3,560,489 and Grea~
Britsin 9859747 and 1,054,806. .Newer cephalo~-
porins include cefa~olin ~nd cephapirin; see U.S.
p~tent 3~516,997 ~and also Netherlands 68/~5179
~F~rmdoc 34,328) ~nd South ~Africa 68/4513]~ and
.S~ paten~ 3,422, lOOo
The literature on cephalosporins he~ ~een
revie~ed by E.P. Abraham, Quart, Rev. ~London3
~1, 231 ~1967) by E. Van Heyningen, Ad~an. Drug
Res., 49 1-70 (1967) and briefly in Annual Report~
in Medlcinal Chemis~ry, Academ~c Press, Inc.,
lll Fifth Avenue9 New York, New York, 10003, by
L. C. Cheney on pflges 96 and 97 (1967) and by
K. Gerzon and R. B. Morin on pages 90~-93 (1968~
~nd by Gerzon on p~ges 79-80 (1969~ and by L. H.
Gonover on page3 101-102 (1970). New cepha~o -
porin~ are frequently reported at the annu~l
Interscience Conference on Ant~microbial Agent8
~nd Chemotherapy ~8 illustrated by Sa~siver et al.,
An~im-~crobial Agents and Chemotherapy -1968,
American Society ~or Microbiology, Bethe8d~, -.
M~ryland, p~ges 101~114 ~19~69~ and by Nishi~a
- 2
~ .
.. . . . . . . .... . _ . .. .... : . . . _ _. _... . _ . _ . . . . . : . . . _ . . .. . ..
~,6'27~
et ,~1 ., ibid ,, 236^243 (1970) . rwo excellent
rev~ew,~3 are The Cepha losporin,~s; Microb~ologic,al
Shemical ,and Pharmacological Properties and U,3e
iTI Chemotherapy of Infection, L. We~nste~n ~nd
R. ~apl~n, Annals of Internal Medicine, 723
729-739 (1970) and Structure Ac~civity Relat~on-
shlps A~ong Semisynthetic Cephalosporin,3, M.L.
Sas"~ver ~nd A. Lewi,s" ,Advances in Applled Micro-
b~ol~y, edited by D. ~erlman, 13, 163-236 (1970),
Ac~d~ c Press, New York. Two more recen~ review,~3
,~re ~ Lactam Antibiotlcs: Thelr Physicochemic~l
P~oper~ies ~nd Biological Activi~ie3 in E~ela'cion
to Structure, J.P. Hou ,and J.W. Poole, J.
Ph~rmaceutical Sciences, ~4~, 503-532 (April9 ..
1971) and Chemistry o~ Cephalosporin Antibiotics,
R. ~. Morin and B. G. Jackson, Fortschr. Chem.
Org. Naturst, 28, 343-403 (1970) which ~ncludes
a "~eetlon on nucleophilic di.splacement of the
3ce~te group ,~t pages 370-373.
The preparation of various 7- [a-amino-
arylacetamidol- cephalosporanic acids and the
eorre~ponding desacetoxy compounds in ~hich aryl
represents unsubs~ituted or substituted phenyl
or 2- or 3-thienyl is described, for example9
in ~ritish Specif~cations 98S,7479 1,0173624,
1,054,806 and 1,1239333, in Belg~um patent
6969026 (Farmdoc NoO 29,494)~ in U.S. patents
3,311~6~1, 3,35~8589 3,48g,750, 3S48O,751,
3,489~752~ 3,513,260 ,and 3,575,969, in J~panese
patent 16871/66 (Farmdoc 23,231), by Spencer
et ,31., J. Med. Chem.~ ~ , 746-750 (1966),
by Ryan et al., J. Med Chem., 12, 310-313 (1969)
,~nd by Kurita et ,al., J. Antibiotic,s (Tokyo) ~A)
': ':'' '
- 3 -
~6~27~L
19, 243-249 (19S6) and see also U.S. patent
3,485,819. Briti~h Specification 19073,530
includes a disclosure of the preparation of
~uch compounds by acyla~cion of silylated 7-ACA.
Netherl~rlds patents 68111676 (Farmdoc
36,349) and 68/12382 ~Fanndoc 36,496) and U.S.
patents 3,489,750 ~nd 31489,751 disclose ring-
substituted cephaloglycins .
B . 3 -Thiomethylc epha losporins
V~rious cephalosporins, including cephal-
osporLn C on occasion but not cephaloglycin,
have been reacted with nucleophilic? aromatic
mercapt~n~ to produce compounds having the
~truoture
Acyl ~ C~ 2
O--C l~ C - CH2 - S - Ar
\~
..
COOH.
In U~S. p~t~nt 3~278"531 Ar ~ phenyl or certsin
8ub8tituted phenyl8 or certain aro~tic hetero-
cyclie rings named, ~or example, in column 5.
Siniilar nucleoph~les~ e.g, 2-mercaptopyrimidines,
~re di8closed in ll.S. 3,261,832 and Great Brita~n
1,101,422 and U.S. 3,479,350 and U.S.~ 39502,665J!
all issued to Glaxo. A parallel disclo~ure i~
found.in Great Britaill 1,109,525 to Ciba, ~,g,
in de~inition "hl1 for R3. Additional nucleo
phll~s o~ this type were disclosed by~ Fu~isawa
in Belglum 7149518 (Farmdoc 35,307; Netherl~nds
_4_
Z7C~L
68/06129 ~nd South Africa 2695/68), in Canada
818,501 (Farmdoc 38,845), in Great Br~tain
1,187,323 (Farmdoc 31,936; Netherlands 67,14888),
in U.S. 3,530,123 and in U.S. 3,516,997 (Farmdoc
34,328; Ne~herlands 68/û5179) which includes the
compound named cefaz~lin, which has ~ tetrazoly-
l~cetyl s~decha~n on the 7-amino group and a 5-
methyl-thladlazolylthiomethyl group at the
3-position and is described at ~ome length ln the
scientiflc literature, e.g. in Antimicrobial
Agent~. and Chemotherapy - 1969, American Society
for Mlcrobiology, Bethesda, M~ryland ~ pages
236~243 ~nd in JO Antibiotics (Japan) 23(3),
131-1~8 (1970).
Replacement of the 3-,acetoxy group of a
cephalosporin by various heterocyclic thiol.~ has
been disclosed in U.S. 3,563,983 an~ in Netherlands
70105slg ~Farmdoc 80,188R) where the ~idçchains
were, for ex~mple, 7-a-amlnophenylacetamido and
~ypical heterocyclic thiols were 2-methyl-1,3,4-
thiadiazole-5-thiol and 1-methyl-1,2,3,4-tetrazole-
5- chiol . ~
Various cephalvsporins having ~hP structure
, ~
/S\
Acyl - - NH - CH ~:H ~H2
o~ I t
~ CH2 - S - a lkyl
- ~C : ' '
COO~
:
~n which acyl represents various sldechaine
including a-aminophenylacetyl have been d0scribed
,. .. , . ..... . .. . . . .. _ . . . . _ . .. .. _ . . . .. . . .
~0627(~
in some of the a~ove ~nd by Glaxo in ~elgium
734,532 (Farmdoc 419619) and in Belgium 734,533
(Farmdoc 41,620) ~nd by Lilly in Belgium 743,754
(Farmdoc 41,150R).
Cephalosporins hav~ng the structure
Acy~ - NH - CH ~ CH2
~ ~ =L _ N ~ - CH2- X
- \C~
.
COOH
S N -
'. Il 11' ~
where X ~nclude~ - S - C - ~3nd - S - C - sre
disclosed in m~ny patents including some of ~he
above and in U~S. `3,239,516, 3,239,515, 3,243,435 9
3,25~,4~, 3,4319259, 3,4469~03, 3,278,53~ -
3~261,83~ and 3~573,298.
: Related p~blications ln ~he scient~fic
.
l~terat~re include J. Med. Chem. 8, 174-181 (1965)
: and Ji~Chem. Soc. ~London~ 1595-1605 (1965),
5015-5031 (1965) and 195~-1963 (1967).
: C. 3-AcylthiomethylcePhalospor~n~ - -
~ The following publication~ and patents dis=
: close certain ~dditional 7-ACA derivatives
containing a 3-acylthior,;ethyl moiety (in which
phenyl is abbrevlated as Ph): ~
l.~:G. F. H~ Green, J. E. Page, ~nd S. E.
: ~ Stanifo~th, J. Ghem7 Soc., 1545-605 (1965).
Thi~ re~erence gives the proton ma~netic re~on-
~nce spectra of the 3-benzoylthiomethyl d~er~va- `.
tive o~cephalothin.
Co~ker et ~1., J. Chem. Soc.~ 1142-1151 :`
(19S6) ~dds thiopicolinyl ~nd references Belgium
650,444 .
6-
. .
1~6Z7~
.
2. J. D. Cocker, et 81. 9 J. Chem. Soc.,5015-31 (1965) discloses compound having the
structure
~NoF~
`1 ~CH2- S - C ~
QûH
wherein R ha~ the following meanings: PhCH2-,
CH2-, CH3-S-C~12-, Ph-CO-S-C~-, HOO~ (CH~ 3-
3. Glaxo~s U.S. 3,261,8'32 disoloses compounds
havin~ the ~truc~ure
- :
. . _ .
~SllC112CON~ S~1
N~f ~`CH~ -Y : '
COOH
wherein Y ha~, ~or example, the follo~ing mean-
lngs ~
'5~~ s-co~3 s-co ~here
R is C1130-, ~N02, -CN~ CH3S~
_ 7 _
627
-s~ s--~o~
5 ~o~ S-CO-CH2~, -s-co-(cH2)3cH3
Equ~valents are Netherlands 64/08066 (Farmdoc
15534) and Great Britain l~:L01,424.
4O Glaxo'~ Netherlands 65/0S818 ~Farm~o~
1~306) discloses the react~Lon
H2N~S
J=N~cl~2-s~cl)-ph ~ CH2COCl : :
COOH ~ ~
:, .
~
~ N \ GH2-S-CO-Ph
AT1 ~quiv~ler~ U, S . 3 " 502, 665 .
' ~ .,
: ~ /
~ ~ ~2 7~ ~
5. Gl~xo's Netherlands 64/11521 ~Chem. Abstr. 9
63: 13,281d (196S)] discloses the reac~ion
~ep~3 C ~in~5i~L~ HOOC-CH (CH2)3CONH ~ S ~
NH2 ~ ~ N ~ CH2-y
COOM
whereln Y -S-CO-Ph or -S-CO ~
Equ~valent~ are Great Britain 1,101,422 and Can&da
796,747 (Farmdoc 17362).
6. Cib~'~ U.S. 3,555,017 disclo~es compounds
having the structure
. R
: R / C~-CO-NH ~ ~
COOH ~;
Rl ~nd R2 ~ halogen. ;- :
As usual in Ciba 18 patents directed prim~rily
to novel ~id~ch~ins ~t the 3-posltion, the R group
~bove i~ defined broadly ~s the residue o~ ~
c~rboxylic acid and m~y be illustrated by phenyl,
the residue of thi~benzolc acid. Equlv~lents
~re Belgium 7O~D24~ rmdoc 33~276), Great Britain
1,211,747 ~nd French 19575~554.
O g O
.... . ... . . .. .. . .. .. . . .. . .
~L~627(~
7. Ciba 's British 1,211~718 discloses com-
pounds havlng the structure
r
O ~ C ~S .
1 COOH
R ~s in 6 above.~quivalents are Belgium 708,311 (Farmdoc 339277)
and U.S. 39557,104. ::
8. Ciba 's Belgium 7519526 ~Farmdoc 90,178R)
d~ sclo~es compounds having ~the s~ructure
N3~ H2C-NH~ S ~
SC-R
COO~I '
':
R a~: ~in~ 6 above.
An equ~valent i~ Netherland~ 70/08237.
:~ : 9. Ciba's South Africa 69l8436 di3closes : -
. : compound~ having the structure
`, ~N ~U ~C~ ~/ ~ O ". ~.
N ~ ~ S~
COOH
R a~ in 6 above.
.
E~ivalents ase Belgium 743,014 (Farmdoc 43,126RS
and ~etherlan~ds 69l18611.
.
- 10 -
~OÇ;Z7~ :
10. Ciba's ~outh Africa 69/8399 disc1ose8
compounds having the ~tructure
H2 S O
N~; N~C \ CO-NH
~,==1 '~ H2
COOH
R a~ in 6 above.
Equlva1erlt~ are Bel~ium 742,933 ~rmdoc 41,568R)
~nd Netherlands 69/18531.
11. Giba's South Africa 68/8185 disc1oses
compounds having the struc~ure
H2 '
0~ H2
R as ~n 6 above, COOH
An equivalent ~s Netherland~ 68118868.
12 . Ciba ' s Netherlands 68/18868 d~ sclose~
compounds having the structure
_~ H2 : ' .
N ~ V~ O-NH
N~ ~ SC.-R
OOH
.
R a5 in 6 abov~. ~
Equivalents are South Africa 8120t68~ German
1,817,121 and Belg,lum 726~316.:
: ': -
... ....... .. . . . . ..... .. . .. . .. .. : . . .. . .
~(~6~7(~1
13, Fu~isawal~ Great Brital~ 19187,323
for example, ~ page 5, lines 67-71 disclose~
compounds having the structure
- ..
~ O
o\/ ~ Z ~ ~ S ~
R / R O / ~ / SC-R
, COO~
in which R represents ~ethyl, thienyl, pyridyl9
etc. ~nd wherein general disclosure is m~de of
other heterocycllc groups a~: at pages 1 and 2.
Equivalents are Netherlands 67/14888
(Farmdoc 31,936) and U.S. 3,530~123.
.
~ 14. Fu~isawa~ Belgium 714,518 (Farmdoc
359307) discloses ~among many others) compounds
having:the ~tructure
R . :.
/ ~ B ~s 1l
C-R
~ ~,CO~
w~ereln~ is as 13 above.
Equivalents are Netherlands:68/06129 and
South~African 2695/68.
,
...
:: .
~ - 12 - ~
.. ... . . . , . _ . _ , . .. . _ . . ., . . _ . .
3L[36;27ai1
15 . Gl~xo ' s U . S . 3, 243 ,435 and Belgium
650,444 (Farmdoc 15,535) disclose generally a
va~t variety of compounds h~ving the structure
Acyl-NU-CO-llH~ CH~S
COOH
wherei.n ~, is defined, e.g. in column~ 1 and 4,
t~ ~nclude various heterocycllc groups.
16. Cibals South Africa 65/6950 (Farmdoc
22 ~192) discloses compounds having ~he struc~cure
N~ ~ C~lR2-~-N~S
,~N )~ SC-R
.` ~00~
in ~ich R in Example 20 is phenyl.
Equivalen~s ~re Great Br~tain 1,109,,525 ~nd Canada
807 ,651.
~ 17 . Glaxo ' s U. S ~ 3 ~47g , 350 d~sclo~os ~ proces~
for producing 3-pyridiniuImnethyl cephalosporin~
which utilizes ~s ~n intermediate compounds of the
type~deser~bed in rcference~ 2 and 3 above~
' :
.
13 ~
~62710~L
18. Ciba 's U S. patent 3,7579013 d~scloses
compounds of the formula
' 2~ ~\~ CH2-S-C-R
COO
wherein R3 i~ (lower3 alkyl and R is as in 6 above.
~ Lg. Bristol9s Belgi~n patent 795,811
disoloses compounds of the general fonn~lla
Il ,S O
Ar- l~-C~ ~ rr
NH2 `o~l N ~CH2-S-C-Z
COQR
wherein ~Ar is phenyl" 2-th~enyl or 3-thienyl; R
~ : : ls hydrogen, pivaloyloxymethyl, acetoxyme~chyl,
; methoxyme~hyl, acetonyl or phenacyl; and Z is ~.
H3 , _ N
~CU3 ~
~: 3-i~oth~zolyl 9 4-isothiazolyl or 5-isothiazolyl .
:
- 14 - ~
..
. . . ... .. ............. ., .. .. . .... . . . . . .. . . ....... ... , . . . .. ~ .
~9627~
This specification comprises the novel compounds
having the D-configuration in the 7-sidechain and the formula
~r-CH-C-NH
~H2 ~ ~ ~ C~2~
COOR ::
wherein Ar is phenyl, 2-thienyl or 3-thienyl; R is hydrogen, :~ -
pivaloyloxymethyl, acetoxymethyl, methoxymethyl, acetonyl or
phenacyl; and R' is 2-thiazolyl or 5-methyl-2-thiazolyl or -~
3-methyl-1,2,5-oxadiazol-4-yl, and their pharmaceutically
acceptable salts. ;~
Summary of the Invention
In a broad aspect the present invention provides a
process for the preparation of a compound having the D- .
configuration in the 7-sidechain and having the formula `
H-I-N~ ~ S ~ 9 (I)
H2 ~ N ~ C~ C-R'
eOOR
: ~ .
whereLn R is hydrogen, pivaloyloxymethyl, a~etoxymethyl,
: met oxymethylp acetonyl or phenacyl; and R' is 2-thiazolyl or
5-methyl-2-thiazolyl or 3-methyl-1,2,5-oxadiazol-4-yl; or a `
pharmaceutically acceptable salt thereof, comprising:
~a1 when the starting material includes the desired final
substituent in the 7 position of the cephem nucleus:
reacting a compound of the formula `--
Q ~ .
~ fH-C-NH 3
NH2 ~ ~ CH~OCOCH3
C2~ :
15 - ~
.. .. . . . ~ ~.. . . ~ .. . .
~(~36Z 17~L
or an easily cleavable ester or salt ~hereof wi.th a hetero-
aromatic thiolcarboxylic acid of the formula
o
R'-C-SH
wherein R' is as defined above or a salt thereof to form the
desired compound of formula I, or , '
(b) when the starting material includes the desired ~:~
final substituent in the 3-position of the cephem nucleus~
10 reacting a compound of the formula , '
~2N ~ S ~
O N ~ CH~S-C-R'
CO2~ .
:
wherein R' is as,defined above or an leasily cleavable ester or .~
salt thereof with acid having the formula '. '
.. ~... ...
CH-COOH
I
NHB ' ''
or an acylating derivative thereof, wherein B is an Emino-
protecting group and removing said amino-protecting group B to : :
produce the desired compound of formula I or an easily cleavable
ester or,pharmaceutically acceptable salt thereof; -' . -':
and, if dPsired, in the case of (b) either before or after ~,
removal of protecting group B ~i) converting the product in the
form of the free acid or salt thereof to a corresponding easily
cleavable ester or pharmaceutically acceptable salt thereof or ,.
(ii) converting the product in the form of an easily cleavable
~ -'15(a) ~
. - . ... .
:
. .:
7~
ester or salt thereof to the corresponding free acid compound
or pharmaceutically acceptable salt thereof.
The pharmaceutically acceptable salts referred to
above include the nontoxic carboxylic acid salts when R is
hydrogen, e.g. nontoxic metallic salts such as sodium,
potassium, calcium and aluminum, the ammonium salt and salts
with nontoxic amines, e.g. trialkylamines, procaine, dibenzyl-
amine, N-benzyl-pLphenethylamine, l-ephenamine, N,N'-dibenzyl-
ethylenediaminel N-alkylpiperidine and other amines which have
been used to form salts of penicillins. Also included within
the definition of pharmaceutically acceptable salts are the
nontoxic acid addition salts (amine salts) of the acids and ~
esters of Formula Ia, e.g. salts with mineral acids such as
hydrochloric, hydrobromic, hydroiodic, phosphoric and sulfuric
and salts wi~h organic acids such as maleic, acetic, citric,
oxalic, succinic, benzoic, tartaric, fumaric, mandelic,
ascorbic and malic.
: . ...:
- 15(b) -
.. ~, . .
1~627~
Preferred c~pounds of the present lnvention
~re the eompounds h~ving ~he D-configuratlon ln
t:he 7~idech~in ~nd ~he formula
Ax ~CH-C-NH
N~2 ~ c~2_s_~
COOR
Ib
wherein Ar i6 phenyl, 2-thieriyl or 3-thienyl ~nd
R iz hydrogen, p~v~loyloxymlethyl~ acetoxymethyl,
~ethoxyme~chyl s acetonyl or Iphenacyl; and the
ph~rmaeeutically aeceptable salts thereof.
Preferred compounds of formula Ib are those in
which ~9r i~ phenyl. An e~plecially preferred
~ompound of formula Ib ~ tElat in which Ar i8
ph~nyl ~nd R i9 hy~rogen; or the sodium or
potas~ium s~lt ~her~of.
More preferred compounds of the present
invention are the compourlds having the D-con-
figuratiorl in the 7-sldQch~in and the fo~mula
Q
Ar -CN-C -NU ~l CN2 _ 5 _C ~ CU3
COOR
. Ic
wherein Ar i~ phenyl, 2-th~enyl or 3-thienyl
and R i~ hydrogen, pivaloylox~nethyl9 acetoxy-
methyl, methoxymethyl, ~cetonyl or phenacyl 9
~nd the ph~rmaceutic~lly ~ccept~ble salts
thereo~. Preferred compound~ of formul~ Ic
are tho e in whieh Ar is phenyl. An especi~lly
~L~627~
preferred compound of formula Ic is that in which
Ar is phenyl and R is hydrogen; or the sodium or
potassium salt thereof.
Further preferred compounds of the invention
are the compounds having the D-configuration in the
7-sidechain and the formula
A~ N~ H -5-~
Id
wherein Ar and R have the meanings given above
and the pharmaceutically acceptable salts thereof.
Preferably Ar is phenyl and R is hydrogen; or the
sodium or potassium salt thereof.
Also included in this invantion ~re the
co~pounds ~u~ed as sither int~ermediates or met~-
bolie precursors) in ~hlch thle amino group i8
"blocked" by substituents suclh a~ t-butoxycarbonyl,
c~rbobbn~yloxys~formy~ o-nitrophenylsul~enyl9
-trichloroethoxycarbcnyl~ 4-oxo-2-pentenyl-2,
l-c~rb~me~hoxy-l-prspenyl-2 snd the like. P~rtic-
ularly lncluded in ~uch blocking groups are the
ketones (especially acetone) snd the ~ldehydea
(espec~ally formaldebyde ~nd acetaldehyde) di~-
closed for example ln U.S. patents 3,1989804 ~nd
~347,851 and the ~ketoesters ~nd the.~-diketones
di~closed for ~x~mple ln U.S. patent ~9325,479
~nd the ~ketoamides disclosed in Jap~n 71/24714.
The pr~ent in~ention also includes a process
for the p~eparation of ~ eompound having the
formula
p
A~_q~ ~T~S
H2 ~ ~ CH2-S-C-R'
CC)~
'
wherein Ar is pheny~ t~ienyl or 3-thienyl;
R' is 2-thiazolyl or 5-methyl-2-thiazolyl or 3-
methyl-1,2,5-oxadiazol-4-yl; and easilY cleavable
esters and pharmaceutically acceptable salts thereof;
which process comprises either
~A) reacting ~ compound o~ the formula
., M2N --- I , s ~
o~ ~CH2S-C~R'
C02H
II
_._
wherein R' is as defined above or an easily
cleavable es~er or salt thereof with an acyla lng
deriv~tive of an acid having the for~ula
:
Ar-~H-COOH
~HB .
III `
, ~ , .. .
wherein B is an amino~protecting group and Ar
~s a8 defined above and removing sa~d amino-
protecting group B to produce the desired com-
pound o formula I or an easily cleavable es~er
or ph~rmaceut~cally acceptable s~lt thereof and,
if deslred~ ei~her before or after removal o~
pro~ecting group B (a) converting by methods
-known ~ se the product ~n the form of the
free acid or 8alt the~eof to a corresponding
e~sily cleavable es~er or pharm~ceutically ~ccept-
able sàlS thereof or ~b) converting by methods
known~per se the product in the ~orm of an easily
cleavab1e ~ster or ~alt thereof to the correspondlng
free aci~d compound or pharmaceutically acceptable
s~lt thereo~; or
,
.
~8 -
.
l~Z7~1
(B) reac~ing a compound of the formula
Ar-CH-C-NH ~ ~
~ 2 0 ~ ` ~ CH2ococH3
C02H
IV
whereln Ar is 3S defined above or an easily
cleavable es~er or salt thereof with a hetero- `
aromatic thiolcarboxylic acid. of the formula
R'-C-SH
:~ .
where~n R' is as defined abo~e or a s~lt thereof
to form a compound of formula I or an easily
cleavable ester or pharmaceutically acceptable
8alt thereof and, if desired, (a) converting by
methods known ~ se the product in the form of
the free acid or salt thereof to ~ cor~esponding
easil~ cleavable ester or pharmaceutieally accept- :
able salt thereo~ o~ (b~ converting by methods `
~nown ~ se~the product in the form of a~n easily
cleavab-le ester or salt thereof to the corresponding
free acid compound or pharmaceutically ~cceptable
sal~c ~ thereof.
. .
The easily cleavable esters referred eo above
include ester groups which are removable by methods,
e.g. chemical or:enzymatic hydrolysis~ which do
not result ~n any appreciable destruct~on of the
remaining~-portion of the cephalosporin molecule.
~xamples of suitable esters include those disclo~ed
in U.S. patents 3,284,451 ~nd 3,249,622 and U.K.
patents 1,229,453 and 1,073,530. Parti~ularly
. .
- 19 - ' ,
~ ~ ~2 7~ ~
preferred esters are the piv~loyloxymethyl,
acetoxymethyl9 methoxymethyl, acetonyl and phen~cyl
esters.
In one method of preparing the novel cephalo-
~porin compounds of the present invent~on, a 3-thio-
lated-7-aminocephalosporanlc acid compound of
form~l~ II or an easily cleavable ester or sa1t
of ~id acid or ester 18 acylated w~th ~he appro-
priate acylating derivative of formula III.
The 3^thiolated-7~amlnocephalospor~nic ~cid
lntermed~a~e of formul~ II may be prepared by
- di~placement of the 3-ace~oxy group of 7-amino-
cephalosporanic acld or a salt ~hereof wi~h the
appropriate heteroaromatic thiolcarboxylic ~cid
or g salt thereof. The displacement of an ester
group with a thiol group is a known reaction and
i~ preferably accomplished iLn aqueous solution at
a temper~ure oi ~t. least room temperature and
preferably within the range of about 50 to 100C.
. iLn the presence of ~ mild base such as sodium
b~carbon~te.
Th~ claimed compounds may then be vbta~ned
; by a~ylatlo~ ~ccording ~o known methods of the
7-amino group o~ intermediate II with the acyl3ting
agent of`formula I~I.
: Because of the low solub~lity of the compound~
of formNla II in common aqueous an~ non-aqueous
: 801~ent~, lntermediate II ls preferably converted
prior to:the acylation reac~ion ~o an`easily
cte3va~1e~ester or ~cid~addi~ion salt thereofo
The procedures for preparing such es~ers are
d~sclo~ed in the literature ~nd are well-known
t~ those skilled in the art of penicillin and
cephalosporin chemistry. One preferred me~hod
espec~ally useful for preparing 'ch~ most preferred
e~sily hydrolyzed esters, i.e. the piv~oylox.ymethyl,
- ~0 - ;
, . .. .. . . _ . . _ .. . , _. . . . . . ..
1~6Z~7~1
acetoxymethyl 3 methoxymethyl, acetonyl and phen-
acyl esters, is disclosed in U.S. patent 3,284,451
This reference descrlbes the esterification of
sodium.cephalothin with the appropriate active
chloro or bromo compound (e.g. phenacyl bromide,
~hloroacetone, chloromethyl methyl ether, pivaloyloxy;
methyl chloride, acetoxymethyl chloride3 followed by
enzymat~c removal o~ the thienylacetic acid ~ide-
ch~in. In another good method ~he ~rie~hylamine
salt of 7-aminocephalosporanic ~c~d i~ reacted
directly with the active halogen compound as ln
U.K. patent 1,229,453. The compound of formNls
II n~y also be converted to ~ ~ilyl ester as by
the methods described ln the literature, e~g. .
U.S. patent 3,249,622. The silyl ester group
may be removed following the acylation reaction : .
by hydrolysis or alcoholysls. ~ -
Prior to the ~cyla~ion reaction the amino
group o~ acylating agent III is protected by a
conveneion~l amino-protect-img group B which may
be read~:ly re~oved ~t the conolusion of the
react~on. Examples of suitable amino-protect~ng
groups include tbutoxycarbonyl, carbobenzyloxy,
2-hydroxy-l naphthcarbonyl, trichlor~ethoxyc~rbonyl,
2-ethoxycarbonyl-1-methylvinyl and 2-methoxycarbonyl-
l-methylvinyl. A p~rticularly valuable ~locking
group~is;a prOtOII, as in the compound of the formNls
.
Ar-~H-COCl
NH2 HC1
wherein Ar i~ phenyl, 2-thienyl or 3 thienylO The
preferred amino-protecting groups are t-butoxy-
carbonyl, the proton and a ~-diketone or a ~-keto~ -
ester as in U.K. paten~ 1,123p333 or U.S. patents
.
.. ... . .. ... . . .. . , . . . . _ .. . . . . . .
~L062~
3,325,479 and 3,316,247, e.g. methyl acetoacetate9
or a ~^ketoamide as in Japan 71/24714. When the
t-butoxycarbonyl~ ~-ketoester, ~ diketone or
~-ketoamide protecting groups are employed~ it
ls preferred to convert the acylating acid con-
taining the blocked amino group to a mixed
nnhydride~ e.g. with ethyl or isobutyl chloro-
formate, before reaction with compound II or an
e~ter or ~alt thereof. After the acylàtion
coupling reaction, the amino-protecting group B
m~y be r~moved by methods known ~ se to form
the desired product of formula I. Thus, for
example, the t-butoxycarbonyl group m~y be removed
by use of formic acid, the carbobenzyloxy group
by catalytic hydrogenation, the 2-hydroxy-1-naphth-
carbonyl~group by acid hydrolysis, the trichloro-
ethoxycarbonyl group by tre~stment with zinc dust
ln glacial acetic acid, ~he proton by neutrali-
zation, etc. Obviously other func~ion~lly equ~v~
alen~ blocking groups for an amino group can be
used and such groups are considered within the
scope of this invention.
Acylation of a 7-~mino group of a cephal-
~sporin ~ 8 a well-known reaction and ~ny o~ the
func~ional equivalents of formula III commonly
used ~s acylating agents ~or primary amino group~
m~y be employed. Example~ o sui~able acylating
derivatives~of the free acld include the co~re5-
ponding ~cid anhydride~, mixed anhydr~des, e~g.
alkoxyformic anhydrides, ~cid halides, acid az~des~
~ctive esters an~ active ~hioesters~ The free
acid m~y be coupled wi~h compound II ~fter first
reacting said free acid with N,N1-dimet~ylchloro-
~ormimin~um chlor~de or by the use of enzyme6 ~r
.
'~ ' ''' .
- 22 -
, . . .. . ... . . . . .. . ... . . . . . . .. .. . .. . .. . . . .
~ 0 6Z 7
of ~n N,N'~carbony1diimidazole or an N,N' c~rbonyl~
ditr~azo1e or a c~rbodiimide reagent, e.g. N,N!-
diisopropylcarbodiimide. N9N'-dicyclohexylc~rbodi-
imide or N-cyclohexyl-NI ~2-morpholinoethyl)~
c~rbodiimide or of alky1ylamine reagent or of an
i~oxa~olium salt re~gent. Another equivale~ of
~he free ac~d i~ ~ corre~ponding azollde, i.e.,
an amide of the corresponding acid whose a~ide
nltrogen i~ a member of ~n quasiaromatic five
membered ring containing ~t least two nitrogen
~toms, ~.eO 3 i~idazole, pyrazole, ~he triazoles,
benzimidazole, benzotri~zole and their ~ub~tituted
deriv~t$ves. Another react~ve derivat~ve of the
pheny:lglycine acid of formNla III i8 thè N~carboxy
anhydride (Leuch'~ anhydrid~) . In this structure
~he group which activfltes the earbo~cyl group also
serves to protect the ~m~no group. A particularly
preferred acylating agent i8 the acid chloride
hydrochloride of the iEormula
Ar-~H-eOCl
NH2 ~ HCl
,.
whioh also ~erves ~ du~l function of osrboxyl
~ctivation and amino proteotion. Mention was
m~de above of the use of enzymes to couple the
free ~cid with its blocked amino group wi~h c~m-
pouFad II. Included in the scope of 6ueh proce~ses
~re ~he use of an ester, e.g. the methyl ester, of
that free acid with enzyme~ provided by v~riolls
microorg~nisms, e.g. those described by T. Takahashi
et al., J~ Amer. Chem. Soc., 94(11~ 9 4035-4037 (1972
~nd by T. Nara e~ ~1., J. A~tibiotics (Japan), 24(5),
321-323 tl471) and ln West Germ~ny 292169113.
- 23 -
:: - , . .. , .. ,. . , .. , . ~ , .
~ 0 6~ ~0 ~
The particular proce~s conditions, e.g.
tempersture~ solvent, react~on time, e~c. ~elec~ed
for the acylatlon coupling reactlon are determined
by the nature of the acylation method used and
~re known to those skilled in the art. Generally
it i~ useful to add an organic tertiary amine,
e.g. tr~ethyLamine, N~N-dimethylsniline, ethyl-
piperidine, 2,6-lutidine or quinoline, to ~erve
as a proton acceptor or salt-forming agent. A
preferred method ~llustrated in the examples
which follow involves formation of a s`ilyl ester,
e.g. with trimethylchlorosilane, of the inter-
mediate of formula II and acylation of this sily~
l~ted intermediate ~n dry methylene chloride at
temperature of below room temperature ~nd prefer-
ably about 0C. with the appropriate chloride
hydrochloride acylating age!nt of formula III in
the presence of ~n organic tertiary am~ne.
At ~he concluæion of the acylation reaction,
the acylated intermediate is sub~ected to aqueous
hydrolys~s to provide the desired cephalo~porin
produo t .
~ The eompounds of the present invention m~g
be isolated in any of the ways ~ustomarily
empIoyed for ~he isolation of similar cephalos-
porin~. Thus 9 the product may be ob~ained ~ -
~he neutral moleeule~ although thi~ is prvbably
more~accurately represented ~s the æwitterion,
or ie m~y be ~solated as a ~al~. Form~tion of
the de~ired pharmaceutically aceepta~le carboxylic
acid or acid addition salt ~s carried out by known
methods, e.g. reaction of the ~cid with ~n appro~
pria~ base or acld. ~ ~ :
At the conclusion of the acylation reaction
~he product obt~ned m~y be converted (before or
1 0 6 2 7~ ~
after r~moval of the ~mino-proteceing group) by
methods known per _ to another desired product
of formula I. Thus, the compound of formwla I
in the orm of the free acid or a s~l~ thereof
m~y be converted by known methods ~o a corres~
pondlng easily cleavable ester or pharm~ceutic~lly
~ccep~able s~lt thereof. Similarly, the product
of formula I in the form of ~n eaælly cleavable
ester or s~f~ thereof may be converted to the
ree acid product or pharm~ceutically ~cceptable
~alt thereof by removal of the esterifyi~g group9
e.g~ by ~queous or enzymatic hydrolysis ~a~ wlth
human or ~nimal serum~ or acidic or alk~line
hydrolysls or by catalytic hydrogenation or by
treatment with sodlum thiophenoxide as t~ught in
U.S. patent 3,284,451.
In another method of preparing the compounds
of the present invention, 7-am~nocephalosporanic
~cid or a salt thereof is acylated with the acid
oiE formul~ III or an acylating deriv~tive thereof
to fo~m ~ 7-acylated cephalosporin compound of the
formula
~ .
Ar-lH_ 3 ~H - -- f ~
NH2 ~ ~ CH20COCH3
CO2~' , .,
. I~
Compound IV in the form of the free acid or an easily
cleav~ble ester or salt thereof is then reacted
~ccording to the process of the present invention
with ~ heterocyclic thiolc~rboxylic acid of formul~
V or a salt thereo~ mos~ preferably the sodium
- 25 -
~L~6Z7~1
or potassium salt. The displacement resction
i8 preferably conducted in aqueous solution ~t
temperatures of about 50CO or higher in an
inert atmosphere, e.g. under nitrogen. The
product of the displacement reaction m~y, if
desired~ be converted to a pharmaceutically
acceptable salt by treatment with an appropr~ate
acld or base. As in the ca~e of the alternate
process described above for prepara~ion of the
compounds of formNla I, the product in the form
of the free acid or salt thereof may be converted
to a corresponding easily cleavable ester or
pharnaceutically acceptable salt thereof or,
alternatively, ~he product in the form of an
easi1y cleavable ester or salt thereof may be .
converted to the free acid or pharmaceu~ically
scceptable salt thereof.
The easily cleavable esters of the compound
of formula I are use~ul as i.ntermediate8 in the
produc~lon of the free ~cid product. The piv~l-
oyloxymethyl 9 acetoxymethyl and methoxymethyl
esters are al~o useful as active antibac~erial
agent~s 6ince on oral administration they are
rapldly~hydrolyzed ~o the active me~aboli~e.
These three esters are of particular ~nterest
because~ they provide on oral administration
different ra~es and amounts of ab~orption and
give differing concentrations of ~he active anti-
bacterial agent in blood and tissues.
The preferred and most active compounds of '
the presen~ invention ~re those having the D-
configuration at the a-carbon atom in the 7-side- l
chain, that is, those m~de from D~ 2-phenyl-~
glycine, which is also called D-~ a-amin~phenyl- .
acet~c ac~d,.and D-(-)-2-thienylglycine and D-(-~-
- 26 -
~062~C)1
3-thienylglycine. In addition, the conf~gura-
tion at the two optically active asymmetric
centers in the ~-lactam nucleus is that found
in cephalospor~n C produced by fermentation and
in ~he 7-aminocephalosporanic acid derived there-
from.
The pharm~ceutically active compounds of
the present invention are potent antibacterial :
~gents useful in the treatment of infertious
dlseases in poultry ~nd animals, including man,
caused by m~ny Gram-posi~ive and Gram-negative
bacteria. The active compounds are also of
value ~s nutritional suppllements in animal feeds .
and as agen~s ~or the trealtment of mastitis in
ca~le. The preferred compounds have also been
unexpectedly found to be efficiently absorbed
uposl oral administration.
Despite the synthesis of a large number of
cephalosporins reported in the scientific and
patent liter~ture, the only cephalosporin at th~
present ~me having suffic;Lent actlv~ty ~nd or~l
~bsorption for general: oral use is cephalexin.
In our search for new orally active cephfllosporins,
we ha~ve found ~hat the compounds claimed~ in the
present ln~ention fiurprlsingly and unexpectedly
possess:~good or~l absorption and at ~he~lsame
~ime appear to be superior to cephalexin ~n the~r
activity against certain impor~ant pathogen~c
org~ni~ms. Thi combinat~on of good oral absorp-
tion~and high antibacterlal ace~vity~ln a~ceph-
~losporin while highly desirable is quite uncommon
in compounds reported to date. M~king~any reliable
predict$on as to artivlties or oral ~bsorptions of
new cephalosporin compounds from a~ examLnation of
.
- 27 -
~62~
the propert~es of structurally analogous prlor
~rt compound~ has also b~en found to be essen-
tially impossible. To illustrate the unpredic-
t~bill~y of oral absorption and antibacterial
activity in ~ closely related series o~ cephal-
o~po~in compounds 9 Tables 1-8 below compare in
vitro activitie~ ~nd oral absorption as tes~ed
in the mouse of the compoun(l~ of the formula
H_~_N~ S
NH2 ~ CH2-S-C-Z
C02H
D~
wherein Compound No.
.. . .
æ ~ 2-thlazolyl 567
- 4-th~azolyl 591
5-~hiazolyl ~02
4-me~hyl-2-~h~azolyl 556
5-methyl-2-~hiazolyl 586
2 methyl-4-thiazolyl 607
- 4,5~dimethyl-2-thiazolyl 587
,
Tab~es 1-8 inslude data on the commercial or~l
cephalosporin, cephalexin.
'
.
2B -
.... . . .. , .. ... ....... . . ..... . .. . .. " . . . . .. . .. .
-
. :
1~627~1
Samples of the seven cephalosporin compoundc
having the compound numbers reported above after
~ol~tion ln DMSO ~dimethyl sulfoxide) at 14 mgm./
ml. followed by dilution with Nutrient Broth
were found to exhibit the following Minimum
Inh~bitory Concentrations ~M.I.C.) ~n mcg./ml.
versus the indicated m~c~oorgan~sm~ as determined
by overnight incubation ~t 37C. by Tube Dilution.
The in vitro activity of cephalexin W9S also
tested.
~.
- : -
',~`. ' ~: . ...
~ ,
: .
' . ' :
.
29 -
~L0627~:~
T~ble I
~i. 1. C . in mc~ . /ml .
Compound Cepha-
r~anism No. 586 lexin
D .pneumonia e ~ A9585 .16 . 6
5% serum *
Str . pyogenes + A9604 . 3 . 3
5/O serum *
S . aureus Smith $ A9537 . . 3 1. 3
S . aureus Smith + A9537 >63 2 . 5
50% s erurn ~: :
S . aureus PsX 1633-2 A9606 . 6 4
~ t 10- 3 d ilution -
S. allreus BX 1633-2 A96n6 4 8
at 10-2 dilution
S. aureus methicil~in- A15t)97 4 32
resis~ant ~t 10- -
dilution .
S. aureus at 10-3 A9748 8 32
dilution
S. aureus~ at 10~ 2 A9748 63 l25
dilution
Sal. enterltidis $ A9531 ,3 4
E. coli Juhl ~: A15119 2 8
E. coli ~ A9675 4 16
~, pneum~ni~e $ A9977 4 8
K. pneumoniae ~ A15130 3~ :~ 16
~ .
Pr . mirab~lis =~ A9900 16 ~ ~ 4
Pr. morganii ~ A15153:63. ~ 125
Ps . aeruginosa ~ A9843A>125 ~125
Ser. marcescens ~ A20019>125 ~ >125
.
* 50% Nutrient Broth _ 45D/o An~ibiotlc Ass~y Broth
:~ ~t 10-~ dilu~ion
~ 30~
~L~6270~3L
Table II
M. I . C . in m~ . /ml .
Compound Cepha-
Organism No. 567 lexin
D . pneumoniae ~ A9585 . 04
5% s erum*
Str . pyogenes ~ A9604 . 04 . 3
5% ~erum *
S, aureu~ Smith $ A9537 ~3 o6
S. aureu~ Smith ~ A9537 8 2 5
50h ~erum 7 -
S . aurèu~ BX 1633-2 A9606 . 6 2
~t 10-~ dilution
S. aureus BX 1633-2 A9606 . 2 4
at 10-2 dilution
S. aureus methicillin- AlS097 4 32
res is tant a t 10-3
dilution
S. aureus at 10-3 A9748 4 32
dilution
S~ aureus :at 10-2 A9748 16 125
dilution
Sal. enteritldis ~: A953i - .08 2
E. coli Juhl ~ A15119 1 ~ 8
E. coli ~:: A9675 b,~ lS
K. pneumoniae~ A9977 2 4
K. pneumoniae* A15130 8 16
~' ,' . .
Pr. mirabilis ~: A9900 2 ~ 4
Pr. morganii $ A15153 63 ~ ~ ~125
Ps. aeruginosa ~ A9843A >125 ~125
Ser. marcescens ~: A20019 125 >125
* 50%~Nutrient Broth ~ 45% Antibiotic :Assay Broth
:~ at 10-4 dilutLon
- 31 -
62
Table III
M. I . C . in mcg . /ml .
CompoundCepha-
~ No._591lexin
D . pneumoniae ~ A95B5 . ~2 . 3
5VL serum *
Str . pyogenes ~ A9604 . 02 . 6
5% serum *
5. aureu~ Smith ~t A9537 .3 . 1.3
S. aureus Smil:h + A4537 8 2.5
50% serum *
. . .
S. aureus BX 1633-2 A9606 .6 4
~t 10-3 dilution
S. aureus BX 1633-2 A9606 2 4
at 10-Z dilution
S. aureus methicillin- Al5lD97 2 63
resistant at 10-3
dilution
S. aur~us:a~ 10-3 A9748 4 63
dilution
S. aureus: ~t 10-~ A9748 16 125
dilution ~
Sal. enteritidis $ A9531 .16 4
1~. coli Juhl $ A15119 1 ~ ~ 8
E, coli ~ A9675 4 ~ 32
K. pneumoniae ~ A9977 ~ 1 4
K~ pneumoniae $ A15130 8~ ~ 32
Pr. mirabilis ~ A9900 ~ 4
Pr. morgani~ * A1515332 ~125
Ps. aeruginosa ~ A9843A>125 : ~125
Ser. marcescens :~ A20019125 ~ >125
* 50% Nutrient Broth ~ 45% Antib~otic As~ay Broth
* a~ 10-4 dilution
32
-
.. . . . .. .. . ... . . . . .. . .... . . . . . . ... .
~L06Z7(;1~
Table IV
M I.C. in mcg./ml.
Compound Cepha- I
Or~nlsm No. 607 lexin
D. pneumoniae ~ A9585 .16 .16
5% serum *
Str. pyogenes + A9604 .16 .16
5% ~erum *
S. aureus Smith ~ A9537 .3 o6
S. sureus Smlth + A9537 63 1.3
50% serum ~ I
S. aureus BX 1633-2 A9606 .6 2 1 .
~t 10-3 dilution
S. aureua BX 1633-2 A9606 4 8 ~l
~t 10 ~ dilution
S. aureus methlcil3in~ A15097 8 63 .
resistant a~ 10-
dilution
S. ~ureus at 10-3 A9748 8 63 .
dil~tion
s. Aureus At 10 ? A9748 16 125 ~
dilution ~ . .
Sal. enter~tidis $ A9531 .6 4 .
: ~ E. coli Juhl $ A15119 8 . 8 .
E. coli . ~ ~ A9~75 16 ~ ~ 16 ~
K~ pneumoniae ~ A997716 .~ 4 .
: ~ pneumonia~.i A15130125 ~ ~ 16 .
Pr. mirabills $ A9900 `8 ~ ~ 8
Pr. morgan~ $ A151533~ : >125
p~. aerugiDosa $ A9843A~125 - >125
-Ser. marceScena ~ A20019~2$ ~125
* 50% Nutrient Bro~h - 45~ ~ntibiotic Assay Broth .
$~t 10-4 dilu~on - ~
~ ' . '
,. ~ 33
~1~627~
Table V
M.I.C. ~n mc~. /ml.
Compound Cephs-
Or~anLsm No. 602_ lexin_
û ~ pneumon~ ae ~ A9585 . 60 3
5% serum *
S tr . pyogenes -~ A9604 ~ $ . 6
S% serum *
S. ~ureus Smith ~ A9537 ,3 1.3
S . aureus Smith + A9537 >63 2 . 5
50% ser~m ~
S . aureus BX 1633-2 A96061. 3 4
st 10-3 dilu~ion
S. aureus BX 1633-2 A960616
at 10-2 dilution
. S. aureus methicillin- A15097 4 32
resi~tant at 10-3
d llutlon
S~ au~eus at 10-3A9748 8 32
~ilut~on
S. aureus at 10-2A9748 63 . 63
dilutiorl
Sal. enteritidis ~ A9531 . 3 4
E. coli Juhl ~: A15119 ~ :~ 8
E. coli ~ ~ A9675 16 32
K. pneumonlàe ~ ~ A9977 16 8
K. pneumoniae ~ A1513032 ~ 16
Pr. mirabllis i A9900 16 8
Pr. morganii =~ A15153125. ~125
P8. aeruginos~ ~ A9843A>125 >125 .
Ser. marcescens $ A20019 ~12$ ~125
~k 50% Nutrient Broth ~ 45% Antib~ot~c Ass~y Broth :
~ ~t 10-4 dilution ~ ¦
~ 34 -
~a~6~7
Table VI
M . I . C . in mc ~ . /ml .
C:ompoundCepha-
m No. 587lexin
D O pneumon~ ae ~ Ag.~85 2 . 5 . 3
5% serum *
Str~ pyogenes + A9604 2 . 5 1. 3
S% serum *
S . aureu.s Sm~th ~ A9537 . 3 1. 3
S, aureus Smith ~ A9537 >63 2. 5
50% ~e~
S . aureus BX 1633-2 A9606 . 6 . 4
flt 10-3 dilut~on
S. ~ureus BX 1633-2 A9606 1 4
~t 10-2 dllutlon
S. a~lreus methicillirl- Al5097 4 63
resistant a 10 3
dilut~on
S. aur.eus at 10-3 A9748 4 63
dilution
S. aureus at 10-2 A9748 1~: 125
dilution
Sal. enterit~dis $ A9531 2 . 5 4
E. coli Juhl ~ A15119 I~ 8
E. coli ~ A9675 32 16 -
K. pneumoniae =~ A997732 4
K. pneumoniae =~ A15130 ,~125 16
Pr . m~rabilis ~ A9900 >12 5~ ~ 4
Pr. morganii ~3: A15153 >125 >125
Ps. aeruginosa ~: A9843A ~125 . >125
Ser. marGes~cens ~ A20019 ,~125 ~ ~125
* 50/O Nutrient Broth - 45% Antibiotic As8ay Broth
~t 10-4 dilution
3S -
:~CD62763:~L
Table VII
M~IoC~ in mcg./mlO
Compound Cepha-
~ No. 556 lexin
D. pneumoniae + A9585 1.3 .16
5% serum *
Str. pyogenes + A9604 2.5 .08
5% ~erum *
S. aureus Smith ~ A9537 1.3 .6
S. aureus Smith + A9537 63 1.3
50% s~rum ~ .
S. aureus BX 1633-2 A9606 1.3 2
~t 10-3 dilution
S. aureus BX 1633-2 A9606 4 4
at 10-2 dilution
S. aureus methic~llin- A15097 4 32
resistant at 10-3
dilutlon
S. aureùs ~t 10-3 A9748 ~ 32
: dilution
s. sureus a~ 10-2 A9748 8 : 63
: : ~ dilution
Sal. en~eritidis ~ A9531 ~ 2
E. coli 3uhl ~ ~ A15119 32 ~ 8
: E. coI~ $ A9~75 32 : 16
~ .
K~ pneumoni~e ~ ~A9977 3~ 4
K. pneumoniae $: A15130 125 16
PL~. mirabllis =~ A99ûO 32 4
Pr . morganii ~ A15153 12 5 >125
~s. aerug~nosa $ A9843A 125 >125
Ser. marceseens-~ A20019 63 >125
* 50~/~ Nutrient Broth - 45% Ant:~blot~c Assay Broth
at 10-4 dllution
:
36 -
1~6Z'7~
T~ble VIII
Blood levels in the mouse after oral admini~tration were
determined with the following results:
. ~ , . .
- ._ Bloc d Level _in mc~. /ml.
fi~ S Dose O.5 1 2 3.5
~CH-GONH--~ ~Hrg. aft2r ~dminis-
I . l Imgm. /kg. tration.
~2 6 ~:H2R
C02H
R 8
.. . , ' ,. ~
-S-C ~H3 1.00 34 . 8 30 . 7 13 . 0 7 . O
586
., _ . .... ,._
, ., '
11~3 100 l16.0:14.1 3.4<0.4
567 ~ : -
. ~,
~ . ..
-s-~ ~
I ~ lo~ 6 s 7.9 4.4 3.2
591 : ~
_ .. . .... _~ - --
~1CH3 ~ 1.2 1.4 1.3 1.0
607
,
3 7
~62~
Blood Level in ~g./ 1.
Dose O.S 1 2 3.5
Hrs. after adminis-
m~m. /k~. tration
_ ' .,
. . ...
-sd~ oo Ill.7 17.6 9.7 3.3
602 . .
-S-d;~CH3 100 6.3 S.9 4.3 2.0
587
__ . . '':,~
I CH3 :.
-æ-~ ~sl 100 15.2 16.2 7.8<2.1
556 .
: _ . .
, . .~ .
-H 10044 . 6 ~ 3 . 4 6 . 1 1. 7
(cephalexin) ~onohydrate
. -
~:
~,
', ' ': : '' -
.
.~ 8 ..
.... . , ... ... . . , . . . .... . . . . . _.. . ~ . .. ... .. . . . . .. . .
~627~
An examinat~on of Table VIII shows that
very small struc~ural changes in the 3-acyl-
thiomethyl substituent can greatly affect oral
~bsorption, The very closely-related compounds
S86, 6~7 and 556,` for example, have blood levels
after 3b minutes of 34.8, 1.2 and 15.2 mcg./ml.
An examination o~ Tables I - VII shows the same
unpredictability with respect to in vitro activi-
ties. Compounds 586 and 567 claimed in the
present invention surprisingly and unexpectedly
showed both excellent activity relative to
cephalexin in the primary screening tests and
good or-l absorption proper~ies.
.
. - , '
.~ . .
.
,, .
' ~
..
~ . - 39 -
-~
i270
The novel medicaments provided by the present
inven~on may be formulated as pharmaceutical com-
posltions comprising, in addition to the active
ingredient, a pharmaceu~ically acceptable carrier
or diluent. The compounds may be administered
both orally and parenterally. The pharmaceutical
preparations may be in solid form such as capsules,
~ablets or dragees, or in liquid form such as
solutlons, suspensions or emuls~ons. In the
treatment of bacterial infections in man, the
compounds of th~s invention may be administered
in an amount of from about 5 to 200 mg./kg./day
in divided dosage, e.g. 3 to 4 times a day.
They are administered in dosage units containing
e.g. 125, 250 or 500 mg. of active ingredient
with suitable physiologically ~ccep~able carriers
or excipients.
In the experimental s'ections which follow,
all temperatures unless indicated are in degrees
Centigrade. The abbreviation 'tMeC12" is used
to refer to methylene chloride while '~EA" is
used to indicate triethylamine.
~' :
','':
, ~ :
`
-
~,
.
- 40 -
'
1~627~
PreE~ration Of Starting Materials
Thiazole-2-thiocarboxylic acid dicyclohexylamine
salt
A mixture of 14.2 g. (0.11 moles) of 2-carboxy-
thiazole, 220 ml. of methylene chloride, 13.9 g.
(0.11 moles) of oxalyl chloride and 0.5 ml. of
N,N-dimethylformamide was stirred for 3 hours.
The insoluble material was removed by filtration,
washed with methylene chlorid~ and the filtrate
was evaporated under reduced pressure.to a solid.
This obtained acid chloride was-added portionwise
to a st~rred and cooled solution of 24.2 g. (0,22
moles) o sodium sulfhydrate trihydrate in 247.5
ml.:of ethanol and 27.5 ml. of water ~t such a
rate as to maintain the temperature of the reaction
mixture at 10-15. After the addition was completed,
the mixture was stirred for 40 minutes at 5-10.
Then the ethanol was removed under reduced pres~ure
and the residue was dissolved in 145 ml. of water.
The pH o the solution was lowered to 2.8 by the
addition of 6 N hydrochloric acid, and n~intained
there:while the mixture was ex~racted w~*h 5 x
200 ml. of ethyl acetate. The eombined extracts
were.washed with ice water, dried over:MgS04,
filtered and evaporated under reduced pressure
$o a reddish solid. This was weighe~d,-redissolved ;~.
in 100 ml. of warm ethyl acetate and l:equivalent :-.
of dicyclohexylsmine was added. Bright yellow
crystals start2d to precipitate immediately.
The mixture was cooled in an ice-bath ~or 1 hour.
Then the crystals were removed by filtra~tion?
w~hed with e~her and dried under reduced.pressure
.:
, - 41 -
. .
~627~
for 15 hours; weight 15.2 g. (42.5% yield).
Analysis:
Calcd. for C16H26N20S2: C, 58.88; H, 8.04;
N, 8.62; S9 19.60.
Found: C~ 58.47; H, 8.11;
N~ 8.74; S, 19.91.
7-Amino-3-(2-thiazolyl)carbonylthiomethyl-3-cephem
4-carboxylic acid
Fifteen g. of thiazole-2-thiocarboxylic acid
dicyclohexylamine salt was ~lurried in 175 ml. of
wa~er and layered with 175 ml. of ethyl acetate.
The pH of the cooled solution was lowered to 2.2
by the addition of 6 N hydrochloric acid. The
layers were separated and the aqueous phase was
extracked with 2 x 175 ml. of ethyl acetate. The
combined extrac~s were driecl over MgS04, filtered
and concentrated to a red solid, weight 5.35 g.
The infrared spectrum indicated thioacid.
To a ~tirred solution of 9.8 g. (0.036 moles)
o 7-aminocephalosporanic acid and 6.05 g. (0.072
moles) o~ sodium bicarbonate in 170 ml. of aqueous
phosphate buffer at pH 6.4 was added 5.35 g. (0.036
moles) of thia201e-2-thiocarboxylic acid. The
mixture was stirred in a nitrogen a~mosphere at
50 for S hours keeping the pH at 6.6 with 42%
phosphoric acid. Then the mixture was cooled to
20 and t~e precipitated solid was ~emoved by
filtration, washed with water, acetone and ether ~-
~nd dried in _cuo over phosphorus pentoxide to
provide 4,6 g. (35% yield) of a tan crystalline
solid. Infrared ~nd NMR spectra were consistent
with the structure.
- 42 -
,
.
~ ~ ~Z 7~ ~
Pivaloyloxymethyl 7-amino-3-~2-thiazol~l)carbonyl-
thiome~yl-3-cephem-4-carboxylate_
Method A. The title compound is produced
by substituting for the 7-aminocephalosporanic
acid used immediately above an equimolar weight
of pivaloyloxymethyl 7-aminocephalosporanate
hydrochloride prepared according to Example 2
of U.K. 1,229,453 from 7-aminocephalosporanic
~cid. German 1,904,585 (Farmdoc 39,445~ ls
equLvalent to U.K. 1,3399453.
Method B. The title compound is produced
by substituting for the 0.025 mole (6.8 g.)
7-aminocephalosporanic acid used in the pro-
cedure of Example 2 o~ U.K. 1,229,453 an equi^
molar weight of 7-amino-3-t2-thiazolyl)carbonyl-
thiomethyl-~-cephem-4-carboxylic acid.
The respective acetoxymethyl, methoxy-
methyl, acetonyl and phenacyl esters o~ 7-amino-
3-(2-th~azolyl)carbonylthiomethyl-3-cephem-
4-carboxyl~c acid are prepared by substitut~ng
in Method B above for the chloromethyl pivalate
used therein an equimolar weight of chloromethyl
acetate, chloromethyl methyl ether, chloroacetone
and phenacyl bromide, respectively.
5-Methylthiazole-2-thiocarboxylic acid
dicvclohexvlamine salt
A mixture of 14.3 g. (O o l mole) of 5-methyl-
thiazole-2-carboxylic ~cid in 200 ml.~of dry
methylene` chloride, 12.6 g. (0.1 mole) of oxalyl
chloride~and 0.5 ml. of N,~-dimethylformamide
. .
was stirred for 3 hours at room temperature until
a clear solution resulted. It was concentrated
to a greenish oil, which was identified by in-
frared as the acid chloride. This was added
~ ~3 -
,
Z7~
slowly over 5 minutes to a s~irred and cooled
~olution of 22.0 g. ~0~2 moles) of sodium sulf-
hydrate trihydrate in 225 ml. of 100% ethanol
and 25 ml. of water at such a rate as to keep
the temperature of the mixture at 10-15C.
After the addition was completed, ~he reactio~
mix~ure wa~ stirred for 40 minutes at 5-10.
Then most of the ethanol was removed under
reduced pressure and the residue was dissolved
in 130 ml. of water. The pH of the solution was
lowered to 2.8 with 6 N hydrochloric acid and
was maintained therP, while the mixture was
extracted with 5 x 200 ml. of ethyl a etate.
The combined extracts were washed with ice water,
dried over anhydrous magnesl.um sulfate, ~iltered
and concen~rated under reduced ~ressure to an
orange solid. This was weighed, redissolved.in
100 ml. of warm ethyl acetate and 1 equivalent
(8.25 ml.~ 0.067 mole~) of dicyclohexylamine was
added. Bright yellow crystals started to preclp-
itate immediately. The mixture was cooled for
2 hours in an ice bath. Then the cry~tals were
removed by filtrat~on,washed with ether,and dried
ln vacuo yielding 14 ~. ~41% yield3. IR and NMR
~pectra~were consistent with structure.
Analysis:
Calcd. ~or C17H2~N20S2-1/2.H20: C, 58941; H,~ 8.35
, 8.02; S, 18.35.
Found: C, 58.~8; H, 8.22;
. N, 8.11; s,i 19.30.
5-méthylthiazole-2-~hiocarboxylic:acid
dicycloh~xylam~ne ssle (13.5 g.) was slurried in
- 44 -
~06~7~ 1
150 ml, of water and layered wlth 150 ml. of ethyl
acetate. The pH of the cooled solution was lowered
to 2.2 with ~N hydrochloric acid. The layers were
separated and the aqueous phase was extracted with
3 x 100 ml. of ethyl acetate. The combined
extracts were dried over anhydrous magnesium
sulfate, filtered and concentrated to a red solid
whichr~as identified by infrared as thioacid;
weight 5~44 g.
To a stirred solution of 9.3 g. ~0O034 moles)
of 7-aminocephalosporanic acid and 5.75 g. (0.068
moles) of sodium bicarbonate in 204 ml.: of aqueous
phosphate buf~er at pH 6.4 was added 5.44 g. ~0.034
moIes) of 5-methyl~hiazole-2 thiocarboxylic acid.
The mixture was stirred in a nitrogen atmosphere
at 50 for 5 hours keeping ~:he pH at 6.5 with
42% phosphoric acid. Then l:he mixture was cooled
to 20 and the precipitated solid was removed by
filtration, washed with water, flcetone and e~her
and dried in vacuo over pho~3phorus pèntoxide to
prov~de 4.4 g. (35% yiel~ of ~ ~an crystalline
~olid.~Infrared and N~ spectra were consistent
with the structure.
Pivalo~loxymethyl 7-amino-3-~ me~hyl~iazol-2-
yl)carbonylthiomethyl-3-cephem-4-carboxylate
Method A. The title compound is~produced
by ~ubstituting for the 7-aminocephalosporanic
.
acid used immediately above an equimolar weight
-
o pivaloyloxymethyl 7~aminocephalosporan~te
hydrochloride prepared according to Example 2
of U.K. 1,229,453 from 7-aminocephalosporanic
acid.~Germ~n 1,904,585 (Farmdoc 39,445~ is
equivalent ~o U.K. 1,339,453.
~ '~ ; ..
` ` ,
~ 45 -
'~ .
1062701
Method B. The ~itle compound is produced .
by substituting for the 0.025 mole (6.8 g.)
7-aminocephalosporanic acid used in the pro-
cedure of Example 2 of U.K. 1,229,453 an equi-
molar weight of 7-amino-3-(5-methylthiazol-2-
yl)carbonylthiomethyl-3-cephem-4-carboxylic .
acid. .
The respective acetoxymethyl, methoxy- .
methyl, acetonyl and phenacyl esters of 7-amino-
3-(5-methylthiazol-2-yl)carb~nylthiomethyl-3- .
cephem-4-carboxylic acid are prepared by sub-
8tituting in Method 8 above for the chloro-
methyl pivalate used therein an equimolar weight
of chloromethyl acetate, chloromethyl methyl .
ether, chloroacetone and phenacyl bromide, .
re~pectively.
,, .'
,
~ !
: ` ' `~ '
:
'
''" ~ , ~ ~ '
" '
, ` ~ ' '
,~
~ .
'~ " ,
q~, :
- 46 -
.... ... ,. . .... .. _ . . . . . _ _ . , . . . ... . ._ . . . . . .
~ 7 ~ ~
3-Methyl-1,2~5-oxadiazole-4-thiolcarboxylic acid
A mixture of 10.0 g. (7.8 mmole) of 3-methyl-
1,2,5-oxadiazole-4-carboxylic acid, 40 mlO of
thionyl chloride and 0.5 ml. of N,N-dimethyl-
formamlde was heated under reflux for 66 hours.
The volatLle components were evaporated under
reduced pressure ~t 35C./20 ~m" benzene was
added to the residue and the ~ixture was re-evapor-
ated. The oily acid chloride so obtained was
dissolved in 10 ml. o~ dry benzene and the solu-
~ion wàs added dropwise to a ~;tirred solution of
15~8 g. (17.2 mmole) of sodium sulfhydrate dihydrate
ln 150 ml. of 90~/0 aqueous e~hanol 3t such ~ rate
that the reaction temperature was in the range~
10-12C. After the addition was completed~ the
slurry was stirred f~r 50 minutes at 10-15~C. nnd
then f~ltered. The filtrate was evaporated under
reduced pressure and the residue was dissolved ln
100 ml. of water. The pH of the solution was
lowered ~o 2.5 with 6N hydrochloric acid~nd the
product;was extracted into three 100 ml. portions
of ether. The combined extracts were washed wi~h
wa~er, dried over anhydrous magnesium sulfate ~nd
evaporated to dryness under reduced pressure, The
~ ''
10 6'~7 0 1
resi(3ue was dis~illed to provide a yellow oilD b~p.
40~42C/0.8 mm, Yield 105 g. (13%~. .
7-Amino-3-(3-methyl-1,2~5-oxadiazol 4-yl)carbnYl- .
~_~ .
To a s~irred solut~on of 8.1 g. (29.8 mmole)
o~ 7-aminocephalosporan~c acid and 5.0 g. (59.6
mmole) of sodium bicarbonate in 140 ml. of 0.1 M
~queous phosphate (buffered at pH 6.4) was added
a solut~on of 4.3 g. (29.8 nnnolej of 3~methyl-1,
2,5-oxadiaæole-4-thiolcarboxylic acid in 15 mlO of
acetone. The mixture was ætirred under a nitrogen
~tmosphere for 16 hours at 35C. The product was
collecte~d by filtration, washed with water and .
acetone and dried in vacuo over phosphorus pentoxlde
~o afford 2.77 g. (26~/o) Of tan solid. ~
Analysis:~ .
Calcd.for: Cl2H~2N4o5s2 C9 40.45; H, 3.40;
N, 15.73.
, .
Found: C, 40.47; H, 3.50;
N~ 15.36.
. ,~ .
L~
.. .
4-yl)carbonylthiomethyl~3-ce~hem-4-carboxylate .
Me~hod A.
The title compound is produced by substituting
Por the 7-aminocephalosporanic acid used immediately
above an equimolar weight of pivaloyloxymethyl
7-aminocephalosporanate hydrochloride prepared
~L0~2701
accordlng to Example 2 of U.K. 1~229,453 from
7-ari~lnocephalosporanic acid. German ï 9 904,585
(Farmdoc 39,445) is equivalent to U.X. lj339,453.
Me~hod B.
The title compound is produced by substitutin~
for the 0.025 mole (6.8 g.) 7-aminocephalosporanic
~cid used in the procedure of Example 2 of U.K.
1,229,453 an equlmolar weight of 7-amino-3-(3-methyl-
~ S-oxadiazol-4-yl)carbonylthiomethyl-3-cephem~
4-c~rboxylic acid.
The respective ace~oxymethyl, methoxymethyl, .
ace~ony~ and phenacyl esters of 7-amino-3-(3~methyl-
1,2,5-oxadiazol-4-yl)carbonylthiomethyl-3-cephem-
4-carboxylic acid are prepared by substituting in
Method B above for the chloromethyl pivalate used
therein an equimolar weight of chloro~ethyl acetateJ
chlor~methyl methyl e~her, chloroacetone and phen~cyl
bromide~, respectively.
' :
-
''.
;
~ 4 ~6 -
~ ,, ~
~(~6~7~
EXAMPLES
. .
The following examples are given ~n illus~
tration of 9 but not in limitation of, the present
invention.
~xample 1
:
7-~D~ a-Amino~henylacet~mido~-3-(thiazol-2- -
~=~ L -.
CH-~-NH ~.S ~ ~
~H2 ~ ~ CH~-S-~ ~ S J
COO~ . -
~8L-S567)
T~ a stirred slurry of 4.5 g. (0.0126 m~le~)
of 7-~mino-3-(thiazol-2 yl)carbonylthiomethyl-3~
cephem-4~carboxylic acid in 125 ml. of d~y methylene
chloride were ~dded successively 3052 mI. tO.0252
moles): of triethylamine, 1.62 ml. (0.0126 moles)
of N, N-dimethylaniline and 4.72 mlO (0~0378 moles)
of trimethylchlorosilane. After being refluxed for
0.5 hour a clear brown solution resul~ed. It was
cooled~to 0-5 and 2.B6 g. (0.0138 molea) of D~ 2-
phenylglycyl chloride hydrochloride was added.
The resulting slurry w2s stirred for 2` h~oura letting
the temperature rise to 25. This was then added
to 125 ml. of ice water. The resulting tan precipi-
~ate was s~irred for 15 minutes at room ~emperature~
filtered~ w~shed with water, acetone and eeher
~nd ~ried in vacuo over phosphorus pentoxide
y~eldlng~3.8 g. of fl tan solid. The layerfi of the
- 47 - 1
. . _ . . _ . . _. . ,, , ,, . , , j :
~L~6~0~
filtrate were separated and the aqueous phase was cooled,
layered with 100 ml. of ethyl acetate and adjusted with 10%
sodium hydroxide to pH 4.2. The resulting white solid was
removed by filtration, washad with water, acetone and ether
and dried ln vacuo o~er phosphorous pentoxide to give 475 mg.
The 3.8 g. of the first precipitated solid was purified by
slurrying in 50 ml. of water and 50 ml. of ethyl acetate and
acidifying to pH 1.5 with 6 _ hydrochloric acid. It was stirred
for 15 minutes and then filtered~ The filtrate was treated
with 10~ sodium hydroxide to give pH 4.5. The solid which
precipitated was collected by filtration, washed with water,
acetone and ether and dried in vacuo over phosphorus pentoxide
to give another 900 mg. Combined solids weighed 1.37 ~. (22%).
Infrared and NMR spectra were consistent with structure of
the title product.
Analysis:
Calcd. for C20H18N4O5S3 H2O: C, 47.60; H, 3-98; N~ 11-03-
Found: C, 47.40; H, 3.89; N, 10.79.
Example 2
.
Sodium 7-~D-t-)-~-amino~henylacetamido]-3-(thiazol-2-yl)-
carbonylthiomethyl-3-cephem-4-carboxylate
CH C NH ~ S
2 O N ~ 2 ~ S
COONa -
To a stirred aqueous suspension of the zwitter-
ionic form of 7-[D-(-)-~-aminophenylacetamido]-3-(thiazol-2-
yl)carbonylthiomethyl-3-cephem-4~carboxylic acid (0.8 mmole)
is added lN aqueous NaOH at room temperature until a clear
solution (pH 10.8)
,''.''''' ~
- 48 -
....... .. . .....
iZ701
i~ obtained. The solution is ~m~edifltely freeze-
dried to give impurej solid sodium 7-[D~ a-
amlnophenylDcetamido)-3-(thiazol-2-yl~)carbonyl-
thiomethyl-3-cephem-4-carboxylate~
Following the same general procedure as abov.e,
u~e of lN KOH in place of the lN NaOH used therein
produces potassium 7- 1D-(-) -a-amlnophenylacetamldo]
-3-(t~iazol-2-yl)carbonylthiomethyl-3-cephem-4-
carboxylate.
~ .
7 ^ ~_ a _no -a- (3-thienyl)acetamido]-3-(thiazol-2-
yl~c~rbonylthiomethyl-3-ce~hem-4-car xvlic acid
r3 - CH-~-NH ~ 4 ~IN
COOH
The 3bove compound is prepared by s~bstituting
an equ~molar weight o~ D-(-)-a-amino-a-(3-thienyl~
acetyl chlorlde hydrochloride in ~he procedure of
: . Ex~mple 1 for the D-(-)-a-amino-~-phenylacetyl
:~ chloride hydrochlorlde used ~herein.
: Example 4
a-amino-~-~2-thieny~2acetamido~-3-(_h~azol-
I~CH-C NH
NH2 ~ ~ CH2~ S~ 11 S
The above compound is prepared by substituting
~n equimolar weight of D~ a-amino-a~(2-th~enyl)
49 ~ :
.
,
~0 6~7 ~ ~
acetyl chloride hydrochloride in the procedure of
Example 1 for the D~ a-amino-~-phenylacetyl
chloride hydrochloride used therein.
Example 5
Acetoxymethyl 7~ amino~henylacetamldo¦-3-
H-~-NH ~ S
NH2 ~ ~ CH2-S-~
COOCH20COCH3
.
To a solution of acetoxymethyl 7-amino-3-
(2-thiazolyl)carbonylthiomethyl-3-cephem-4-
carboxylate (regenerated fxom 00009 mole of its
hydrochloride) in 30 ml. ethyl acetate ~s added
0.020 mole pyr~d~ne. The ~ixture iB co~led in
ice and s~irred while 0.010 mole D-~-)-2-phenyl-
glycyl chloride hydrochloride in 30 ml. ethyl
~cetate is added over ten minutes. After a
further 20 minutes ` in the cold, stirring ~ s
continued at room temperature for 1 hour. Then
the mixture is washed successively wit~ aqueous
NaHC03, 0.1 N HCl and water, dried ~nd evaporated
in vacuo to leave the desired aeetoxymethyl
7 - 1D~ aminophenylacetamidol-3-(thiazol-
2-yl)carbonylthiomethyl-3-cephem-4-c~rboxylate
a~ ~n oll which crystallizes upon tritura~ion in
cycl~hexane.
The re~pective pivaloyloxymethyl~ methoxy-
methyl~, acetonyl and phenacyl esters corresponding
.
..
- 50 -
627~L
to the absve acetoxymethyl ester are produced by
replacing ~he acetoxymethyl 7-amino-3-(2-thiazolyl)-
carbonylthiomethyl-3-cephem-4-carboxylate hydro-
chloride used in the above procedure with 0.009
mole of the hydrochlor~de of pivaloyloxymethyl,
methoxymethyl, acetonyl and phenacyl esters of
7-amino-3-(2-thiazolyl)carbonylthiomethyl-3-
cephem-4-carboxylic acid, respectively.
F,xample 6
Acetoxymethyl 7-[D-a-amino-~-(3-thienyl~acetamido]-
3-~thiazol-2-yl~carbonvlthiomethyl-3-ce~hem-4-
carboxylate
o
CH-C-NH ~.S N
NH2 ~ N~ ~ CH2-S~
' ~OOCH20COCN3
. The above compound is prepared according to
Example 5 by substituting for the D~ 2-phenyl-
glycyl:chloxide hydrochloride used therein
an equimolar amount of D-(-) -a-amino-a- (3~thienyl~
- ace~yl chloride hydrochloride.
~ The respective pivaloyloxymethyl, methoxy-
methyl, acet~nyl and phenacyl esters corresponding
- to the~:above acetoxymethyl ester are produced by
replacing the acetoxymethyl 7-amino-3 ~2-thlazolyl)-
c~rbonylthiomethyl-3-cephem-4-carboxylate hydro-
chloride used in the ~bove procedure with 0.009
mole of the hydrochloride of plvaloyIoxymethyl,
methoxymethyl, acetonyl and phenacyl~esters of
7-amLno~3~(2-thiazolyl~c~rbonyl~hiomethyl-3-cephem-
4-carboxylic acid, respectively. `
.
- 51 -
~627
Example 7
A ~ o-a-~2-thienyl~acetamido~
-3-(thiaæol-2-yl)carbonylthlomethyl-3-cephem-4- -
. .
carboxylate
1~ CH-C-IIH~S~ _~3
; 2 ~ CH2-S-C
COOCH20COCH3'
The above compound is prepared according to
Example 5 by substituting for the D-(-)-2-phenyl-
glycyl:chloride hydrochloride used there~n an
equimolar amount of D-(-)-a-amino-a-(2-th~enyl)
ace~yl chloride hydrochloriLde.
The respective pivaloyloxymethyl9 methoxy-
methyl, acetonyl and phenac:yl esters corresponding
to the above acetoxymethyl ester are produced by
replacing the acetoxymethyl 7-amino-3-(2-thiazolyl)-
carbonylthiome~hyl-3-cephem-4-carboxylate hydro-
chloride used in ~he above procedure with 0.009
mole of the hydrochloride of pivaloyloxymethyl,
methoxymethyl, ac,etonyl and phenacyl eseers of
7-amino-3-(2-thiazolyl~carbonylthiomethyl-3-
: cephcm-4-carboxyllc acid, respectively.
:
.
,
: - 52 -
;~ ,
~6Z~
Example
7- [D~ a-Aminophenylac2tamido 1-3- (5-methylthiazol-
2-y~?carbonylthiomethyl-3-cephem-4-carboxylic acid
o
H_C_NH ~S ~ ~
NH2 ~ CH2_S-C ~ ~ H3
~ ~ B s
(BL-S586~ CO2H
To a ~tirred slurry of 4.4 g. (0.0119 mole~)
of 7-amino-3-(5-methylthiazol-2-yl)carbonylthiomethyl-
3-cephem-4-carboxylic acid in 120 ml. of dry methylene
chloride were added successively 3.34 ml. (0.023
moles~ of triethylam~ne~ 1.51 ml. (0.011~ moles~ of
M,N-dimèthylaniline and 4.45 ml. (0.0357 moles) of
trimethylchloro~ilane. After being refluxed for 40
minutes, a clear yellow 801ution resulted. It was
cooled to 3~ C. and 2.7 g. (0.0119 moles) of D~ 2-
phenylgl:ycyl chloride hydrochloride was added with
vigorous stirring. The resulting ~lurry was stirred
for 2 hours letting the ~emperatur2 rise to 20. This
was then added to 120 ml. o~ ice water and the
resulting tan precipitate was stirred for 30 ~nutes
~t room temperature. It was filtered, washed wi~h
wa~erj~acetone, and ether and.dried in vacuo over
phosphorus pentoxidè yielding 4.1 g. of a tan solid.
The layers of the filtrate of the tan ~olid were
~epar~ted and the aqueous phase was cooled, layered
with lOO ml. of ethyl acetate and adjustèd with 10%
sodium:hydroxide to pH 4.2. The resulting white
solid was removed by filtration, washed with water,
acetone; and ether and dried in vacuo~to give 75 mg,
The 4.1 g. of the first precipit~ted solid was
purifled by slurrying in 50 ml. of w~ter and 50 ml.
,.
~ 53 ~
~ ~ 6 ~ 7~ ~ :
of ethyl acetate and acidifyi~g to pH 1.5 wlth 6 N
hydrochloric acid. It was stirred for 15 minutes and
the insoluble m~terial was filtered off. The filtrate
was treated with 10% sodium hydroxide ~o give pH
4.5. The solid which precipitated was collected by
filtration, washed with water, acetone3 and ether
and dried in vacuo over phosphorus pentoxide to give
575 mgl Combined solids weighed 650 mg. ~ /o yield).
Infrared and NMR spectra were consistent with
~truc~ure.
Analysis:
Calcd. for C21~20N4OsS3 2H2o N 10 35'
Found: C, 47.06; H, 4.97;
N, 9.35. :
Example 9
Sodium~7-[D~ aminophenylacetamido~-3-~5-methyl-
thiazol-?.-yl~carbonylthiomethyl-3-cephem-4-carbo ylate
H~_NH ~ S ~ ~
N~2 ~ ~ H2-S~ CH3
. CO~Na
To a st~rred aqueous suspension of the zwitterionic
for~ o~ 7- 1D~ a-aminophenylacetamido]-3-(5-methyl-
thiazo~-2-yl)carbonylthiomethyl-3-cephem-4-carboxylic
acid (0.08 mmole) is added lN aqueous NaOH at room
temperature until a clear solution ~pH 10.8) is obtsined.
The solution is lmmediately freeze-dried to give impure,
solid sodium 7-~D~ -amlnophenylacetamido]-3-(5-methyl-
thiazol-2-yl)carbonylthiomethyl-3-cephem-4-carboxylate.
'
. - 54 -
,-- ,
, ;", ,- ; . I
, .. - . . _ . . . .
6Z7~1
Following the same general procedure a~ above~
use of lN KOH in pl~ce of the lN NaOH used therein
produces potassium 7-[D~ a-aminophenylacetamido]-
3-(S-methylthi~zol-2 yl)carbonylthiomethyl-3-cephem-
4-carboxylate.
Example 10
acid ' -:
3 ~H ~ ~ ~ CU S C ~ ~ CU
IJ2H
The above compound is prepared by substituting
an equimol~r weight of D-(~ amino ~-(3~thienyl)-
acetyl chloride hydrochloride in the procedure of
Example 8 for the D~(-)--2~phenylglycyl chloride
hydrochloride used therein.
7-~D-~-amino-~-S2-thienyl)acetamido]-3~o(5-methyl
~cid
H_C NH
2 O~ ~ CH2-~-p CH3 :~
CO~H
The ~bove compound is prepared by substltuting
~n equimo~r weight of D-(-)-a-amino-a-(2^thienyl)-
;. . - 55 -
acetyl chloride hydrochloride in the procedure
of Example 8 for the D-(-)-.alpha.-amino-2-phenylglycyl
chloride hydrochloride use therein.
Example 12
Acetoxymethyl 7-[D-(-)-.alpha.-aminophenylacetamido]-3-
(5-methylthiazol-2-yl)carbonylthiomethyl-3-cephem-4-
carboxylate.
<IMG>
To a solution of acetoxymethyl 7-amino-3-
(5-methylthiazol-2-yl)carbonylthiomethyl-3-cephem-
4-carboxylate (regenerated from 0.009 mole of its
hydrochloride) in 30 ml. ethyl acetate is added
0.002 mole pyridine. The mixture is cooled in
ice and stirred while 0.010 mole D-(-)-2-phenyl-
glycyl chloride hydrochloride in 30 ml. ethyl
acetate is added over ten minutes. After a further
20 minutes in the cold, stirring is continued at
room temperature for 1 hour. Then the mixture is
washed successively with aqueous NaHCO3, 0.1 N HCl
and water, dried and evaporated in vacuo to leave
the desired acetoxymethyl 7-[D-(-)-.alpha.-aminophenyl-
acetamido[-3-(5-methlthiazol-2-yl)carbonylthiomethyl-
3-cephem-4-carboxylate as an oil which crystallizes upon
trituration in cyclohexane.
The respective pivaloyloxymethyl, methoxymethyl,
acetonyl and penacyl esters corresponding to the
above acetoxymethyl ester are produced by replacing
- 56 -
3L~62~
the ~cetoxymethyl 7-amino-3- (5-methylthiazol-2-yl) -
carbonylthiomethyl-3-cephem-4 carboxylate hydro-
chloride used in the ~bove procedurc with O . 009
mole o~ the hydrochloride of pivaloyloxymethyl,
methox~ethyl, ~cetonyl and phenacyl esters of
7-amino-3-~5-methylthiazol-2-yl~carbonylthiomethyl-
3-cephem-4-carboxylic acid respeetively.
,
Example 13
~ -.
3-~5-methylthiazol-2-yl)carbonylthiomethyl-3-cephem-
4-carboxylate
,
H2-S~ SJ--CI~3
COOCH20COC H3
- ' . :
The above compound is prepared according to
: Example 12 by ~ub~tituting for the D-(-)-2-phenyl- :-
:~lycyl chloride hydrochloride used therein an
equimolsr amount of D~ mino-a-(3-thienyl~
acetyl chloride hydrochlor~de.
: The~respective pivaloyloxymethylg me~hoxy-
methy~ cetonyl and phenacyl esters cor~esponding
to ~he~a~ove ~cetoxyme~hyl ~ster are produced.by
repla~ing the acetoxymethyl 7-amlno-3-(5~methyl
thiazol-2-yl)carbonylthiomethyl-3-cephem-4-carboxylate
hydrochloride used in the above procedure with 0.009
mole of the hydrochloride of plvaloyloxymethyl,
methoxymethyl, ~cetonyl and phenacyl esters of
. 7~mino-3-(5-me~hylthiazol-2-yl)carbonylthiomethyl-
~ ;3-cephem-4-carboxylic acid, respectively~
.- ',:''^" ' . ........................... ' '
..
57
1062~
Ex~mple 14
Acetoxymethyl 7-[D-a-amino-a-(2-thienYl)acetamidO1-
3-(5-methylthiazol-2-yl?carbonylthiomethyl-3-cephem
4-c~rboxylate
CH ~_NU S IN ~ C
O ~ CH2-S-~ ~ S H3
COOCH~OCOCH3
.,
The above compound is prepared according
to Example 12 by substitut:ing for the D~
2-phenylglycyl chloride hydrochioride used
therein ~n equimolar amount of D-(-)-a-amino-
a-(2.-thienyl)-acetyl chlor.ide hydrochloride.
The respective pivaloyloxymethyl, me~hoxy-
methyl,.acetonyl and phenacyl esters correspondin~
to the~above acetoxymethyl ester are prep~red by
r2pl~ing the acetoxymethyl 7-~mino-3~(5-methylthiazol- -
2-yl)car~onyl~hiomethyl-3-cephem-4-carboxylate hydro-
chloride used in the above procedure with 0.009 mole
of the hydrochloride of pivaloyloxymethyl, methoxy-
methyl, acetonyl and phenacyl esters ~of 7-amino-3-
(S-methylthiazol-2-yl)carbonylthiome~hyl-3-cephem-
4-carbaxylic acid, rcspectively.
Example 15
,
` The general procedure of Example 2 is repeated
using the zwitterionic form~ of the acids shown below
.
. 58 -
:, , . ' , ': ' . , , . ,. , -
~L~627~
in place of the 7 [D~ a-aminophenylacetamidol-
3-(thiazol-2-yl)carbonylthiomethyl-3-cephem-4-
carboxylic acid ~sed therein.
' Use Of:
- 7-lD-a-amino--(3-thienyl)acetamido]-3-
~thiazol-2-yl)carbonylthiQmethyl-3-cephem-4-
carboxylic acid,
7-[D-a-amino-a-(2-thienyl)acetamido]-3-
(thiazol-2-yl)carbonylthiomethyl-3-cephem-4-
carboxylic acid,
7-[D-a-amino-a-(3-thienyl)acetamido]-3-
(5-methylthiazol-2-yl)carbonylthiomethyl-3-
cephem-4-carboxylic acid, and
7-[D-a-amino-a-(2-thienyl)acetamido]-3-
(5-methylthiazol-2-yl)carbonylthiomethyl-3-
cephem-4'carboxylic acid
produc,ed9 respectively,
sodium 7-[D-~-amino-a-('3-thienyl)acetamido]- , '
3-~thiaæol-2-yl)carbonylthiomethyl-3-cephem-4-
carboxylate,
pot~s~ium 7-~D-a-amino-a-(3-thienyl)acetamido]-
3-(thia:zol-2-yl)carbonylthiomethyl-3-cephem-4- .
carboxylate,
sod~ùm 7-lD-a-amino a-(2-thienyl~aeetamido~-3
, (thiazol-2-yl)carbonylthiomethyl-3-cephem-4-carbox-
ylate~ ~
.' potasslum 7-1D--amino~ 2-thienyl)acetamido]-
, 3-(~hiazol-2-yl)carbonylthiomethyl-3-cephem-4-
.;,., carboxylate,
. sodi~um 7-[D-a-amino-~-(3-thienyl)a'cetamido]-
.` ~3-(5-methylthiazol-2-yl)carbonylthiomethyl-3-cephem-
~.;.4-c~rboxyla~e~
: potassi~m 7-[D-a-smino-a-(3-thienyl)~ace~amido]-
.-'.3-(5-me~hylthiazol-2-yl)carbonylthio~,ethyl-3-cephem-
.`' 4-carboxylate,
, .
....:~
. " _ 59 _
...... .. _, .
.. . .. ..
3~06Z70~
sodium 7-1D-a-amino-a-(2-thienyl)acetamido]~
3-(5-methylthiazol-2-yl)carbonylthiomethyl 3-cephem-
4-carboxylate, and
potassium 7-[D-a-amino-a-(2-thienyl)acetamidol-
3-(5-methylthlazol-2-yl)carbonylthiomethyl-3-cephem-
4 c~rbcxylate.
.
~` -
.
" ',~
. : ;:
- 60 ~
` ~ ~ 62 7
xample 16
7-[D-~ a-Aminophenylacetamido]-3-(3-me~hyl-l~2,
5 oxadiazol-4 -Yl? carbonYlthiomethYl-3-cePhem-4-
carboxylic acid
.
N
N~2 ~-S~
. ~ ...
To a stirred slurry of 2.70 g. (7.6 mmole) of
7-amlno-3-(3-methyl^l,2 9 5-oxadiazol-4~yl)carbonyl- .
thiome~hyl-3-cephem-4-carboxylic 3cid in lO0 ml.
of dry methylene chlor~de were added in succession
1~54 ~.;(15~2 mmole) of triethylam~ne~ 0.~92 g. ~7.6
mmole) of N,N-dLmethylanil~ne and 2.48~g. ~7.~ mmole)
of trimethylchl~rosilane~ The mixture was heated .
under reflux for 20 minutes and the resùl~ing c~ear
60lutlon was cooled to ~O :In one poxtion, 1.57 g. ~:
~70~ mmole) o D~ 2-phenylglycyl chloride hydro-
chloride was added and the mixture was stirred:vigorously
for 1 hour at 2~5 and for l hour without ex~ern~l
,
. cooline.~ Addition of 50 ml. of water c~u~ed the
,
:.
., . ., . . , . .. , . , . . . . . .. : . . . .. 1
~ ~Z 7 ~ ~
product to precipit~te and the solid was collected by
f~ltration, washed with wster and acetone and dried
in vacuo over phosphorus pen~oxide to provide 2.1 g.
(56%) of amorphous solid, mp 180-182C~ (decO). The
infrared spectrum (KBr disc) showed absorption
maxima (cm~l) at 1780 (~-lactam carbonyl)~ 1690
(amide carbonyl), 166n (thiolester carbonyl), 1620
and 1395 tcarboxylate) an~ 710 (phenyl~. The NMR
~pectrum of a solution in d6-dimethylsulfoxide and
deuterium oxide gave signals (ppm from tetramethyl-
~lane) which were assigned as follows: 7.47 (s, 5H)
due to the benzene ring proton~:; 5.72 (d, lH) for
the C7 proton; 5.03 ~s, lH) far the benzylic proton;
4.~7 (d,: lH) for the C6 proton~ 2.50 (s~ 3H) for the
methyl protons; AB quartets centered at 4.15 and 3.50
~or the exomethylene and C~ methylene protons respec-
~ively.
This sample of 7-lD~ -aminophenylacetamido]-
3-(3-methyl-1,2,5-oxadia~ol-4-yl)carbonylthiomethyl~
3-oephem-4-carboxyllc acid (called New Compound).after
~olution:in ~MS0 (dimethyl sulfoxide) at 14 mgm./ml.
followed by dilution with Nutrient Broth was found
to exhibit the following Minimum Inhibitory Concen~
tr~tions (M.I.C.) in mcg./ml. versus the indicated
mlcroorgani~sms as determined by overnight incub~tion
at 37~C. by tube dilution. The in v~tro activity
of cephalexin, a commercial o~al cephalosporin, is .
included in Table I.
- 62 -
... . . . ... . . . . ..
7~L
Table I
M. I . C in mc$ . /ml .
New Cepha- -
~ ~ lexin
D. pneumoniae ~ A9585 . ûl . 08
57O serum *
Str . pyogenes ~ A9604 . Ol ~ 08
5Z serum *
S, aureus Smith $ .A9537 . 6 . 6
S . aureus Smith + A9537 32 l. 3
50% serum $
S. aureus BX 1633-2 A9606 2 . 5
at lO-3 dilution
S, aureu~ BX 1633-2 A961D6 8 2
st lO- dilu~ion
S. aureus me~hi~illin- Al5097 32 16
resistant at 10-3
dilut ion
S. aureus a'c 10~3 A97483 2 16
dilut io n
S,. aureus at lO-2 A9748 32 ` 63
: dilution
Sal, enteritidis ~ A9531 1 2
E~, coli Juhl ~ Al5119 32 8
~:E. coll ~$ A~675 32 . ~ 16
X . pneumoniae ~ A9977 8 ~ ~ 4;. .
K. pneumon~iae $ Al5l30 63 ~ 16
Pr. miràbilis t A9900 4 4
Pr. mor~anii ~ A15153>125 ~125
Ps. aeruginosa ~: A9843A>125 .>125 `;
Ser. marceseens ~ ; A20019~l25 >l25 -.
* 5070 Nutrient Broth - 457O Antlbiotic Assay Bro~h
at 104 dilution
_ 63_
. .
'
~ 6iZ7~1
Blood levels in the mouse afoer oral admlnistration
were determined with the following results: -
Blood Level in mcg./ml.
R Dose 0.5 1 2 3.5
CH-C-NH~r-- ~ ~ mgm./kg. HrsO after adminis-
NH~ ~ ~ ~ -CH2 - tral:iGn,
C02H
~ ~ .. ........ .. . --' , _
CH3
100 ¦ 38.6 Z8.3 I3.7 4.4
' -- ~ ,
loo 4104 26. 7 6 .o o . 87
cephalexin) monohydrate
..
.~ ,
,
.
. ,. ? , ~. ' . i ' ,
, ,", . ~ ~ 9 . .
., , .~
'; ' ' ' ',: ,. . .
` _ '; ~', " ',- *,, ' ' :
64 ~
~ ,. ..; ..; .; ,,~,;,.. ,.,:...
6~ 7
__ 7
~ ,.
~CH ~ H ~ S~
NH2 o~N ~H2-S-~
To a stirred aqueous suspension of the zwitter~
ionic form of 7-lD~ a~aminophenylace~am~do]-3~
~3 methyl-19~,5-oxadiazol-4~yl)carbonylthiomethyl-
3 cephem~4-carboxylic acid (0.8 mmole) is added
lN aqueous NaOH at room temperature untll a clear
solution (pH 10.8) is ob~ained. The solution is
~mmediately freeze-dried to give impure, solLd
sodium 7~[D~ aminophenylacetamido]-3-(3-methyl-
1,~,5-oxadiazol-4 yl)carbonylthiomethyl-3-cephem-
4~carboxylate.
Following ~he same general procedure as above,
use of lN XOH in place of the NaOH used therein
produces potass~um 7 lD-(-3-~-aminophenylacetamido]-
3~t3-methyl-1?2,5-oxadlazol-4-yl)carbonylthiomethyl-
3-cephem-4~carboxylate~ . .
- ~5 ~ .
t ~ ~r~ r
7~
7 --1D~ a-Amino-a- (3-thienyl)acetamidol-3-(3-methyl-
1~2,5-oxadiazol-4-Yl~arbon~lthiomethyl-3-cephem-4-
c~rboxylic acid
h_C_NH
NH2 N H~-S-~
COOH
The above compound ~s prepared by substitut~ng
an equimolar weigh~ of D~ mino-~-(3-thienyl)-
~cetyl chlorlde hydrochloride in the procedure of
Examplel~ for the D-(-)-2-phenylglycyl
chloride hydrochloride used therein
Example19
~rbollvlic ~-id,
.
~H-C-NH ~ S ~ C ~
~ CH~ S ~ ¦
The ~bove compound is prepared by ~obstituting
an ~quimolar weight of D-(-)-a~amino~a-(~2-thienylj-
acetyl chloride hydrochlor~de in the procedure of
Example 16 for the D-(~)-2~phenylglycyl
chloride hydrochloride used therein. :
:~ 66 ~ `
3L~62
~e~Q
A ~ ~ b~5~5~L~ooa~2
3-cephem-4-carboxylate
~IH-RC-~ L R
NH2 ~ CH2-S-C ~ ~
COOCH20COCH3
To a ~olution of acetoxymethyl 7-amino-3-
~3-methyl-1,2,5-oxadiazol-4-yl)carbonylthiomethyl~
3-cephem-4-carboxylate (regenerated from 0.009 mole
of l~s hydrochlor~de) in 30 ml. ethyl acet~te is
added 0.020 mole pyridine. Th~ mixture is cooled
in ice and st~rred while 0.010 mole D-(-)-2-phenyl-
glycyl chloride hydrochloride in 30 ml. ethyl acetate
i3 ~dded over ten minu~es. After a furtller 20
m~nute~ in the cold, stirring ls continued at rooD
temperature ~or 1 hour. Then the mixture is washed
success~vely with aqueous NaHC03, O.lN HCl and
water, drled ~nd evaporated in vacuo to leave
~he desired ~cetoxy~ethyl 7-[D~ aminophenyl-
sce~amido3~3-~3-methyl-1,2 5-oxadia2O1-4-yl)carbonyl- ;
thiomethyl-3-cephem-4-carboxylate as an oil which
crystallizes upon trltura~ion ln cyclohexane,
The re~pec~ive pivaloyloxymethyl~ methoxy-
methyl, acetonyl and phenacyl esters correspondlng
~ 7
~6Z7~1
to the above acetoxymethyl es~er are produced by
repl~cing the acetoxymethyl 7 amino-3-(3-methyl-
1,2,5-oxadiazol-4-yl)carbonylthiomethyl-3-cephem-
4-carboxy-late hydrochloride used in the above
procedure with 0.009 mole of the hydrochloride of
piv~loyloxymethyl~ methoxymethyl, acetonyl and
phenacyl esters of 7 amino-3-(3-methyl-1,2,5-
oxadiazol-4-yl)carbonylthiome~hyl-3-cephem-4_
carboxylic ecid, respectively.
Example2,-1
Acetoxymethyl 7-[D~ -amino-~-(3-thien~l)-
acet~m~do~-3-(3-methy~ 2,5-o:Kadiazol-4-Yl)carbonyl
thiome~hyl-3-cephem-4-carboxylate .
~H2 ,~Cd2-s R~I
COOCH20COCU3 -- -
The above compound is prepared according to
Example aPby substituting for the D-(-)-2-phenylglycyi
chloride hydrochloride used therein an equimolar
amo~mt of D~ -amlno~:a-(3-thienyl)acetyl chloride
hydrochloride. ~ ~
The respective pivaloyloxymethyl, me~hoxymethyl,
~cetonyl;and phenaeyl esters correspondlng to the
above ocetDxymethyl e~ter ~re produced by replacing
the acetoxymethyl 7~amino-3-(3-methyl-1,2,5-ox~diazol
- ~8
,
- - -
- ~ \
~ 6 Z7 ~ ~
4-yl)carbonyl~hiomethyl-3-cephem-4~carboxylate
hydrochloride used ln the above procedure with
0.009 mole of the hydrochloride of pivaloyloxy-
methyl, methoxymethyl, acetonyl and phenacyl
ester~i of 7-amino-3-(3-methyl-1,2 9 5-oxadiazol-
4-yl)carbonylthiomethyl-3-cephem-4-carboxylic
acid, respectively.
-
Acetoxymethyl 7-[D-(-)-a-amino ~ -thienyl)-
acetamldo]-3~(3-methyl-1,2,5-oxadiazol-4-yl)carbonyl-
thiometh~l-3-cephem-4-carboxylate
.
NH ~ ~ ~ ~ N
2 ~ N ~ CH2-S~
COOCH~OCOCN3
The a~ove compound is prepared accord~ng to
Example2~ by su~stituting for the D~ 2-phenyl-
glycyl chlorlde hydrochloride used therein an
equimolar amount o~ D~ -amlno~-(2~th1enyl3-
~cetyl chloride hydrochloride.
The respeetiYe pivaloyloxyme~hyl, methoxy~
methyl, acetonyl and phenacyl esters corresponding
to the above ~cetoxyme~hyl ester are produced
by replncing the acetoxymethyl 7~amino-3-(3-me~hyl-
1, 2, 5 -oxadlazol ~4-y~) carbonylthiomethyl-3-c ephem-
4-carbo~ylate hydrochloride used ~ n the above
procedure with 0.009 mole of the hydrochloride of
.
_ 6~ _
~ ~ 6Z 7~ ~
pivaloyloxymethyl, methoxymethyl, ~cetonyl snd
phenaeyl esters of 7-amino-3-~3-methyl-1,295-
oxadiazol-4-yl)carbonylthiomethyl-3-cephem~4-
c~rboxylic acid, respectively.
Example 2-3
The general procedure of Example 1~ is repeated
using the zwitterionic forms of the acids shown
below in place of the 7-~D~ a-aminophenylacetamido~
3~3-methyl-1,2,5-oxadiazol-4-yl~earbonylthiomethyl-
3-cephem-4-carboxylic acid used therein.
Use of:
7-[D~ a-amino-a-(3-thienyl)acetamido]-3-
(3-me~hyl-1,2 9 5-oxadiazol-4-yl)carbonyl~hiomethyl-
3-cephem-4-carboxyl~c acid, and
7 - [D~ a~amino-a- (2-~hienyl)acetamido]-3-
(3-methyl-1,2,5-oxadia~ol-4-yl)carbcnylthiomethyl-
3-cephem-4-carboxylic acid produeed, respectively,
Sodi~m 7 lD~ a-amino-a-(3-thienyl)acetam~dol^
3-(3~methyl-l,2,5-ox~d~szol-4-yl)carbonylthiomethyl- -
3-cephem-4-carboxylate,
Potassium 7-[D~ a-amino-a-(3-thieny~)ace~amido3
3- (3-methyl-1, 2, 5 -oxadlazol~4-yl) carbonylthiomethyl-3 -
cephem~4-carboxylate,
Sodium ~[D-(-) Da-amino ~a- (2-thienyl)~acetamido]- -
3-(3-methyl-192,5-oxad~azol-4-yl~carbonylthiomethyl~
3~cephem-4~carboxylate, ~nd
. ~ , . - ' .
_ 70 ,
~06;~70~
Potassium 7-[D-~ ~-a-amino-a-(2-th~enyl)-
~cetamido]-3-(3-methyl-1,2,5-oxadiazol-4-yl)-
carbonylthLomethyl-3-cephem-4-carboxylate.
' ` .
: - :
: :
.
- -
:
,
.
