Note: Descriptions are shown in the official language in which they were submitted.
2 ~ 0 ~3
The in~ention relates to p-lactam compounds of
the general formula (I~
H2N ~ S,~IH-CO-N (I)
NH2 ~R 1
COOH
in which
R1 - repre~ents halogen or
- represents straight-ch~in or branched alXyl, alkyl~
thio or alkenyl ha~ing up ~o 10 carbon atoms, which
is optionally substituted by halogen, straight-
chain or branched alkoxy having up to 8 carbon atoms
or by a 5-membered unsa~ura~ed heterocycle having up
to 4 heteroatoms from the series comprising nitrogen
or sulphur, which for its part may be substituted by ~-
~traight-chain or branched alkyl or alkylaminodi-
alkyl having up to 6 carbon atoms,
- or which is optionally substituted by a group of the formula -OCOR2,
in which
R2 _ denotes amino or straight-chain or branched
alkyl having up to 6 carbon atoms, ..
- represents straight-chain or branched alkoxy having
up to 8 carbon atoms,
Le A 27 337 - 1 -
. - .. . . .
: ~ : ., .
- .
~ ~3 ;~
- represents a group of the formula -CH2-S-R3,
in which
R3 - denote~ a 5-membered unsaturated heterocycle
having up to 4 heteroatoms from the series
comprising nitrogen or sulphur, which is
optionally substituted by straight-chaln or
branched al~yl or alkylaminodialkyl having up
to 6 carbon atoms,
X - represents oxygen, sulphur or the radical -NH,
and their physiologically ~cceptable salts.
The compounds of the formula 5I) can be present as
free acids, esters, as inner salts or as non-toxic
pharmaceutically tolerable salts of the acidic carboxyl
groups, such as sodium, potassium, magnesium, calcium,
aluminUm or a~monium salts, with amines such as di- or
tri-lower alkylamines, procaine~ dibenzylamine, N,N~-di-
benzylethylenediamine, N-benzyl-~-phenyl-ethylamine,
N-methyl- and N-ethylmorpholine, l-ephenamine, dihydro-
abietylamine, N,N'-bis-dihydroabietylethylenediamine,
N lower alkylpiperidine and other amines which can be
used for the formation of salts of penicillins and
cephalosporins.
Non-toxic, pharmaceutically tolerable salts of
the basic amino groups with inorganic or organic acid
radicals which may preferably be mentioned are, for
example, chloride, bromide, iodide, sulphate, hydrogen
sulphate, phosphate, carbonate, hydrogen carbonate, or
sulphonates such as methylsulphonate, ethanesulphonate,
toluenesulphonate, benzenesulphonate, naphthalenedi-
sulphonate, or carboxylates such as acetate, formate,
',', . ~ '
~e A 27 337 - 2 -
:: : . .
.- ..
-- , .. . .. . .
- : ~ - . -:: - . . - , . ,
:. , '', i - ~: , : .
. :. . .
0~10~3'~3
oxalate, tartrate, citrate, maleate, fumarate, benzoate,
succinate or lactate.
On account of the presence of the as~nmetric
carbon atom designated by *, the new ~-lactam antibiotics
S o the formula (I) include the D-, L- and D,L-form. The
D forms of the compounds of the general formula (I~
according to the invention are preferred.
Both ths diastereomer mixtures and the D-form and
L-form of the compounds according to the invention can be
employed for the treatment of bactexial infectious
diseases.
Preferred compounds of the general formula (I) are
those
in which
R1 - represents fluorine, chlorine or bromine, or
- represents straight-chain or branched alkyl, alkyl-
thio or alkenyl having up to 8 carbon atoms, which
is optionally substituted by fluorine, chlorine,
bromine or by straight-chain or branched alkoxy
having up to 6 carbon atoms or by tetrazolyl,
thiazolyl, triazolyl or thiadiazolyl, which for
their part may be substituted by straight-chain or
branched alkyl or alkylaminodialkyl having up to
4 carbon atoms, h
- or which is optionally substituted by a group of the formula -OCOR2,
in which
R2 _ denotes amino or straight-chain or branched
alkyl having up to 4 carbon atoms, or
- represents straight-chain or branched alkoxy having ::
up to 6 carbon atoms,
Le_A 27 337 - 3 -
- :.
- ,
` ~ . - .-. : :..... : ... . -
: : :, . - :- .. , : -:
,,: : . : . :
- - - , ,.
, ~ : . : --
, ~ - , : : : -
:~ : :: ;
~03~
X - represents oxygen or sulphur,
and their physiologically acceptable salts.
Particularly preferred compounds of the general
formula (I) are those
in which
R1 - represents chlorine or straight-chain or branched
alkyl or alkenyl having ~p to 6 carbon atoms, which
is optionally substituted by fluorine, chlorine or
straight-chain or branched alkoxy having up to
4 carbon atoms, or
- represents straiyht~chain or branched alkoxy having
up to 4 carbon atom~,
X - represents sulphur,
and their physiologically acceptable salts.
In addikion, a process has been found for the
preparation of the compounds of the general formula (I)
X
H2N~S~H-CO-Nl~f ~ ( I ) ; .
NH2 ( R~
COOH
: .
in which
R1 and X havs the abovementioned meanings, ; -
20 characterized in that either ~:~
[A] in a 4-component reaction, compounds of the general
formulae ~II), (III) and (IV), :~ ~ :
.
Le A 27 337 - 4 -
: : ~:: . . . ...
. . . -, ~ , ~, . . .
.... . . .
-
: .
: .
2~31~.3~3~
X CN~T----_~S~ and
R4R5N l N,~ S~--~CHo , ~--N ~ Rl R7
C02R6
~II) (III) ~IV)
in which
R1 and X have the aboveme~tioned meaning~,
R4 and R5 are identical or different and repre~nt an
amino protecting ~roup, for example tert.-butoxy-
carbonyl (Boc),
R6 represents a carboxyl pro~ecting group,
and0 R7 - represents an easily removable benzylically or
glycosidically bonded radical, such as, for example,
4,4'-dimethoxybenzhydryl or 2,4-dimethoxybenzyl or
tetra-O-pivaloylgalactosyl, or
- represents a benzylic chiral radical, such as, for
example, ~-ferrocenyl-(C2-C6)-alkylamino,
are reacted in the presence of a carboxylic acid of the
formula (V)
RB-COOH (V~
in which0 RB _ denotes hydrogen, straight-chain or branched al~yl
having up to 6 carbon atoms or a radical of the
Le A_27 337 - 5 -
. . : -. . ~:
2 ~ l3 g
formula
C6H5` S 1I H-CH2- ,,
in inert solvents, if appropriate in the presence of a
ca~alyst, to give compounds of the general formula (Ia)
R~R5N ~ 5 ~ ~-Co-N ~ ~ ~Ia)
N-COR8 C,~I~Rl ~ - :
R7 COOR6
in which
Rl, R4, R5, R6, R7, R8 and X have the abovementioned mean~
ings,
then the protecting groups R4, R5, R5 and the radicals R7
and -COR~ are removed with acids, ~ :
or in that
[B~ carboxylic acids of the general formula (VI)
x ~. :
R4 R5 NJ~s~cH - c ooH ( VI )
NHR
. ,
, ~ :
,~ ,
e A 27 337 - 6 -
.
. . , -
: . - :- ,, . , ,, : :
- - : :, . , .: : : :
: .: . .~ : .,
, - , :: :
,
2~3~1,3~
in which
R3, R4 and X have the abovementioned meaning
and
R7 - has the abovementioned meaning of R7 and i8 identi-
cal to or different from this, or
- represents an amino protecting group,
are re~cted, after activation of the carboxyl group by a
customary method, with a p-lactam compound of the general
formula (VII)
Hz ~ ~ -
~ Rl (~II) .
C02R6
in which .
Rl and R6 have the abovementioned meanings/
in iner~ solvents and in the last step the protecting .
groups R4, R5, R6 and R7 are optionally removed. :
The process variants according to the invention can
be illustrated by the following equation-~
tA]
soc~ I ~ C ~ ~ IH3 ~:
N ~ s ~ CHo ~ ~ ;
sOc~ C02-CH2 ~ CH3
NH
I z
~ ~ ~ HCOOH
H3C ~ CH3
Le A 2? 337 - 7 -
. - . . :.. . . . . .
-' ~: , .
- : ~ , . ;
~3~ 3~
N ~ ~ CONH~ ~ CH3
NCHO
~ ~ C02-CHz~OCH3
H3C OCH3
¦ CF3COOH / C6H5ocH3
H2N ~ S ~ CONH ~ S CH3
HNCHO o ~ ~
C02H : . :
¦ HCl, H20, CH30H
H2N ~ CONH ~ ~ CH3 ~ :
NH2 ~ ~J -' "
c02H ~ :
HzN ~ HBoc* ~ CH3 ~.
C02CH2 ~ 0CH3
1.) Activation
2.) Coupling ~ -
: ~
, ' -
,.
Le A 2? 337 - 8 - ~
::
- :
, . . . .
. - , - :
'
~31~
S~CON S CH 1
NH ~J
Boc* CO2-cH~ocH3
¦ CF3COOH
H 2N 1N~S~C ON ~ C H 3
C2H
*Boc=(CH3)3-C-~-CO-
Amino protecting gxoup in the context of the above-
mentioned definition in general represents a protecting
group custom~ry in ~-lactam chemistry from the ~eries
comprisin~: 4-methyoxyphenyl, 4-methoxymethyloxyphenyl,
4-[(2-methoxyethoxy)-methyloxyJphenyl, 3,4-dLmethoxy~
phenyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-methoxy~
benzyl, 2,4~dLmethoxyben~yl, 3,4-dimethoxybenzyl,
2,4,6-trLmethoxybenzyl, vinyl, allyl, tert-butoxy-
carbonyl, benzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,
4-nitrobenzyloxycarbonyl, formyl, acetyl, chloroacetyl,
trichloroacetyl, trifluoroacetyl, benzoyl, methoxy-
carbonyl, allyloxycarbonyl, 2,4-dLmethoxybenzyloxy-
carbonyl, 2,2-diethoxyethyl, methoxycarbonylmethyl, tert-
butoxycarbonylmethyl, allyloxymethyl, benzoylmethyl,
Le A 27 337 - 9 -
. : . ~ .. .. .
:. ~ : . . ,
~ ~ 3 ~
bis-(4-methoxyphenyl)methyl, methox~nethyl, methyl-
thiomethyl, methoxyethox~methyl, 2-(methylthiomethoxy)-
ethoxycarbonyl, 2-hydroxy-2-phenylmethyl, methoxy-(4-
methoxyphenyl)methyl, trimethyl-, triethyl, triphenyl-
silyl, tert-butyl-dLmethylsilyl, tert-butyl-diphenyl-
silyl, [2-(trLmethylsilyl)ethoxy]methyl, 1-methyl-2-
benzoyl-vinyl, l-methyl-2-ethoxy- or 2-methoxyvinyl,
mesyl- and ethylsulphonyl.
Carboxyl protecting group in the context of the
abovementioned definition repra~ents the carboxyl pro-
tecting group customary in ~-lactam chemistry. ~asily
removable groups may preferably be mentioned, ~uch as,
for example: tert.butyl, 2,2,2-trichloroethyl, diphanyl-
methyl, triphenylmethyl, acetoxymethyl, allyl, benzyl,
4-methoxyphenyl,4-nitrobenzyl, 2-nitrobenzyl, 4-methoxy-
benzyl, 2,4-dLmethoxybenzyl, trLmethylsilylethyl, tri-
methylsilyl, tert.butyl-dimethylsilyl, acetonyl,
l-phenoxyethyl or 2-methyl 2-propenyl. ~ -
Suitable solvents for process variant lA~ ;
(4-component reaction) are the customary organic solvents
which do not change under the reaction conditions. These
preferably include ethers such as diethyl ether,
butylmethyl ether, dioxane of tetrahydrofuran, or hydro- -~
carbons such as benzene, toluene, xylene or cyclohexane,
or amides such as dimethylformamide or hexamethyl-
phosphoramide, or alcohols such as methanol, ethanol,
propanol or isopropanol, or chlorohydrocarbons such as
methylene chloride, chloroform or carbon tetrachloride,
or acetone, acetonitrile or ethyl acetate. It is also
possible to use mixtures of the solvents mentioned.
Le A 27 337 - 10 -
- ~ ... '. ,.................. : : .................. .
,
~ ~ 3 ~ f)
Methanol is preferred.
The reaction can be carried out in a temperature
range from OJC to +50~C, preferably at room temperature.
In general, the reaction is carried out at normal
pressure. However, it is also possible to work at reduced
pressure or at elevated pressure (for example from O.5
to 5 bar).
The carboxylic acids of the general formula (V)
are known. Preferably, formic acid or N-dithiocarbo-
benzyloxyglycine are employed.
In the case of the 4-component reaction, the
carboxylic acid is employed in an amount of 1 to
20 moleq, preferably 10 moles, relative in each case to
1 mole of the compound~ of the general formulae (II),
(III) and (IV).
In the case in which R7 in the formula (IV)
represents a glycosidically bonded radical, the use of
catalysts is necessary in the case of the 4-component
reaction [A]. Suitable catalysts are zinc ~alts and
titanium complexes, such as, for example, zinc chloride
and Ti(4) isopropoxide. The catalyst is employed in an
amount of 0.5 to 5 moles, preferably 1 mole, relative ~o
1 mole of the compounds of the formula (IV).
The removal of the amine and carboxyl protecting
groups for the processes [A3 and [B] is preferably
carried out with trifluoroacetic acid. However, it is
also possible to use other methods known from the liter-
ature.
The compound~ of the general formula (Ia) are
al~o new.
..
~ .
Le A 27 337
: ,'
'-: '
'' ' ' , ~ ' '
, ;: : ,
. . .
~t~ g
The subsequent removal of the formyl or acyl
group ~rom the c~mpo~nds of the general formula (Ia) is
also carried out with trifluoroacetic acid, if R8 doefi
not denote hydrogen. In the case in which R8 represents
hydrogen, protonic acids, preferably aqueous hydrochloric
acid, are employed in a methanol/water mixture.
The removal of the radical R7 (compounds of the
formula Ia) i8 facilitated by adding auxiliaries, such
as~ for example, anisole, phenol, thiophenol or phenyl
thioethers, preferably anisole.
The removals o$ the protecting groups and the
acyl/formyl group are in general carried out in a temper-
ature range from 0C to +80C, preferably at room temper-
ature.
lS The removals can be carried out both at normal
pressure and at elevated or reduced pressure (for example
0.5 to 5 bar), preferably at normal pressure.
Suitable solvents for process variant [B] are all
solvents which do not change under the reaction condi-
tions. These preferably include ethers such as, for
example, diethyl ether, dioxane or tetrahydrofuran, or
chlorohydrocarbons such as methylene chloride, chloroform
or tetrachloromethane, or amides such as dimethyl-
formamide or hexamethylphosphoramide, or acetonitrile or
acetone. It is also possible to employ mixtures of the
solvents mentioned. ~ethylene chloride is preferred.
The condensation is in general carried out in a
temperature range from 0C to +60C, preferably at room
temperature and at normal prassure.
The removal of the protecting groups is carried
~a A 27 337 - 12 -
. ,
.
, .
:
,
,
~, ~ 3 ~ 3
out by the method described under [A].
The activation of the carboxyl group in the
compounds of the general formula (VI) is in general
carried out by converting into a mixed anhydride with
5 chloroformic acid esters or sulphonic acid derivatives,
such as, for example, ethyl chloroformate, isobutyl
chloroformate or methanesulphonyl chloride, by converting
into the corresponding acid halide, or by con~erting into
an activated ester, for example with N-hydroxybenzotri-
azole and dicyclohexylcarbodiimide. Reaction with ethyl
chloroformate and methanesulphonyl chloride is preferred.
Suitable ~olvent3 for the introduction of the
amino protecting groups in process variants lA] and [B]
are all solvents which do not change under the reaction
lS conditions. These preferably include chlorohydrocarbons
such as methylene chloride, chloroform or carbon tetra-
chloride, or amides such as dimethylformamide or hexa-
methylphosphoramide, or acetonitrile, formic acid,
acetone, pyridine or dimethyl sulphoxide. Pyridine,
dimethyl sulphoxide and dLmethylformamide are preferred.
The compounds of the general formula (II) are new
and can be prepared by reactin~
compounds of the general formula (VIII) ~
~ ',
N - C = N~S~CH O ( VI I I ) -~
R1O/
in which
R9 and R10 are identical ~r different and ~ ;
Le A 27 337 - 13 -
.: . ~ ` . :
,. ,~ :,
. . .
.;
'.
.:
~ 1~ 3 1 ~ 3 ~J
represent straight-chain or branched alkyl having up
to 6 carbon atoms or phenyl,
reacting by a customary method, for example by thio-
cyanation, nitration and then reduction or formylation
with s~bsequent oxidation in inert solvents to give
compounds of the general formula (IX)
R11 ~ (IX)
N-c-N ~ 5 H0
in which
Rll, for example, represents ~he group -NH2, 0-C-H or -SCN
and
R9 and Rl have the abovementioned meanin~s,
and then cyclizing in weakly acidic aqueous medium, such -
as, for example, wi th Br-CN or in acetic acid/water, to
give compounds of the general formula (IIa)
X~ (IIa)
H2N~S~CHO ,
in which
X has the abovementioned meaning,
and in a last step blocking the amine function by intro- :
ducing the protecting groups (R4/~5). ~
~ .
Le A 27 337 - 14 - ~
~ ~ .
,, :
The introduction of the radical Rll is carried out
by methods known from the literature.
Suitable solvents for the introduction of the
r~dic~l Rll are the solvents mentioned under process [A],
5 Alcohols or chlorohydrocarbons, such as, ~or example,
methanol, ethanol, propanol, isopropanol or methylenechloride, are preferre~.
The reaction proceeds in a temperature range from
O~C to ~80C, preferably at room temperature and at
normal pressure.
The cycli~ation is carried out in a temperature
range from 40C to 150C, prefexably at 50C to 80~C and
at normal pressure.
The compounds of the general formula tVI) are new
and can be prepared by reacting
compounds of the general formula (II)
x il ll 5II)
R4R5N, ~5~CHO
:,
in ~7hich
R4, R5 and X have the abovementioned meanings,
with alkali metal cyanides, such as, for example, potas~
sium cyanide, or trimethylsilyl cyanide and amines of the
formula (IV)
1~2N ,!
I (IV)
Le A 27 ~7 - 15 -
,. , ... ,
,: : , .
~: : ,, :. . - ,. -
- -: , ::
in which
R7 has the abovementioned meaning,
or with ammonium acetate or ammonia to give compounds of
the general formula (X)
s
R R N~--N15 C~NH ( X )
R 1 2
in which
R4 and R5 have the abovementioned meanings,
and
Rl2 - has the abovementioned scope of meaning of R7 and in
the case of ammonia also denotes hydrogen,
and then removing the pro~ecting groups R4, R5 and R12
(Rl2 $ H) and hydr~lyzing the CN-group with acids, for example :
hydrochloric acid, and, if appropriate, introducing another of
the abovementioned amino protecting groups.
15The reaction with the cyanides in general pro-
ceeds in a temperature range from O~C ~o +5 0 C, prefer- :
ably at room temperature and normal pressure.
The removal of the amine protecting groups is ~ ~ :
carried out by the abovementioned method in a temperature
20range from +60C to +150C, preferably at +70c to ~90c
at normal pressure.
The compounds of the general formulae (VIII) and
(I~) are known per se or can be prepared by processes
which are known per se. ~
: ~'
Le_A ?7 33? _ 16 -
: , ~ .. : .
2V~ LO~
The compounds of the general fo~nula (VII) are
known per se or can be prepared by a customary method
[compare DE-OS (German Offenlegungsschrift) 3,402,642,
US Patent 4,639,448].
The compounds of the gener~l formula (III) are
kn~wn in ~ome cases or are new and can be prepared in
both cases in analogy to methods known from the litera-
ture [compare DOS (~erman Offenlegungsschrift)
2,337,107].
The amines of the general formula (IV) are known
per se or ~an be prepared by a customary method.
The stereochemically uniform D- or L-form of the
compounds of the formula (I) according to the invention
is obtained when the diastereomer mixture is isolated by
preparative HPLC separa~ion methods.
On the other hand, the pure D- or L-form (prefer-
ably the D-form~ i8 obtained when chemical resolution of
the racemate, for example with dehydroabietylamine,
phenylethylamine or camphorsulphonic acid, or resolution
of the racemate, for exa~ple, via N-acetyl-amino acid
derivatives, for example with subtilisin, penicillin
acylase or porcine renal acylase, is carried out already ~- -
at the stage of the protected or unprotected racemic amino acid
of the formula (VI) and the stereochemically uniform D- or L-forms of ;~
the compounds of the formula (VI) are then reacted in the
manner indicated, or by separating directly into the
individual diastereomers a~ the stage of the formula (X)
in which R12 represents one of the abovementioned chiral
radicals.
The compo~nds of ~he general formula (I)
Le A 27 337 - 17 -
., , : ', :: ,: ' ' ' :
. . : : : ~ :
- . ., - - . :
.,~ . . . . .
according to the invention have a wide antibacterial
spectrum against gram-positive and gram-negative micro-
organisms together with low toxicity. These properties
make possible their use as chemotherapeutic active
compounds in human and veterinary medicine.
The compounds according to the invention are
active against a very wide spectrum of microorgani~ms.
With their aid, gram-negative and gram-positive bacteria
and bacteria-like microorganisms can be controllad and
the disorders caused by these pa~hogens can be prevented,
improved and~or cured.
The compound6 according to the invention are
particularly active against bacteria and bacteria-like
microorgani~ms. They are therefore particularly highly
suitable in human and veterinary medicine for the prophy-
laxis and chemotherapy of local and 6y6temic infections
which are caused by such pathogens.
The minLmum inhibitory concentrations (~IC) were
determined by the serial dilu~ion method on Iso-Sensitest
agar (Oxoid). For each test substance, a ~eries of agar
plates were prepared which contained decreasing con-
centrations of the active compound at twice the dilution
in each case. The agar plates were inoculated using a
multi-point inoculator (Denley). Overnight cultures of
the pathogens which had previously been diluted in such
a way that each inoculation point contained about 104
colony-forming particles were used for inoculating. The
inoculated agar plates were incubated at 37C, and the
growth of microorganism was read off af~er about
20 hours. The MIC value (~g/ml) indicates the lowest
Le A 27 337 - 18 -
_
~' - `, ' , ~:
,.. . - , . ~ ,
:
& ~
active compound concentration at which it was not pos-
sible to detect any growth of microorganism using the
naked eye.
Use Example
MIC values: agar dilution/multi-point
Compound of Exam~le 13a:
~ .
Strain MIC (~g/ml)
_
lO E coli A 261 4
Klebs. 6097 2
Staph. aur. 25455 ~ 0.25 ` `
Staph. epi. 25185 ~ 0.25
Strept. faec. 27101 16
Enterococc. 27185
The present invention includes pharmaceutical
preparations which contain one or more compounds accord-
ing to the invention in addition to non-toxic inert
pharmaceutically suitable excipients or which are com-
posed of one or more active compounds according to the
invention and processes for the production of ~hese
preparations.
The active compound(s) may optionally also be
present in microencapsulated form with one or more o~ the
abovementioned excipients.
The therapeutically active compounds should
preferably be present in the abovementioned pharma-
ceutical preparations in a concentration of about
, ~,
Le A 27 337 - l9 - ~ ~
.
.. . . .
,
- ~ .
2n'3~3~
0.1 to 99.5, preferably of about 0.5 to 95~by weight of
the total mixture.
The abovementioned pharmaceutical preparations
may also contain pharmaceutical active coMpounds in
addition to the compounds according to the invention.
In general, i~ has proYed advantageous both in
human and in veterinary medicine to administer the active
compound(s) according to the invention in total amounts
of about 0.5 ~o about 500, preferably 5 to 100 mg/kg of
body weigh~ every 24 hours, if appropriate in the form of
several individual doses, to achieve the desired results.
An indi~idual dose preferably contains the active com-
pound(s) according to the invention in amo~nts of about
1 to about 80, in particular 3 to 30,mg/kg of body
weight~
The new compounds can be combined in the cus-
tomary concentrations an~ preparations, together with the
food or lactamase inhibitors, for example with penicil-
lins which are particularly resistant to penicillinase
and with clavulanic acid. Such a combination would be,
for example, that with oxacillin or dicloxacillin.
The compounds according to ths invention can also
be combined with aminoglycoside antibiotics, such as, for
example, gentamicin, sisomicin, kanamycin, amikacin or
tobramycin for the purpose of extending the spectrum of
action and in order to achieve an increase in action.
Le A 27 337 - 20 -
,
.
: ~ ' ' : ' '
'~ 3 ~
Startinq compounds
Example l
5-Dimethylaminomethyleneamino-4-thiocyanato-2-thiophene-
carboxaldehyde
NCS~
( H3C ) 2N--~S~CHO
10.O ml (194 mmol) of bromine are 810wly added
dropwise at room temperature to a solution of 32 . O g
(176 mmol) of 5-dimethylaminomethyleneamino-2-thiophene-
carboxaldehyde and 40.1 g of ammonium thiocyanate
(527 mmol) in 2.2 1 of methanol. The mixture is stirred
at room temperature for l h, about 2 l of an ice/water
mixture are added, the mixture is subseguently stirred
for 45 minutes, and the precipitate formed is filtered
off with suction at 5C, washed with water and dried in
vacuo.
Yield: 24.4 g (58% of theory)
~-NMR (CD3SOCD3): ~ 3.12 and 3.20 (2s, each 3H,
5'-CH3); 8.00 (s, lH; 3-H); 8.20
(s, lH, N-CH=N); 9.63 (s, lH; :~
CHO).
Example 2
2-Amino-5-thieno[2,3-d]thiazolecarboxaldehyde ~ :
~ " ~, .
H2N 5~A`~HO
,. ,
Le A 27 337 - 21 -
: .: ::: . ,: - ::
-: , ~
., `" ': . ~ :' . . . . . .
24.4 9 (102 mmol) of the compound from Example 1
are suspended in 170 ml of 90~ strength acetic acid and
the mixture is heated to 60-65C, whereupon the aldehyde
goes into solution. After 24 h at 60-65C, the mixture is
allowed to cool to room temperature. After a further
24 h, the black crystals are filtered off with suction,
washed with toluene and dried in vacuo.
Yield: 15.4 g ~82% of theo~y~
~H-NMR (CD3SOCD3): ~ = 8.05 (s, lH, 6-H); 8.22 (s, 2H,
NH2); 9-74 (~, lH, CHO)-
Example 3
2-Ace~amido-5-thieno[2,3-d]thiazole-carboxaldehyde
o s
Il 1~
H3C-CNH~5~CHO
A solution of 58.6 ml (824 mmol) of acetyl
chloride in 660 ml of anhydrous chloroform is added
dropwise at 15-20C in the course of 1 h to a solution
of 15.4 g (84 mmol) of the compound from Example 2 in
660 ml of anhydrous pyridine. After 30 minutes, the
mixture is poured into a mixture of 1 1 of water and 1 1
of chloroform, ~he phases are separated and the organic
phase is washed several times with water. The organic ~ -~
phase is filtered through a layer of silica gel a few
centimeter9 thick and then concentrated in vacuo. The
residue thus obtained is stripped off several times with
toluene until it crystallizes. The red-brown crystals are
stirred overnight with 450 ml of methanol, filtered off
,
Le A 27 337 - 22 -
. : .. .. .
- :
with sucti.on, washed with methanol and drisd in vacuv.
Yield: 11.2 9 (5~ of theory)
H-NMR (CD3SOCD3): ~ 2.23 (s~ 3H, CH3CO); 8.30 ts,
lH, 6-H); 9.91 (s, lH, CHO);
12.65 (s, lH, NH).
Example 4
2-Formamido-5-thieno[2/3-d]thiazole-carboxaldehyde
HCONH~CHO
20 ml (212 mmol~ of acetic anhydride are added
dropwise at 15-20C to 1.84 g (10 mmol) of the compound
from Example 2 in 100 ml of formic acid. The mixture i5 -
stirred overnight at room temperature, then 500 ml of ice :
water are added and the precipitate which has deposited
is filtered off with suction. The crystals are stirred
with ethyl acetate, filtered off with suction and dried -~
in vacuo.
Yield: 1.10 g (52% of theory)
H-NMR (CD3SOCD3): ~ = 8.33 (s, lH, 6-H); 8.64 (s, lH, : :
N-CHO); 9.92 (s, lH, C-CHO);
12.85 (s, lH, NH).
Example 5
2-(N,N-Di-t-butyloxycarbonyl-amino)-5-thieno[2,3-d]-
thiazolecarboxaldehyde
s
Boc\N ~
Boc~ S~CHO
Le A 27 337 - 23 -
.. . . . .
: . : -,: - , , :: :: - :: . . . , ~ :
.
-, :: : . -
:, . ,, : ,.
. , ., ,
.. ~ ' :' . . ~ . - "
: , ' :- : : : .
~ ~3 ~ 3 S~
21.8 g (100 mmol) of di-t-butyl pyrocarbonate are
added at room temperature to a fiolution of 1,84 g
(10 mmol) of the compound from Example 2 and the mixture
is then stirred overnight at the same temperature. 3 ml
of water are added dropwise, the mixture is concentrated
in vacuo and the residue is stripped off several times
with toluene. Chromatography on silica gel using
toluene/ethyl acetate (97:3) yields 1.30 g (34% of
theory) of the desired aldehyde.
lH-NMR (CD3SOCD3): ~ = 1.55 (s, 18H, Boc); 3.35 ts, lH,
6-H); 9.96 (s, lH, CHO).
Example 6
2-Amino-2-(2-amino-5-thieno[2,3-d]thiazolyl)-acetic acid
I ~ ~CO2H
H2N~ ~NH2 :. ,
360 mg (5.5 mmol3 of potassium cyanide and 1.23 g
(16.0 mmol) of ammonium acetate are added to a suspension
of 904 mg (4.0 mmol) of the compound from Example 3 in
25 ml of ethanol and the mixture is stirred at room
temperature for 72 h. The reaction mixture is concen-
trated to dryness, the residue is taken up in 100 ml of
6 N hydrochloric acid and the solution is heated under
reflnx for 2 h. The solution is concentrated to dryness
in vacuo at a bath temperature of 50C. The residue is
dissolved in 200 ml of water and the solution is then
adjusted to pH 5 with sodium acetate. The suspension is
boiled and filtered hot. The almost colorleSs filtrate
is concentrated to dryness and chromatographed on RP-8
Le A 27 337 - 24 -
. . , -, .
~ , .. .
- ,, .. - . : - :: :: - -
-,
. , ., : . - , . -: ,
~" ~ rS ~ J
using water.
Yield: 29.5 mq (3~ of theory)
-NMR (DCOOD): ~ = 5.78 ~6; lH, 2 H); 7.58 (s; lH,
6'-H).
Example 7
p-Methoxybenzyl (6R, 7R)-7-formamido-3-[(Z)-l-propenyl]-
3-cephem-4-carboxylate
~ }I '
HCON~ ~ CH3
~1 ,
C2 - CH2~3~CH3
A solution of 45 ~ (125 mmol) of p-methoxybenzyl
10~6R, 7R)-7-amino-3-[(Z)-l-propenyl]-3-cephem-4-carboxyl-
ate, 9.5 ml (252 ~mol) of formic acid and 53.8 g of
dicyclohexylcarbodiimide (261 mmol) in 750 ml of
acetonitrile is stirred overnight at room temperature.
'rhe precipitate which has deposited is separa~ed off, the
filtrate is concentrated in vacuo and the residue is
chromatographed on silica gel using toluene/ethyl acetate
(3~
Yield: 38 g (78% of theory)
1H-NMR (CDCl3): ~ = 1.57 (dd, J=6Hz, J = lHz, 3H, CH3-C);
3.36 and 3.50 (2d, J = 19 Hz, each
lH, 2-H); 3.82 (s, 3H, CH30); 5.02
(d, J = 6 Hz, lH, 6-H); 5.17 (s, 2H,
CH2); 5.68 (dq, J = 11 Hz, J = 5 Hz,
lH, 3'-H); 5.88 (dd, J = 9 Hz,
L~ A 27 337 - 25 -
:: : .
~, . .
3 ~
J = 6 Hz, 1~l, 7-~1); 6.12 (d,
J = 11 Hz, 1~1, 3'-H); 6.5B (d,
J = 9 Hz, lH, NH); 6.8B and 7.32
( 2d , J = 8 Hz , each 2H , Ar-H ~; 8 . 2 8
( s, lH, NCHO ) .
Example 8
p-Methoxybenzyl (6R, 7R)-7-isocyano- 3 -[(Z)-1-propenyl]-
3-cephem-4-carboxylate
H H
Cl~ CH3
C 2 - CH 2~)C H 3
2.4 ml t20 mmol) of trichloromethyl chloroormate
are added dropwise at -78C to a ~olution of 7.8 g
(20 mmol) of the compound from Example 7 and 6.9 ml
~85 mmol) of pyridine in 120 ml of anhydrous methylene
chloride. After lO minutes, the mixture is allowed ~o
warm to 0C, ice water is added, the organic phase is
separated off and the aqueous phase is extracted ~wice
with methylene chloride. The combined organic pha~es are
washed with water, dried over sodium sulphate and con-
centrated. Chromatography on silica gel u~ing methylene
chloride yields 3.1 g (42% of theory) of the title
compound.
H-NMR (CDCl3): ~ = 1.63 (dd, J = 6 Hz, 3 = 1 Hz, 3H,
C-CH3); 3.42 and 3.48 (2d, J = 18 Hz,
each lH, 2-H); 3.80 (s, 3H, GCH3);
Le A 27 337 - 26 -
- : . :. : - , ~: , :. : . :- ,, ;
,: - - : , :. , ~: ~ -
-: ,: : .. : . , .~. ,: , : .
:.. .:; : ::,: . , :: :
,f,'3 ~ J
4.97 (d, J = 6 Hz, lH, 6-H); 5.17
(m, 3H, 7-H and 4'-CH2l; 5.75 (dql
J = 11 Hz, J = 6 Hz, lH, 3'-H); 6.26
(d, J = 11 Hz, lH, 3'-H); 6.90 and
7.32 (2d, J = 8 Hz, each 2H, Ar-H).
ExamPle-9
p-Methoxybenzyl 7-{2-[2-(N,N-di-t-butyloxycarbonyl-
amino)-5-thienol2,3-d]thia~olylJ-2 [N-(4,4'-dimethoxy-
benzhydryl)-N-formamido]-acetamido}-3-[(Z)-1-propenyl]-
(6R, 7R)-3-rephem-4-carboxylate
s~c~ ~ H H
~oc~ N ~ CO ~ S~ CH3
NCHO
~ co2-CH2
H3~ CH3 ~:
~ solution of 1.30 g (3.5 mmol) of the compound
from Example 8, 1.35 g (3.5 mmol) of the compound from
Example 5, 0.85 g (3.5 mmol) of 4,4'-dLmethoxybenzhydryl- :
amine and 1.3 ml (35 mmol) of formic acid in 13 ml of
methanol and 1.3 ml of dLmethylformamide is stirred at
room temperature for 5 days. The solution is ccncen-
trated; the residue is chromatographed on silica gel
using toluene/ethyl acetate (8:2). :
Yield: 0.25 g (7% of theory)
Rf = 0.31 (silica gel 60, F 254, Merck No. 5549;
toluene/ethyl acetate 3:1)
Le A 27 337 - 27 -
: . ,: , : , .
: .: .
~ h~ 3
Exam~
Benzhydryl (6R, 7R)-7-formamido-3-[~Z)-l-propenyl]-3-
cephem-4-carboxylate
HCON~ C H 3
c02CH ( C6H5 ~ Z
In ~nalogy to the procedurs of Example 7, 8.0 g
1g2% of theory) of the title compound are obtained from
8.1 g (20 mmol~ of benzhydryl (6R, 7R)-7-amino-3-[(Z)-l-
propenyl~-3-cephem-4-carboxylate, 1.5 ml (40 mmol) of~
formic acid and 4.9 g (23.7 mmol) of dicyclohexyl-
carbodiLmide in 70 ml of acetonitrile.
H-NMR (CDCl3/CD3SOCD3): ~ = 1.44 (dd, J = 6 Hz,
J = 1 Hz, 3H, CH3); 3.40 and
3.50 (2d, J = 18 Hz, each
lH, 2-H); 5.08 (d, J = 6 Hz,
lH, 6-H); 5.56 (dq,
J = 11 Hz, J = 6 Hz, lH,
3'-H); 5.83 (dd, J = 9 Hz,
J = 6 Hz, lH, 7-H); 6.12 (d,
J = 11 Hz, lH, 3'-H); 6.92
(s, lH, Ph2CH); 7.25 - 7.43 .;
(mt 10H, Ph-H); 8.24 (s, lH,
CHO); 8.87 (d, J = 9 Hz, lH,
N-H).
L~ ~ 27 33? - 28 -
: , : .. . .
~, ,
,~ f'L ~3 ~3 ~
Example 11
senzhydryl (6R,7R)-7 isocyano-3-[(Z)-l-propenyl]-3-
cephem-4-carboxylate
H H
C~ 3
co2CH(c6Hs) 2
In analo~y to the procedure of Example 8, 2.05 g
(49% of theory) of the title compound are obtained from
4.35 g ~10 mmol) of the compound from Example 10, 3.5 ml
(43 mmol) of pyridine and 1.2 ml (10 mmol) of trichloro-
methyl chloroformate in 60 ml of anhydrous methylene
chloride.
H-NMR (CDCl3): ~ = 1.53 (dd, J = 6 Hz, J = 1 Hz, 3H,
CH3); 3.43 and 3.46 (2d, J = 18 Hz,
each lH, 2-H); 5.01 (d, J = 6 Hz,
lH, 6-H); 5.20 (d, J = 6 ~z, lH,
7-H); 5.69 (dq, J = 11 Hz, J = 6 Hz,
lH, 3'-H); 6.29 ~d, J = 11 Hz, lH,
3 -~t; ~-95 (s, lH, CHPh2);
7.28 - 7.42 (m, lOH, Ph-H).
Example 12
20 Benzhydryl 7-{2-[2-(N,N-di-t-butyloxycarbonyl amino)-5-
thienot2,3-d]thiazolyl]-2-[N-(tetra-O-pivaloyl-l-
galactosyl)-N-formamido]-(2S)-acetamido}-3-[(Z)-l-
propenyl]-(6R, 7R)-3-cephem-4-carboxylate
Le A 27 337 - 29 -
,. . : . - - . ; : .: : .: ~ -
:' `; ' ~: ' ' ' `' ' ' '' .
.: :, . . .
. . ~ , , . ~ , :, . .
~ ç a~,
s
1~¦ H H
Boc-N~N~`5~CO-Nt~S~ 1~13
Boc - 0~
tBU-Co-oll2c - o~N-~::Ho co2C~l(C6H5)2
L Bu - C O - C O - CO - t ~u
O-CO- tBu
0.6 ml (2.0 mmol) of titanium(IV) isopropoxide i~
added to a BOlutiOn of 1 . O g ( 2.6 mmol) of the compound
from Example 5, 1.29 g (2.5 mmol) of tetra-0-pivaloyl-
galactosylamine, 0.92 g ~2.2 mmol) of the compound fromExample 11 and 1.0 ml ~26.5 ~mol) of formic acid in 30 ml
of anhydrous tetrahydrofuran and the mixture is stirred
at room temperature for 5 days. After stripping off the
solvent, the residue is chromatographed on silica gel
u~ing toluene~ethyl acetate (3
Yield: 0.31 g ~10~ of theory)
Rf = 0.28 (silica gel 60, F 254, Merck No. 5549,
toluene/ethyl acetate 3:1)
Example 13
7-[2-(2-Amino-5-thienot2,3-d]thiazolyl)-2-formamido-
acetamido]-3-[(Z)-l-propenyl]-(6R,7R)-3-cephem-4-
carboxylic acid (trifluoroacetate)
Le A 27 337 - 30 -
-~ : . , : .
. :: ., , , ~ - . .
f~
H H
H2N~ 5~CONH~S~ CH3
NHCHO o~N~
C02H x CF ~C02}3
250 mg tO.24 mmol) of the compound from Example 9
are trea~ed at room temperature for 1 h with a mixture of
1 ml of anisole and 10 ml of trifluoroacetic acid. After
S concentrating, the product is precipitated with ether,
filtered off with suction, washed wi~h ether and dried in
vacuo. , :
Yield: 110 mg (76% of theory)
Example 13a (general formula (I))
7-[(2S)-2-(2-amino-5-thieno[2,3-d]thiazolyl)-2-amino-
acetamido]-3-[(Z)-l-propenyl]-t6R,7R)-3-cephem-4-
carboxylic acid
s
H2N~I,~CON~ CH3 ;
NH2 ~wJ
C02H
: ~ '
107 mg (0.18 mmol) of the compound from :~
lS Example 13 are dissol~ed in 10 ml of methanol. 1 ml of
concentrated hydrochloric acid is added and the mixture
is allowed to stand at room temperature for 48 h. It is
,
Le A 27 33? - 31 -
'~;, ~''.
~ ~ z~
then diluted with 200 ml of water and ad~usted to pH 5
with sodium acetate. Chromatography on HP-20 u6ing
water/acetonitrile yields the pure D-isomer.
Yield: 7 mg (9% of theory)
lH-NMR ~DCOOD): ~ = 1.66 (dd, J = 7 Hz, J = 1 Hz, 3H,
CH3); 3.44 and 3.54 (2d, J = 18 Hz,
each lH, 2-H~; 5.28 (d, J = 6 Hz,
lH, 6-H); 5.84 (d, J = 6 Hz, lH,
7-H); 5.80 (dq, J = 11 Hz, J = 7 Hz,
lH, ~'-H); 5.93 (8, lH, N-CH-CO);
6.23 (d, J = ll Hz, lH, 3'-H); 7.64
(~, lH, Ar-H).
It is understood that the specification and examples
are illustrative but not limitative of the present ihvention
and that other embodiments within the spirit and scope of
the invention will suggest themselves to those skilled in
the art.
Le A 27 337 - 32 -
.,~ . , -
, . : : ,- : : ,
,
