Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
5~
- 2 - HOE 79/F 087
Subject of the present invention are cephem derivati
ves of the formula I
O R1 (O~ :
C- CNH ~ S~
b CH3 O N ~ CH2R
COOH
~--~
wherein
n is O or 1,
R1 is hydrogen or low-molecular alcoxy and
R2 is azido or a radical -SR3, in which R3 is an op-
tionally substituted five- or six-membered hetero-
cycle, optionally carrying a fused benzene nucleus, or
in which R3 is low-molecular alkyl or acyl,
the methoximino group being in syn-position,
and pharmalogically acceptable salts and esters thereof.
Subject of the present invention further is a process
for the manufacture of the cephem compounds of the formula
I, which co~prises
a) reacting cephem compounds of the formula II
R1 ()n
~ ~ C -CON~ ~
OCH3 O N I CH2OCOCH3 II
COOH
wherèin n and R1 are as defined above, in the presence
of a solvent and a base, with an azide or with compounds of
the formula HSR3, in which R3 is as defined above, or
~;
~ : .
. :' , ~, .' :
. . .
5 ~
- 3 - ~OE 79tF 087
b) reac~ing cephem compounds of the formula III in the form
of their salts or esters
R1 (~n
H2N ~ ~
o~ N ~CH 2R
COOH
wherein n, R1 and R2 are as defined above, with
reactive derivatives of 2~ 3-thiazol-4-yl)-2-syn-
methoximinoacetic acid and, if desired, in the compounds
obtained according to a) or b)
c~) converting a salt obtained into the free carboxylic
acid and optionally further esterifying the latter or
~) converting a salt obtained directly into an ester or
d~ saponifying an ester obtained and optionally convert-
ing the carboxylic acid obtained into a salt or
~) subsequently oxidizing a compound of the formula I
wherein n is zero or subsequently reducing a compound
of the formula I in which n is 1 and, if desired,
further converting the resulting cephem compounds ob-
tained according to steps ~,~or ~.
25` If in the compounds of the formula I R1 is low-mole-
cular alkoxy, possible examples of this are alkoxy groups
with 1 to 4 carbon atoms, such as methoxy, ethoxy, isoprop-
oxy or n-butoxy.
Compounds in which R1 is hydrogen or methoxy are
preferred.
If R2 is a radical -SR3 and R3 is low-molecular
acyl, possible acyl radicals are in particular aliphatic
acyl radicals having 1 to 4 carbon atoms, preferably acetyl
or propionyl. If R3 is low-molecular alkyl, examples of
this are straight-chain or branched alkyl with 1 to 4
carbon atoMs, such as methyl, ethyl, isopropyl or butyl,
preferably methyl.
- ,
.. . ~. ..
. - . ., . ~ . ,
: . - ~ : .
5~L
4 - HOE 79/F 087
If R3 is an optionally substituted 5- or 6-membered
heterocycle, possible examples thereof are heterocycles
that contain from 1 to 4 hetero atoms, such as nitrogen,
sulfur and/ or oxygen as ring atoms.
The following fundamental ring systems may be mention-
ed as examples of the radical R3:
thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl,
thiadiazolyl, oxdiazolyl, tetrazolyl, pyridyl, pyrimidyl,
pyrazinyl, thiazinyl, pyridazinyl, oxazinyl, imidazolinyl,
as well as benzo-fused derivatives such as benzoxazolyl,
benzthiazolyl, benzimidazolyl and indolyl.
Preferred ring systems are 5-membered ring systems
with 1 to 2 nitrogen atoms and optionally an oxygen atom,
such as oxazolyl, preferably oxazol-2~yl, oxadiazolyl, such
as 1,3,4-oxadia~olyl, imidazolinyl, preferably imidazolin-
2-yl and 6-membered ring systems with 1 to 3, preferably
with 1 to 2, in particular with one nitrogen atom and op-
tionally a sulfur atom, such as pyridyl, for example pyrid-
2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidyl, preferably pyri-
mid-2-yl and pyrimid-4-yl, pyrazinyl or pyridazinyl and
5-membered ring systems with 1 to 4 nitrogen atoms and op-
tionally a sulfur atom, in particular with 1 to 2 nitrogen
atoms and one sulfur atom or with 3 or 4 nitrogen atoms, in
particular with 3 nitrogen atoms, such as thiazolyl, in
particular thiazol-2-yl, thiadiazolyl, in particular 1,3,4~
thiadiazolyl-5-yl and 1,2,4-thiadiazol-5-yl, triazolyl,
preferably 4-H-1,2,4-triazol-3-yl and tetrazolyl, preferably
lH-tetra~ol-5-yl.
If R is a heterolytic radicalg it can be mono- or
polysubstituted, examples of possible substituents being the
following: straight--chain or branched, optionally substitut-
ed alkyl with 1 to 15 carbon atoms, such as methyl, n-prop-
yl, i propyl, n-butyl, undecyl and pentadecyl, preferably
those with 1 to 4 carbon atoms, in particular methyl, or
hydroxy, amiro, C1 4 alkylamino, C1 4dialkyl-amino,
phenyl or heterocyclic radicals,in particular 5- or 6-mem-
bered heterocyclic radicals that have 1 to 2 nitrogen
atoms and/or one sulfur or oxygen atom in the ring for exam-
le pyrid-2-yl, pyrid-3-yl, pyrid-4--yl, thien-2-yl or
~- thien-3-yl.
. .
,:
~s~
5 - HOE 79/F 087
If R3 is a heterocyclic radical, preferred hetero-
lytic radicals are those being unsubstituted or substituted
by amino, thienyl or straight-chain or branched alkyl with
1 to 4 carbon atoms, possible substituents for alkyl being,
for example, carboxy, halogen, in particular fluorine. such
as methyl, ethyl, isopropyl, n-butyl, carboxymethyl, tri-
fluormethyl or pentafluoroethyl.
Examples or pharmacologically acceptable salts of the
cephem compounds of the formula I are inorganic and organic
salts, in particular the alkali metal and alkaline earth
metals salts, preferably the sodium, potassium, magnesium
and calcium salts; tertiary or quartenary ammonium salts,
such as the triethylammonium or tetraethylammonium salts or
the procaine salt. Examples of pharmacologically acceptable
esters are in particular easily cleavable esters, such as
the acetoxymethyl ester, the pivaloyloxymethyl ester , the
1-acetoxyethyl ester or the phthalide ester.
The cephem compounds of the formula II in accordance
with the present invention are the subject of German
Offenlegungsschrift 28 22 860.
The cephem compounds of the formula I can be obtained in
accordance with the present invention in the following
manner:
The cephalosporin derivatives of the formula I are reacted
with azides, preferably alkali metal azides, in particular
the sodium azide, or with mercapto compounds Or the formula
HSR . The reaction is run particularly prefer-ably in
aqueous solution or in mixtures of water and of solvents
miscible with water, such as acetone, a pH of approximately
from 5.5 to 7.5 being adjusted by the addition of bases.
Suitable bases are, for example, alkali metal carbonates,
such as sodium bicarbonate or potassium bicarbonate, or
mixtures of primary and secondary alkali metal phosphate.
The reaction is run preferably at elevated temperature
from approximately 50 to 100C , preferably from 50 to
80~. The reaction time depends on the temperature, at
which the reaction is run. 3
The mercapto compounds of the formula HSR l that are
known in the literature or obtainable according to proces-
ses known in the literature, can be used alternatlvely in
the form of their salts, in particular the alkali metal
;- :
. : ~
~15~
- 6 - HOE 79/F 087
salts, preferably the sodium and potassium salts, provided
that these are easier to handle during the manufacture. The
compounds of the formula II, too, can be used alternatively
in the form of their salts, such as the alkali metal salts,
in particular the sodium or potassium salts.
The final products obtained according to the above
process variant can be isolated easily according to proces-
ses common in laboratory work. For example, the acid deri-
vatives Or the formula I are obtainable by precipitating
the cephem acids from the reaction solution by adding
mineral acids. Suitable mineral acids are in particular
dilute acids, such as dilute hydrochloric acid or sulfuric
acid.
In this process variant the cephem compounds of the
formula I are in most cases obtained as amorphous solids or
in crystalline form. Alternatively they can be separated as
the free acids by extraction at a pH frorn approximately 2
to 1. Examples of suitable extraction agents are organic
solvents immiscible with water, such as halogenated hydro-
carbons, for example methylene chloride, esters such asacetic acid ethyl esters or acetic acid n-butyl esters, or
ketones, such as methylisobutylketone.
The corresponding cephem acids of the formula I are
obtained from the extracts in substance, for example by
concentration, or they are converted directly into a form
suitable for application, for example into a pharmacologi-
cally acceptable salt or ester.
The compounds of the formula I can be obtained alterna-
tively according to the invention in the following manner:
Cephem compounds of the formula III in the form of their
salts or esters are acylated with a reactive derivative of
the 2-(1,3-thiazol-4-yl)-2-syn-methoximino-acetic acid. The
cephem compounds of the formula III are known in the lite-
rature. The 2-(1,3-thiazol-3-yl)-2-syn-methoximino-acetic
acid is the subject of German Offenlegungsschrift 28 22
860. The 2-(1,3-thiazol-4-yl?-2-syn-methoximino-acetic acid
is reacted with the cephem compounds of the formula III in
known manner, for example by activating the carboxylic acid
~ .
s~
- 7 - HOE 79/F 087
groups by conversion into a group capable of forming an
amide, preferably into an active ester, for exarnple the
hydroxybenztriazole ester, or by conversion into an acid
halide, preferably an aci.d chloride, or by conversion into
a symmetrical or asymmetrical anhydride. All of these me-
thods are known in the literature.
Activation of the carboxylic acid has to be carried
out under reaction conditions as mild as possible, such as
are described in the literature for analogous reactions, to
prevent any possible flipping over the syn-oxime into the
trans-oxime derivative represented by the following formula:
~C----COOE~
~ /
- C~30
Activation should be carried out at a temperature as
low as possible in the range from approximately -50 to
~50C, preferably from -20 to ~20C. Suitably rather acid
reaction conditions should moreover be avoided.
The cephem carboxylic acids of the formula III can be
dissolved in various manner, for example by adding bases or
by conversion into silyl esters. The silylation agents may
be any common reagents, in particular the trimethylchloro-
silane which is used in the presence of a stoichiometrical
quantity of a base, or especially preferably the O,N-bis- `
trimethylsilylacetamide which may be used without the addi-
tion of a base. For attaining good yields the silylation
agent is suitably used in a ratio of approximakely 2 equi-
valents of a silyl compound per mol of cephem cornpound
of the formula III.
Suitable bases which can be used for dissolving a
35 great number of 7-amino-~ 3-cephem-4-carboxylic acids, are
inorganic or organic bases. Thus, tertiary amines, such as
triethylamine, N,N-dimethylaniline or N-methylmorpholine,
,
5~
- - 8 - HOE 79/F 087
have proved partlcularly suitable for the preparation Or
~ solutions in organic solvents.
In general the bases are added in an at least stoi-
chiometrical amount, relative to the desired reaction. An
excess of base of, for example a~out 20 to 80 ~, can be
advantageous.
In the case of compounds of the formula III which are
sensitive towards bases, the pH can be kept constant at
about 4 to 8, preferably 6 to 7, depending on the reaction
course, by continuously adding the base.
The compounds of the formula III can be dissolved in a
wide temperature range. However, in the case of derivatives
that are sensitive towards bases, it is advisable to choose
a temperature range from about O to 15C.
The acylation of the cephem compounds of the formula
III with the 2-t1,3-thiazol-4-yl)-2-syn-methoximinoacetic
acid can be carried out under variable experimental condi-
tions, for example, using various solvents. Examples of
suitable solvents are organic solvents, such as halogenated
hydrocarbons, for example methylene chloride or chloroform,
but also tertiary amines, such as dimethylformamide or
~imethylacetamide.
If cephem esters of the formula III are used, the re-
action is carried out in organic solvents, in which most of`
the esters are readily soluble. Examples of such solvents
are likewise halogenated hydrocarbons or the tertiary
amides.
Examples of suitable esters are compounds of the for~
mula III, in which R4 in the ester group -CooR4 may stand
for straight-chain or branched alkyl with 1 to 6 carbon
atoms, for example methyl, ethyl, tert.-butyl, isoamyl or
hexyl, it being possible for the alkyl group to be further
substituted, preferably in ~-position, for example by tri-
chloromethyl, acyloxy with 1 to 6 carbon atoms, preferably
acetoxy or pivaloyloxy, or by one or two phenyl radicals,
it being possible for the latter to be substituted by alk-
oxy with 1 to 4 carbon atoms, preferably methoxy, or nitro,
.
- 9 - HOE 79/F 087
or R4 may starld for the phthalide group. Examples of the
above definitions are the tert.-butyl esters, the trichlo-
roethyl esters, the p-methoxybenzyl esters, the benzhydryl
esters, the acetoxymethyl esters, the 1-acetoxyethyl esters,
the 1-propionyloxypropyl esters, the 1-acetoxy-n-butyl
esters, the pivyloyloxymethyl esters or the phthalide
esters.
The activated 2-(1t3-thiazol-4-yl)-2 syn-methoximino-
acetic acid is added to the cephem derivatives of the for-
mula III present in dissolved or suspended state or toesters thereof, in dissolved state or suspended in an inert
solvent or in substance.
The reaction temperature depends greatly on the reacti-
vity of the activated 2-(1,3-thiazol-4-yl)-2-syn-methoximi-
noacetic acid, a temperature interval from approximately -50
to ~50C having proved advantageous, a temperature from
approximately -20 to +20C being particularly advantageous.
In order to reach higher yields, the activated acid
derivative is used in an at least stoichiometrical amount,
excess from approximately 5 to 25 % being possibly advan-
tageous~
The final products obtained upon acylation are isolat-
ed in known rnanner, for example such as are described here-
inbefore for the final products obtained by exchange of the
acetoxy group. For example, if the symmetrical anhydride of
the 2-(1,3-thiazol-4-yl)-2-syn-methoximinoacetic acid has
been used, the side chain acid liberated during the acyla-
tion may be separated, for example by extraction or preci-
pitation.
The compounds of the formula I wherein n is 1 can beprepared alternatively by oxidizing compounds of the
f`ormula I wherein n is 0.
The oxidation of the sulfur in the cephem ring has
been described repeatedly. This oxidation may yield ~- and
~-oxides (Cf. E. Flynn, Cephalosporins and Penicillins,
Chemistry and Biology, Academic Press, 1972, pages 135 et
se~.), depending on the oxidant used.
~ ` .
- 10 - ~OE 79/F 087
For example, if peracetic acid is used in glacial ace-
tic acid, there are obtained R-S-oxides. The reaction tem-
perature is not critical. It is,however, advisable to carry
out oxidation at room temperature, in order to avoid unde-
sired sequence reactions, and to add the oxidant in an atleast stoichiometri.cal amount, an excess from 10 to 100 %
being frequently advantageous, as long as the temperature
of the reaction is not increased substantially.
The cephem-S-oxides obtained in this way can be iso-
lated without difficulty, for example by precipitation, forexample using non-polar organic solvents, followed by filt-
ration, or by extraction, for example using n-butanol.
A possibly intended reduction of the S-oxides of the
compounds of the formula I can be carried out according to
processes known from the literature, for example by treat-
ing the oxides with phosphorotrihalides, triphenylphosphine
or phosphoropentasulfide.
The cephem compounds of the formula I can be alterna-
tively converted into the physiologically acceptable esters
of the formula I by subsequent esterification according to
processes known from the literature. For example the acet-
oxymethyl esters or the pivaloyloxymethyl esters may be ob-
tained by reacting the alkali metal salts, preferably the
sodium salts, or the ammonium salts, preferably the tri-
ethylammonium salts, with the corresponding halogenomethyl-
acyl compounds, such as chloromethylacetate, chloromethyl-
propionate or pivaloylic acid chloromethyl ester.
A subsequènt esterification of the carboxy group can
be dispensed with, as far as the esters, in particular the
physiologically acceptable esters, are obtained during the
acylation.
The esters directly obtained in the reaction in accor-
dance with the present invention, such as the p-methoxyben-
zyl esters, the p-nitrophenyl esters, the tert.-butyl
esters or the benzhydryl esters, can alternatively be con
verted lnto the free carboxylic acids of the ~ormula I in
a manner known from the literature, for example by acid
cleavage or hydrogenation.
,
.. :
- 11 - HOE 79/F 087
The salts are obtainable in known manner by reaction
o~ the carboxylic acid with suitable bases.
The cephem derivatives of the formula I are valuable
antibiotics which possess a surprisingly powerful action
against Gram-positive and Gram-negative bacteria and which
have an unexpectedly good action against penicillinase-for-
ming Staphylococci.
The co~pounds of the invention can be used as such or
in conjunction with the pharmaceutically usual auxiliaries
and excipients, such as tragacanth, lactose, talc, solvents
etc. in the form of galenical formulations, such as tablets,
dragées, capsules, suspensions, solutions et.c., perorally,
but preferably parenterally, the active ingredient being ge-
nerally contained in an amount from approximately 50 to
1,000 mg, preferably from about 100 to 500 mg, in one
indivivual dose.
The solvents used for parental application are those
common for therapeutical use, in particular solvents dis-
solved in water.
The compounds of the present invention can alternati-
vely be combined with other active ingradients. For example
other antibiotics, such as those of the series of the peni-
cillins, cephalosporins, aminoglycoside antibiotics or com-
pounds acting on the symptomatic of bacterial infections,
such as antipyretics, antiphlogistics or analgetics, may be
applied simultaneously with the compounds of the invention.
The following compounds may be prepared, by way of
example, according to the present invention in addition to
the cephem derivatives of the formula I, described in the
examples:
7-/~-syn-Methoximino-2-(1,3-thiazol-4-yl)-acet-
amido7-3-(2-ethyl-1,3,4-thiadiazol-5-yl)-thiome-
- thyl-3-cephem-~-carboxylic acid
7-~-syn-Methoximino-2-(1,3-thiazol-4-yl)-acet-
amido7-3-(2-methyl-1,3,!l-thiadiazol-5-yl)-3-
cephern-4-carboxylic acid pivaloyloxymetnyl ester
- 12 - HOE 79/F ~87
7-/~-syn-Methoximino-2-(1,3-thiazol-4-yl)-acet-
amido7-3-(1-methyl-lH-tetrazol-5-yl)-thiomethyl-
3-cephem-4-carboxylic acid 1-~-oxide
7-/~-syn-Methoximino-2-(1,3-thiazo'-4-yl~-acet~
amido7-3-(2-ethyl 113,4-oxdiazol-5-yl)-thiome-
thyl-3-cephem-4-carboxylic acid
7-/~-syn-Methoximino-2-(1,3-thiazol-4-yl)-acet-
amido7 3-(6-methoxy-pyridazin-3-yl)-thiomethyl-
cephem-4-carboxylic acid
7-/~-syn-Methoximino-2-(1,3-thiazol-4-yl)-acet-
amido7-3-azidomethyl-3-cephem-4-carboxylic acid
1~-S-oxide
Example 1
7-~-syn-Methoximino-2-(1,3-thiazol-4-yl)-acet
amido7-3~ thien-2-yl-1,3,4-triazol-5-yl7-thio-
methyl-3-cephem-4-carboxylic acid
1.86 g of 2-syn-methoximino-2-(1,3-thia~ol-4-yl)-acetic
acid are dissolved in 67 ml of dioxane. After adding 1.35 g
of 1-hydroxybenzotriazole and 2.1 g of dicyclohexylcarbo-
imide, the reaction mixture is stirred for 1 hour at room
temperature. The precipitate of dicyclohexylurea is suc-
tion-filtered. Next, a solution of 3.95 g of 7-amino-3 (2-
thien-2-yl-1,3,4-triazol-5-yl)-thiomethyl-3-cephem-4~carb-
oxylic acid and of 1.7 g of sodium bicarbonate in 50 ml ofwater is added to the filtrate and the mixture is stirred
for 4 hours at room temperature. After removing the dioxane
in the water jet vacuum, the pH is adjusted to 4 with 2N
hydrochlorid acid. Thus substantially 1-hydroxybenzotriazole
precipitates. Upon acidification to pH 2 the title compound
precipitates. It is subsequently washed with 50 m] portions
of water, acetone and ether and dried in vacuo over phos~
phorus pentoxide.
.
5~
- 13 - HOE 79/F 087
~iese l ~1(
~r~ Rf -value( ~ /Merck,n-butanol:water:acetic acid:
ethanol 10:4:3:3 V/V)= 0.4
NMR (d6-DMSO, 60 MHz)
~= 3.95 ppm tsinglet, 3 H,= N - OCH3)
~= 4.25 ppm (AB-spectrum, 2 H, 3 - CH2 - S -3
J= 5.17 ppm (doublet, 1 H, 6 - CH)
~= 5.79 ppm (quartet, 1 H, 7 - CH)
~= 7.1 - 7.6 ppm (multiplet, 3 H, thienyl)
~= 7.94 - 9.17 ppm (2 doublets, 2 H, thiazolyl)
~= 9.66 ppm (doublet, 1 H, -CONH)
Example 2
7 ~ yn-Methoximino-?-(1,3-thiazol-4-yl)-acet-
~mido7-3-azidomethyl-3-cep~em-4-carboxylic acid
The title compound is obtained in analogous manner as in
Example 1 by reacting equivalent quantities of 2-syn-meth-
oximino-2-(1,3-thiazol-4-yl)-acetic acid as the activated
ester with 7-amino-3-azido-methyl-3-cephem-4-carboxylic
acid.
Rf-value (carrier material and solvent identical to those
in Example 1) =0.3
: NMR (d6-DMSO, 60 MHz)
S= 3.92 ppm (singlet, 3 H, - N OCH3)
J= 4.17 ppm (AB-spectrum, 2 H, 3 - CH2N3)
~- 5.20 ppm (doublet, 1 H, 6-CH)
J= 5.~7 ppm (quartet, 1 H, 7-CH)
~= 7.94 and 9.17 ppm (2 doublets, 2 H, thiazolyl)
~= 9.73 ppm (doublet, 1 H, - CONH - )
.
.
. .
- 14 _ HOE 79/F 087
Example 3
7-/2-syn-Methoximino-2-(1,3-thiazol-4 yl)-acetamido7-
3-(1-methyl-1H-tetrazol-5-yl)-thiomethyl-3-cephem-4-carb-
.... _ _
oxylic acid
.
4.4 g of 7-J~-syn-Methoximino-2-(1,3-thiazol-4-yl)-
acetamido7-cephalosporanic acid are dissolved in 10 ml of
1 N sodium hydroxide solution and in 50 ml of water. After
adding 1.75 g of 2-mercapto-1-methyl-1H-tetrazole (sodium
salt) dissolved in 25 ml of water, the reaction solution is
stirred under nitrogen at 60C for 6 hours. After cooling,
the pH is adjusted to 2 with 2N hydrochloric acid while
cooling with ice. The precipitated title compound is washed
with water and subsequently dried in ~acuo over phosphorus
pentoxide.
Rf~value (kieselgel/Merck,n-BuOH:glacial acetic acid:water=
3:1:1 V/V) = 0.60
NMR (d6-DMSO, 60 MHz)
~= 4.0 ppm (singlet, 3 H, - N - OCH3)
~= 4.25 ppm (AB-spectrum, 2 H, 3 - CH2- S )
~= 5.10 ppm (doublet, 1 H, 6-CH)
~- 5.76 ppm (quartet, 1 H, 7-CH)
~= 7.91 and 9.12 ppm (2 doublets, 2 H, thiazolyl)
~- 9.59 ppm (doublet, 1 H, - CONH - )
Example 4
7-/2-syn-Methoximino-2-(1,3-thiazol-4-yl)-acetamido7-
3-(2-methyl-1,3,4-tiadiazol-5-yl)-thiomethyl-3-cephem-4-
carboxylic acid
4.4 g of 7-/2-syn-methoximino-2-(1,3-thiazol-4-yl)-
acetamido7-cephalosporanic acid and 1.3 g of 5-mercapto-2-
methyl-1,3,4-thiadiazole are suspended in 75 ml of water.
After carefully adding 20 ml of 1 N sodium hydroxide solu-
tion while stirring, the mixture is subsequently heated to
15 - HOE 79/F 0~7
-
80C for 2 hours, cooled with ice and acidified to pH 2
with hydrochloric acid. The precipitated title compound is
suetion-filtered, thoroughly washed out with water and dried
in vacuo over phosphorus pentoxide.
Rf(DC, carrier material and solvent as in Example 3) - 0.60
NMR Sd6-DMSO, 60 MHz)
~- 2.73 ppm ~singlet, 3 H, CH3)
10~= 3.96 ppm ~singlet., 3 H, ~ OCH
= 4.40 ppm (AB-spectrum, 2 H, 3 - CH2S-~
~= 5.2t ppm (doublet, 1 H, - 6 - CH)
~= 5.83 ppm (quartet, 1 H, 7 - CH -)
J- 7.94 and 9.20 ppm (3 doublets, 2 H, thiazolyl)
~= 9.66 ppm (doublet, 1 H, - CINH - )
Example 5
7-/~-syn-Methoximino-2-(1,3-thiazo1-4-yl)-acetamido7-
3-(1H-1-methyl-2-triflourmethyl-1,3,4-triazol-5-yl)-thio-
methYl-3-cephem-4-carboxylic acid
4.4 g of 7-/2-syn-methoximino-2-(1,3-thiazol-4-yl)-
aeetamido7-cephalosporanie aeid are suspended in 50 ml of
water and 10 ml of 1 N sodium hydroxide solution are added
earefully while stirring. After adding 1.8 g of 5-mercapto
1H-1-methyl-2-trifluoromethyl-1,3,4-triazole, dissolved in
1~5 ml of water and 10 ml of 1 N sodium hydroxide solution,
the solution is stirred under nitrogen at 50C for 10
hours. Subsequently its pH is adjusted to 2 while eooling
with iee, the precipitated title compound is suction-fil-
tered, washed thoroughly with water and dried in vacuo over
phosphorus pentoxide.
Rf~value (DC,carrier material and solvent as in Example 1)-
9.25
r ~ .
.' ': , ' .
L5~
- 16 - HOE 79/F 087
NMR (d6-DMSO, 60 MHz)
= 3.94 ppm (singlet, 3 H, = N ~ OCH3)
~ = 4.12 ppm (AB-spectrum, 2 H, 3-CH2-S~
~ = 5.13 ppm (doublet, 1 H, - 6 - CH)
~= 5.81 ppm (quartet, 1 H, 7 - CH)
~= 7.92 and 9.17 ppm (2 doublets, 2 H~ thiazolyl)
~= 9.68 ppm (doublet, 1 H, - CONH - )
Example 6
7-/2-syn-Methoximino-2-(1~3-thiazol-4-yl)-acetamido7-
3-(4~6-diamino-pyrimidin-2-yl)-thiomethyl-3-cephem-4-carb-
___ _ _ _ _ .._...._
oxylic acid
The title compound is obtained in analogous manner as
in Example 3 by reacting equivalent quantities of
7-/2-syn-methoximino-2-(1,3-thiazol-4-yl)-acetamido7-
cephalosporanic acid and 4,6-diamino-2-mercapto-pyrimidine.
Rf-value (DC-solvent as in Example 1)= 0.24
NMR (d6-DMSO, 60 MHz)
~ = 3.94 ppm (singlet, 3 H, = N - OCH3)
d= 5.17 ppm (doublet, 1 H, 6 - CH)
~= 5.79 ppm (quartet, 1 H, 7 - CH)
~= 6.15 ppm (singlet, 1 H, pyrimidine)
~= 6.38 ppm (singlet, 4 H, diamino )
~= 7.92 and 9.17 ppm (2 doublets, 2 H, thiazolyl)
~= 9.63 ppm (doublet, 1 H, - CONH - )
`' ~ , ,'-, i' ' ' . ., . ' ' ,. .1. ' . ' ,~ , ,' ' .
: - . .. -
, . . . ~. , ~ ,
,
17 - HOE 79/F 087
E mple 7_
7-~-syn-Methoximino-2-(1,3-thiazol-4-yl)-acetamido7-3-
(5-carboxymethyl-4-methyl-thiazol-2-yl)-thiometh~1-3-cephem-
4-carboxylic acid
The title compound is obtained in analogous manner as
in Example 3 by reacting equivalent quantities of 7-/~-
syn-methoximino-2-(1,3-thiazol-4-yl~-acetamido7-cephalo-
sporanic acid and of 5-carboxy-methyl-2-mercapto-4-methyl-
thiazole.
Rf-value:(kieselgel/Merck,acetone:glacial acetic acid =
20:1, V/V) _ 0.32
NMR (d6-DMSO, 60 MH~
~= 2.20 ppm (singlet, 3 H, 4-CH3)
J= 3.89 ppm (singlet, 3 H, = N - OCH3)
~= 5.10 ppm (doublet, 1 H, 6 - CH)
J= 7.88 and 9.10 ppm (2 doublets, 2 H, thiazolyl)
~= 9~58 ppm (doublet, 1 H, - CO - NH - )
Example 8
7-/2-syn-Methoximino-2-(1 3-thiazol-4-yl)-acetamido7-3-
(1-methyl-1H-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic
acid
To a suspension of 7.4 g of 2-syn-methoxymino-2-(1~3-
thiazol-4-yl)-acetic acid in 75 ml of methylene chloride
there is added 3.6 ml of dimethylacetamide at -10C with
the exclusion of humidity and subsequently at -1QC there
is added dropwise 25 ml of a 21.3 ~ phosgene solution in
toluene, in 15 minutes. The reaction mixture is stirred for
2 hours, while the 2-syn~methoxymino-2 (1,3-thiazol~4-yl)~
acetic acid chloride is formed. Next, a solution of 13.1 g
of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)-thiomethyl-3-ce-
phem -4-&arboxylic acid in 200 ml of methylene chloride,
10.3 ml of triethylamine and 6.8 g of pyrolidone is added
5~
- 18 - HOE 79/F o87
dropwise at -1~C to the reaction mixture. The reaction
mixture is stirred for 2 hours at -5~C. After adding wa-
ter to the organic phase, its pH is adjusted to 7. The
aqueous phase is separated and its pH is adjusted to 3.5.
The precipitated product is separated and its pH is adjus-
ted to 1 with acidification. The title compound precipita-
tes as an amorphous solid, which is isolated, washed with
water and dried over P205 in a high vacuum. According to
the thin layer chromatogram, to NMR and IR, the resulting
compound is identical to that obtained in Example 3.
Example 9
7-/2-syn-Methoximino-2-(1,3-thiaz 1-4-yl)-acetamido7-3-
(2-methyl-1,3,4-oxdiazol-5-yl)-thiomethyl-3-cephem-4-carb-
.
oxylic acid
580 mg of 2-mercapto-5-methyl-1,3,4-oxadiazole are add-
ed to a solution of 1,32 g of 7-/2-syn-methoximino-2-(1,3-
thiazol-4-yl)-acetamido7-cephalosporanic acid and of
0.75 g of sodium bicarbonate in a mixture of 30 ml of water
and of 10 ml of acetone. The reaction mixture is heated to
65C for 6 hours. The acetone is removed in vacuo, the pH
of the aqueous solution is adjusted to 4 with acidification
and the excess oxadiazole is removed with ether. The pH of
the aqueous phase is adjusted to 1.5 with acidification,
with the title compound precipitating in the form of cream-
colored crystals, which are washed with water and ether
subse~uently and dried in vacuo over phosphorus pentoxide.
Rf-value(kieselgel/Merck, n-BuOH:water:glacial acetic acid:
ethanol 10:4:3:3 V/V) _ 0.34
NMR (CF3COOD, 60 MHz)
~= 2.88 ppm (singlet, 3 H, CH3-oxdiazolyl)
~_ 3.88 ppm (broadened singlet, 2 H, S - CH2)
~= 4.45 ppm (singlet, 3 H, = N - OCH3)~
~= 4.55 ppm (AB, 2 H, 3-CH2-S-)*
* total integration 5 H
.
- 19 - HOE 79/F 087
~= 5.33 ppm (doublet, 1 H, 6-CH)
~= 6.10 ppm (doublet, 1 H, 7-CH)
~= 8.66 ppm (doublet, 1 H, 2. thiazol-H in CF3COOD
thiazol-H in d6-DMSO, 60 MHz : 7.90 and 9.13
(2 doublets, 2 H)
Example 10
7-/2-syn-Methoximino-2-(1,3-thiazol-4-yl)-acetamido7 3-
(benzthiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid
1.32 g of 7-/2-syn-methoximino-2-(1,3-thiazol-4-yl)-
acetamido7-cephalosporanic acid are dissolved in 30 ml of
water and 10 ml of acetone with 0.75 g of sodium bicarbonate
and 0.85 g of 2-mercaptobenzthiazole is added whi.le stirr-
ing. The reaction mixture is stirred for 6 hours at 65C,subsequently cooled, acidified to a pH of 1 and extracted
several times ~ith methylene chloride. The combined ex-
tracts are dried with sodium sulfate and concentrated. The
residue is digested with ether, leaving a cream-colored
solid, which is isolated, washed with ether and dried over
P2O5 in a high vacuum.
Rf-value(DC, carrier material and solvent as in Example 1)=
~.53
NMR: (d6-DMSO, 60 MHz)
J= 3.g2 ppm (singlet, 3 H, - NOCH3)
~= 4.53 ppm (AB-spectrum, 2 H, -CH2~S)
~= 5.12 ppm (doublet, 1 H, 6-CH)
~= 5.76 ppm (quartet, 1 H, 7-CH)
~= 7.2 - 8.1 ppm (multiplet, 4 H, benzthiazole and
doublet 7.90 1 H, thiazolyl)
~= 9.13 ppm (doublet9 1 H, thiazolyl)
~= 9.65 ppm ~doublet, 1 H, CONH)
:
20 - HOE 79/F 087
Example 11
7~ syn-Methoximino-2-(1,3-thiazol~4-yl)-acetamido7-3-
(6-hydroxy-pyridazin -3-yl)-thiomethyl-3-cephem-4-carboxylic
acid
7-/~-syn-methoximino 2-(1,3-thiazol-4-yl)-acetamido7-
cephalosporanic acid are reacted with 6-hydroxy-3-mercapto-
pyridazine in the manner described in Example 10. The title
compound is obtained upon extraction with acetic ester and
digestion with ether in the form of a beige-colored solid.
4-carboxylic acid
~f-value (kieselgel/Merck, solvent of Example 1~ = 0.35
NMR (d6-DMSO, 60 MHz)
J= 3.90 ppm (singlet, 3 H, = NOCH3)
~= 4.50 ppm (AB-spectrum, 2 H, -CH2-S)
~= 5.12 ppm (doublet, 1 H, 6-CH)
~= 5.70 ppm (quartet, 1 H, 7-CH)
~= 6.88 and 7.65 ppm (2 doublets, each 1 H, pyridazinyl)
~= 7.90 and 9.05 ppm (2 doublets, each 1 H, thiazolyl)
J. 9 . 45 ppm (doublet, 1 H, CONH)
--
~.
.....
