PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF SYSTEMIC INFLAMMATORY RESPONSE SYNDROME

COMPOSITIONS PHARMACEUTIQUES POUR TRAITER LE SYNDROME DE REPONSE INFLAMMATOIRE SYSTEMIQUE

English Abstract

The present invention relates to the use of certain benzimidazoles for
preparing a pharmaceutical composition for the treatment of systemic
inflammatory response syndrome and particularly sepsis.

Claims

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CLAIMS:
1. Pharmaceutical composition comprising:
(a) at least one active substance selected from
the group of benzimidazoles of general formula (I)
<IMG>
wherein
Ar denotes a phenylene or naphthylene group optionally
substituted by a fluorine, chlorine or bromine atom, by a
trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group,
a thienylene, thiazolylene, pyridinylene, pyrimidinylene,
pyrazinylene or pyridazinylene group optionally substituted
in the carbon skeleton by a C1-3-alkyl group,
A denotes a C1-3-alkylene group,
B denotes an oxygen or sulphur atom, a methylene, carbonyl,
sulphinyl or sulphonyl group, an imino group optionally
substituted by a C1-3-alkyl group wherein the alkyl moiety
may be mono- or disubstituted by a carboxy group,
R a denotes a R1-CO-C3-5-cycloalkyl group wherein
R1 denotes a C1-3-alkoxy, amino, C1-4-alkylamino or
di-(C1-4-alkyl)-amino group, wherein in each case the alkyl
moiety may be substituted by a carboxy group,
a 4- to 7-membered cycloalkyleneimino or
cycloalkenyleneimino group which may be substituted by one
or two C1-3-alkyl groups, while an alkyl substituent may

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simultaneously be substituted by a hydroxy, C1-3-alkoxy,
carboxy, carboxy-C1-3-alkoxy, carboxy-C1-3-alkylamino,
N- (C1-3-alkyl) -N- (carboxy-C1-3-alkyl) -amino,
carboxy-C1-3-alkylaminocarbonyl, N- (C1-3-alkyl) -
N- (carboxy-C1-3-alkyl) -aminocarbonyl,
carboxy-C1-3-alkylaminocarbonylamino, 1- (C1-3-alkyl) -
3- (carboxy-C1-3-alkyl) -aminocarbonylamino, 3- (C1-3-alkyl) -
3-(carboxy-C1-3-alkyl)-aminocarbonylamino or
1,3-di- (C1-3-alkyl) -3- (carboxy-C1-3-alkyl) -aminocarbonylamino
group,
a 4- to 7-membered cycloalkyleneimino group
substituted by a hydroxy group,
a 5- to 7-membered cycloalkyleneimino group
optionally substituted by a C1-3-alkyl group, to which a
phenyl ring is fused via two adjacent carbon atoms,
a morpholino, piperazino, N-(C1-3-alkyl)-
piperazino, pyrrolino, 3,4-dehydro-piperidino or pyrrol-l-yl
group,
a R2-CX-C3-5-cycloalkyl group wherein
R2 denotes a phenyl, naphthyl or monocyclic 5- or
6-membered heteroaryl group optionally substituted by a
C1-3-alkyl group, while the 6-membered heteroaryl group
contains one, two or three nitrogen atoms and the 5-membered
heteroaryl group contains an imino group optionally
substituted by a C1-3-alkyl group, an oxygen or sulphur atom
or an imino group optionally substituted by a C1-3-alkyl
group and an oxygen or sulphur atom or one or two nitrogen
atoms and the abovementioned alkyl substituent may be
substituted by a carboxy, carboxy-C1-3-alkoxy,
carboxy-C1-3-alkylamino or N- (C1-3-alkyl) -carboxy-
C1-3-alkylamino group, and

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X denotes an oxygen atom, a C1-3-alkylimino,
C1-3-alkoxyimino, C1-3-alkylhydrazino, di-(C1-3-alkyl)-
hydrazino, C2-4-alkanoylhydrazino, N-(C1-3-alkyl)-
C2-4-alkanoylhydrazino or C1-3-alkylidene group each of which
may be substituted by a carboxy group in the alkyl or
alkanoyl moiety or in the alkyl and alkanoyl moiety,
a C1-3-alkyl or C3-5-cycloalkyl group substituted by an
imidazole or imidazolone group, wherein
the imidazole ring may be substituted by a phenyl
or carboxy group and by one or two C1-3-alkyl groups or by
one, two or three C1-3-alkyl groups, while the substituents
may be identical or different and one of the abovementioned
alkyl substituents may simultaneously be substituted by a
carboxy group or in the 2 or 3 position by an amino,
C2-4-alkanoylamino, C1-3-alkylamino, N-(C2-4-alkanoyl)-
C1-3-alkylamino or di-(C1-3-alkyl)-amino group, and
the imidazolone ring may be substituted by a
C1-3-alkyl group, while the alkyl substituent may be
substituted by a carboxy group or in the 2 or 3 position by
an amino, C2-4-alkanoylamino, C1-3-alkylamino,
N-(C2-4-alkanoyl)-C1-3-alkylamino or di-(C1-3-alkyl)-amino
group, and
additionally a phenyl or pyridine ring may be
fused to the abovementioned imidazole and imidazolone rings
via two adjacent carbon atoms,
an imidazolidin-2,4-dion-5-yl group which may be substituted
by one or two C1-3-alkyl groups, while simultaneously an
alkyl substituent may be substituted by a carboxy group,
a C1-4-alkyl group which is substituted

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by a C1-3-alkyl-Y1-C1-3-alkyl, HOOC-C1-3-alkyl-
Y1-C1-3-alkyl, tetrazolyl-C1-3-alkyl-Y2, R3NR4 or
R3NR4-C1-3-alkyl group and
by an isoxazolidinylcarbonyl group optionally
substituted by a C1-3-alkyl group, by a pyrrolinocarbonyl,
3,4-dehydro-piperidinocarbonyl, pyrrol-1-yl-carbonyl,
carboxy, aminocarbonyl, C1-3-alkylaminocarbonyl,
di-(C1-3-alkyl)-aminocarbonyl or 4- to 7-membered
cycloalkyleneiminocarbonyl group, while in the
abovementioned groups the cycloalkyleneimino moiety may be
substituted by one or two C1-3-alkyl groups and
simultaneously in each case an alkyl moiety or alkyl
substituent of the abovementioned C1-3-alkylaminocarbonyl,
di-(C1-3-alkyl)-aminocarbonyl or cycloalkyleneiminocarbonyl
groups may be substituted by a carboxy group, and the
remaining hydrogen atoms of the C1-4-alkyl group may be
wholly or partly replaced by fluorine atoms, wherein
R3 denotes a hydrogen atom or a C1-3-alkyl
group optionally substituted by a carboxy group and
R4 denotes a hydrogen atom, a C1-3-alkyl-
Y1-C1-3-alkyl-Y2, carboxy-C1-3-alkyl-Y1-C1-3-alkyl-Y2,
C1-3-alkyl-Y2 or carboxy-C1-3-alkyl-Y2 group or
R3 and R4 together with the nitrogen atom
between them denote a 4- to 7-membered cycloalkyleneimino
group optionally substituted by a carboxy, C1-3-alkyl or
carboxy-C1-3-alkyl group, wherein
Y1 denotes a carbon-carbon bond, an oxygen atom, a
sulphenyl, sulphinyl, sulphonyl, -NH, -NH-CO or -NH-CO-NH
group and

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Y2 denotes a carbon-nitrogen bond or a carbonyl,
sulphonyl, imino or -NH-CO group, while the carbonyl group
of the -NH-CO group is linked to the nitrogen atom of the
R3NR4 group, and the imino groups mentioned in the definition
of the groups Y1 and Y2 may each additionally be substituted
by a C1-3-alkyl or carboxy-C1-3-alkyl group,
a C1-3-alkyl or C3-5-cycloalkyl group substituted by a
R5NR6 group, wherein
R5 denotes a hydrogen atom, a C1-3-alkyl,
C5-7-cycloalkyl, phenylcarbonyl, phenylsulphonyl or pyridinyl
group and
R6 denotes a C1-3-alkyl, carboxy-C1-3-alkyl or
carboxy-C1-3-alkylcarbonyl group,
a C1-3-alkyl group which is substituted by a C2-4-alkanoyl or
C5-7-cycloalkanoyl group and by a C1-3-alkyl group substituted
by a chlorine, bromine or iodine atom,
R b denotes a hydrogen atom or a C1-3-alkyl group and
R c denotes a cyano group or an amidino group optionally
substituted by one or two C1-3-alkyl groups, wherein
the carboxy groups mentioned in the definition of
the abovementioned groups may also be replaced by a group
which may be converted in vivo into a carboxy group or by a
group which is negatively charged under physiological
conditions or
the amino and imino groups mentioned in the
definition of the abovementioned groups may also be
substituted by a group which can be cleaved in vivo, while

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by a group which may be converted into a carboxy
group in vivo is meant a hydroxymethyl group, a carboxy
group esterified with an alcohol wherein the alcoholic
moiety is a C1-6-alkanol, a phenyl-C1-3-alkanol, a
C3-9-cycloalkanol, while a C5-8-cycloalkanol may additionally
be substituted by one or two C1-3-alkyl groups, a
C5-8-cycloalkanol wherein a methylene group in the 3 or 4
position is replaced by an oxygen atom or by an imino group
optionally substituted by a C1-3-alkyl, phenyl-C1-3-alkyl,
phenyl-C1-3-alkoxycarbonyl or C2-6-alkanoyl group and the
cycloalkanol moiety may additionally be substituted by one
or two C1-3-alkyl groups, a C4-7-cycloalkenol, a C3-5-alkenol,
a phenyl-C3-5-alkenol, a C3-5-alkynol or phenyl-C3-5-alkynol,
with the proviso that no bond to the oxygen atom starts from
a carbon atom which carries a double or triple bond, a C3-8-
cycloalkyl-C1-3-alkanol, a bicycloalkanol with a total of
8 to 10 carbon atoms which may additionally be substituted
in the bicycloalkyl moiety by one or two C1-3-alkyl groups, a
1,3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of formula
R d-CO-O- (R e CR f) -OH,
wherein
R d denotes a C1-8-alkyl, C5-7-cycloalkyl, phenyl or
phenyl- C1-3-alkyl group
R e denotes a hydrogen atom, a C1-3-alkyl,
C5-7-cycloalkyl or phenyl group and
R f denotes a hydrogen atom or a C1-3-alkyl group,
by a group which is negatively charged under
physiological conditions is meant a tetrazol-5-yl,
phenylcarbonylaminocarbonyl,
trifluoromethylcarbonylaminocarbonyl,

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C1-6-alkylsulphonylamino, phenylsulphonylamino,
benzylsulphonylamino, trifluoromethylsulphonylamino,
C1-6-alkylsulphonylaminocarbonyl,
phenylsulphonylaminocarbonyl, benzylsulphonylaminocarbonyl
or perfluoro-C1-6-alkylsulphonylaminocarbonyl group
and by a group which can be cleaved from an imino
or amino group in vivo is meant a hydroxy group, a benzoyl
group optionally mono- or disubstituted by fluorine,
chlorine, bromine or iodine atoms, by C1-3-alkyl or
C1-3-alkoxy groups, while the substituents may be identical
or different, a pyridinoyl group or a C1-16-alkanoyl group, a
3,3,3-trichloropropionyl or allyloxycarbonyl group, a
C1-16-alkoxycarbonyl or C1-16-alkylcarbonyloxy group, wherein
hydrogen atoms may be wholly or partly replaced by fluorine
or chlorine atoms, a phenyl-C1-6-alkoxycarbonyl group, a
3-amino-propionyl group wherein the amino group may be mono-
or disubstituted by C1-6-alkyl or C3-7-cycloalkyl groups and
the substituents may be identical or different, a
C1-3-alkylsulphonyl-C2-4-alkoxycarbonyl, C1-3-alkoxy-
C2-4-alkoxy-C2-4-alkoxycarbonyl, R d-CO-O- (R d CR f) -O-CO,
C1-6-alkyl-CO-NH- (R g CR h) -O-CO or C1-6-alkyl-CO-O- (R g CR h) -
(R g CR h) -O-CO group, wherein R d to R f are as hereinbefore
defined and
R g and R h, which may be identical or different,
denote hydrogen atoms or C1-3-alkyl groups,
a tautomer thereof, a stereoisomer thereof, a mixture
thereof or a salt thereof, and
(b) at least one active substance selected from
the group consisting of an inhibitor of platelet function, a
thrombolytically active substance, a physiological activator
of a patient's clotting system or a recombinant

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analogue thereof, a physiological inhibitor of a patient's
clotting system or a recombinant analogue thereof, a
substance with an antagonistic effect on endotoxins, an
interleukin, TNF, bradykinin, a prostaglandin, a
cyclooxygenase, NO, platelet activating factor, an
acetylhydrolase, an inflammation inhibitor, an
immunosuppressant substance, an antibiotic and a
catecholamine.
2. A pharmaceutical composition according to claim 1,
wherein the inhibitor of platelet function is selected from
acetylsalicylic acid, a fibrinogen receptor antagonist, an
inhibitor of ADP-induced aggregation, a P2T receptor
antagonist and a combined thromboxane receptor
antagonist/synthetase inhibitor.
3. A pharmaceutical composition according to
claim 1 or 2, wherein the thrombolytically active substance
is selected from alteplase, reteplase, tenecteplase,
urokinase, staphylokinase and streptokinase.
4. A pharmaceutical composition according to any one
of claims 1 to 3, wherein the activator or inhibitor of
clotting function is selected from Protein C, recombinant
human activated Protein C, TFPI and antithrombin.
5. Pharmaceutical composition according to claim 1,
wherein (a) and (b) are :
(a) (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-
[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-
benzimidazole, optionally in the form of a pharmaceutically
acceptable acid addition salt and optionally in the form of
a hydrate or solvate thereof, and
(b) a PAF-AH or a PAF-AH derivative.

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6. Pharmaceutical kit comprising:
(a) (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-
[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-
benzimidazole, optionally in the form of a pharmaceutically
acceptable acid addition salt and optionally in the form of
a hydrate or solvate thereof;
(b) a PAF-AH or a PAF-AH derivative; and
(c) instructions for the prevention or treatment
of systemic inflammatory response syndrome (SIRS), sepsis or
bacteraemia.
7. Pharmaceutical kit comprising:
(a) (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-
[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-
benzimidazole, optionally in the form of a pharmaceutically
acceptable acid addition salt and optionally in the form of
a hydrate or solvate thereof;
(b) a tumor necrosis factor alpha (TNF-alpha)
antagonist; and
(c) instructions for the prevention or treatment
of systemic inflammatory response syndrome (SIRS), sepsis or
bacteraemia.
8. Use of a PAF-AH or a PAF-AH derivative or a TNF-
alpha antagonist for preparing a pharmaceutical composition
for combined use with a(R)-2-(4-amidinophenylaminomethyl)-
1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-
ethyl]-benzimidazole.

Description

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Pharmaceutical compositions for the treatment of
systemic inflammatory response syndrome
This is a divisional application of Canadian patent application
Serial No. 2,489,545 filed on June 16, 2003.
The subject-matter of this divisional application is directed to
pharmaceutical
compositions comprising a benzimidazole and an additional active ingredient.
It is to be understood that the expression "the present invention" or the like
used in this specification encompasses not only the subject-matter of this
divisional application but that of the parent also.
The present invention relates to the use of specific benzimidazoles of general
formula (I)
Ra ~A-B -Ar R,
N
I
Rb (I)
and particularly the compound of formula (II)
O
H OH
H2N H HC N
HCl x N N
H N \--<
N <
H 3 C 0
(II)
for preparing a pharmaceutical composition for the treatment of systemic
inflammatory response syndrome.
"Systemic inflammatory response syndrome" (hereinafter abbreviated to
"SIRS"; Bone R.C. et al.: "Definitions for Sepsis and Organ Failure and
Guidelines for the Use of Innovative Therapies in Sepsis", ACCP / SCCM
Consensus Conference Committee, Chest (1992) 101: 1644) is observed in

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connection with insults or traumas of all kinds. The typical symptoms of a
system inflammatory response occur, such as, in particular:
(a) raised or lowered body temperature of over 38 C or below 36 C,
(b) a heart rate of more than 90 beats per minute,
(c) rapid breathing at a rate of more than 20 breaths per minute or
hyperventilation with a PaCO2 of less than 32 mmHg,
(d) changes in the white blood picture with leukocyte numbers of more than
12,000/mm3 or less than 4,000/mm3 or the presence of more than 10%
immature neutrophils.
The causes of the occurrence of SIRS are numerous. One typical cause is
infections, particularly those brought about by gram-positive or gram-negative
bacteria, fungi, viruses or eukaryotic single-cell organisms, as well as mixed
infections with different pathogens (Balk R.A.: "Severe Sepsis and Septic
Shock", Critical Care Clinics (2000) 16: 179; Riewald M., Riess H.: "Treatment
Options for Clinically Recognized Disseminated Intravascular Coagulation",
Seminars in Thrombosis and Hemostasis (1998) 24: 53). The clinical picture
of sepsis or septicaemia frequently also occurs. Sepsis is defined as a
general infection with symptoms arising as a result of the constant or
periodic
dissemination of microorganisms from a source of infection into the
bloodstream. Frequently occurring sepsis pathogens are gram-negative
pathogens such as e.g. Escherichia coli and other Enterobacteriaceae
(Klebsiella, Proteus, Enterobacter), Pseudomonas aeruginosa, Neisseria
meningitidis, Salmonella, Serratia and Bacteroides. Gram-positive pathogens
include, for example, Staphylococci, Streptococci, Pneumococci, Enterococci
and Clostridium perfringens. Clinical symptoms of sepsis are typically high
intermittent fever, chills and significantly impaired general condition
extending
to confusion. As the illness progresses there may be (soft) spleen and liver
enlargement as well as infectious-toxic damage to internal organs (kidneys,
lungs, heart). The therapy essentially consists of treatment with antibiotics,
the choice of antibiotic depending on the pathogen (often cephalosporins or
penicillinase-resistant penicillins combined with an aminoglycoside). The

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prognosis is serious even when intensive medical treatment is administered.
The mortality rate is around 50%. Older, sick or immuno-compromised
patients are particularly critically affected.
Examples of non-infectious causes of SIRS are: pancreatitis, systemic and
organ-limited ischaemia, trauma of various kinds (e.g. multiple bone
fractures), tissue damage, large-area burns, lengthy operations, shock
produced by various causes including blood loss and a condition after
cardiovascular failure extending to loss of pulse and condition after
resuscitation, immunomediated organ failure and inflammatory reactions
induced by administering potential mediators of an inflammatory process,
such as e.g. Tumour Necrosis Factor and other cytokines.
Compounds of general formula (I)
N
Ra I >_A_B -Ar Rc
N
I
Rb (I)
and particularly the compound (R)-2-(4-amidinophenylaminomethyl)-1-methyl-
5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole of
formula (Ila)
0
H H - H N OH
O
HN \_4 I N
N
(Ila)
are known from WO 00/01704. Their antithrombotic activity is also known
from WO 00/01704.

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Surprisingly it has now been found that benzimidazoles of general formula (I)
N
Ra I \A-B -AY Rc (I)
N
I
Rb
wherein
Ar denotes a phenylene or naphthylene group optionally substituted by a
fluorine, chlorine or bromine atom, by a trifluoromethyl, C1_3-alkyl or C1_3-
alkoxy group,
a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or
pyridazinylene group optionally substituted in the carbon skeleton by a C1_3-
alkyl group,
A denotes a C1_3-alkylene group,
B denotes an oxygen or sulphur atom, a methylene, carbonyl, sulphinyl or
sulphonyl group, an imino group optionally substituted by a C1_3-alkyl group
wherein the alkyl moiety may be mono- or disubstituted by a carboxy group,
Ra denotes a R1-CO-C3_5-cycloalkyl group wherein
R1 denotes a C1_3-alkoxy, amino, C1_4-alkylamino or di-(C1_4-alkyl)-
amino group, wherein in each case the alkyl moiety may be substituted
by a carboxy group,
a 4- to 7-membered cycloalkyleneimino or cycloalkenyleneimino group
which may be substituted by one or two C1_3-alkyl groups, while an alkyl
substituent may simultaneously be substituted by a hydroxy,
C1_3-alkoxy, carboxy, carboxy-C1_3-alkoxy, carboxy-C1_3-alkylamino,

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N-(C1-3-alkyl)-N-(carboxy-C1_3-alkyl)-amino, carboxy-
C1_3-alkylaminocarbonyl, N-(C1_3-alkyl)-N-(carboxy-C1_3-alkyl)-
aminocarbonyl, carboxy-C1_3-alkylaminocarbonylamino, 1-(C1-3-alkyl)-
3-(carboxy-C1_3-alkyl)-aminocarbonylamino, 3-(C1_3-alkyl)-3-(carboxy-
C1_3-alkyl)-aminocarbonylamino or 1,3-di-(C1-3-alkyl)-3-(carboxy-
C1_3-alkyl)-aminocarbonylamino group,
a 4- to 7-membered cycloalkyleneimino group substituted by a hydroxy
group,
a 5- to 7-membered cycloalkyleneimino group optionally substituted by
a C1.3-alkyl group, to which a phenyl ring is fused via two adjacent
carbon atoms,
a morpholino, piperazino, N-(C1_3-alkyl)-piperazino, pyrrolino,
3,4-dehydro-piperidino or pyrrol-1-yi group,
a R2-CX-C3_5-cycloalkyl group wherein
R2 denotes a phenyl, naphthyl or monocyclic 5- or 6-membered
heteroaryl group optionally substituted by a C1_3-alkyl group, while the
6-membered heteroaryl group contains one, two or three nitrogen
atoms and the 5-membered heteroaryl group contains an imino group
optionally substituted by a C1_3-alkyl group, an oxygen or sulphur atom
or an imino group optionally substituted by a C1_3-alkyl group and an
oxygen or sulphur atom or one or two nitrogen atoms and the
abovementioned alkyl substituent may be substituted by a carboxy,
carboxy-C1_3-alkoxy, carboxy-C1_3-alkylamino or N-(C1_3-alkyl)-carboxy-
C1_3-alkylamino group, and
X denotes an oxygen atom, a C1_3-alkylimino, C1_3-alkoxyimino,
C1_3-alkylhydrazino, di-(C1_3-alkyl)-hydrazino, C2-4-alkanoylhydrazino, N-

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(C1_3-alkyl)-C2_4-alkanoylhydrazino or C1_3-alkylidene group each of
which may be substituted by a carboxy group in the alkyl or alkanoyl
moiety or in the alkyl and alkanoyl moiety,
a C1_3-alkyl or C3_5-cycloalkyl group substituted by an imidazole or
imidazolone
group, wherein
the imidazole ring may be substituted by a phenyl or carboxy group and
by one or two C1_3-alkyl groups or by one, two or three C1_3-alkyl
groups, while the substituents may be identical or different and one of
the abovementioned alkyl substituents may simultaneously be
substituted by a carboxy group or in the 2 or 3 position by an amino,
C2_4-alkanoylamino, C1_3-alkylamino, N-(C2_4-alkanoyl)-C1_3-alkylamino
or di-(C1_3-alkyl)-amino group, and
the imidazolone ring may be substituted by a C1_3-alkyl group, while the
alkyl substituent may be substituted by a carboxy group or in the 2 or 3
position by an amino, C2_4-alkanoylamino, C1_3-alkylamino,
N-(C2_4-alkanoyl)-C1_3-alkylamino or di-(C1_3-alkyl)-amino group, and
additionally a phenyl or pyridine ring may be fused to the
abovementioned imidazole and imidazolone rings via two adjacent
carbon atoms,
an imidazolidin-2,4-dion-5-yl group which may be substituted by one or two
C1_3-alkyl groups, while simultaneously an alkyl substituent may be
substituted
by a carboxy group,
a C1_4-alkyl group which is substituted
by a C1_3-alkyl-Y1-C1_3-alkyl, HOOC-C1_3-alkyl-Y1-C1_3-alkyl, tetrazolyl-
C1_3-alkyl-Y2, R3NR4 or R3NR4-C1.3-alkyl group and

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by an isoxazolidinylcarbonyl group optionally substituted by a C1_3-alkyl
group, by a pyrrolinocarbonyl, 3,4-dehydro-piperidinocarbonyl, pyrrol-
1-yl-carbonyl, carboxy, aminocarbonyl, C1_3-alkylaminocarbonyl, di-
(C1_3-alkyl)-aminocarbonyl or 4- to 7-membered cyclo-
alkyleneiminocarbonyl group, while in the abovementioned groups the
cycloalkyleneimino moiety may be substituted by one or two C1_3-alkyl
groups and simultaneously in each case an alkyl moiety or alkyl
substituent of the abovementioned C1_3-alkylaminocarbonyl, di-
(C1_3-alkyl)-aminocarbonyl or cycloalkyleneiminocarbonyl groups may
be substituted by a carboxy group, and the remaining hydrogen atoms
of the C1_4-alkyl group may be wholly or partly replaced by fluorine
atoms, wherein
R3 denotes a hydrogen atom or a C1_3-alkyl group optionally
substituted by a carboxy group and
R4 denotes a hydrogen atom, a C1_3-alkyl-Y1-C1_3-alkyl-Y2,
carboxy-C1_3-alkyl-Y1-C1_3-alkyl-Y2, C1.3-alkyl-Y2 or carboxy-
C1_3-alkyl-Y2 group or
R3 and R4 together with the nitrogen atom between them denote
a 4- to 7-membered cycloalkyleneimino group optionally
substituted by a carboxy, C1_3-alkyl or carboxy-C1_3-alkyl group,
wherein
Y1 denotes a carbon-carbon bond, an oxygen atom, a sulphenyl,
sulphinyl, sulphonyl, -NH, -NH-CO or -NH-CO-NH group and
Y2 denotes a carbon-nitrogen bond or a carbonyl, sulphonyl, imino or
-NH-CO group, while the carbonyl group of the -NH-CO group is linked
to the nitrogen atom of the R3NR4 group, and the imino groups

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mentioned in the definition of the groups Y1 and Y2 may each
additionally be substituted by a C1_3-alkyl or carboxy-C1_3-alkyl group,
a C1_3-alkyl or C3_5-cycloalkyl group substituted by a R5NR6 group, wherein
R5 denotes a hydrogen atom, a C1_3-alkyl, C5_7-cycloalkyl,
phenylcarbonyl, phenylsulphonyl or pyridinyl group and
R6 denotes a C1_3-alkyl, carboxy-C1_3-alkyl or carboxy-C1_3-alkylcarbonyl
group,
a C1_3-alkyl group which is substituted by a C2_4-alkanoyl or C5_7-
cycloalkanoyl
group and by a C1_3-alkyl group substituted by a chlorine, bromine or iodine
atom,
Rb denotes a hydrogen atom or a C1_3-alkyl group and
Rc denotes a cyano group or an amidino group optionally substituted by one
or two C1_3-alkyl groups, wherein
the carboxy groups mentioned in the definition of the abovementioned
groups may also be replaced by a group which may be converted in vivo
into a carboxy group or by a group which is negatively charged under
physiological conditions or
the amino and imino groups mentioned in the definition of the
abovementioned groups may also be substituted by a group which can
be cleaved in vivo, while
by a group which may be converted into a carboxy group in vivo is
meant a hydroxymethyl group, a carboxy group esterified with an alcohol
wherein the alcoholic moiety is a C1_6-alkanol, a phenyl-C1_3-alkanol, a

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C3_9-cycloalkanol, while a C5_8-cycloalkanol may additionally be
substituted by one or two C1_3-alkyl groups, a C5_8-cycloalkanol wherein a
methylene group in the 3 or 4 position is replaced by an oxygen atom or
by an imino group optionally substituted by a C1_3-alkyl, phenyl-C1_3-alkyl,
phenyl-C1_3-alkoxycarbonyl or C2_6-alkanoyl group and the cycloalkanol
moiety may additionally be substituted by one or two C1_3-alkyl groups, a
C4_7-cycloalkenol, a C3_5-alkenol, a phenyl-C3_5-alkenol, a C3_5-alkynol or
phenyl- C3_5-alkynol, with the proviso that no bond to the oxygen atom
starts from a carbon atom which carries a double or triple bond, a C3.8-
cycloalkyl-C1_3-alkanol, a bicycloalkanol with a total of 8 to 10 carbon
atoms which may additionally be substituted in the bicycloalkyl moiety by
one or two C1.3-alkyl groups, a 1,3-dihydro-3-oxo-1-isobenzofuranol or
an alcohol of formula
Rd-CO-O-(ReCRf)-OH,
wherein
Rd denotes a C1_8-alkyl, C5_7-cycloalkyl, phenyl or phenyl- C1_3-alkyl
group
Re denotes a hydrogen atom, a C1_3-alkyl, C5_7-cycloalkyl or phenyl group
and
Rf denotes a hydrogen atom or a C1_3-alkyl group,
by a group which is negatively charged under physiological conditions is
meant a tetrazol-5-yl, phenylcarbonylaminocarbonyl,
trifluoromethylcarbonylaminocarbonyl, C1_6-alkylsulphonylamino,
phenylsulphonylamino, benzylsulphonylamino,
trifluoromethylsulphonylamino, C1.6-alkylsulphonylaminocarbonyl,

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phenylsulphonylaminocarbonyl, benzylsulphonylaminocarbonyl or
perfuoro-C1.6-alkylsulphonylaminocarbonyl group
and by a group which can be cleaved from an imino or amino group in
vivo is meant a hydroxy group, a benzoyl group optionally mono- or
disubstituted by fluorine, chlorine, bromine or iodine atoms, by C1_3-alkyl
or C1-3-alkoxy groups, while the substituents may be identical or
different, a pyridinoyl group or a C1_16-alkanoyl group, a 3,3,3-
trichioropropionyl or allyloxycarbonyl group, a C1_16-alkoxycarbonyl or
C1_16-alkylcarbonyloxy group, wherein hydrogen atoms may be wholly or
partly replaced by fluorine or chlorine atoms, a phenyl-
C1_6-alkoxycarbonyl group, a 3-amino-propionyl group wherein the amino
group may be mono- or disubstituted by C1.6-alkyl or C3_7-cycloalkyl
groups and the substituents may be identical or different, a
C1_3-alkylsulphonyl-C2-4-alkoxycarbonyl, C1.3-alkoxy-C2-4-alkoxy-
C2_4-alkoxycarbonyl, Rd-CO-O-(RdCRf)-O-CO, C1_6-alkyl-CO-NH-
(RgCRh)-O-CO or C1-6-alkyl-CO-O-(RgCRh)-(RgCRh)-O-CO group,
wherein Rd to Rf are as hereinbefore defined and
Rg and Rh, which may be identical or different, denote hydrogen atoms
or C1_3-alkyl groups,
the tautomers, stereoisomers, mixtures thereof and the salts thereof, may also
be used to prepare a pharmaceutical composition for the treatment or
prevention of SIRS, acute cardiovascular failure, organ failure after
resuscitation, acute lung failure and acute respiratory distress syndrome in
adults (ARDS) and particularly sepsis.
Accordingly, the invention relates to the use of benzimidazoles of the above
formula (I) wherein Ra, Rb, Rc, A, B and Ar are as hereinbefore defined,
optionally in the form of the pharmaceutically acceptable acid addition salts
thereof, as well as optionally in the form of the hydrates or solvates
thereof,

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for preparing a pharmaceutical composition for the treatment of SIRS,
bacteraemia and/or sepsis, including severe sepsis, acute cardiovascular
failure, organ failure after resuscitation, acute lung failure and ARDS.

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Preferably, benzimidazoles of general formula (la)
N
R \>-A-B I
Rb
are used wherein
A denotes a C1_3-alkylene group,
B denotes an oxygen or sulphur atom, a methylene, carbonyl, sulphinyl or
sulphonyl group, an imino group optionally substituted by a C1_3-alkyl group
wherein the alkyl moiety may be mono- or disubstituted by a carboxy group,
R. denotes a R1-CO-C3_5-cycloalkyl group wherein
R1 denotes a C1.3-alkoxy, amino, C1.4-alkylamino or di-(C1-4-alkyl)-
amino group, wherein in each case the alkyl moiety may be substituted
by a carboxy group,
a 4- to 7-membered cycloalkyleneimino or cycloalkenyleneimino group
which may be substituted by one or two C1_3-alkyl group, while an alkyl
substituent may simultaneously be substituted by a hydroxy,
C1_3-alkoxy, carboxy, carboxy-C1_3-alkoxy, carboxy-C1_3-alkylamino,
N-(C1_3-alkyl)-N-(carboxy-C1_3-alkyl)-amino, carboxy-
C1.3-alkylaminocarbonyl, N-(C1.3-alkyl)-N-(carboxy-C1_3-alkyl)-
aminocarbonyl, carboxy-C1_3-alkylaminocarbonylamino, 1-(C1_3-alkyl)-
3-(carboxy-C1_3-alkyl)-aminocarbonylamino, 3-(C1_3-alkyl)-3-(carboxy-
C1_3-alkyl)-aminocarbonylamino or 1,3-di-(C1_3-alkyl)-3-(carboxy-
C1_3-alkyl)-aminocarbonylamino group,

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a 4- to 7-membered cycloalkyleneimino group substituted by a hydroxy
group,
a 5- to 7-membered cycloalkyleneimino group optionally substituted by
a C1_3-alkyl group, to which a phenyl ring is fused via two adjacent
carbon atoms,
a morpholino, piperazino, N-(C1_3-alkyl)-piperazino, pyrrolino,
3,4-dehydro-piperidino or pyrrol-1-yl group,
a R2-CX-C3_5-cycloalkyl group wherein
R2 denotes a phenyl, naphthyl or monocyclic 5- or 6-membered
heteroaryl group optionally substituted by a C1.3-alkyl group, while the
6-membered heteroaryl group contains one, two or three nitrogen
atoms and the 5-membered heteroaryl group contains an imino group
optionally substituted by a C1_3-alkyl group, an oxygen or sulphur atom
or an imino group optionally substituted by a C1_3-alkyl group and an
oxygen or sulphur atom or one or two nitrogen atoms and the
abovementioned alkyl substituent may be substituted by a carboxy,
carboxy-C1_3-alkoxy, carboxy-C1_3-alkylamino or N-(C1.3-alkyl)-carboxy-
C1.3-alkylamino group, and
X denotes an oxygen atom, a C1_3-alkylimino, C1.3-alkoxyimino,
C1_3-alkylhydrazino, di-(C1_3-alkyl)-hydrazino, C2_4-alkanoylhydrazino, N-
(C1_3-alkyl)-C2_4-alkanoylhydrazino or C1_3-alkylidene group each of
which may be substituted by a carboxy group in the alkyl or alkanoyl
moiety or in the alkyl and alkanoyl moiety,
a C1_3-alkyl or C3_5-cycloalkyl group substituted by an imidazole or
imidazolone
group, wherein

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the imidazole ring may be substituted by a phenyl or carboxy group and
by one or two C1_3-alkyl groups or by one, two or three C1.3-alkyl
groups, while the substituents may be identical or different and one of
the abovementioned alkyl substituents may simultaneously be
substituted by a carboxy group or may be substituted in the 2 or 3
position by an amino, C2_4-alkanoylamino, C1_3-alkylamino,
N-(C2_4-alkanoyl)-C1.3-alkylamino or di-(C1_3-alkyl)-amino group, and
the imidazolone ring may be substituted by a C1_3-alkyl group, while the
alkyl substituent may be substituted by a carboxy group or may be
substituted in the 2 or 3 position by an amino, C2_4-alkanoylamino,
C1_3-alkylamino, N-(C2_4-alkanoyl)-C1.3-alkylamino or di-(C1_3-alkyl)-
amino group, and
additionally a phenyl or pyridine ring may be fused to the
abovementioned imidazole and imidazolone rings via two adjacent
carbon atoms,
an imidazolidin-2,4-dion-5-yl group which may be substituted by one or two
C1_3-alkyl groups, while simultaneously an alkyl substituent may be
substituted
by a carboxy group,
a C1-4-alkyl group which is substituted
by a C1_3-alkyl-Y1-C1.3-alkyl, HOOC-C1.3-alkyl-Y1-C1_3-alkyl, tetrazolyl-
C1_3-alkyl-Y2, R3NR4 or R3NR4-C1.3-alkyl group and
by an isoxazolidin-1-ylcarbonyl group optionally substituted by a
C1_3-alkyl group, by a pyrrolinocarbonyl, 2,3-dehydro-
piperidinocarbonyl, pyrrol-1-yl-carbonyl, carboxy, aminocarbonyl,
C1.3-alkylaminocarbonyl, di-(C1_3-alkyl)-aminocarbonyl or 4- to 7-
membered cycloalkyleneiminocarbonyl group, while in the

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abovementioned groups the cycloalkyleneimino moiety may be
substituted by one or two C1.3-alkyl groups and simultaneously in each
case an alkyl moiety or alkyl substituent of the abovementioned
C1_3-alkylaminocarbonyl, di-(C1.3-alkyl)-aminocarbonyl or
cycloalkyleneiminocarbonyl groups may be substituted by a carboxy
group, and the remaining hydrogen atoms of the C1_4-alkyl group may
be wholly or partly replaced by fluorine atoms, wherein
R3 denotes a hydrogen atom or a C1_3-alkyl group optionally
substituted by a carboxy group and
R4 denotes a hydrogen atom, a C1_3-alkyl-Y1-C1_3-alkyl-Y2,
carboxy-C1_3-alkyl-Y1-C1_3-alkyl-Y2, C1.3-alkyl-Y2 or carboxy-
C1_3-alkyl-Y2 group or
R3 and R4 together with the nitrogen atom between them denote
a 4- to 7-membered cycloalkyleneimino group optionally
substituted by a carboxy, C1_3-alkyl or carboxy-C1_3-alkyl group,
wherein
Y1 denotes a carbon-carbon bond, an oxygen atom, a sulphenyl,
sulphinyl, sulphonyl, -NH, -NH-CO or -NH-CO-NH group and
Y2 denotes a carbon-nitrogen bond or a carbonyl, sulphonyl, imino or
-NH-CO group, while the carbonyl group of the -NH-CO group is linked
to the nitrogen atom of the R3NR4 group, and the imino groups
mentioned in the definition of the groups Y1 and Y2 may each
additionally be substituted by a C1_3-alkyl or carboxy-C1_3-alkyl group,
a C1.3-alkyl or C3_5-cycloalkyl group substituted by a R5NR6 group, wherein

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R5 denotes a hydrogen atom, a C1_3-alkyl, C5_7-cycloalkyl,
phenylcarbonyl, phenylsulphonyl or pyridinyl group and
R6 denotes a C1_3-alkyl, carboxy-C1_3-alkyl or carboxy-C1_3-alkylcarbonyl
group,
a C1_3-alkyl group which is substituted by a C2_4-alkanoyl or C5_7-
cycloalkanoyl
group and by a C1_3-alkyl group substituted by a chlorine, bromine or iodine
atom,
Rb denotes a hydrogen atom or a C1_3-alkyl group and
R,. denotes a cyano group or an amidino group which may be substituted by a
hydroxy group, by one or two C1_3-alkyl groups, by one or two
C1_8-alkoxycarbonyl groups,
while the carboxy, amino and imino groups mentioned in the definition of the
abovementioned groups may also be substituted by a group which can be
cleaved in vivo as hereinbefore defined,
as well as the tautomers, stereoisomers and salts thereof.
Preferably, also, benzimidazoles of the above general formula la are used
wherein
A denotes a C1_3-alkylene group,
B denotes an oxygen atom, a methylene, imino or N-(C1_3-alkyl)-imino group
wherein the alkyl moiety may be substituted by a carboxy group,
Ra denotes a C3_5-cycloalkyl group substituted in the 1 position by the R1-CO
group, wherein

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R1 denotes a C1_3-alkoxy, amino, C1_4-alkylamino or di-(C1_4-alkyl)-amino
group, wherein in each case the alkyl moiety may be substituted by a
carboxy group,
a 4- to 7-membered cycloalkyleneimino group which may be substituted by
a hydroxy group or by one or two C1_3-alkyl groups, while an alkyl
substituent may simultaneously be substituted by a hydroxy, C1_3-alkoxy,
carboxy, carboxy-C1_3-alkoxy, carboxy-C1_3-alkylamino, N-(C1_3-alkyl)-
N-(carboxy-C1_3-alkyl)-amino, carboxy-C1_3-al kylaminocarbonyl,
N-(C1_3-alkyl)-N-(carboxy-C1_3-alkyl)-aminocarbonyl, carboxy-
C1_3-alkylaminocarbonylamino, 1-(C1_3-alkyl)-3-(carboxy-C1-3-alkyl)-
aminocarbonylamino, 3-(C1_3-alkyl)-3-(carboxy-C1_3-alkyl)-
aminocarbonylamino or 1,3-di-(C1_3-alkyl)-3-(carboxy-C1_3-alkyl)-
aminocarbonylamino group,
a 5- to 7-membered cycloalkyleneimino group optionally substituted by a
C1_3-alkyl group, to which a phenyl ring is fused via two adjacent carbon
atoms,
a morpholino, piperazino, N-(C1_3-alkyl)-piperazino, pyrrolino, 3,4-Dehydro-
piperidino or pyrrol-1-yl group,
a C3_5-cycloalkyl group substituted in the 1 position by the R2-CX group
wherein
R2 denotes a phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl
group optionally substituted by a C1_3-alkyl group, while the 6-membered
heteroaryl group contains one, two or three nitrogen atoms and the
5-membered heteroaryl group contains an imino group optionally
substituted by a C1.3-alkyl group, an oxygen or sulphur atom or an imino
group optionally substituted by a C1.3-alkyl group and an oxygen or sulphur
atom or one or two nitrogen atoms and the abovementioned alkyl

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substituent may be substituted by a carboxy, carboxy-C1_3-alkoxy, carboxy-
C1_3-alkylamino or N-(C1_3-alkyl)-carboxy-C1_3-alkylamino group, and
X denotes an oxygen atom, a C1_3-alkylimino, C1_3-alkoxyimino or
C1_3-alkylidene group each of which may be substituted in the alkyl or
alkoxy moiety by a carboxy group,
a C1_3-alkyl group substituted in the 1 position by an imidazole or
imidazolone
group, wherein
the imidazole ring may be substituted by a phenyl or carboxy group and by
one or two C1_3-alkyl groups or by one, two or three C1.3-alkyl groups, while
the substituents may be identical or different and one of the
abovementioned alkyl substituents may simultaneously be substituted by a
carboxy group or may be substituted in the 2 or 3 position by an amino,
C2_4-alkanoylamino, C1_3-alkylamino, N-(C2_4-alkanoyl)-C1_3-alkylamino or di-
(C1_3-alkyl)-amino group, and
the imidazolone ring may be substituted by a C1_3-alkyl group, while the
alkyl substituent may be substituted by a carboxy group or may be
substituted in the 2 or 3 position by an amino, C2.4-alkanoylamino,
C1_3-alkylamino, N-(C2.4-alkanoyl)-C1.3-alkylamino or di-(C1.3-alkyl)-amino
group, and
additionally a phenyl or pyridine ring may be fused to the abovementioned
imidazole and imidazolone rings via two adjacent carbon atoms,
an imidazolidin-2,4-dion-5-yl group which may be substituted by one or two
C1_3-alkyl groups, while simultaneously an alkyl substituent may be
substituted
by a carboxy group,
a C1_4-alkyl group which is substituted in the 1 position

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by a R3NR4 or R3NR4-C1_3-alkyl group and
by a pyrrolinocarbonyl, 2,3-dehydro-piperidinocarbonyl, imidazol-1-yl-
carbonyl, carboxy, aminocarbonyl, C1.3-alkylaminocarbonyl, di-(C1_3-alkyl)-
aminocarbonyl, isoxazolidin-1-ylcarbonyl or 4- to 7-membered cycloal-
kyleneiminocarbonyl group, while in the abovementioned groups the
cycloalkyleneimino moiety may be substituted by one or two C1_3-alkyl
groups and simultaneously in each case an alkyl moiety or alkyl substituent
of the abovementioned C1_3-alkylaminocarbonyl, di-(C1_3-alkyl)-aminocar-
bonyl or cycloalkyleneiminocarbonyl groups may be substituted by a carb-
oxy group, and the remaining hydrogen atoms of the C1_4-alkyl group may
be wholly or partly replaced by fluorine atoms, while
R3 denotes a hydrogen atom or a C1_3-alkyl group optionally substituted
by a carboxy group and
R4 denotes a hydrogen atom, C1.3-alkyl-Y2 or carboxy-C1-3-alkyl-Y2 group
or
R3 and R4 together with the nitrogen atom between them denote a 4- to
7-membered cycloalkyleneimino group optionally substituted in the 1
position by a carboxy, C1_3-alkyl or carboxy-C1_3-alkyl group, wherein
Y2 denotes a carbon-nitrogen bond or a carbonyl, imino or -NH-CO group,
while the carbonyl group of the -NH-CO group is linked to the nitrogen
atom of the R3NR4 group, and the imino group occurring in the definition of
the group Y2 may additionally be substituted by a C1_3-alkyl or carboxy-
C1.3-alkyl group,
a C1_3-alkyl or C3_5-cycloalkyl group substituted in the 1 position by a R5NR6
group, wherein

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R5 denotes a hydrogen atom, a C1_3-alkyl, C5_7-cycloalkyl, phenylcarbonyl,
phenylsulphonyl or pyridinyl group and
R6 denotes a C1_3-alkyl, carboxy-C1.3-alkyl or carboxy-C1_3-alkylcarbonyl
group,
a C1_3-alkyl group which is substituted by C2_4-alkanoyl or C5_7-cycloalkanoyl
group and by a C1_3-alkyl group substituted by a chlorine, bromine or iodine
atom,
Rb denotes a C1_3-alkyl group and
Rc denotes an amidino group optionally substituted by a 2,2,2-
trichloroethoxycarbonyl, C1_8-alkoxycarbonyl, acetoxymethyloxycarbonyl,
benzyloxycarbonyl or benzoyl group, while the benzoyl moiety may be mono-
or disubstituted by fluorine, chlorine, bromine or iodine atoms or by C1_3-
alkyl
or C1.3-alkoxy groups and the substituents may be identical or different,
as well as the C1_3-alkanolesters thereof and the tautomers, stereoisomers
and salts thereof.
In a particularly preferred embodiment, the abovementioned pharmaceutical
composition is prepared using benzimidazoles of the above general formula
(la) wherein
A denotes a methylene group,
B denotes an oxygen atom or an imino group,
Ra denotes a cyclopropyl group substituted in the 1 position by the R1-CO
group wherein

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R1 denotes a pyrrolidino or piperidino group optionally substituted by a
methyl or ethyl group, wherein in each case the methyl or ethyl moiety may
be substituted by a carboxy, carboxy-C1_3-alkoxy, carboxy-C1_3-alkylamino
or N-(C1_3-alkyl)-carboxy-C1_3-alkylamino group,
a cyclopropyl group substituted in the 1 position by the R2-CX group wherein
R2 denotes a phenyl, pyridyl or pyrazolyl group optionally substituted by a
C1_3-alkyl group, and
X denotes an oxygen atom, a C1_3-alkoxyimino or C1_3-alkylidene group
each of which is substituted by a carboxy group in the alkyl or alkoxy
moiety,
a C1_2-alkyl group substituted in the 1 position by an imidazole group,
wherein the imidazole ring may be substituted by a phenyl or carboxy
group and by one or two C1.3-alkyl groups or by one, two or three C1_3-alkyl
groups, while the substituents may be identical or different and one of the
abovementioned alkyl substituents may simultaneously be substituted by a
carboxy group or may be substituted in the 2 or 3 position by an amino,
C2_4-alkanoylamino, C1_3-alkylamino, N-(C2_4-alkanoyl)-CI_3-alkylamino or di-
(C1_3-alkyl)-amino group, while additionally a phenyl or pyridine ring may be
fused to the abovementioned imidazole rings via two adjacent carbon
atoms,
a C1_2-alkyl group substituted in the 1 position by a benzimidazolon-1-yl
group, while the imidazolone ring may be substituted by a methyl or ethyl
group optionally substituted by a carboxy group,
a methyl or ethyl group which is substituted in the 1 position
by a R3NR4 or R3NR4-C1_3-alkyl group and

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by a di-(C1_3-alkyl)-aminocarbonyl group, by an isoxazolidin-1-ylcarbonyl
group, by a pyrrolidinocarbonyl or piperidinocarbonyl group optionally
substituted by a C1_3-alkyl group, while in the abovementioned groups in
each case an alkyl moiety or alkyl substituent may be substituted by a
carboxy group, while
R3 denotes a hydrogen atom or a C1_3-alkyl group optionally substituted
by a carboxy group and
R4 denotes a hydrogen atom, a C1_3-alkyl-Y2 or carboxy-C1_3-alkyl-Y2
group or
R3 and R4 together with the nitrogen atom between them denote a 4- to
7-membered cycloalkyleneimino group optionally substituted by a
carboxy group, wherein
Y2 denotes a carbon-nitrogen bond, a carbonyl group or an imino group
optionally substituted by a C1_3-alkyl group,
a C1.2-alkyl group substituted in the 1 position by a R5NR6 group wherein
R5 denotes a pyridinyl, phenylcarbonyl or phenylsulphonyl group and
R6 denotes a C1_3-alkyl or carboxy-C1_3-alkyl group,
an n-propyl group substituted in the 3 position by a chlorine atom, which is
substituted in the 1 position by a cyclopentylcarbonyl group,
a cyclopropyl group substituted in the 1 position by a cyclopentylamino group
which is substituted at the nitrogen atom by a carboxy-C1_3-alkylcarbonyl
group,

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Rb denotes a methyl group and
Rc denotes an amidino group optionally substituted by a C1_8-alkoxycarbonyl,
acetoxymethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl
or benzoyl group,
or the C1.3-alkanol esters, the tautomers, the stereoisomers or the salts
thereof.
It is also preferable to use benzimidazoles of the above general formula (Ia)
wherein
A denotes a methylene group,
B denotes an imino group,
Ra denotes a cyclopropyl group substituted in the 1 position by the R1-CO
group, wherein
R, denotes a pyrrolidino or piperidino group optionally substituted by a
methyl or ethyl group, wherein in each case the methyl or ethyl moiety may
be substituted by a carboxy, carboxy-C1_3-alkoxy, carboxy-C1_3-alkylamino
or N-(C,_3-alkyl)-carboxy-C1_3-alkylamino group,
a cyclopropyl group substituted in the 1 position by the R2-CX group wherein
R2 denotes a phenyl, pyridyl or pyrazolyl group optionally substituted by a
C1_3-alkyl group and
X denotes an oxygen atom, a C1_3-alkoxyimino or C1_3-alkylidene group
each of which is substituted in the alkyl or alkoxy moiety by a carboxy
group,

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a C1_2-alkyl group substituted in the 1 position by an imidazole group wherein
the imidazole ring may be substituted by 1 to 3 methyl groups or is
substituted
by two methyl groups and an ethyl group, while additionally one of the
abovementioned methyl or ethyl substituents may simultaneously be
substituted by a carboxy group,
a methyl or ethyl group which may be substituted in the I position
by a R3NR4 or R3NR4-CH2 group and
by a di-(C1_3-alkyl)-aminocarbonyl group, a pyrrolidinocarbonyl or
piperidinocarbonyl group optionally substituted by a C1_3-alkyl group, while
in the abovementioned groups in each case an alkyl moiety or alkyl
substituent may be substituted by a carboxy group, wherein
R3 denotes a hydrogen atom or a C1_3-alkyl group optionally substituted
by a carboxy group and
R4 denotes a C1.3-alkyl-Y2 or carboxy-C1_3-alkyl-Y2 group, wherein
Y2 denotes a carbon-nitrogen bond, a carbonyl group or an imino group
optionally substituted by a C1_3-alkyl group,
Rb denotes a methyl group and
Rc denotes an amidino group optionally substituted by a C1_8-alkoxycarbonyl,
acetoxymethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl
or benzoyl group,
or the C1.3-alkanol esters, the tautomers, the stereoisomers or the salts
thereof.

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Most particularly preferred is the use of benzimidazoles of general formula
(I)
above and the abovementioned substituents, wherein the group Ra is in the 5
position, or the tautomers, the stereoisomers or the salts thereof.
Examples of preferred compounds are:
(a) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-
1-yl-carbonyl)cyclopropyl]-benzimidazole,
(b) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(pyridin-2-yl)-
(carboxymethyloxyimino)methylene]cyclopropyl]-benzimidazole,
(c) 2-(4-amid inophenylaminomethyl)-1-methyl-5-[1-(2-carboxy-
ethylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole,
(d) 2-(4-amid inophenylaminomethyl)-1-methyl-5-[1-[2-(2-carboxyethyl)-
pyrrolidin-1-yl-carbonyl]cyclopropyl]-benzimidazole,
(e) 2-(4-amid inophenylaminomethyl)-1-methyl-5-[2-(2-carboxyethyl)-4,5-
dimethyl-imidazol-1-yl-methyl]-benzimidazole,
(f) 2-(4-amidinophenylaminomethyl)-1 -methyl-5-[1 -(carboxymethylamino)-
1 -(pyrrolidin-1 -yl-carbonyl)-ethyl]-benzimidazole,
(g) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-methyl-
carboxymethylcarbonylaminomethyl)-1-methyl-l -(pyrrolidin-1-yl-carbonyl)-
ethyl]-benzimidazole,
(h) 2-(4-amidinophenylaminomethyl)-1 -methyl-5-[1 -(carboxymethylamino)-
1-(pyrrolid inocarbonyl)-ethyl]-benzimidazole and

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(I) (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-
(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole, shown in
formula (Ila),
the C1_3-alkanol esters thereof, the N-(C1_8-alkoxycarbonyl)-,
N-benzyloxycarbonyl- and N-benzoyl-amidines thereof, the tautomers,
stereoisomers and salts thereof.
Thus, the abovementioned benzimidazole compounds may be used, for
example, as free bases, as zwitterions or in the form of pharmaceutically
acceptable acid addition salts. Pharmaceutically acceptable acid addition
salts in this context are salts of hydrochloric acid, hydrobromic acid,
sulphuric
acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid,
succinic acid, lactic acid, citric acid, tartaric acid and maleic acid, while
the
salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid
and acetic acid are particularly preferred. Salts of hydrochloric acid, e.g.
the
monohydrochloride or dihydrochloride, are most particularly preferred.
According to a particularly preferred embodiment, the abovementioned (R)-2-
(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-
(pyrrol idinocarbonyl)-ethyl]-benzimidazole is used in the form of a free
base,
shown in formula (Ila)
0 H ~--OH
HN - H N
H N \ ' I - O N N
(Ila)
or in the form of the monohydrochloride, shown in formula (II)

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O
H OH
HN H HC N
HCl x 2\ N N O
H ~--Cz N
N
H3C (II)
for treating the conditions mentioned above or for preparing a pharmaceutical
composition for treating the conditions mentioned above. In aqueous solution,
e.g. when formulated as a solution for infusion, this compound will typically
be
in the form of a zwitterion.
As mentioned earlier, the abovementioned compounds are known to have an
antithrombotic activity, e.g. from WO 00/01704. Surprisingly, it has now been
found that the abovementioned compounds and particularly compounds of
formula (II) or (Ila) are suitable for treating sepsis or bacteraemia and,
more
generally, SIRS, acute cardiovascular failure, organ failure after
resuscitation,
acute lung failure and ARDS. In fact, it was known from investigations into
other antithrombotic active substances known in the prior art that such active
substances are not generally effective against sepsis (cf. e.g. the Kybersept
Study: Warren et al., JAMA 2001; Knaub S, Keinecke HO, Juers M, Schindel
F, Heinrichs H, Opal S: "High-dose antithrombin III in patients with severe
sepsis - The kybersept trial" Thromb. Haemost. (2001), 6-12 July 2001 (Abs
P523)), i.e. it is a particular feature of the abovementioned compounds and
particularly (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxy-
methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole.
As discussed earlier, SIRS can be subdivided into a number of subgroups.
One representative subgroup consists of SIRS caused by infections, which
corresponds to the clinical picture of sepsis (septicaemia; "blood
poisoning").
Another subgroup would be SIRS occurring independently of infections.

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Of particular clinical importance, among the non-infectious causes, is
cardiovascular failure, in particular, as it occurs in a large number of
patients
(estimated number in the USA: up to 450,000 deaths) and with a survival rate
of less than 5% it is an extremely life-threatening condition (Weisfeldt ML,
JAMA 2002; 288: 3035). Even if the patient survives the first cardiac arrest
the
prognosis is very grave and the organ failure which persists in these patients
contributes to a low survival rate even if the patient is successfully
resuscitated at first. This organ failure is maintained by the combination of
the
activation of the clotting system during the stoppage of the cardiovascular
system and the subsequent immune reaction (for the parameters of the
immune reaction see Adrie C, Circulation 2002; 106: 562). Because of the
combined effect of the activation of clotting and the immune reaction, the
very
combination of the efficacy of the compounds of formula I found according to
the invention and particularly the compounds of formulae II and Ila as
antiocoagulants and the simultaneous reduction in the immune parameters in
patients after cardiovascular stoppage is important. The compounds of
formula I may be administered intravenously (as a bolus or infusion) during
the resuscitation procedure, thereby increasing the likelihood of successful
restoration of cardiovascular function, or intravenously (as a bolus or
infusion)
after cardiovascular function has been restored in order to prevent and reduce
the failure of different organs. The drug can be given until the patient has
recovered fully.
As SIRS progresses there may be (soft) enlargement of the spleen and liver
and damage to internal organs (kidney, lung, heart). Administering the
compounds of formula I according to the invention, most preferably
administering compounds of formulae II and Ila, to patients at risk of
developing SIRS can prevent the development of organ failure or, if SIRS is
already present, may prevent further organ damage or shorten the duration of
the illness.

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Forms of organ failure may include: failure of heart function, which leads to
a
critical drop in the patient's blood pressure with further organ failure and
death; kidney failure which can result in death, if left untreated, and
requires
the use of kidney replacement therapies (e.g. dialysis or continuous
filtration)
as a treatment, and acute lung failure.
Organ failure of the lung, in the form of acute lung injury (ALI) or acute
respiratory distress syndrome in adults (ARDS) is particularly important, as
SIRS very often leads to this outcome as a result of the combination of the
activation of inflammatory reaction and clotting. Use of the compounds of
formula I according to the invention, the compounds of formulae II and Ila
being particularly preferred, leads to the prevention of acute lung injury in
patients who may or may not be showing signs of lung injury or early forms
(e.g. patients with corresponding clinical pictures [sepsis, trauma] and with
no
changes showing up on x-ray or with the start of lung infiltration) or for
reducing the period of ventilation in patients with fully developed lung
failure.
The drug may start to be administered intravenously in the form of a bolus or
infusion in these clinical conditions as soon as the situation appears to be
risky or it may be used as a therapy for existing signs of organ dysfunction
(e.g. significantly lowered blood pressure, increasing kidney retention levels
or
a deterioration in the blood gases). Administration of the drug is continued
as
long as there is a perceived risk.
(Literature: Abraham E, Crit Care Med 2000; 28: 232).
Accordingly the invention relates to a process for the treatment or possibly
also the prevention of diseases subsumed under the heading "SIRS" or a
process for preparing a pharmaceutical composition for the treatment or
prevention or accompanying treatment of diseases subsumed under the
heading "SIRS", such as e.g.: SIRS caused by pathogens such as gram-
negative pathogens (such as e.g. Escherichia coli, Klebsiella, Proteus,
Enterobacter, Pseudomonas aeruginosa, Neisseria meningitidis, Salmonella,
Serratia, Bacteroides etc.), gram-positive pathogens (such as e.g.
Staphylococci, Streptococci, Pneumococci, Enterococci and Clostridium

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perfringens), viruses, single-cell eukaryotic parasites or fungi, SIRS with
and
without organ failure, septic shock, septic syndrome, SIRS caused by
pancreatitis, by systemic ischaemia, by organ-limited ischaemia, by burns, by
tissue damage or other trauma, SIRS occurring in connection with tumour
diseases, SIRS occurring after lengthy operations, as a consequence of organ
transplants or as the result of shock of various kinds, e.g. as a consequence
of blood loss, following cardiovascular failure, immuno-mediated organ failure
or inflammatory reactions, as well as SIRS occurring as a consequence of
treatment with inflammation mediators such as for example tumour necrosis
factor alpha and/or tumour necrosis factor beta and/or other cytokines, and
also acute lung injury and ARDS. SIRS may be accompanied by lung
damage, damage to the cardiovascular system with hypotonia, kidney failure,
haematological changes, acidosis as well as multiple organ dysfunction
syndrome (MODS), which can therefore also be treated using the
abovementioned compounds according to the invention.
According to a preferred embodiment the invention relates to the use of
(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-
(pyrrol idinocarbonyl)-ethyl]-benzimidazole and particularly the
monohydrochloride thereof for the treatment of sepsis, infection-related SIRS
and/or SIRS as a consequence of bacteraemia, or for preparing a
pharmaceutical composition for the treatment or accompanying treatment of
sepsis, infection-related SIRS and/or SIRS as a consequence of bacteraemia,
acute cardiovascular failure, organ failure after resuscitation, acute lung
injury
and ARDS.
In addition to their use as monotherapeutic agents the abovementioned
benzimidazole compounds and particularly (R)-2-(4-
amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-
(pyrrolidinocarbonyl)-ethyl]-benzimidazole may be used, according to another
preferred embodiment, in conjunction with suitable additional active
substances.

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These might include, for example:
(a) inhibitors of platelet function such as for example acetylsalicylic acid,
fibrinogen receptor antagonists (e.g. abciximab, eptifibatide, tirofiban,
roxifiban), inhibitors of ADP-induced aggregation (e.g. clopidogrel,
ticlopidine),
P2T receptor antagonists (e.g. cangrelor) and combined thromboxane
receptor antagonists / synthetase inhibitors (e.g. terbogrel),
(b) thrombolytically active substances, such as for example alteplase,
reteplase, tenecteplase, urokinase, staphylokinase and streptokinase,
(c) physiological activators and inhibitors of the clotting system and their
recombinant analogues (e.g. protein C, recombinant human activated Protein
C (rhAPC), tissue factor pathway inhibitor (TFPI), antithrombin),
(d) active substances conventionally used in sepsis such as e.g.
substances with an antagonistic effect on endotoxins, interleukins, TNF,
bradykinin, prostaglandins, cyclooxygenases, NO, PAF such as for example
those which have an antagonistic effect on the associated receptors, those
which interfere with the particular principle of effect and antibodies
specifically
directed against the substances, etc.,
(e) platelet activating factor acetylhydrolase (PAF-AH), preferably human
PAF-AH (described e.g. in Tjoelker LW, Stafforini DM: "Platelet-activating
factor acetylhydrolases in health and disease" Biochim Biophys Acta (2000)
1488:102-123, WO 95/09921 and WO 95/00649) as well as PAF-AH
derivatives such as, in particular, shortened PAF-AH proteins as described for
example in WO 99/09147,
(f) conventional therapeutic agents which are used to inhibit inflammation,
such as e.g. base therapeutics for rheumatic diseases such as chloroquine,
gold preparations, D-peniciIlamine, methotrexate, chlorambucil,
cyclophosphamide, corticosteroids in all forms, cyclosporin, tacrolimus,
sirolimus, azathioprin, mycophenolate mofetil, etc., and
(g) drugs which are conventionally used for treating sepsis, such as e.g.
antibiotics, substances acting on the circulation such as catecholamines, etc.

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The invention therefore also includes combinations of the
abovementioned benzimidazole compounds and particularly
(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxy-
methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole,
optionally in the form of the pharmaceutically acceptable
acid addition salts as well as optionally in the form of the
hydrates or solvates thereof, with one or more of the
substances listed under (a) to (g) above. The combination of
(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxy-
methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole
with a PAF-acetylhydrolase and particularly one of the PAF-
AH-derivatives described in WO 99/09147 such as e.g. rPH.2
or rPH.9 mentioned therein (page 10 ff. of WO 99/09147) are
found to be particularly effective. The combination of
(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxy-
methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole
with an anti-human TNFalpha-antibody, such as e.g.
afelimomab (INN), is also particularly advantageous.
The invention also relates to a pharmaceutical kit
comprising: (a) (R)-2-(4-amidinophenylaminomethyl)-1-methyl-
5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-
benzimidazole, optionally in the form of a pharmaceutically
acceptable acid addition salt and optionally in the form of
a hydrate or solvate thereof; (b) a PAF-AH or a PAF-AH
derivative; and (c) instructions for the prevention or
treatment of systemic inflammatory response syndrome (SIRS),
sepsis or bacteraemia.
The invention also relates to a pharmaceutical kit
comprising: (a) (R)-2-(4-amidinophenylaminomethyl)-1-methyl-
5-[l-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-
benzimidazole, optionally in the form of a pharmaceutically
acceptable acid addition salt and optionally in the form of

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a hydrate or solvate thereof; (b) a tumor necrosis factor
alpha (TNF-alpha) antagonist; and (c) instructions for the
prevention or treatment of systemic inflammatory response
syndrome (SIRS), sepsis or bacteraemia.
The abovementioned benzimidazole active substances or
combinations of active substances are administered in the
usual way, preferably parenterally and more preferably by
intravenous route (i.v.), optionally also subcutaneously.
They may be administered parenterally for example by i.v.
infusion which may also in certain circumstances be given
over a longer period (hours or days) (continuous long-term
infusion) depending on the clinical picture. Doses for i.v.
administration may be, for example, in the range from 0.05
to 2000 mg/24 h. The optimum therapeutic dose depends on
the indication and the formulation used and can be
determined experimentally in a manner known to those skilled
in the art. The proposed dosage range for the active
substance (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-
(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-
benzimidazole, for example, is in the range from
0.0001 mg/kg/h to 1 mg/kg/h, preferably from 0.001 mg/kg/h
to 0.5 mg/kg/h and more preferably from 0.01 mg/kg/h
to 0.3 mg/kg/h. The skilled man will naturally see that it
may be necessary to deviate from the quantities specified,
depending on the patient's body weight or the

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method of administration, the individual response to the drug, the nature of
the formulation and the time or period of time when it is administered. Thus,
in
some cases, it may be sufficient to use less than the minimum amount
specified, whereas in other cases the dosage may have to exceed the upper
limit specified. When administering larger amounts it may be advisable to
spread them out over the day in a number of single doses.
The skilled man will be aware of methods by which to formulate the
benzimidazole active substances and combinations of active substances
mentioned above for particular applications (Gennaro, Alfonso R.:
Remington's Pharmaceutical Sciences. Easton Mack). Solutions for injection
and infusion are prepared in the usual way, e.g. with the addition of buffers,
isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers
such as alkali metal salts of ethylenediaminetetraacetic acid, optionally
using
emulsifiers and /or dispersants, while if water is used as diluent, for
example,
organic solvents may optionally be added as solubilisers or auxiliary
solvents,
and the finished solutions transferred into injection phials or ampoules or
infusion bottles.
The Examples that follow illustrate the invention without restricting its
scope.
Examples
Example 1: Preparation of (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-
1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyll-benzimidazole-
hydrochloride
a.) ethyl 2-amino-2-(4-chloro-3-nitro-phenyl)-propionate
A mixture of 28 g (0.11 mol) of 2-amino-2-(4-chloro-3-nitro-phenyl)-propionic
acid in 200 ml of 5.6N ethanolic hydrochloric acid is refluxed for 36 hours.
After the solvent has been evaporated off the residue is suspended in 300 ml
of ethyl acetate and combined with 300 ml of saturated sodium hydrogen
carbonate solution. The organic phase is washed twice with saturated sodium

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hydrogen carbonate solution and once with water, dried over sodium sulphate
and concentrated by evaporation.
Yield: 21.1 g (68% of theory) light brown oil.
b.) ethyl (R)-(+)-2-amino-2-(4-chloro-3-nitro-phenyl)-propionate
17.33 g (63.6 mmol) of ethyl 2-amino-2-(4-chloro-3-nitro-phenyl)-propionate
are dissolved in 247 ml isopropanol and 207 ml of methanol and combined
with 9.54 g (63.6 mmol) of L-(+)-tartaric acid. The reaction mixture is heated
to 100 C, whereupon a clear solution is formed. The solution is cooled to 27 C
within 3 hours, the precipitate formed is suction filtered, washed with
ethanol
and dried. Then the solid formed (21.5 g) is suspended in 400 ml of ethyl
acetate and combined with 400 ml of saturated sodium hydrogen carbonate
solution. After extraction and phase separation the organic phase is washed
with water, dried and concentrated by evaporation.
Yield: 7.68 g (44.4% of theory) of light yellow oil,
[a]20 = + 4.38 (ethyl acetate)
HPLC analysis: ee value >98.6%

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c.) (R)-(-)-2-amino-2-(4-chloro-3-nitro-phenyl)-propion ic acid
150 mg of ethyl (R)-(+)-2-amino-2-(4-chloro-3-nitro-phenyl)-propionate and
2.5 ml of 2N sodium hydroxide solution are stirred into 10 ml of
tetrahydrofuran for 5 hours at ambient temperature. The tetrahydrofuran is
distilled off and the residue is adjusted to pH 5 with hydrochloric acid. The
crystalline product is suction filtered, washed with water and dried.
Yield: 63% of theory,
[a]2 59.6 (methanol/water 1:1)
d.) (R)-2-tert.butyloxycarbonylamino-2-(4-chloro-3-nitro-phenyl)-propionic
acid
5.7 g of (R)-(-)-2-amino-2-(4-chloro-3-nitro-phenyl)-propionic acid are
dissolved in 50 ml of dioxane and after the addition of 5.5 ml (39.1 mmol) of
triethylamine and 4.8 g of pyrocarbonic acid-di-tert.butyldicarbonate the
mixture is stirred for 18 hours at ambient temperature. Then it is diluted
with
0.5 M potassium hydrogen sulphate solution and extracted with ethyl acetate.
The combined organic extracts are dried and concentrated by evaporation.
Yield: 100% of theory.
e.) (R)-2-tert.butyloxycarbonylamino-2-(4-methylamino-3-nitro-phenyl)-
propionic acid
20.0 g of (R)-2-tert.butyloxycarbonylamino-2-(4-chloro-3-nitro-phenyl)-
propionic acid and 100 ml methylamine solution (40% in H2O) are heated to
80 C in a pressure vessel for five hours. The contents are evaporated to
dryness, dissolved in water and acidified with glacial acetic acid. The
product
precipitated is suction filtered, washed with water and dried.
Yield: 69% of theory.
f.) (R)-2-(4-methylamino-3-nitro-phenyl)-2-tert.butyloxycarbonylamino-1-
pyrrolidino-propanone
12.3 g of (R)-2-tert.butyloxycarbonylamino-2-(4-methylamino-3-nitro-phenyl)-
propionic acid (64.8 mmol) are dissolved in 90 ml of tetrahydrofuran and

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combined with 12.6 g (78 mmol) of carbonyldiimidazole. After 30 minutes at
ambient temperature 10.9 ml (130 mmol) of pyrrolidine are added. After a
further 12 hours at ambient temperature the reaction solution is combined with
800 ml of water. The solid formed is filtered off, washed with water and
dried.
Yield: 48% of theory.
a.) (R)-2-(4-methylamino-3-amino-phenyl)-2-tert.butyloxycarbonylamino-1-
pyrrolidino-propanone
3.1 g of (R)-2-(4-methylamino-3-nitro-phenyl)-2-tert.butyloxycarbonylamino-1-
pyrrolidino-propanone (7.9 mmol) are dissolved in 30 ml of methanol and
hydrogenated for 2 hours at ambient temperature with the addition of
hydrogen/10% palladium on activated charcoal. The catalyst is filtered off and
the solvent is distilled off. The residue is dissolved in 50 ml of methyl-
tert.butylether at 45 C. The solid formed after 12 hours at 5 C is suction
filtered and dried.
Yield: 87% of theory.
h.) (R)-2-(4-cyanophenylaminomethyl)-I-methyl-5-j1-(N-
tert.butyloxycarbonylamino)-1-(pyrrolidinocarbonyl)-ethyll-benzimidazole
11.2 g (63 mmol) of 4-cyanophenylglycine and 10.95 g (67.5 mmol) of
carbonyldiimidazole are stirred in 320 ml of tetrahydrofuran at ambient
temperature for 2 hours. After the addition of 23 g (60 mmol) of (R)-2-(4-
methylamino-3-amino-phenyl)-2-tert.butyloxycarbonylamino-1-pyrrolidino-
propanone the reaction mixture is refluxed for 2 hours. The solvent is
distilled
off, the residue is taken up in 320 ml glacial acetic acid and refluxed for 1
hour. The solid formed after the addition of 500 ml ice water is filtered off,
washed and dried. Yield: 96% of theory.
i.) (R)-2-(4-cyanophenylaminomethyl -1-methyl-5-f1-amino-
1-(pyrrolid inocarbonyl)-ethyll-benzimidazole
1.3 g of (R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(N-
tert. butyloxycarbonylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole are

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dissolved in 20 ml dioxane and after the addition of 6N hydrochloric acid
stirred for two hours at ambient temperature. Ice is added to the solution,
which is made alkaline with ammonia and extracted with ethyl acetate. The
combined organic extracts are dried and concentrated by evaporation.
Yield: 76% of theory.
k.) (R)-2-(4-cyanophenylaminomethyl -1-methyl-5-f 1-
(ethoxycarbonylmethylamino)-l -(pyrrolidinocarbonyl -ethyll-benzimidazole
1.2 g of (R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-amino-1-
(pyrrolidino-carbonyl)-ethyl]-benzimidazole are dissolved in 20 ml acetone and
after the addition of 0.39 ml ethyl iodoacetate and 0.56 g of potassium
carbonate the mixture is refluxed for 3 hours. The reaction mixture is
filtered
and concentrated by evaporation, the residue is chromatographed on silica
gel, eluting with methylene chloride/ethanol (20:1 and 4:1).
Yield: 75% of theory.
I.) (R)-2-(4-amidinophenylaminomethyl -1-methyl-5-[1-
(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyll-benzimidazole-
hydrochloride
1.0 g of (R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-
(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole are
dissolved in 50 ml of saturated ethanolic hydrochloric acid and stirred for
hours at ambient temperature. The solvent is distilled off, the residue is
dissolved in 50 ml of absolute ethanol and combined with 2.3 g (25 mmol) of
ammonium carbonate. After 60 hours at ambient temperature the mixture is
evaporated to dryness. The residue is chromatographed on silica gel, eluting
with methylene chloride/methanol (7:1).
Yield: 95% of theory.
m.) (R)-2-(4-amidinophenylaminomethyl -1-methyl-5-[1-(carboxy-
methylamino)-1-(pyrrolidinocarbonyl -ethyll-benzimidazole-hydrochloride

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150 mg of (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-
(ethoxycarbonyl methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole
and 2.5 ml of 2N sodium hydroxide solution are stirred in 10 ml of ethanol for
hours at ambient temperature. The alcohol is distilled off and the residue is
adjusted to pH 5 with hydrochloric acid. The crystalline product is suction
filtered, washed with water and dried.
Yield: 100% of theory,
C251-131N703 x 2HCI(477.57/550.5)
Mass spectrum: (M+H)+ = 478
(M-H+HCI)" = 512/514 (Cl)
(M-H+2HCI)- = 448/550/552 (CI2)
Example 2: Animal model for systemic inflammatory response syndrome
(SIRS): Intravenous lipopolysaccharide stimulation (modified according to
Isobe et al. Circulation 2001; 104: 1171-1175)
Method 1
Rats (male, approx. 300 g CrIGlxBrIHan:Wi) were anaesthetised with
pentobarbital (60 mg/kg i.p.). To maintain the anaesthetic a pentobarbital
drip
was set up (22.5 mg/kg/h i.p.). The carotid artery was cannulated for taking
blood samples, the left jugular vein was cannulated for administration of the
substance and the right jugular vein was cannulated for administering the
LPS. The administration of (R)-2-(4-)-1-methyl-5-[1-(carboxymethylamino)-1-
(pyrrol id inocarbonyl)-ethyl]-benzimidazole (0.1 mg/kg/h) was started at time
t
= - 60 min as a continuous drip and maintained until the end of the
experiment. One hour after the start of the infusion of the substance, a
single
bolus of LPS was administered (lipopolysaccharide of E. coli serotype
0127:B8 Sigma L-3129 5 mg/kg i.v. bolus) at time t = 0 min. Inorder to
determine the coagulation and inflammation parameters, blood was taken via
the arterial cannulae at times a) before the infusion of placebo or (R)-2-(4-
amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-
(pyrrolidinocarbonyl)-ethyl]-benzimidazole (- 60 minutes), b) before

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administration of the LPS bolus (0 minutes) and c) 240 minutes after the
administration of LPS. From the blood samples the TAT complex (thrombin-
antithrombin) and interleukin-6 (IL-6) were determined by ELISA as
parameters of a systemic inflammatory reaction.
Results
As can be seen from Table 1, under control conditions there was no change in
the measured parameters throughout the observation period. Stimulation with
LPS on the other hand induced a systemic inflammatory reaction, as shown
by the significant rise in the plasma levels of the TAT complex by a factor of
8.6 and the approximately 400-fold increase in the IL-6 at the end of the test
period (Table 2). As can be seen from Table 3, the treatment with (R)-2-(4-
amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-
(pyrrol idinocarbonyl)-ethyl]-benzimidazole inhibited the activation of the
coagulation cascade: The plasma levels of the TAT complex were significantly
lower than in the untreated LPS animals (p<0.02) and were within the control
range. Surprisingly, the treatment with (R)-2-(4-amidinophenylaminomethyl)-
1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-
benzimidazole also resulted in a significant (p < 0.02) reduction in the
plasma
levels of IL-6 (Table 3).
Table 1:
Controls without LPS
Parameter - 60 min 0 min + 240 min
TAT (ng/ml) 4.163 +/-1.45 6.45 +/- 2.78 5.71 +/-1.48
IL-6 (ng/ml) 0.053 +/- 0.011 0.065 +/- 0.019 0.064 +/- 0.018
Table 2:
Controls with LPS
Parameter - 60 min 0 min + 240 min
TAT (ng/ml) 1.43 +/- 0.40 4.13 +/- 0.89 35.69 +/- 5.54
IL-6 (ng/ml) 0.117 +/- 0.070 0.158 +/- 0.067 62.884 +/- 5.438

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Table 3:
LPS + active substance (100 pg/kg/h)
Parameter - 60 min 0 min + 240 min p value vs LPS
TAT (ng/ml) 2.33 +/- 0.89 2.21 +1- 0.79 6.52 +/- 1.33 * 0.021
IL-6 (ng/ml) 0.139 +/- 0.086 0.143 +/- 0.083 43.454 +/- 2.975 * 0.022
Active substance = (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-
(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole (base)
Example 3: Animal model for systemic inflammatory response syndrome
(SIRS): Intravenous lipopolysaccharide stimulation (modified according to
Aoki et al. Drug Res. 50: 809; 2000 and Yamazaki et al. Blood Coag. Fibrinol.
10:321;1999)
Method 2
Rats (male, approx. 300 g CrlGlxBrIHan:Wi) were anaesthetised with
pentobarbital (60 mg/kg i.p.). To maintain the anaesthetic a pentobarbital
drip
was set up (22.5 mg/kg/h i.p.). The left jugular vein was cannulated for
administration of the substance and the right jugular vein was cannulated for
administering the LPS. LPS was given as a continuous infusion for 4 hours
(lipopolysaccharide of E. coli serotype 0127:B8 Sigma L-3129 7.5 mg/kg/h).
(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-
(pyrrolidinocarbonyl)-ethyl]-benzimidazole (0.1 mg/kg/h) was administered as
a continuous infusion (100 pg/kg/h) one hour after the start of the LPS
infusion with a total duration of 3 hours. In order to determine the
inflammation
parameters, blood was taken from the abdominal artery after a total test
period of four hours. From the blood samples the TAT complex (thrombin-
antithrombin), interleukin-1 f3 (IL-113), interieukin-6 (IL-6) and the tumour
necrosis factor alpha (TNF-alpha) were determined by ELISA as parameters
of a systemic inflammatory reaction. Alanine-aminotransferase (ALT) and
creatinin served as enzyme parameters for organ damage to the liver and
kidneys.

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Table 4:
Controls LPS-treated LPS + BIBT 986
(Phys. NaCI) 7.5 mg/kg/h x 4 h 100 pg/kg/h
IL-1Q 17.1 8.9* 8947 1501 4036 1000*
Ipg/ml] (10) (8) (8)
IL-6 31.6 8.4* 209904 +30076 89579 10069*
[pg/ml] (10) (7) (8)
TNF-alpha 3.2 2.4* 4241 +1045 1003 292*
Ip9/ml] (10) (8) (8)
ALT 36.4 7.7* 206.9 82.8 44.2 7.1*
[U/ml] (10) (7) (8)
creatinin 31.1 3.0* 57 4.1 40.1 1.8*
[pmol/L] (10) (8) (8)
mean values standard deviations; number of animals shown in brackets.
* p<0.05 vs. LPS treated animals; p<0.05 vs. controls (Tukey Kramer Test)
Results
As shown in Table 4, the continuous infusion of LPS induces a significant
increase in the indicators of a systemic inflammatory process (TAT complex,
IL-111, IL-6 and TNF alpha) and markers for organ damage (ALT and
creatinin). Treatment with (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-
(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole
surprisingly led to a significant lowering of the TAT complex and to a
significant (p < 0.02) lowering of the plasma levels of IL-113, IL-6 and TNF
alpha. Moreover, in animals treated with (R)-2-(4-
amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-
(pyrrolidinocarbonyl)-ethyl]-benzimidazole, ALT and creatinin were not
significantly different from untreated control animals.

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The results shown lead one to conclude that treatment with the combined
factor Xa/thrombin inhibitor (R)-2-(4-a midinophenylaminomethyl)-1-methyl-5-
[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole
constitutes an effective therapy for treating a systemic inflammatory response
/ SIRS and particularly Llpopolysaccharide-induced systemic inflammatory
response and sepsis (including severe sepsis).
Example 4: Pharmaceutical formulations
a.) Dry ampoule containing 75 mg of active substance per 10 ml
Composition:
active substance 75.0 mg
mannitol 50.0 mg
water for injections ad 10.0 ml
Method:
Active substance and mannitol are dissolved in water. After filling the
solution
is freeze-dried. The solution ready for use is made up with water for
injections.
b.) Dry ampoule containing 35 mg active substance per 2 ml
Composition:
active substance 35.0 mg
mannitol 100.0 mg
water for injections ad 2.0 ml
Method:
Active substance and mannitol are dissolved in water. After filling the
solution
is freeze-dried. The solution ready for use is made up with water for
injections.

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c.) Ampoule solution
active substance 2 mg
sodium chloride 9 mg
water for inj. 5 ml
Example 5: Combination of (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-
[1-(carboxymethylamino)-1_(pyrrolidinocarbonyl)-ethyll-benzimidazole with a
PAF-AH
A dry ampoule according to Example 4a) or 4b) containing (R)-2-(4-
amidinophenyl-aminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-
(pyrrol id inocarbonyl)-ethyl]-benzimidazole monohydrochloride as active
substance is placed together with a vial containing a PAF-AH lyophilisate in a
combined package. To prepare a solution for infusion the dry substances are
dissolved in water for injections and given to the patient by infusion
together
or sequentially.

Representative Drawing