U.S. patent application number 09/735159 was filed with the patent office on 2001-07-05 for benzimidazoles with antithrombotic activity.
Invention is credited to Hauel, Norbert, Kaufmann-Hefner, Iris, Nar, Herbert, Priepke, Henning, Ries, Uwe, Stassen, Jean Marie, Wienen, Wolfgang.
Application Number | 20010006977 09/735159 |
Document ID | / |
Family ID | 27219371 |
Filed Date | 2001-07-05 |
United States Patent
Application |
20010006977 |
Kind Code |
A1 |
Ries, Uwe ; et al. |
July 5, 2001 |
Benzimidazoles with antithrombotic activity
Abstract
Novel benzimidazoles having antithrombotic activity. Exemplary
are: (a)
2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylamin-
o)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole, (b)
2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethox-
ycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole,
and (c)
(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(i-
sobutyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazol-
e.
Inventors: |
Ries, Uwe; (Biberach,
DE) ; Kaufmann-Hefner, Iris; (Attenweiler, DE)
; Hauel, Norbert; (Schemmerhofen, DE) ; Priepke,
Henning; (Warthausen, DE) ; Nar, Herbert;
(Mittelbiberach, DE) ; Stassen, Jean Marie; (Bad
Buchau, DE) ; Wienen, Wolfgang; (Biberach,
DE) |
Correspondence
Address: |
BOEHRINGER INGELHEIM CORPORATION
900 RIDGEBURY ROAD
P O BOX 368
RIDGEFIELD
CT
06877
US
|
Family ID: |
27219371 |
Appl. No.: |
09/735159 |
Filed: |
December 12, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60175163 |
Jan 7, 2000 |
|
|
|
Current U.S.
Class: |
514/381 ;
514/387; 548/250; 548/306.1; 548/307.4 |
Current CPC
Class: |
C07D 235/16 20130101;
C07D 403/06 20130101; C07D 403/12 20130101 |
Class at
Publication: |
514/381 ;
548/250; 514/387; 548/306.1; 548/307.4 |
International
Class: |
A61K 031/41; A01N
043/64; A61K 031/415; A01N 043/52 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 23, 1999 |
DE |
DE 199 62 329.5 |
Claims
What is claimed is:
1. A compound of the formula 8wherein R.sub.a denotes a
straight-chained C.sub.1-3-alkyl group wherein the hydrogen atoms
may be wholly or partially replaced by fluorine atoms and which is
substituted in the 1 position by a pyrrolidinocarbonyl or
2,5-dihydropyrrolocarbonyl group optionally substituted by a
C.sub.1-3-alkyl group and by an amino group which is
monosubstituted by a carboxy-C.sub.1-4-alkyl, cyano-C.sub.1-4-alkyl
or tetrazolyl-C.sub.1-4-alkyl group, or by a C.sub.1-3-alkyl group
which is terminally substituted by an
N-(carboxy-C.sub.1-3-alkylaminocarbonyl)-amino group optionally
substituted by a C.sub.1-3-alkyl group at one or both amino
nitrogen atoms, by a carboxy-C.sub.1-3-alkoxy,
N-(carboxy-C.sub.1-3-alkyl)-amino,
N-(C.sub.1-3-alkyl)-N-(carboxy-C.sub.1-3-alkyl)-amino,
N-(carboxy-C.sub.1-3-alkylsulphonyl)-amino,
N-(C.sub.1-3-alkyl)-N-(carbox- y-C.sub.1-3-alkylsulphonyl)-amino or
tetrazolyl-C.sub.1-3-alkyl group, R.sub.b denotes a C.sub.1-3-alkyl
group and R.sub.c denotes an amidino group, a cyano group or a
1,2,4-oxadiazol-3-yl group substituted in the 5 position by a
C.sub.1-3-alkyl or phenyl group, while the phenyl substituent may
be substituted by a fluorine, chlorine or bromine atom or by a
C.sub.1-3-alkyl group, or a tautomer or prodrug thereof, or a
derivative thereof which contains a group which is negatively
charged under physiological conditions instead of a carboxy group,
or a salt thereof.
2. A compound of the formula I according to claim 1, wherein
R.sub.b and R.sub.c are defined as in claim 1 and R.sub.a is as
hereinbefore defined, with the proviso that one substituent denotes
an unbranched C.sub.1-3-alkyl group or a 2,5-dihydropyrrolocarbonyl
group optionally substituted by a C.sub.1-3-alkyl group, or R.sub.a
denotes an ethyl group which is substituted in the 1 position by a
pyrrolidinocarbonyl group and by an amino group, while the amino
group is substituted by an ethoxycarbonylmethyl group which is
substituted in the ethoxy moiety in the 2 position by a methoxy,
dimethylamino or tolyl group, by a carboxymethyl,
C.sub.3-4-alkoxycarbonylmethyl, cyclohexyloxycarbonylmethy- l,
3-(C.sub.2-3-alkoxycarbonyl)-propyl or tetrazolylmethyl group,
R.sub.b denotes a methyl group and R.sub.c denotes an amidino group
substituted by a benzoyl, methylbenzoyl, fluorobenzoyl group or
trifluoromethylbenzoyl group or R.sub.a denotes an ethyl group
which is substituted in the 1 position by a pyrrolidinocarbonyl
group substituted in the 2 position by a methyl group and by an
amino group, whilst the amino group is substituted by a
carboxymethyl or ethoxycarbonylmethyl group, R.sub.b denotes a
methyl group and R.sub.c denotes an amidino group or R.sub.a
denotes an ethyl group which is substituted in the 1 position by a
pyrrolidinocarbonyl group and by an amino group substituted by a
carboxymethyl, C.sub.3-4-alkoxycarbonylmethyl or tetrazolylmethyl
group or by a methyl group, whilst the methyl group is substituted
by a tetrazolyl, carboxymethoxy, ethoxycarbonylmethoxy,
ethoxycarbonylmethylamino, N-(2-carboxyethyl)-N-methylamino,
N-[2-(C.sub.1-3-alkoxycarbonyl)-ethyl]-N-methylamino,
N-(carboxymethylaminocarbonyl)-N-methyl-amino,
N-(C.sub.1-3-alkoxycarbony- lmethylaminocarbonyl)-N-methyl-amino,
N-(carboxymethylsulphonyl)-N-methyl-- amino or
N-(C.sub.1-3-alkoxycarbonylmethylsulphonyl)-N-methyl-amino group,
R.sub.b denotes a methyl group and R.sub.c denotes an amidino
group, or a tautomer or a salt thereof.
3. A compound of the formula I according to claim 2 with the
exception of (1)
2-[4-(N-phenylcarbonyl-amidino)-phenylaminomethyl]-1-methyl-5-[1-(n-b-
utyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole
and (2)
2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(tetrazol-5-yl-methy-
lamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole, or a tautomer
or salt thereof.
4. A compound of the formula I according to claim 1, wherein
R.sub.a denotes an ethyl group which is substituted in the 1
position by a 2,5-dihydropyrrolocarbonyl group optionally
substituted by a methyl group and by an amino group which may be
substituted by a C.sub.1-4-alkoxycarbonyl-C.sub.1-4-alkyl group
wherein the C.sub.2-4-alkoxy moiety is terminally monosubstituted
by a methoxy, dimethylamino, phenyl or tolyl group, by a
carboxy-C.sub.1-4-alkyl, cyclohexyloxycarbonyl-C.sub.1-4-alkyl or
tetrazolyl-C.sub.1-4-alkyl group, or by a C.sub.1-3-alkyl group
which is terminally substituted by an
N-(carboxy-C.sub.1-3-alkylaminocarbonyl)-amino or
N-(C.sub.1-3-alkoxycarbonyl-C.sub.1-3-alkylaminocarbonyl)-amino
group optionally substituted at one or both amino nitrogen atoms by
a C.sub.1-3-alkyl group, by a carboxy-C.sub.1-3-alkoxy,
C.sub.1-3-alkoxycarbonyl-C.sub.1-3-alkoxy,
N-(C.sub.1-3-alkyl)-N-(carboxy- -C.sub.1-3-alkyl)-amino,
N-(C.sub.1-3-alkyl)-N-(C.sub.1-3-alkoxycarbonyl-C-
.sub.1-3-alkyl)-amino,
N-(C.sub.1-3-alkyl)-N-(carboxy-C.sub.1-3-alkylsulph- onyl)-amino or
N-(C.sub.1-3-alkyl)-N-(C.sub.1-3-alkoxycarbonyl-C.sub.1-3-a-
lkylsulphonyl)-amino or tetrazolyl-C.sub.1-3-alkyl group, R.sub.b
denotes a methyl group and R.sub.c denotes an amidino group
optionally substituted by a benzoyl, methylbenzoyl, fluorobenzoyl
or trifluoromethylbenzoyl group or R.sub.a denotes an ethyl group
which is substituted in the 1 position by a pyrrolidinocarbonyl
group and by an amino group, whilst the amino group is substituted
by an ethoxycarbonylmethyl group which is substituted in the 2
position by a methoxy, dimethylamino or tolyl group, by a
carboxymethyl, propyloxycarbonylmethyl, isopropyloxycarbonylmethyl,
isobutyloxycarbonylmethyl, cyclohexyloxycarbonylmethyl,
3-(C.sub.2-3-alkoxycarbonyl)-propyl or tetrazolylmethyl group,
R.sub.b denotes a methyl group and R.sub.c denotes an amidino group
substituted by a benzoyl, methylbenzoyl, fluorobenzoyl group or
trifluoromethylbenzoyl group or R.sub.a denotes an ethyl group
which is substituted in the 1 position by a pyrrolidinocarbonyl
group substituted in the 2 position by a methyl group and by an
amino group, whilst the amino group is substituted by a
carboxymethyl or ethoxycarbonylmethyl group, R.sub.b denotes a
methyl group and R.sub.c denotes an amidino group or R.sub.a
denotes an ethyl group which is substituted in the 1 position by a
pyrrolidinocarbonyl group and by an amino group substituted by a
carboxymethyl or C.sub.3-4-alkoxycarbonylmethyl group or by a
methyl group, whilst the methyl group is substituted by a
tetrazolyl, carboxymethoxy, ethoxycarbonylmethoxy,
ethoxycarbonylmethylamino, N-(2-carboxyethyl)-N-methyl-amino,
N-[2-(C.sub.1-3-alkoxycarbonyl)-ethyl]- -N-methyl-amino,
N-(carboxymethylaminocarbonyl)-N-methyl-amino,
N-(C.sub.1-3-alkoxycarbonylmethylaminocarbonyl)-N-methyl-amino,
N-(carboxymethylsulphonyl)-N-methyl-amino or
N-(C.sub.1-3-alkoxycarbonylm- ethylsulphonyl)-N-methyl-amino group,
R.sub.b denotes a methyl group and R.sub.c denotes an amidino
group, or a tautomer or salt thereof.
5. A compound selected from the group consisting of: (a)
2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylamino)--
1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole, (b)
2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxyca-
rbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole,
(c)
(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(-
isobutyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazo-
le, (d)
(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[-
1-(n-propyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimid-
azole, (e)
(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethyl-
amino)-1-[(R,S)-1-methyl-pyrrolidinocarbonyl]-ethyl]-benzimidazole,
(f)
2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(2,5--
dihydropyrrolocarbonyl)-ethyl]-benzimidazole and (g)
(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(cycl-
ohexyloxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzim-
idazole, or a tautomer or physiologically acceptable salt
thereof.
6. A physiologically acceptable salt of a compound according to
claim 1, 2, 3, 4 or 5, wherein R.sub.c denotes an amidino group as
defined in claim 1, 2, 3 or 4.
7. A pharmaceutical composition containing a compound according to
claim 1, 2, 3, 4 or 5, wherein R.sub.c denotes an amidino group as
defined in claim 1, 2, 3, 4, or 5, or a salt according to claim 6,
and a pharmaceutically acceptable carrier.
8. A method for inhibiting the formation of thromboses or for
treating thromboses which method comprises administering to a host
in need of such treatment an antithrombotic amount of a compound
according to claim 1, 2, 3, 4 or 5, wherein R.sub.c denotes an
amidino group as defined in claim 1, 2, 3, 4, or 5, or a salt
according to claim 6.
Description
RELATED APPLICATIONS
[0001] Benefit of U.S. Provisional Application Ser. No. 60/175,163,
filed on Jan. 7, 2000, is hereby claimed.
[0002] 1. Field of the Invention
[0003] The present invention relates to novel benzimidazoles,
methods for making them, pharmaceutical compositions comprising
them, and their use as, inter alia, antithrombotic agents.
[0004] 2. Description of the Invention
[0005] The present invention relates to benzimidazoles of general
formula 1
[0006] the tautomers, the stereoisomers, the mixtures thereof, the
prodrugs, the derivatives thereof which contain a group which is
negatively charged under physiological conditions instead of a
carboxy group, and the salts thereof, particularly the
physiologically acceptable salts thereof with inorganic or organic
acids or bases which have valuable properties.
[0007] The compounds of the above general formula I wherein R.sub.a
denotes a straight-chained C.sub.1-3-alkyl group which is
substituted in the 1 position by a pyrrolidinocarbonyl or
2,5-dihydropyrrolocarbonyl group optionally substituted by a
C.sub.1-3-alkyl group and by an amino group monosubstituted by a
cyano-C.sub.1-4-alkyl group, and/or R.sub.c denotes a cyano group
or a 1,2,4-oxadiazol-3-yl group substituted in the 5 position by a
C.sub.1-3-alkyl or phenyl group, while the phenyl substituent may
be substituted by a fluorine, chlorine or bromine atom or by a
C.sub.1-3-alkyl group, are valuable intermediate products for
preparing the other compounds of general formula I, and the
compounds of the above general formula I wherein R.sub.c denotes
one of the following amidino groups, and the tautomers,
stereoisomers, mixtures thereof, the prodrugs, the derivatives
thereof which contain a group which is negatively charged under
physiological conditions instead of a carboxy group, and the salts
thereof, particularly the physiologically acceptable salts thereof
with inorganic or organic salts, and the stereoisomers thereof,
have valuable pharmacological properties, particularly an
antithrombotic activity.
[0008] In the above general formula
[0009] R.sub.a denotes a straight-chained C.sub.1-3-alkyl group
wherein the hydrogen atoms may be wholly or partially replaced by
fluorine atoms and which is substituted in the 1 position
[0010] by a pyrrolidinocarbonyl or 2,5-dihydropyrrolocarbonyl group
optionally substituted by a C.sub.1-3-alkyl group and
[0011] by an amino group which is monosubstituted by a
carboxy-C.sub.1-4-alkyl, cyano-C.sub.1-4-alkyl or
tetrazolyl-C.sub.1-4-al- kyl group,
[0012] or by a C.sub.1-3-alkyl group which is terminally
substituted by an N-(carboxy-C.sub.1-3-alkylaminocarbonyl)-amino
group optionally substituted by a C.sub.1-3-alkyl group at one or
both amino nitrogen atoms, by a carboxy-C.sub.1-3-alkoxy,
N-(carboxy-C.sub.1-3-alkyl)-amino,
N-(C.sub.1-3-alkyl)-N-(carboxy-C.sub.1-3-alkyl)-amino,
N-(carboxy-C.sub.1-3-alkylsulphonyl)-amino,
N-(C.sub.1-3-alkyl)-N-(carbox- y-C.sub.1-3-alkylsulphonyl)-amino or
tetrazolyl-C.sub.1-3-alkyl group,
[0013] R.sub.b denotes a C.sub.1-3-alkyl group and
[0014] R.sub.c denotes an amidino group, a cyano group or a
1,2,4-oxadiazol-3-yl group substituted in the 5 position by a
C.sub.1-3-alkyl or phenyl group, while the phenyl substituent may
be substituted by a fluorine, chlorine or bromine atom or by a
C.sub.1-3-alkyl group.
[0015] The carboxy groups, mentioned in the above definition of the
groups, may also be replaced by a group which can be converted in
vivo into a carboxy group or by a group which is negatively charged
under physiological conditions or
[0016] the amino and imino groups mentioned in the above definition
of the groups may also be substituted by a group which can be
cleaved in vivo. Such groups are described, for example, in WO
98/46576 and by N. M. Nielson et al. in International Journal of
Pharmaceutics 39, 75-85 (1987).
[0017] By a group which can be converted in vivo into a carboxy
group is meant for example a hydroxmethyl group, a carboxy group
esterified with an alcohol wherein the alcoholic moiety is
preferably a C.sub.1-6-alkanol, a phenyl-C.sub.1-3-alkanol, a
C.sub.3-9-cycloalkanol, whilst a C.sub.5-8-cycloalkanol may
additionally be substituted by one or two C.sub.1-3-alkyl groups, a
C.sub.5-8-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 C.sub.1-3-alkyl,
phenyl-C.sub.1-3-alkyl, phenyl-C.sub.1-3-alkoxycarbonyl or
C.sub.2-6-alkanoyl group and the cycloalkanol moiety may
additionally be substituted by one or two C.sub.1-3-alkyl groups, a
C.sub.4-7-cycloalkenol, a C.sub.3-5-alkenol, a
phenyl-C.sub.3-5-alkenol, a C.sub.3-5-alkinol or
phenyl-C.sub.3-5-alkinol, with the proviso that no bond to the
oxygen atom starts from a carbon atom which carries a double or
triple bond, a C.sub.3-8-cycloalkyl-C.sub.1-3-alkanol, a
bicycloalkanol having a total of 8 to 10 carbon atoms which may
additionally be substituted in the bicycloalkyl moiety by one or
two C.sub.1-3-alkyl groups, a 1,3-dihydro-3-oxo-1-isobenzofuranol
or an alcohol of formula
R.sub.d-CO--O--(R.sub.eCR.sub.f)--OH,
[0018] wherein
[0019] R.sub.d denotes a C.sub.1-8-alkyl, C.sub.5-7-cycloalkyl,
phenyl or phenyl-C.sub.1-3-alkyl group,
[0020] R.sub.e denotes a hydrogen atom, a C.sub.1-3-alkyl,
C.sub.5-7-cycloalkyl or phenyl group and
[0021] R.sub.f denotes a hydrogen atom or a C.sub.1-3-alkyl
group,
[0022] by a group which is negatively charged under physiological
conditions is meant a group such as a tetrazol-5-yl,
phenylcarbonylaminocarbonyl, trifluoromethylcarbonylaminocarbonyl,
C.sub.1-6-alkylsulphonylamino, phenylsulphonylamino,
benzylsulphonylamino, trifluoromethylsulphonylamino,
C.sub.1-6-alkylsulphonylaminocarbonyl,
phenylsulphonylaminocarbonyl, benzylsulphonylaminocarbonyl or
perfluoro-C.sub.1-6-alkylsulphonylaminoca- rbonyl group
[0023] and by a group which can be cleaved in vivo from an imino or
amino group is meant, for example, a hydroxy group, an acyl group
such as a benzoyl group optionally mono- or disubstituted by
fluorine, chlorine, bromine or iodine atoms or by C.sub.1-3-alkyl
or C.sub.1-3-alkoxy groups, whilst the substituents may be
identical or different, a pyridinoyl group or a C.sub.1-16-alkanoyl
group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or
hexanoyl group, a 3,3,3-trichloropropionyl or allyloxycarbonyl
group, a C.sub.1-16-alkoxycarbonyl or C.sub.1-16-alkylcarbonyloxy
group wherein hydrogen atoms may be wholly or partially replaced by
fluorine or chlorine atoms, such as the methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,
butoxycarbonyl, tert. butoxycarbonyl, pentoxycarbonyl,
hexoxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl,
decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl,
hexadecyloxycarbonyl, methylcarbonyloxy, ethylcarbonyloxy,
2,2,2-trichloroethylcarbonyloxy, propylcarbonyloxy,
isopropylcarbonyloxy, butylcarbonyloxy, tert.butylcarbonyloxy,
pentylcarbonyloxy, hexylcarbonyloxy, octylcarbonyloxy,
nonylcarbonyloxy, decylcarbonyloxy, undecylcarbonyloxy,
dodecylcarbonyloxy or hexadecylcarbonyloxy group, a
phenyl-C.sub.1-6-alkoxycarbonyl group such as the
benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl
group, a 3-amino-propionyl group wherein the amino group may be
mono- or disubstituted by C.sub.1-6-alkyl or C.sub.3-7-cycloalkyl
groups and the substituents may be identical or different, a
C.sub.1-3-alkylsulphonyl-C.- sub.2-4-alkoxycarbonyl,
C.sub.1-3-alkoxy-C.sub.2-4-alkoxy-C.sub.2-4-alkoxy- carbonyl,
R.sub.d-CO--O-(RdCRf)-O--CO, C.sub.1-6-alkyl-CO--NH--(R.sub.gCR.-
sub.h)--O--CO or
C.sub.1-6-alkyl-CO--O--(R.sub.gCR.sub.h)-(R.sub.gCR.sub.h- )--O--CO
group wherein R.sub.d to R.sub.f are as hereinbefore defined,
[0024] R.sub.g and R.sub.h, which may be identical or different,
denote hydrogen atoms or C.sub.1-3-alkyl groups.
[0025] Furthermore, the saturated alkyl and alkoxy moieties which
contain more than 2 carbon atoms mentioned in the above definitions
also include the branched isomers thereof such as the isopropyl,
tert.butyl, isobutyl group, etc., for example.
[0026] Preferred compounds of general formula I mentioned above are
those wherein
[0027] R.sub.b and R.sub.c are as hereinbefore defined and
[0028] R.sub.a is as hereinbefore defined, with the proviso that
one substituent denotes an unbranched C.sub.1-3-alkyl group or a
2,5-dihydropyrrolocarbonyl group optionally substituted by a
C.sub.1-3-alkyl group,
[0029] or R.sub.a denotes an ethyl group which is substituted in
the 1 position
[0030] by a pyrrolidinocarbonyl group and
[0031] by an amino group, while the amino group is substituted by
an ethoxycarbonylmethyl group which is substituted in the ethoxy
moiety in the 2 position by a methoxy, dimethylamino or tolyl
group, by a carboxymethyl, C.sub.3-4-alkoxycarbonylmethyl,
cyclohexyloxycarbonylmethy- l, 3-(C.sub.2-3-alkoxycarbonyl)-propyl
or tetrazolylmethyl group,
[0032] R.sub.b denotes a methyl group and
[0033] R.sub.c denotes an amidino group substituted by a benzoyl,
methylbenzoyl, fluorobenzoyl group or trifluoromethylbenzoyl group
or
[0034] R.sub.a denotes an ethyl group which is substituted in the 1
position
[0035] by a pyrrolidinocarbonyl group substituted in the 2 position
by a methyl group and
[0036] by an amino group, whilst the amino group is substituted by
a carboxymethyl or ethoxycarbonylmethyl group,
[0037] R.sub.b denotes a methyl group and
[0038] R.sub.c denotes an amidino group or
[0039] R.sub.a denotes an ethyl group which is substituted in the 1
position
[0040] by a pyrrolidinocarbonyl group and
[0041] by an amino group substituted by a carboxymethyl,
C.sub.3-4-alkoxycarbonylmethyl or tetrazolylmethyl group or
[0042] by a methyl group, whilst the methyl group is substituted by
a tetrazolyl, carboxymethoxy, ethoxycarbonylmethoxy,
ethoxycarbonylmethylamino, N-(2-carboxyethyl)-N-methylamino,
N-[2-(C.sub.1-3-alkoxycarbonyl)-ethyl]-N-methylamino,
N-(carboxymethylaminocarbonyl)-N-methyl-amino,
N-(C.sub.1-3-alkoxycarbony- lmethylaminocarbonyl)-N-methyl-amino,
N-(carboxymethylsulphonyl)-N-methyl-- amino or
N-(C.sub.1-3-alkoxycarbonylmethylsulphonyl)-N-methyl-amino
group,
[0043] R.sub.b denotes a methyl group and
[0044] R.sub.c denotes an amidino group,
[0045] the tautomers, the isomers and the salts thereof.
[0046] Particularly preferred compounds of the above general
formula I are the abovementioned compounds of general formula I
with the exception of
[0047] (1)
2-[4-(N-phenylcarbonyl-amidino)-phenylaminomethyl]-1-methyl-5-[-
1-(n-butyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimida-
zole and
[0048] (2)
2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(tetrazol-5-yl-met-
hylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole,
[0049] the tautomers, the isomers and the salts thereof.
[0050] Most particularly preferred compounds of the above general
formula I are those wherein
[0051] R.sub.a denotes an ethyl group which is substituted in the 1
position
[0052] by a 2,5-dihydropyrrolocarbonyl group optionally substituted
by a methyl group and by an amino group which may be substituted by
a C.sub.2-4-alkoxycarbonyl-C.sub.1-4-alkyl group wherein the
C.sub.2-4-alkoxy moiety is terminally monosubstituted by a methoxy,
dimethylamino, phenyl or tolyl group, by a carboxy-C.sub.1-4-alkyl,
cyclohexyloxycarbonyl-C.sub.1-4-alkyl or tetrazolyl-C.sub.1-4-alkyl
group, or
[0053] by a C.sub.1-3-alkyl group which is terminally substituted
by an N-(carboxy-C.sub.1-3-alkylaminocarbonyl)-amino or
N-(C.sub.1-3-alkoxycarb- onyl-C.sub.1-3-alkylaminocarbonyl)-amino
group optionally substituted at one or both amino nitrogen atoms by
a C.sub.1-3-alkyl group, by a carboxy-C.sub.1-3-alkoxy,
C.sub.1-3-alkoxycarbonyl-C.sub.1-3-alkoxy,
N-(C.sub.1-3-alkyl)-N-(carboxy-C.sub.1-3-alkyl)-amino,
N-(C.sub.1-3-alkyl)-N-(C.sub.1-3-alkoxycarbonyl-C.sub.1-3-alkyl)-amino,
N-(C.sub.1-3-alkyl)-N-(carboxy-C.sub.1-3-alkylsulphonyl)-amino or
N-(C.sub.1-3-alkyl)-N-(C.sub.1-3-alkoxycarbonyl-C.sub.1-3-alkylsulphonyl)-
-amino or tetrazolyl-C.sub.1-3-alkyl group,
[0054] R.sub.b denotes a methyl group and
[0055] R.sub.c denotes an amidino group optionally substituted by a
benzoyl, methylbenzoyl, fluorobenzoyl or trifluoromethylbenzoyl
group
[0056] or R.sub.a denotes an ethyl group which is substituted in
the 1 position
[0057] by a pyrrolidinocarbonyl group and
[0058] by an amino group, whilst the amino group is substituted by
an ethoxycarbonylmethyl group which is substituted in the 2
position by a methoxy, dimethylamino or tolyl group, by a
carboxymethyl, propyloxycarbonylmethyl, isopropyloxycarbonylmethyl,
isobutyloxycarbonylmethyl, cyclohexyloxycarbonylmethyl,
3-(C.sub.2-3-alkoxycarbonyl)-propyl or tetrazolylmethyl group,
[0059] R.sub.b denotes a methyl group and
[0060] R.sub.c denotes an amidino group substituted by a benzoyl,
methylbenzoyl, fluorobenzoyl group or trifluoromethylbenzoyl group
or
[0061] R.sub.a denotes an ethyl group which is substituted in the 1
position
[0062] by a pyrrolidinocarbonyl group substituted in the 2 position
by a methyl group and
[0063] by an amino group, whilst the amino group is substituted by
a carboxymethyl or ethoxycarbonylmethyl group,
[0064] R.sub.b denotes a methyl group and
[0065] R.sub.c denotes an amidino group or
[0066] R.sub.a denotes an ethyl group which is substituted in the 1
position
[0067] by a pyrrolidinocarbonyl group and
[0068] by an amino group substituted by a carboxymethyl or
C.sub.3-4-alkoxycarbonylmethyl group or
[0069] by a methyl group, whilst the methyl group is substituted by
a tetrazolyl, carboxymethoxy, ethoxycarbonylmethoxy,
ethoxycarbonylmethylamino, N-(2-carboxyethyl)-N-methyl-amino,
N-[2-(C.sub.1-3-alkoxycarbonyl)-ethyl]-N-methyl-amino,
N-(carboxymethylaminocarbonyl)-N-methyl-amino,
N-(C.sub.1-3-alkoxycarbony- lmethylaminocarbonyl) -N-methyl-amino,
N-(carboxymethylsulphonyl)-N-methyl- -amino or
N-(C.sub.1-3-alkoxycarbonylmethylsulphonyl)-N-methyl-amino
group,
[0070] R.sub.b denotes a methyl group and
[0071] R.sub.c denotes an amidino group,
[0072] the tautomers, the isomers and the salts thereof.
[0073] The following may be mentioned as examples of particularly
preferred compounds:
[0074] (1) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1
-(ethoxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzim-
idazole,
[0075] (2)
2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-
-(ethoxycarbonylmethylamino)-
1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzim- idazole,
[0076] (3)
(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl--
5-[1-(isobutyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzi-
midazole,
[0077] (4)
(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl--
5-[1
-(n-propyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benz-
imidazole,
[0078] (5)
(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethyl-
amino)-1-[(R,S)-1-methyl-pyrrolidinocarbonyl]-ethyl]-benzimidazole,
[0079] (6)
2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamin-
o)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole and
[0080] (7)
(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl--
5-[1-(cyclohexyloxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-eth-
yl]-benzimidazole,
[0081] the isomers and the salts thereof.
[0082] According to the invention, the compounds of general formula
I are obtained by methods known per se, for example by the
following methods:
[0083] a) In order to prepare a compound of general formula I
wherein R.sub.c denotes a cyano group or a 1,2,4-oxadiazol-3-yl
group substituted in the 5 position by a C.sub.1-3-alkyl or phenyl
group, while the phenyl substituent may be substituted by a
fluorine, chlorine or bromine atom or by a C.sub.1-3-alkyl
group:
[0084] cyclising a compound of general formula 2
[0085] optionally formed in the reaction mixture
[0086] wherein
[0087] R.sub.a and R.sub.b are as hereinbefore defined,
[0088] R.sub.c' denotes a cyano group or a 1,2,4-oxadiazol-3-yl
group substituted in the 5 position by a C.sub.1-3-alkyl or phenyl
group, while the phenyl substituent may be substituted by a
fluorine, chlorine or bromine atom or by a C.sub.1-3-alkyl
group,
[0089] Z.sub.1 and Z.sub.2, which may be identical or different,
denote amino, hydroxy or mercapto groups optionally substituted by
alkyl groups with 1 to 6 carbon atoms or
[0090] Z.sub.1 and Z.sub.2 together denote an oxygen or sulphur
atom, an imino group optionally substituted by an alkyl group with
1 to 3 carbon atoms, an alkylenedioxy or alkylenedithio group with
2 or 3 carbon atoms.
[0091] The cyclisation is conveniently carried out in a solvent or
mixture of solvents such as ethanol, isopropanol, glacial acetic
acid, benzene, chlorobenzene, toluene, xylene, glycol,
glycolmonomethylether, diethyleneglycoldimethylether, sulpholane,
dimethylformamide or tetraline or in an excess of the acylating
agent used to prepare the compound of general formula II, e.g. in
the corresponding nitrile, anhydride, acid halide, ester or amide,
for example at temperatures between 0 and 250.degree. C., but
preferably at the boiling temperature of the reaction mixture,
optionally in the presence of a condensing agent such as phosphorus
oxychloride, thionyl chloride, sulphuryl chloride, sulphuric acid,
p-toluenesulphonic acid, methanesulphonic acid, hydrochloric acid,
phosphoric acid, polyphosphoric acid, acetic acid, acetic
anhydride, N,N-dicyclohexyl-carbodiimide or optionally also in the
presence of a base such as potassium ethoxide or potassium
tert.butoxide. The cyclisation may, however, also be carried out
without a solvent and/or condensing agent.
[0092] b) In order to prepare a compound of general formula I
wherein R.sub.c denotes an amidino group:
[0093] reacting a compound of general formula 3
[0094] optionally formed in the reaction mixture
[0095] wherein
[0096] R.sub.a and R.sub.b are as hereinbefore defined and
[0097] Z.sub.4 denotes an alkoxy or aralkoxy group such as the
methoxy, ethoxy, n-propoxy, isopropoxy or benzyloxy group or an
alkylthio or aralkylthio group such as the methylthio, ethylthio,
n-propylthio or benzylthio group, with ammonia or with the salts
thereof.
[0098] The reaction is conveniently carried out in a solvent such
as methanol, ethanol, n-propanol, tetrahydrofuran or dioxane at
temperatures between 0 and 150.degree. C., preferably at
temperatures between 0 and 80.degree. C., with ammonia or one of
its salts such as for example ammonium carbonate or ammonium
acetate.
[0099] A compound of general formula III is obtained for example by
reacting a corresponding cyano compound with a corresponding
alcohol such as methanol, ethanol, n-propanol, isopropanol or
benzylalcohol in the presence of an acid such as hydrochloric acid
or by reacting a corresponding amide with a trialkyloxonium salt
such as triethyloxonium-tetrafluoroborate in a solvent such as
methylene chloride, tetrahydrofuran or dioxane at temperatures
between 0 and 50.degree. C., but preferably at 20.degree. C., or a
corresponding nitrile with hydrogen sulphide, conveniently in a
solvent such as pyridine or dimethylformamide and in the presence
of a base such as triethylamine and subsequent alkylation of the
thioamide formed with a corresponding alkyl or aralkyl halide.
[0100] c) In order to prepare a compound of general formula I
wherein R.sub.a contains a carboxy group and R.sub.c is as
hereinbefore defined:
[0101] Converting a compound of general formula 4
[0102] wherein
[0103] R.sub.b and R.sub.c are as hereinbefore defined and
[0104] R.sub.a' has the meanings given hereinbefore for R.sub.a,
with the proviso that R.sub.a contains a group which can be
converted into a carboxy group by hydrolysis, treatment with an
acid or base, thermolysis or hydrogenolysis,
[0105] by hydrolysis, treatment with an acid or base, thermolysis
or hydrogenolysis into a compound of general formula I wherein
R.sub.a contains a carboxy group.
[0106] A group which may be converted into a carboxy group may be,
for example, a carboxyl group protected by a protecting group such
as the functional derivatives thereof, e.g. the unsubstituted or
substituted amides, esters, thioesters, trimethylsilylesters,
orthoesters or iminoesters thereof, which are conveniently
converted into a carboxyl group by hydrolysis,
[0107] the esters thereof with tertiary alcohols, e.g. the
tert.butyl ester, which are conveniently converted into a carboxyl
group by treatment with an acid or thermolysis, and
[0108] the esters thereof with aralkanols, e.g. the benzyl ester,
which are conveniently converted into a carboxyl group by
hydrogenolysis.
[0109] The hydrolysis is conveniently carried out either in the
presence of an acid such as hydrochloric acid, sulphuric acid,
phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic
acid or the mixtures thereof or in the presence of a base such as
lithium hydroxide, sodium hydroxide or potassium hydroxide in a
suitable solvent such as water, water/methanol, water/ethanol,
water/isopropanol, methanol, ethanol, water/tetrahydrofuran or
water/dioxane at temperatures between -10 and 120.degree. C., e.g.
at temperatures between room temperature and the boiling
temperature of the reaction mixture.
[0110] If a compound of formula IV for example contains the
tert.butyl or tert.butyloxycarbonyl group, this may also be cleaved
by treatment with an acid such as trifluoroacetic acid, formic
acid, p-toluenesulphonic acid, sulphuric acid, hydrochloric acid,
phosphoric acid or polyphosphoric acid optionally in an inert
solvent such as methylene chloride, chloroform, benzene, toluene,
diethylether, tetrahydrofuran or dioxane, preferably at
temperatures between -10 and 120.degree. C., e.g. at temperatures
between 0 and 60.degree. C., or also thermally, optionally in an
inert solvent such as methylene chloride, chloroform, benzene,
toluene, tetrahydrofuran or dioxane and preferably in the presence
of a catalytic amount of an acid such as p-toluenesulphonic acid,
sulphuric acid, phosphoric acid or polyphosphoric acid, preferably
at the boiling temperature of the solvent used, e.g. at
temperatures between 40 and 120.degree. C.
[0111] If a compound of formula IV contains the benzyloxy or
benzyloxycarbonyl group, for example, this may also be cleaved
hydrogenolytically in the presence of a hydrogenation catalyst such
as palladium/charcoal in a suitable solvent such as methanol,
ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane
or dimethylformamide, preferably at temperatures between 0 and
50.degree. C., e.g. at room temperature, and at a hydrogen pressure
of 1 to 5 bar.
[0112] d) In order to prepare a compound of general formula I
wherein R.sub.c denotes an amidino group which is substituted by a
group which can be cleaved in vivo:
[0113] reacting a compound of general formula 5
[0114] wherein
[0115] R.sub.a and R.sub.b are as hereinbefore defined, with a
compound of general formula
Z.sub.5-R.sub.9 (VII),
[0116] wherein
[0117] R.sub.9 denotes the acyl group of one of the abovementioned
groups which can be cleaved in vivo and
[0118] Z.sub.5 denotes a nucleofugic leaving group such as a
halogen atom, e.g. a chlorine, bromine or iodine atom, or a
p-nitrophenyl group.
[0119] The reaction is preferably carried out in a solvent such as
methanol, ethanol, methylene chloride, tetrahydro furan, toluene,
dioxane, dimethylsulphoxide or dimethylformamide optionally in the
presence of an inorganic or a tertiary organic base, preferably at
temperatures between 20.degree. C. and the boiling temperature of
the solvent used.
[0120] With a compound of general formula VII wherein Z.sub.5
denotes a nucleofugic leaving group, the reaction is preferably
carried out in a solvent such as methylene chloride, acetonitrile,
tetrahydrofuran, toluene, acetone/water, dimethylformamide or
dimethylsulphoxide, optionally in the presence of a base such as
sodium hydride, potassium carbonate, potassium tert.butoxide or
N-ethyl-diisopropylamine at temperatures between 0 and 60.degree.
C.
[0121] e) In order to prepare a compound of general formula I
wherein R.sub.c denotes one of the abovementioned amidino groups:
catalytic hydrogenation of a compound of general formula 6
[0122] wherein
[0123] R.sub.a and R.sub.b are as hereinbefore defined and
[0124] R.sub.c" denotes a 1,2,4-oxadiazol-3-yl group substituted in
the 5 position by a C.sub.1-3-alkyl or phenyl group, wherein the
phenyl substituent may be substituted by a fluorine, chlorine or
bromine atom or by a C.sub.1-3-alkyl group, and if necessary
subsequent hydrolysis of a compound thus obtained.
[0125] The catalytic hydrogenation is preferably carried out in a
suitable solvent such as methanol, ethanol, ethanol/water, glacial
acetic acid, ethanol/glacial acetic acid, ethyl acetate, dioxane or
dimethylformamide in the presence of a hydrogenation catalyst such
as palladium/charcoal, preferably at temperatures between 0 and
50.degree. C., e.g. at room temperature, and at a hydrogen pressure
of 1 to 5 bar.
[0126] The hydrolysis which may follow is conveniently carried out
either in the presence of an acid such as hydrochloric acid,
sulphuric acid, phosphoric acid, acetic acid, trichloroacetic acid,
trifluoroacetic acid or mixtures thereof or in the presence of a
base such as lithium hydroxide, sodium hydroxide or potassium
hydroxide in a suitable solvent such as water, water/methanol,
water/ethanol, water/isopropanol, methanol, ethanol,
water/tetrahydrofuran or water/dioxane at temperatures between -10
and 120.degree. C., e.g. at temperatures between room temperature
and the boiling temperature of the reaction mixture.
[0127] f) In order to prepare a compound of general formula I
wherein R.sub.a denotes an amino-C.sub.1-3-alkyl group in which the
amino group is monosubstituted by a carboxy-C.sub.1-4-alkyl or
tetrazolyl-C.sub.1-4-alkyl group:
[0128] alkylating a compound of general formula 7
[0129] wherein
[0130] R.sub.b and R.sub.c are as hereinbefore defined and
[0131] R.sub.a" denotes an amino-C.sub.1-3-alkyl group, with a
compound of general formula
R.sub.a'"-Z.sub.7 (X)
[0132] wherein
[0133] R.sub.a'" denotes a carboxy-C.sub.1-4-alkyl or
tetrazolyl-C.sub.1-4-alkyl group and
[0134] Z.sub.7 denotes a nucleofugic leaving group such as a
halogen atom or a sulphonic acid ester group, e.g. a chlorine,
bromine or iodine atom, or a p-nitrophenyl group.
[0135] The alkylation is conveniently carried out in a solvent such
as methylene chloride, tetrahydrofuran, dioxane,
dimethylsulphoxide, dimethylformamide or acetone, optionally in the
presence of a reaction accelerator such as sodium or potassium
iodide and preferably in the presence of a base such as sodium
carbonate or potassium carbonate or in the presence of a tertiary
organic base such as N-ethyl-diisopropylamine or
N-methyl-morpholine, which may simultaneously also act as solvent,
or optionally in the presence of silver carbonate or silver oxide
at temperatures between -30 and 100.degree. C., but preferably at
temperatures between -10 and 80.degree. C.
[0136] If according to the invention a compound of general formula
I is obtained wherein R.sub.a contains a carboxy group, this may
subsequently be converted by esterification into a corresponding
compound wherein R.sub.a contains an esterified carboxy group,
and/or
[0137] if a compound of general formula I is obtained wherein
R.sub.a contains an esterified carboxy group, this may subsequently
be converted by transesterification into a corresponding compound
wherein R.sub.a contains another esterified carboxy group,
and/or
[0138] if a compound of general formula I is obtained wherein
R.sub.a contains a cyano group, this may subsequently be converted
into a corresponding compound wherein R.sub.a contains a tetrazolyl
group.
[0139] The subsequent esterification is carried out with a
corresponding alcohol, usefully in a solvent or mixture of solvents
such as methylene chloride, benzene, toluene, chlorobenzene,
tetrahydrofuran, benzene/tetrahydrofuran or dioxane, but preferably
in an excess of the alcohol used, optionally in the presence of an
acid such as hydrochloric acid or in the presence of a dehydrating
agent, e.g. in the presence of isobutyl chloroformate, thionyl
chloride, trimethylchlorosilane, hydrochloric acid, sulphuric acid,
methanesulphonic acid, p-toluenesulphonic acid, phosphorus
trichloride, phosphorus pentoxide, N,N'-dicyclohexyl carbodiimide,
N,N'-dicyclohexyl carbodiimide/N-hydroxys- uccinimide,
N,N'-carbonyldiimidazole or N,N'-thionyldiimidazole,
triphenylphosphine/carbon tetrachloride or
triphenylphosphine/diethyl azodicarboxylate, optionally in the
presence of a base such as potassium carbonate,
N-ethyl-diisopropylamine or N,N-dimethylamino-pyridine,
conveniently at temperatures between 0 and 150.degree. C.,
preferably at temperatures between 0 and 80.degree. C., or with a
corresponding halide in a solvent such as methylene chloride,
tetrahydrofuran, dioxane, dimethylsulphoxide, dimethylformamide or
acetone, optionally in the presence of a reaction accelerator such
as sodium or potassium iodide and preferably in the presence of a
base such as sodium carbonate or potassium carbonate or in the
presence of a tertiary organic base such as
N-ethyl-diisopropylamine or N-methyl-morpholine, which may also
serve as solvent at the same time, or optionally in the presence of
silver carbonate or silver oxide at temperatures between -30 and
100.degree. C., but preferably at temperatures between -10 and
80.degree. C.
[0140] The subsequent transesterification is carried out with a
corresponding alcohol, conveniently in a solvent or mixture of
solvents such as methylene chloride, benzene, toluene,
chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane,
but preferably in an excess of the alcohol used, conveniently in
the presence of an acid such as hydrochloric acid or in the
presence of a compound such as
2,8,9-trimethyl-1-phospha-2,5,8,9-tetraazabicyclo[3.3.3]undecane at
temperatures between 0 and 150.degree. C., preferably at
temperatures between 0 and 80.degree. C.
[0141] The subsequent conversion of a cyano group into a tetrazolyl
group is preferably carried out in a solvent such as benzene,
toluene or dimethylformamide at temperatures between 80 and
150.degree. C., preferably at 120 and 130.degree. C. The hydrazoic
acid needed is conveniently liberated during the reaction from an
alkali metal azide, e.g. from sodium azide, in the presence of a
weak acid such as ammonium chloride. The reaction may also take
place with another salt or derivative of hydrazoic acid, preferably
with aluminium azide or tributyl tin azide, the tetrazole compound
optionally obtained in this way being liberated from the salt
contained in the reaction mixture by acidification with a dilute
acid such as 2N hydrochloric acid or 2N sulphuric acid.
[0142] In the reactions described hereinbefore, any reactive groups
present such as carboxy, amino or alkylamino groups may be
protected during the reaction by conventional protecting groups
which are cleaved again after the reaction.
[0143] For example, a protecting group for a carboxy group may be a
trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or
tetrahydropyranyl group and
[0144] protecting groups for an amino or alkylamino group may be an
acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl,
tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or
2,4-dimethoxybenzyl group and additionally, for the amino group, a
phthalyl group.
[0145] Any protecting group used is optionally subsequently cleaved
for example by hydrolysis in an aqueous solvent, e.g. in water,
isopropanol/water, acetic acid/water, tetrahydrofuran/water or
dioxane/water, in the presence of an acid such as trifluoroacetic
acid, hydrochloric acid or sulphuric acid or in the presence of an
alkali metal base such as lithium hydroxide, sodium hydroxide or
potassium hydroxide or by ether cleavage, e.g. in the presence of
iodotrimethylsilane, at temperatures between 0 and 100.degree. C.,
preferably at temperatures between 10 and 50.degree. C.
[0146] However, a benzyl, methoxybenzyl or benzyloxycarbonyl group
is cleaved hydrogenolytically, for example, with hydrogen in the
presence of a catalyst such as palladium/charcoal in a solvent such
as methanol, ethanol, ethyl acetate, dimethylformamide,
dimethylformamide/acetone or glacial acetic acid, optionally with
the addition of an acid such as hydrochloric acid at temperatures
between 0 and 50.degree. C., but preferably at room temperature,
and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5
bar.
[0147] A methoxybenzyl group may also be cleaved in the presence of
an oxidant such as cerium(IV)ammonium nitrate in a solvent such as
methylene chloride, acetonitrile or acetonitrile/water at
temperatures between 0 and 50.degree. C., but preferably at room
temperature.
[0148] A 2,4-dimethoxybenzyl group, however, is preferably cleaved
in trifluoroacetic acid in the presence of anisol.
[0149] A tert.butyl or tert.butyloxycarbonyl group is preferably
cleaved by treating with an acid such as trifluoroacetic acid or
hydrochloric acid, optionally using a solvent such as methylene
chloride, dioxane or ether.
[0150] A phthalyl group is preferably cleaved in the presence of
hydrazine or a primary amine such as methylamine, ethylamine or
n-butylamine in a solvent such as methanol, ethanol, isopropanol,
toluene/water or dioxane at temperatures between 20 and 50.degree.
C.
[0151] An allyloxycarbonyl group is cleaved by treating with a
catalytic amount of tetrakis-(triphenylphosphine)-palladium(O),
preferably in a solvent such as tetrahydrofuran and preferably in
the presence of an excess of a base such as morpholine or
1,3-dimedone at temperatures between 0 and 100.degree. C.,
preferably at room temperature and under inert gas, or by treating
with a catalytic amount of
tris-(triphenylphosphine)-rhodium(I)chloride in a solvent such as
aqueous ethanol and optionally in the presence of a base such as
1,4-diazabicyclo[2.2.2]octane at temperatures between 20 and
70.degree. C.
[0152] The compounds of general formulae II to X used as starting
materials, some of which are known from the literature, are
obtained by methods known from the literature, and moreover their
preparation is described in the Examples.
[0153] The chemistry of the compounds of general formula II is
described for example by Jack Robinson in J. Chem. Soc. 1941, 744,
that of the benzimidazoles is described by Katritzky and Rees in
Comprehensive Heterocyclic Chemistry, Oxford, Pergamon Press, 1984,
by Schaumann in Hetarene III, Methoden der organischen Chemie
(Houben-Weyl), 4th edition, published by Thieme, Stuttgart
1993.
[0154] Thus, for example, a compound of general formula II is
obtained by acylating a corresponding o-diamino compound with a
corresponding reactive acyl derivative,
[0155] a compound of general formulae III, IV, VI, VIII and IX is
obtained by cyclising a corresponding, substituted compound
according to process a) and if necessary subsequently converting a
cyano compound thus obtained into the desired starting compound
using known methods.
[0156] Moreover, the compounds of general formula I obtained may be
resolved into their enantiomers and/or diastereomers.
[0157] Thus, for example, the compounds of general formula I
obtained which occur as racemates may be separated by methods known
per se (cf. Allinger N. L. and Eliel E. L. in "Topics in
Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their
optical antipodes and compounds of general formula I with at least
2 asymmetric carbon atoms may be resolved into their diastereomers
on the basis of their physical-chemical differences using methods
known per se, e.g. by chromatography and/or fractional
crystallisation, and, if these compounds are obtained in racemic
form, they may subsequently be resolved into the enantiomers as
mentioned above.
[0158] The enantiomers are preferably separated by column
separation on chiral phases or by recrystallisation from an
optically active solvent or by reacting with an optically active
substance which forms salts or derivatives such as e.g. esters or
amides with the racemic compound, particularly acids and the
activated derivatives or alcohols thereof, and separating the
diastereomeric mixture of salts or derivatives thus obtained, e.g.
on the basis of their differences in solubility, whilst the free
antipodes may be released from the pure diastereomeric salts or
derivatives by the action of suitable agents. Optically active
acids in common use are e.g. the D- and L-forms of tartaric acid or
dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid,
mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid
or quinic acid. An optically active alcohol may be for example (+)
or (-)-menthol and an optically active acyl group in amides, for
example, may be a (+)-or (-)-menthyloxycarbonyl.
[0159] Furthermore, the compounds of formula I may be converted
into the salts thereof, particularly for pharmaceutical use into
the physiologically acceptable salts with inorganic or organic
acids. Acids which may be used for this purpose include for example
hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric
acid, fumaric acid, succinic acid, lactic acid, citric acid,
tartaric acid or maleic acid.
[0160] Moreover, if the new compounds of formula I contain a
carboxy group, they may subsequently, if desired, be converted into
the salts thereof with inorganic or organic bases, particularly for
pharmaceutical use into the physiologically acceptable salts
thereof.
[0161] Suitable bases for this purpose include for example sodium
hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine,
diethanolamine and triethanolamine.
[0162] As already mentioned, the new compounds of general formula I
and the salts thereof have valuable properties. Thus, the compounds
of general formula I wherein R.sub.c denotes a cyano group are
valuable intermediate products for preparing the other compounds of
general formula I, and the compounds of general formula I wherein
R.sub.c denotes one of the amidino groups mentioned hereinbefore,
and the tautomers, the stereoisomers and the physiologically
acceptable salts thereof have valuable pharmacological properties,
particularly an antithrombotic effect which is preferably based on
influencing thrombin or factor Xa, e.g. on an inhibitory effect on
thrombin or factor Xa, on an effect of prolonging the aPTT time and
an inhibitory effect on related serine proteases such as e.g.
trypsin, urokinase factor VIIa, factor IX, factor XI and factor
XII.
[0163] For example, the following compounds:
[0164]
A=2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethy-
lamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole-dihydrochlorid-
e,
[0165]
B=(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylam-
ino)-1-[(R,S)-2-methyl-pyrrolidinocarbonyl]-ethyl]-benzimidazole-dihydroch-
loride and
[0166] C=(2)
2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylam-
ino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole-dihydrochloride
[0167] were investigated as follows for their effects on prolonging
the aPTT time:
[0168] Materials: plasma, from human citrated blood. PTT reagent,
Boehringer Mannheim (524298), Calcium solution (0.025 mol/l),
Behring Werke, Marburg (ORH 056/57), Diethylbarbiturate acetate
buffer, Behring Werke, Marburg (ORWH 60/61), Biomatic B10
coagulometer, Desaga, Wiesloch.
[0169] Method:
[0170] The aPTT time was determined using a Biomatic B10
coagulometer made by Messrs. Desaga.
[0171] The test substance was placed in the test tubes prescribed
by the manufacturer together with 0.1 ml of human citrated plasma
and 0.1 ml of PTT reagent. The mixture was incubated for three
minutes at 37.degree. C. The clotting reaction was started by the
addition of 0.1 ml of calcium solution. The time is measured using
the apparatus from the addition of the calcium solution up to the
clotting of the mixture. Mixtures to which 0.1 ml of DBA buffer
were added were used as the controls.
[0172] According to the definition, a dosage-activity curve was
used to determine the effective concentration of the substance,
i.e. the concentration at which the aPTT time is doubled compared
with the control.
[0173] The Table which follows contains the results found:
1 aPTT time Substance (ED.sub.200 in .mu.M) A 0.13 B 0.12 C
0.22
[0174] The compounds prepared according to the invention are well
tolerated since no toxic side effects could be detected at
therapeutic doses; moreover, the corresponding prodrugs, for
example the compounds of Examples 1(6), 2, 3(2) and 3(5), exhibit
good oral resorption.
[0175] In view of their pharmacological properties the new
compounds and the physiologically acceptable salts thereof are
suitable for the prevention and treatment of venous and arterial
thrombotic diseases, such as for example the treatment of deep leg
vein thrombosis, for preventing reocclusions after bypass
operations or angioplasty (PT(C)A), and occlusion in peripheral
arterial diseases such as pulmonary embolism, disseminated
intravascular coagulation, for preventing coronary thrombosis,
stroke and the occlusion of shunts. In addition, the compounds
according to the invention are suitable for antithrombotic support
in thrombolytic treatment, such as for example with rt-PA or
streptokinase, for preventing long-term restenosis after PT(C)A,
for preventing metastasis and the growth of clot-dependent tumours
and fibrin-dependent inflammatory processes, e.g. in the treatment
of pulmonary fibrosis.
[0176] The dosage required to achieve such an effect is
appropriately 0.1 to 30 mg/kg, preferably 0.3 to 10 mg/kg by
intravenous route, and 0.1 to 50 mg/kg, preferably 0.3 to 30 mg/kg
by oral route, in each case administered 1 to 4 times a day. For
this purpose, the compounds of formula I prepared according to the
invention may be formulated, optionally together with other active
substances, with one or more inert conventional carriers and/or
diluents, e.g. with corn starch, lactose, glucose, microcrystalline
cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid,
tartaric acid, water, water/ethanol, water/glycerol,
water/sorbitol, water/polyethyleneglycol, propyleneglycol,
cetylstearyl alcohol, carboxymethylcellulose or fatty substances
such as hard fat or suitable mixtures thereof, to produce
conventional galenic preparations such as plain or coated tablets,
capsules, powders, suspensions or suppositories.
[0177] The Examples which follow are intended to illustrate the
invention:
Example 1
[0178]
(R)-2-[4-[N-(4-methyl-phenylcarbonyl)-amidino]-phenylamino-methyl]--
1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-b-
enzimidazole
[0179] a.
(R)-5-(4-chloro-3-nitro-phenyl)-5-methyl-imidazolidin-2,4-dione
[0180] 10.0 g (4.45 mmol) of
(R)-5-(4-chlorophenyl)-5-methyl-imidazolidin-- 2,4-dione are added
batchwise to 50 ml of fuming nitric acid at -25 to -35.degree. C.
After 45 minutes at -25 to -20.degree. C. the reaction mixture is
poured onto ice water. The crystalline product is suction filtered,
washed with water and dried.
[0181] Yield: 10.5 g (100 % of theory),
[0182] Melting point: 173-178.degree. C.
[0183] R.sub.f value: 0.30 (silica gel; cyclohexane/ethyl
acetate=1: 1)
[0184] b. (R)-2-amino-2-(4-chlor-3-nitro-phenyl)-propionic acid
[0185] 10.5 g (0.044 mol) of
(R)-5-(4-chloro-3-nitro-phenyl)-5-methyl-imid- azolidine-2,4-dione
are refluxed in 200 ml of dioxane and 700 ml of 6N hydrochloric
acid for 5 days. The solution is concentrated by evaporation, the
residue is taken up in water and extracted with ethyl acetate. The
aqueous phase is concentrated by evaporation, mixed with toluene
and evaporated to dryness. The residue is triturated with ether,
suction filtered and dried.
[0186] Yield: 6.8 g (63% of theory),
[0187] R.sub.f value: 0.24 (Reversed phase RP8, 5% saline
solution/methanol=1:1)
[0188] c.
(R)-2-tert.butyloxycarbonylamino-2-(4-chloro-3-nitro-phenyl)-pro-
pionic acid
[0189] 72.5 g (0.296 mol) of
(R)-2-amino-2-(4-chloro-3-nitro-phenyl)-propi- onic acid are
dissolved in 850 ml dioxane and 200 ml water and after the addition
of 108.7 ml (0.78 mol) of triethylamine and 136 g (0.623 mol) of
di-tert.butyl dicarbonate stirred for 18 hours at room temperature.
After the addition of 800 ml of 1N sodium hydroxide solution the
solution is stirred for 30 minutes and then extracted 3.times. with
500 ml of ether. The aqueous phase is adjusted to pH 7 with 1N
hydrochloric acid and then to pH 4 with 5% citric acid. After
extracting 4 times with 500 ml of ethyl acetate, the combined
organic phases are washed with water, dried, suction filtered
through magnesium sulphate and concentrated by evaporation.
[0190] Yield: 86.8 g (85 % of theory),
[0191] R.sub.f value: 0.3 (silica gel; methylene chloride/methanol
4:1+1% ammonia)
[0192] C.sub.14H.sub.17ClN.sub.2O.sub.6 (344.7)
[0193] Mass spectrum: (M-H).sup.-=343
[0194] d. (R)-2-tert.butyloxycarbonylamino-2-(4-methylamino-3
-nitro-phenyl)-propionic acid
[0195] 96 g (0.278 mol) of
(R)-2-tert.butyloxycarbonylamino-2-(4-chloro-3--
nitro-phenyl)propionic acid and 440 ml of methylamine solution (40%
solution in water) are heated to 90.degree. C. in a pressurised
vessel for seven hours. After cooling, the reaction solution is
adjusted to pH 3.5 by the addition of glacial acetic acid, whilst
cooling with ice, and extracted with ethyl acetate. After the
solvent has been evaporated off, the residue remaining is washed
with ether and dried.
[0196] Yield: 70 g (74 % of theory),
[0197] R.sub.f value: 0.30 (silica gel; methylene
chloride/ethanol=19:1+1% glacial acetic acid)
[0198] C.sub.15H.sub.21N.sub.3O.sub.6 (339.3)
[0199] Mass spectrum: (M-H).sup.-=338
[0200] e.
(R)-2-(4-methylamino-3-nitro-phenyl)-2-tert.butyloxycarbonylamin-
o-1-pyrolidino-propanone
[0201] 50 g (0.147 mol) of
(R)-2-tert.butyloxycarbonylamino-2-(4-methylami-
no-3-nitro-phenyl)propionic acid are dissolved in 275 ml of
dimethylformamide and after the addition of 47.5 g (0.147 mol) of
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate, 24.5 g (0.334 mol) of pyrrolidine and 30 ml of
(0.273 mol) of N-methyl-morpholine the mixture is stirred for 20
hours at room temperature. The solution is poured onto ice water
and acidified with citric acid (pH 5-6). The precipitate formed is
suction filtered, washed with water and dried.
[0202] Yield: 45.5 g (79% of theory),
[0203] R.sub.f value: 0.6 (silica gel; petroleum ether/ethyl
acetate=1:1)
[0204] f.
(R)-2-(4-methylamino-3-amino-phenyl)-2-tert.butyloxycarbonylamin-
o-1-pyrrolidino-propanone
[0205] 25.5 g (65 mmol) of
(R)-2-(4-methylamino-3-nitro-phenyl)-2-tert.but-
yloxycarbonylamino-1-pyrrolidino-propanone are dissolved in 650 ml
of methanol and after the addition of 4.0 g of palladium on
activated charcoal (20%) the mixture is hydrogenated for 2 hours at
room temperature. Then the catalyst is filtered off and
concentrated by evaporation.
[0206] Yield: 21.4 g (91% of theory),
[0207] R.sub.f value: 0.31 (silica gel; ethyl acetate+1%
ammonia)
[0208] g.
(R)-2-[4-methylamino-3-(4-cyanophenylaminomethylcarbonylamino)-p-
henyl]-2-tert.butyloxycarbonylamino-1-pyrrolidino-propanone
[0209] Prepared analogously to Example 1e from
(R)-2-(4-methylamino-3-amin-
o-phenyl)-2-tert.butyloxycarbonylamino-1-pyrrolidino-propanone,
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumtetrafluoroborate,
4-cyano-phenylglycine and N-methyl-morpholine in
dimethylformamide.
[0210] Yield: 100% of theory,
[0211] R.sub.f value: 0.47 (silica gel; ethyl acetate)
[0212] h.
(R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(N-tert.butyloxyc-
arbonylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole
[0213] 47.7 g (0.042 mol) of
(R)-2-[4-methylamino-3-(4-cyanophenylamino-me-
thylcarbonylamino)-phenyl]-2-tert.butyloxycarbonylamino-1-pyrrolidino-prop-
anone are refluxed in 300 ml of glacial acetic acid for 2 hours.
The reaction mixture is added to ice water and adjusted to pH 8
with conc. ammonia. The precipitate formed is filtered off, washed
with water and dried.
[0214] Yield: 46 g (100 % of theory),
[0215] R.sub.f value: 0.3 (silica gel; ethyl acetate+1%
ammonia)
[0216] i.
(R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-amino-1-(pyrrolid-
inocarbonyl)-ethyl]-benzimidazole
[0217] 25.1 g (50 mmol) of
(R)-2-(4-cyanophenylaminomethyl)-1-methyl-S-[1--
(N-tert.butyloxycarbonylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazol-
e are dissolved in 500 ml of 6N hydrochloric acid at 35.degree. C.
and stirred for one hour at this temperature. The solution is mixed
with ice, made alkaline with ammonia and extracted with ethyl
acetate. The combined organic extracts are dried and concentrated
by evaporation.
[0218] Yield: 17.8 g (88% of theory),
[0219] R.sub.f value: 0.5 (silica gel; methylene
chloride/ethanol=4:1+1% ammonia)
[0220] k.
(R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-(1-ethoxycarbonylmet-
hylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole
[0221] 4.2 g (10.44 mmol) of
(R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[-
1-amino-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole are dissolved
in 100 ml of acetone and combined with 2.3 g (16.65 mmol) of
potassium carbonate and 2.25 ml (20.2 mmol) of ethyl bromoacetate.
The suspension is heated to 60.degree. C. for 5 hours. After
cooling the reaction mixture is stirred into 400 ml of ice water,
the precipitate formed is filtered off, washed with water and
dried. The crude product is chromatographed on silica gel, eluting
with methylene chloride/ethanol (19:1 and 9:1). The uniform
fractions are combined and concentrated by evaporation.
[0222] Yield: 3.1 g (61% of theory),
[0223] R.sub.f value: 0.4 (silica gel; ethyl
acetate/ethanol=9:1)
[0224] 1.
(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(1-ethoxycarbon-
ylethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-hydrochloride
[0225] 6.8 g (13.8 mmol) of
(R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-
-ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole
are dissolved in 400 ml of saturated ethanolic hydrochloric acid
and stirred for 23 hours at room temperature. The solvent is
distilled off, the residue is dissolved in 200 ml of absolute
ethanol and combined with 20 g (0.21 mol) of ammonium carbonate.
After 20 hours at room temperature 100 ml of ethanol are added and
after another 10 hours' stirring at room temperature the mixture is
filtered and evaporated to dryness. The residue is stirred in 200
ml of acetone, filtered off, washed with ether and dried.
[0226] Yield: 7.6 g (100% of theory),
[0227] R.sub.f value: 0.61 (Reversed phase RP8; 5% sodium chloride
solution/methanol=3:2)
[0228] C.sub.27H.sub.36N.sub.7O.sub.3.times.HCl (505.64/542.09)
[0229] Mass spectrum: (M+H).sup.+=506
[0230] m.
(R)-2-[4-[N-(4-methyl-phenylcarbonyl)-amidino]-phenylaminomethyl-
]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-
-benzimidazole
[0231] A suspension of 0.7 g (1.2 mmol) of
(R)-2-(4-amidinophenylaminometh-
yl)-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethy-
l]-benzimidazole-dihydrochloride in 25 ml of methylene chloride is
combined with 4.0 ml (28 mmol) of triethylamine and 0.8 g (3.0
mmol) of 4-nitrophenyl 4-methyl-benzoate and heated to 50.degree.
C. for 3.5 hours, whereupon a clear solution is formed. After
cooling, it is washed with sodium bicarbonate solution, saline
solution and water, dried over magnesium sulphate and concentrated
by evaporation. The crude product is purified on silica gel,
eluting with ethyl acetate/ethanol (50:1 and 9:1). The uniform
fractions are combined, concentrated by evaporation, triturated
with ether, suction filtered and dried.
[0232] Yield: 0.5 g (66% of theory),
[0233] R.sub.f value: 0.50 (silica gel; ethyl
acetate/ethanol=9:1)
[0234] C.sub.35H.sub.41N.sub.7O.sub.4 (623.75)
[0235] Mass spectrum: (M+H).sup.+=624 (M+Na).sup.+=646
(M-H).sup.-=622
[0236] The following compounds are obtained analogously to Example
1:
[0237] (1)
(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(isopropyloxyc-
arbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-acetate
[0238] Yield: 69% of theory,
[0239] R.sub.f value: 0.2 (silica gel; methylene
chloride/ethanol=7:3+1% glacial acetic acid)
[0240] C.sub.28H.sub.37N.sub.7O.sub.3.times.CH.sub.3COOH
(519.65/579.70)
[0241] Mass spectrum: (M+H).sup.+=520 (M-H).sup.-=518
[0242] (2)
(R)-2-[4-[N-(4-fluorophenylcarbonyl)amidino]-phenylaminomethyl]-
-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]--
benzimidazole
[0243] Yield: 40% of theory,
[0244] R.sub.f value: 0.4 (silica gel; ethyl acetate/ethanol=9:1+1%
ammonia)
[0245] C.sub.34H.sub.38FN.sub.7O.sub.4 (627.72)
[0246] Mass spectrum: (M+H).sup.+=628 (M+Na).sup.+=650
(M-H).sup.-=626
[0247] (3)
(R)-2-[4-[N-(4-trifluoromethyl-phenylcarbonyl)amidino]-phenylam-
inomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbony-
l)-ethyl]-benzimidazole
[0248] Yield: 47% of theory,
[0249] R.sub.f value: 0.53 (silica gel; methylene
chloride/methanol/conc. ammonia=9:0.9:0.1)
[0250] C.sub.35H.sub.38F.sub.3N.sub.7O.sub.4 (677.73)
[0251] Mass spectrum: (M+H).sup.+=678 (M+Na).sup.+=700
(M-H).sup.-=676
[0252] (4)
(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl--
5-[1-(tetrazol-5-yl-methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidaz-
ole
[0253] (5)
2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmet-
hylamino)-
1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole-dihydrochlo-
ride
[0254] Yield: 94% of theory,
[0255] R.sub.f value: 0.2 (Reversed phase RP8; 5% saline
solution/methanol2:3)
[0256] C.sub.27H.sub.33N.sub.7O.sub.3.times.2 HCl
(503.6/576.51)
[0257] Mass spectrum: (M+H).sup.+=504 (M-H+HCl).sup.-=538/540
(Cl)
[0258] (6)
2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-
-(ethoxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimi-
dazole
[0259] Yield: 71% of theory,
[0260] R.sub.f value: 0.3 (silica gel; ethyl acetate/ethanol=9:1)
C.sub.34H.sub.37N.sub.7O.sub.4 (607.72)
[0261] Mass spectrum: (M+H).sup.+=608 (M+Na).sup.+=630
(M-H).sup.-=606
[0262] (7) (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5
-[1-(ethoxycarbonylmethylamino)-1-[(R,S)-1-methyl-pyrrolidinocarbonyl]-et-
hyl]-benzimidazole-dihydrochloride (mixture of diastereomers)
[0263] Yield: 88% of theory,
[0264] R.sub.f value: 0.3 (Reversed phase RP8; 5% saline
solution/methanol=3:2)
[0265] C.sub.28H.sub.37N.sub.7O.sub.3.times.2 HCl
(519.65/592.56)
[0266] Mass spectrum: (M+H).sup.+=520 (M+Cl).sup.-554/6 (Cl)
[0267] (8)
(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl--
5-[1-(3-ethoxycarbonyl-propylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimi-
dazole
[0268] Yield: 19% of theory,
[0269] R.sub.f value: 0.44 (silica gel; methylene
chloride/methanol=4:1+1% glacial acetic acid)
[0270] C.sub.36H.sub.43N.sub.7O.sub.4 (637.79)
[0271] Mass spectrum: (M+H).sup.+=638 (M-H).sup.-=636
[0272] (9)
(R)-2-[4-(N-n-hexyloxycarbonylamidino)-phenylaminomethyl]-1-met-
hyl-5-[1-(n-propyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-b-
enzimidazole
[0273] Yield: 70% of theory,
[0274] R.sub.f value: 0.37 (silica gel; ethyl
acetate/ethanol=9:1)
[0275] C.sub.35H.sub.49N.sub.7O.sub.5 (647.82)
[0276] Mass spectrum: (M+Na).sup.+=670 (M-H).sup.-=646
Example 2
[0277]
(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-
-(n-butyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidaz-
ole
[0278] A solution of 0.3 g (0.53 mmol) of
(R)-2-[4-(N-phenylcarbonylamidin-
o)-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrroli-
dinocarbonyl)-ethyl]-benzimidazole in 5 ml of n-butanol is mixed
with 0.1 g (0.46 mmol) of
2,8,9-trimethyl-1-phospha-2,5,8,9-tetraazabicyclo[3.3.3]- undecane
and stirred for 1 hour at room temperature. The reaction mixture is
purified on silica gel, eluting with ethyl acetate/ethanol/conc.
ammonia (50:0.95:0.05 and 20:0.95:0.05). The uniform fractions are
combined and concentrated by evaporation.
[0279] Yield: 0.19 g (57% of theory,
[0280] R.sub.f value: 0.45 (silica gel; ethyl
acetate/ethanol=9:1+1% ammonia)
[0281] C.sub.36H.sub.43N.sub.7O.sub.4 (637.78)
[0282] Mass spectrum: (M+H).sup.+=638 (M+Na).sup.+=660
(M-H).sup.-=636
[0283] The following compounds are obtained analogously to Example
2:
[0284] (1)
(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl--
5-[1-(isobutyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzi-
midazole
[0285] Yield: 16% of theory,
[0286] R.sub.f value: 0.48 (silica gel; ethyl
acetate/ethanol=9:1+1% ammonia)
[0287] C.sub.36H.sub.43N.sub.7O.sub.4 (637.78)
[0288] Mass spectrum: (M+H).sup.+=638 (M+Na).sup.+=660
(M-H).sup.-=636
[0289] (2)
(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl--
5-[1
-(2-methoxy-ethyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethy-
l]-benzimidazole
[0290] Yield: 43% of theory,
[0291] R.sub.f value: 0.31 (silica gel; ethyl
acetate/ethanol=9:1+1% ammonia)
[0292] C.sub.35H.sub.41N.sub.7O.sub.5 (639.76)
[0293] Mass spectrum: (M+H).sup.+=640 (M-H).sup.-=638
[0294] (3)
(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl--
5-[1-(2-dimethylamino-ethyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-
-ethyl]-benzimidazole
[0295] Yield: 23% of theory,
[0296] R.sub.f value: 0.26 (silica gel; methylene
chloride/methanol/ammoni- a=9:0.9:0.1)
[0297] C.sub.36H.sub.44N.sub.8O.sub.4 (652.8)
[0298] Mass spectrum: (M+H).sup.+=651 (M-H).sup.-=653
[0299] (4)
(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl--
5-[1-(2-(2-methylphenyl)-ethyloxycarbonylmethylamino)-1-(pyrrolidinocarbon-
yl)-ethyl]-benzimidazole
[0300] Yield: 23% of theory,
[0301] R.sub.f value: 0.52 (silica gel; ethyl
acetate/ethanol/ammonia=9:0.- 95:0.05)
[0302] C.sub.41H.sub.45N.sub.7O.sub.4 (699.86)
[0303] Mass spectrum: (M+H).sup.+=700 (M+Na).sup.+=722
(M-H).sup.-=698
[0304] (5) (R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-
1-methyl-5-[1-(cyclohexyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)--
ethyl]-benzimidazole
[0305] Yield: 34% of theory,
[0306] R.sub.f value: 0.49 (silica gel; ethyl
acetate/ethanol=9:1+1% ammonia)
[0307] C.sub.38H.sub.47N.sub.7O.sub.4 (663.83)
[0308] Mass spectrum: (M+H).sup.+=664 (M+Na).sup.+=686
(M-H).sup.-=662
Example 3
[0309]
(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-
-(isopropyloxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-b-
enzimidazole
[0310] 2.1 ml of conc. sulphuric acid are added dropwise to a
solution of 0.5 g (0.82 mmol) of
(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl-
]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-
-ethyl]-benzimidazole in 12.3 ml of isopropanol. After 4 hours at
85.degree. C. the solution is cooled and poured onto 250 ml of ice
water. The pH is adjusted to 8.5 by the addition of conc. ammonia.
The precipitate formed is suction filtered, dried and purified on
silica gel, eluting with methylene chloride+2% methanol+0.01%
ammonia. The uniform fractions are combined and concentrated by
evaporation, the residue is triturated with ether, filtered off and
dried.
[0311] Yield: 0.19 g (37% of theory),
[0312] R.sub.f value: 0.46 (silica gel; ethyl
acetate/ethanol=9:1+1% ammonia)
[0313] C.sub.35H.sub.39N.sub.7O.sub.4 (621.75)
[0314] Mass spectrum: (M+H).sup.+=622 (M+Na).sup.+=644
(M-H).sup.-=620
[0315] The following compounds are obtained analogously to Example
3:
[0316] (1)
(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl--
5-[1-(n-propyloxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl-
]-benzimidazole
[0317] Yield: 33% of theory,
[0318] R.sub.f value: 0.46 (silica gel; ethyl
acetate/ethanol=9:1+1% ammonia)
[0319] C.sub.35H.sub.39N.sub.7O.sub.4 (621.75)
[0320] Mass spectrum: (M+H).sup.+=622 (M+Na).sup.+=644
(M-H).sup.-=620
[0321] (2)
(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl--
5-[1-(n-propyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzi-
midazole
[0322] Yield: 36% of theory,
[0323] R.sub.f value: 0.45 (silica gel; ethyl
acetate/ethanol=9:1+1% ammonia)
[0324] C.sub.35H.sub.41N.sub.7O.sub.4 (623.76)
[0325] Mass spectrum: (M+H).sup.+=624 (M+Na).sup.+=646
(M-H).sup.-=622
[0326] (3)
(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(n-butyl-oxyca-
rbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-dihydrochl-
oride
[0327] Yield: 8% of theory,
[0328] R.sub.f value: 0.44 (silica gel; methylene
chloride/methanol=4:1+1% ammonia)
[0329] C.sub.29H.sub.39N.sub.7O.sub.3.times.2 HCl
(533.69/606.6)
[0330] Mass spectrum: (M+H).sup.+=534 (M-H).sup.-=532
[0331] (4)
(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(n-propyloxyca-
rbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-sulphate
[0332] Yield: 7% of theory,
[0333] R.sub.f value: 0.36 (silica gel; methylene
chloride/methanol=4:1+1% ammonia)
[0334] C.sub.28H.sub.37N.sub.7O.sub.3.times.H.sub.2SO.sub.4
(519.65/617.7)
[0335] Mass spectrum: (M+H).sup.+=520
[0336] (5)
(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl--
5-[1-(cyclohexyloxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-eth-
yl]-benzimidazole Yield: 22% of theory,
[0337] R.sub.f value: 0.60 (silica gel; ethyl
acetate/ethanol=9:1+1% ammonia)
[0338] C.sub.38H.sub.43N.sub.7O.sub.4 (661.81)
[0339] Mass spectrum: (M+H).sup.+=662 (M+Na).sup.+=684
(M-H).sup.-=660
[0340] (6)
(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl--
5-[1-(3-(isopropyloxycarbonyl)-propylamino)-1-(pyrrolidinocarbonyl)-ethyl]-
-benzimidazole
[0341] (7)
(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl--
5-[1-(3-(n-propyloxycarbonyl)-propylamino)-1-(pyrrolidinocarbonyl)-ethyl]--
benzimidazole
Example 4
[0342]
(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(tetrazol-5-yl-met-
hylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole
[0343] a. 4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylamino-ethyl
acetate
[0344] Prepared analogously to Example 1k from
4-(5-methyl-1,2,4-oxadiazol- -3-yl)-aniline and ethyl bromoacetate
in N-ethyl-diisopropylamine.
[0345] Yield: 78% of theory,
[0346] R.sub.f value: 0.60 (silica gel; ethyl acetate/petroleum
ether=1:1)
[0347] b.
4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenyl-N-tert.butyloxycarbonyl-
amino-ethyl acetate
[0348] Prepared analogously to Example 1c from
4-(5-methyl-1,2,4-oxadiazol- -3-yl)-phenylaminoethyl acetate and
di-tert.butyldicarbonate/N-ethyl-diiso- propylamine in dioxane.
[0349] Yield: 63% of theory,
[0350] R.sub.f value: 0.48 (silica gel; ethyl
acetate/cyclohexane=1:2)
[0351] c.
4-(5-methyl-1.2.4-oxadiazol-3-yl)-phenyl-N-tert.butyloxycarbonyl-
-aminoacetic acid
[0352] A solution of 3.5 g (9.7 mmol) of
4-(5-methyl-l,2,4-oxadiazol-3-yl)-
-phenyl-N-tert.butyloxycarbonylamino-ethyl acetate in 10 ml of
tetrahydrofuran and 4 ml of methanol is combined with 9.7 ml of 1N
sodium hydroxide solution (9.7 mmol) and stirred for 3 hours at
room temperature. The reaction mixture is evaporated down to half
its volume and mixed with water. The pH value is adjusted to 4-5 by
the addition of glacial acetic acid, the precipitate formed is
filtered off, washed with water and dried.
[0353] Yield: 2.8 g (87% of theory),
[0354] R.sub.f value: 0.5 (Reversed phase RP8; 5% saline
solution/methanol=1:3)
[0355] d.
(R)-2-[4-(5-methyl-1.2.4-oxadiazol-3-yl)-phenyl-N-tert.butyloxyc-
arbonyl-aminomethyl]-1-methyl-5-[2-tert.butyloxycarbonylamino-1-(pyrrolidi-
nocarbonyl)-ethyl]-benzimidazole
[0356] Prepared analogously to Example 1g/h from
(R)-2-(4-methylamino-3-am-
ino-phenyl)-2-tert.butyloxycarbonylamino-1-pyrrolidino-propanone,
4-(5-methyl-1
,2,4-oxadiazol-3-yl)-phenyl-N-tert.butyloxycarbonyl-aminoac- etic
acid and carbonyldiimidazole in tetrahydrofuran and subsequently
treated with glacial acetic acid.
[0357] Yield: 47% of theory,
[0358] R.sub.f value: 0.46 (silica gel; ethyl acetate)
[0359] e.
(R)-2-[4-(5-methyl-1.2.4-oxadiazol-3-yl)-phenylaminomethyl]-1-me-
thyl-5-[1-amino-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole
[0360] Prepared analogously to Example 1i from
(R)-2-[4-(5-methyl-1,2,4-ox-
adiazol-3-yl)-phenyl-N-tert.butyloxycarbonyl-aminomethyl]-1-methyl-5-[2-te-
rt.butyloxycarbonyl-amino-1-(pyrrolidino-carbonyl)-ethyl]-benzimidazole
and 6N hydrochloric acid.
[0361] Yield: 91% of theory,
[0362] R.sub.f value: 0.44 (silica gel; methylene
chloride/methanol/ammoni- a=9:0.9:0.1)
[0363] f.
(R)-2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylaminomethyl]-1-me-
thyl-5-[1-cyanomethylamino-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole
[0364] Prepared analogously to Example 1k from
(R)-2-[4-(5-methyl-1,2,4-ox-
adiazol-3-yl)-phenylaminomethyl]-1-methyl-5-[1-amino-1-(pyrrolidinocarbony-
l)-ethyl]-benzimidazole and bromoacetonitrile/potassium carbonate
in acetone.
[0365] Yield: 72% of theory,
[0366] R.sub.f value: 0.54 (silica gel; ethyl
acetate/ethanol=9:1+1% ammonia)
[0367] C.sub.27H.sub.30N.sub.8O.sub.2 (498.59)
[0368] Mass spectrum: (M+H).sup.+=499 (M-H).sup.-=497
(M+Na).sup.+=521
[0369] g. (R)-2-[4-(5-methyl-1,2,4-oxadiazol-3
-yl)-phenylaminomethyl]-1-m-
ethyl-5-[1-(tetrazol-5-yl-methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benz-
imidazole
[0370] 1.1 g (2.2 mmol) of
(R)-2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenyl-
aminomethyl]-1-methyl-5-[1-cyanomethylamino-1-(pyrrolidinocarbonyl)-ethyl]-
-benzimidazole are suspended in 20 ml of toluene and 60 ml of
dioxane and combined with 2.2 g (6.6 mmol) of tributyl tin azide.
The reaction mixture is heated to 130.degree. C. for 6 hours. After
the solvent has been evaporated off, the residue is triturated with
petroleum ether, filtered, washed with petroleum ether and dried.
The crude product is purified on silica gel, eluting with methylene
chloride/methanol 20:1 and 9:1. The uniform fractions are combined
and concentrated by evaporation.
[0371] Yield: 0.7 g (59% of theory)
[0372] R.sub.f value: 0.33 (silica gel; methylene
chloride:methanol=9:1)
[0373] C.sub.27H.sub.31N.sub.11O.sub.2 (541.6)
[0374] Mass spectrum: (M-H).sup.-=540 (M+Na).sup.+=564
[0375] h.
(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(tetrazol-5-yl--
methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole
[0376] Prepared analogously to Example 1h from (R)-
2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylaminomethyl]-1-methyl-5-[1-(te-
trazol-5-yl-methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole
and hydrogen/palladium (20% on activated charcoal) in
ethanol/glacial acetic acid.
[0377] Yield: 63% of theory,
[0378] R.sub.f value: 0.35 (Reversed phase RP8; 5% saline
solution/methanol=4:3)
[0379] C.sub.25H.sub.31N.sub.11O (501.6)
[0380] Mass spectrum: (M+H).sup.+=502 (M-H).sup.-=500
Example 5
[0381]
2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylo-
xymethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-acetate
[0382] a. methyl
2-(4-chloro-phenyl)-3-hydroxy-2-methyl-propionate
[0383] 35 ml of a 1.6 molar solution of n-butyllithium in hexane
(61 mmol) are added dropwise to a solution of 8.1 ml of
diisopropylamine (85 mmol) in 20 ml of tetrahydrofuran at
-78.degree. C. Then a solution of 10.0 g (50 mmol) of methyl
2-(4-chloro-phenyl)-propionate in 30 ml of tetrahydrofuran is added
dropwise at -78.degree. C. Gaseous formaldehyde is piped into the
reaction mixture at -20.degree. C. for 30 minutes. After the
addition of 5% citric acid and glacial acetic acid the mixture is
extracted with ethyl acetate. The organic phases are washed with 1N
sulphuric acid, water, saturated sodium bicarbonate solution and
saline solution and dried over magnesium sulphate. The crude
product is purified on silica gel, eluting with cyclohexane/ethyl
acetate (19:1; 9:1; 4:1; 1:1 and 0:1). The uniform fractions are
combined and concentrated by evaporation.
[0384] Yield: 9.7 g of yellow oil (84% of theory),
[0385] R.sub.f value: 0.25 (silica gel; petroleum ether/ethyl
acetate=4:1)
[0386] b. 2-(4-chloro-phenyl)-3-hydroxy-2-methyl-propionic acid
[0387] Prepared analogously to Example 8 from methyl
2-(4-chloro-phenyl)-3-hydroxy-2-methyl-propionate and sodium
hydroxide solution in ethanol.
[0388] Yield: 83% of theory,
[0389] R.sub.f value: 0.55 (silica gel; ethyl
acetate/cyclohexane=2:1+1% glacial acetic acid)
[0390] c. 2-(4-chloro-3-nitro-phenyl)-2-methyl-3-nitroxy-propionic
acid
[0391] Prepared analogously to Example 1a from
2-(4-chloro-phenyl)-3-hydro- xy-2-methyl-propionic acid and nitric
acid.
[0392] Yield: 90% of theory,
[0393] Melting point: 129-132.degree. C.
[0394] C.sub.10H.sub.9ClN.sub.2O.sub.7 (304.64)
[0395] d. 2-(4-chloro-3-nitro-phenyl)-2-methyl-3-hydroxy-propionic
acid
[0396] Prepared analogously to Example 1i from
2-(4-chloro-3-nitro-phenyl)- -3-nitroxy-2-methyl-propionic acid and
6N hydrochloric acid in dioxane.
[0397] Yield: 98% of theory,
[0398] C.sub.10H.sub.10ClNO.sub.5 (259.65)
[0399] Mass spectrum: (M-H).sup.-=258/60 (Cl) (2M-H).sup.-=517/9
(Cl.sub.2)
[0400] e.
2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-hydroxy-p-
ropionic acid
[0401] Prepared analogously to Example 1e from
2-(4-chloro-3-nitro-phenyl)- -3-hydroxy-2-methyl-propionic acid and
N-methyl-benzylamine.
[0402] Yield: 81% of theory,
[0403] C.sub.18H.sub.20ClN.sub.2O.sub.5 (344.37)
[0404] Mass spectrum: M.sup.+=344
[0405] f.
2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-hydroxy-1-
-pyrrolidin-1-yl-propan-1-one
[0406] Prepared analogously to Example 1e from
2-[4-(N-benzyl-methylamino)-
-3-nitro-phenyl]-3-hydroxy-2-methyl-propionic acid and
pyrrolidine.
[0407] Yield: 96% of theory,
[0408] C.sub.22H.sub.27N.sub.3O.sub.4 (397.48)
[0409] Mass spectrum: M.sup.+=398 (M+Na).sup.+=420
[0410] g.
2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-ethoxycar-
bonylmethyloxy-1-pyrrolidino-propan-1-one
[0411] A solution of 8.0 g (20 mmol) of
2-[4-(N-benzyl-methylamino)-3-nitr-
o-phenyl]-2-methyl-3-hydroxy-1-pyrrolidino-propan-1-one and 5 ml
(48 mmol) of ethyl diazoacetate in 50 ml of methylene chloride is
mixed with 2.0 ml of boron trifluoride-diethylether complex (16
mmol) at room temperature and refluxed for 14 hours. After cooling,
the reaction solution is stirred into ice water and the organic
phase is separated off. The aqueous phase is extracted three times
with methylene chloride, the combined organic phases are washed
with saline solution, dried over sodium sulphate and concentrated
by evaporation. The residue is dissolved in ethyl acetate and
purified on silica gel, extracting initially with petroleum ether,
then with petroleum ether/ethyl acetate (1: 1). The uniform
fractions are combined and concentrated by evaporation.
[0412] Yield: 2.5 g (26% of theory),
[0413] R.sub.f value: 0.6 (silica gel; ethyl acetate)
[0414] C.sub.26H.sub.33N.sub.3O.sub.6 (483.57)
[0415] Mass spectrum: (M+H).sup.+=484
[0416] h.
2-(4-methylamino-3-amino-phenyl)-2-methyl-3-ethoxycarbonylmethyl-
oxy-1-pyrrolidino-propan-1-one
[0417] Prepared analogously to Example 1f from
2-[4-(N-benzyl-methylamino)-
-3-nitro-phenyl]-2-methyl-3-ethoxymethyloxy- 1-pyrrolidin-
1-yl-propan-1-one and hydrogen/palladium on activated charcoal.
[0418] Yield: 81% of theory,
[0419] R.sub.f value: 0.40 (silica gel; methylene
chloride/ethanol=19:1)
[0420] i.
2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethyl-
oxmethyl)-1-(pyrrolidinocarbonyl)-ethyl-benzimidazole
[0421] Prepared analogously to Example 1 g/h from
2-(4-methylamino-3
-amino-phenyl)-2-methyl-3-ethoxycarbonylmethyloxy-1-pyrrolidino-propan-1--
one,
4-cyano-phenylglycine/O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluron-
ium tetrafluoroborate and subsequently treated with glacial acetic
acid.
[0422] Yield: 77% of theory,
[0423] R.sub.f value: 0.40 (silica gel; methylene
chloride/ethanol=19:1)
[0424] C.sub.28H.sub.33N.sub.5O.sub.4 (503.61)
[0425] Mass spectrum: (M+H).sup.+=504 (M+Na).sup.+=526
[0426] k.
2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmeth-
yloxymethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-acetate
[0427] Prepared analogously to Example 11 from
2-(4-cyanophenylaminomethyl-
)-1-methyl-5-[1-(ethoxycarbonylmethyloxymethyl)-1-(pyrrolidinocarbonyl)-et-
hyl]-benzimidazole and hydrochloric acid/ammonium carbonate in
ethanol.
[0428] Yield: 64% of theory,
[0429] R.sub.f value: 0.25 (silica gel; methylene
chloride/ethanol=4:1+1% glacial acetic acid)
[0430] C.sub.28H.sub.36N.sub.6O.sub.4.times.CH.sub.3COOH
(520.63/580.69)
[0431] Mass spectrum: (M+H).sup.+=521
Example 6
[0432]
2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(1H-tetrazol-5-yl-meth-
yl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-hydrochloride
[0433] a.
2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-methanesu-
lphonyloxy-1-prrolidino-propan-1-one
[0434] A solution of 1.2 g (3.0 mmol) of
2-[4-(N-benzyl-methylamino)-3-nit- ro-phenyl]-2-methyl-3
-hydroxy-1-pyrrolidino-propan-1-one in 20 ml of tetrahydrofuran is
combined at room temperature with 1.3 ml of (9.3 mmol) of
triethylamine. Then 0.27 ml (3.5 mmol) of methanesulphonylchloride
are added dropwise at 2-5.degree. C. After 2 hours at room
temperature the precipitate formed is suction filtered and the
filtrate is concentrated by evaporation. The crude product is
reacted further without purification.
[0435] Yield: 1.4 g (98% of theory).
[0436] b.
2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-cyano-1-p-
yrrolidine-propan-1-one
[0437] A solution of 8.2 g (17 mmol) of
2-[4-(N-benzyl-methylamino)-3-nitr-
o-phenyl]-2-methyl-3-methanesulphonyloxy-1-pyrrolidino-propan-1-one
in 125 ml of dimethylformamide is mixed with 1.38 g (27 mmol) of
potassium cyanide and heated to 100.degree. C. for 2 hours. After
cooling, the reaction solution is stirred into ice water and
extracted 3.times. with ethyl acetate.
[0438] The combined organic phases are washed with saline solution
and dried over sodium sulphate. The crude product is dissolved in
methylene chloride and purified on silica gel, eluting initially
with methylene chloride, then with methylene chloride/ethanol (50:1
and 25:1). The uniform fractions are combined and concentrated by
evaporation.
[0439] Yield: 5.0 g (72% of theory)
[0440] R.sub.f value: 0.45 (silica gel; methylene
chloride/ethanol=19:1)
[0441] C.sub.23H.sub.26N.sub.4O.sub.3 (406.49)
[0442] Mass spectrum: M.sup.+=406 (M+Na).sup.+=429
[0443] c.
2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-(1H-tetra-
zol-5-yl)-1-pyrrolidino-propan-1-one
[0444] Prepared analogously to Example 4g from
2-[4-(N-benzyl-methylamino)-
-3-nitro-phenyl]-2-methyl-3-cyano-1-pyrrolidino-propan-1-one and
tributyl tin azide.
[0445] Yield: 37% of theory,
[0446] R.sub.f value: 0.55 (silica gel; methylene
chloride/ethanol=9:1)
[0447] C.sub.23H.sub.27N.sub.7O.sub.3 (449.52)
[0448] Mass spectrum: (M+Na).sup.+=472 (M-H).sup.-=448
[0449] d.
2-[4-(N-methylamino)-3-amino-phenyl]-2-methyl-3-(1H-tetrazol-5-y-
l)-1-pyrrolidino-propan-1-one
[0450] Prepared analogously to Example 1f from
2-[4-(N-benzyl-methylamino)-
-3-nitro-phenyl]-2-methyl-3-(1H-tetrazol-5-yl)-1-pyrrolidino-propan-1-one
and hydrogen/palladium on activated charcoal.
[0451] Yield: 48% of theory,
[0452] R.sub.f value: 0.3 (silica gel; methylene
chloride/ethanol=9:1)
[0453] C.sub.16H.sub.23N.sub.7O (329.41)
[0454] Mass spectrum: (M+H).sup.+=330 (M-H).sup.-=328
[0455] e.
2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(1H-tetrazol-5-yl-met-
hyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole
[0456] Prepared analogously to Example 1g/h from
2-[4-(N-methylamino)-3-am-
ino-phenyl]-2-methyl-3-(1H-tetrazol-5-yl)-1-pyrrolidino-propan-1-one,
4-cyano-phenylglycine/O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate and subsequently treating with glacial acetic
acid.
[0457] Yield: 17% of theory,
[0458] R.sub.f value: 0.25 (silica gel; methylene
chloride/ethanol=9:1)
[0459] C.sub.25H.sub.27N.sub.9O (469.55)
[0460] Mass spectrum: (M-H).sup.-=468
[0461] f.
2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(1H-tetrazol-5-yl-m-
ethyl-D-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-hydrochloride
[0462] Prepared analogously to Example 11 from
2-(4-cyanophenylaminomethyl-
)-1-methyl-5-[1-(1H-tetrazol-5-yl-methyl)-1-(pyrrolidinocarbonyl)-ethyl]-b-
enzimidazole and hydrochloric acid/ammonium carbonate in
ethanol.
[0463] Yield: 25% of theory,
[0464] R.sub.f value: 0.35 (Reversed phase RP8; 5% saline
solution/methanol=1:1)
[0465] C.sub.25H.sub.30N.sub.10O.times.HCl (486.58/523.05)
[0466] Mass spectrum: (M+H).sup.+=487
Example 7
[0467]
2-(4-amidinophenylaminomethyl)-1-methyl-5-1-(ethoxycarbonylmethylam-
inomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-diacetate
[0468] a.
2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-azido-1-p-
yrrolidino-propan-1-one
[0469] Prepared analogously to Example 6b from
2-[4-(N-benzyl-methylamino)-
-3-nitro-phenyl]-2-methyl-3-methanesulphonyloxy-1-pyrrolidino-propan-1-one
and sodium azide in dimethylformamide.
[0470] Yield: 100% of theory,
[0471] R.sub.f value: 0.75 (silica gel; ethyl acetate/petroleum
ether=1:1)
[0472] C.sub.22H.sub.26N.sub.6O.sub.3 (422.49)
[0473] Mass spectrum: M.sup.+=422
[0474] b.
2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-amino-1-p-
yrrolidino-propan-1-one
[0475] A solution of 24.75 g (59 mmol) of
2-[4-(N-benzyl-methylamino)-3-ni-
tro-phenyl]-2-methyl-3-azido-1-pyrrolidino-propan-1-one and 15.7 g
(60 mmol) of triphenylphosphine in 250 ml of tetrahydrofuran and
1.8 ml of water is stirred for 60 hours at room temperature. After
evaporation of the solvent the residue is purified over silica gel,
eluting first with methylene chloride, then with methylene
chloride/ethanol (50:1, 9:1, 8:2 and 7:3). The uniform fractions
are combined and concentrated by evaporation.
[0476] Yield: 21.7 g (93% of theory),
[0477] R.sub.f value: 0.25 (Reversed phase RP8; 5% saline
solution/methanol=2:3)
[0478] C.sub.22H.sub.28N.sub.4O.sub.3 (396.49)
[0479] Mass spectrum: (M+H).sup.+=397
[0480] c.
2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-tert.buty-
loxycarbonylamino-1-pyrrolidino-propan-1-one
[0481] Prepared analogously to Example 1c from
2-[4-(N-benzyl-methylamino)-
-3-nitro-phenyl]-2-methyl-3-amino-1-pyrrolidino-propan-1-one and
di-tert.butyldicarbonate/N-ethyl-diisopropylamine in dioxane.
[0482] Yield: 98% of theory,
[0483] R.sub.f value: 0.55 (silica gel; methylene
chloride/ethanol=19:1)
[0484] C.sub.27H.sub.36N.sub.5O.sub.4 (496.61)
[0485] Mass spectrum: M.sup.+=496 (M+Na).sup.+=519
(M-H).sup.-=495
[0486] d.
2-[4-(N-methylamino)-3-amino-phenyl]-2-methyl-3-tert.butyloxycar-
bonylamino-1-pyrrolidino-propan-1-one
[0487] Prepared analogously to Example 1f from
2-[4-(N-benzyl-methylamino)- -3-nitro-phenyl]-2-methyl-3
-tert.butyloxycarbonylamino-1-pyrrolidino-prop- an-1-one and
hydrogen/palladium on activated charcoal.
[0488] Yield: 23% of theory,
[0489] R.sub.f value: 0.4 (silica gel; methylene
chloride/ethanol=19:1)
[0490] C.sub.20H.sub.32N.sub.4O.sub.3 (376.5)
[0491] Mass spectrum: (M+Na).sup.+=399 (M-H).sup.-=375
[0492] e.
2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(tert.butyloxycarbony-
laminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole
[0493] Prepared analogously to Example 1g/h from
2-[4-(N-methylamino)-3-am-
ino-phenyl]-2-methyl-3-(tert.butyloxycarbonylamino)-1-pyrrolidino-propan-1-
-one, 4-cyano-phenylglycine/carbonyldiimidazole and subsequent
treatment with glacial acetic acid.
[0494] Yield: 58% of theory,
[0495] R.sub.f value: 0.5 (aluminium oxide; methylene
chloride/ethanol=19:1)
[0496] C.sub.29H.sub.36N.sub.6O.sub.3 (516.65)
[0497] Mass spectrum: M.sup.+=516 (M+Na).sup.+=539
[0498] f.
2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-aminomethyl-1-(pyrrol-
idinocarbonyl)-ethyl]-benzimidazole
[0499] Prepared analogously to Example 1i from
2-(4-cyanophenylaminomethyl-
)-1-methyl-5-[1-(tert.butyloxycarbonylaminomethyl)-1-(pyrrolidinocarbonyl)-
-ethyl]-benzimidazole and 6N hydrochloric acid in dioxane.
[0500] Yield: 82% of theory,
[0501] R.sub.f value: 0.25 (silica gel; methylene chloride/ethanol
9:1)
[0502] g.
2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethyl-
aminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole
[0503] Prepared analogously to Example 1k from
2-(4-cyanophenylamino-methy-
l)-1-methyl-5-[1-aminomethyl-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole
and ethyl bromoacetate/potassium carbonate in acetone.
[0504] Yield: 25% of theory,
[0505] R.sub.f value: 0.6 (silica gel; methylene
chloride/ethanol=9:1)
[0506] C.sub.28H.sub.34N.sub.6O.sub.3 (502.62)
[0507] Mass spectrum: (M+H).sup.+=503 (M+Na).sup.+=525
(M-H).sup.-=501
[0508] h.
2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmeth-
ylaminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-diacetate
[0509] Prepared analogously to Example 11 from
2-(4-cyanophenylaminomethyl-
)-1-methyl-5-[1-(ethoxycarbonylmethylaminomethyl)-1-(pyrrolidinocarbonyl)--
ethyl]-benzimidazole and hydrochloric acid/ammonium carbonate in
ethanol.
[0510] Yield: 66% of theory,
[0511] R.sub.f value: 0.35 (silica gel; methylene
chloride/ethanol=4:1+1% glacial acetic acid)
[0512] C.sub.28H.sub.37N.sub.7O.sub.3.times.2 CH.sub.3COOH
(519.65/639.76)
[0513] Mass spectrum: (M+H).sup.+=520
[0514] The following compounds are obtained analogously to Example
7:
[0515] (1)
2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-(2-ethoxycarbon-
yl-ethyl)-N-methyl-aminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazo-
le
[0516] (2)
2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-ethoxycarbonylm-
ethylsulphonyl)-N-methyl-aminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzi-
midazole
[0517] (3)
2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-ethoxycarbonylm-
ethylaminocarbonyl-N-methyl-aminomethyl)-1-(2,5-dihydropyrrolocarbonyl)-et-
hyl]-benzimidazole-hydrochoride
[0518] Yield: 55% of theory,
[0519] R.sub.f value: 0.4 (Reversed phase RP8; 5% saline
solution/methanol=1:1)
[0520] C.sub.30H.sub.38N.sub.8O.sub.4.times.HCl (574.36/610.81)
[0521] Mass spectrum: (M+H).sup.+=575 (M-H).sup.-=573
(M+Cl).sup.-=609/611 (Cl)
Example 8
[0522]
(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamin-
o)-1-[(R,S)-2-methyl-pyrrolidinocarbonyl]-ethyl]-benzimidazole-dihydrochlo-
ride (mixture of diastereomers)
[0523] A solution of 500 mg (0.84 mmol) of
(R)-2-(4-amidinophenylaminometh-
yl)-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-[(R,S)-2-methyl-pyrrolidin-
ocarbonyl]-ethyl]-benzimidazole-dihydrochloride (mixture of
diastereomers) in 4 ml of water is mixed with 2.7 ml of 1N sodium
hydroxide solution and stirred for 45 minutes at room temperature.
The pH value of the solution is adjusted to 3.5 by adding 1N
hydrochloric acid. The solution is concentrated by evaporation with
the addition of toluene and the residue is mixed with a little
methanol. After the undissolved inorganic material has been
filtered off, the filtrate is concentrated by evaporation and
triturated with ether. The solid formed is filtered off and
dried.
[0524] Yield: 480 mg (100% of theory),
[0525] R.sub.f value: 0.5 (Reversed phase RP8; 5% saline
solution/methanol=1:1)
[0526] C.sub.26H.sub.33N.sub.7O.sub.3.times.2 HCl
(491.6/564.51)
[0527] Mass spectrum: (M+H).sup.+=492 (M+Na).sup.+=514
[0528] The following compounds are obtained analogously to Example
8:
[0529] (1)
2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamin-
omethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-dihydrochloride
[0530] Yield: 70% of theory,
[0531] R.sub.f value: 0.45 (Reversed phase RP8; 5% saline
solution/methanol=1:1)
[0532] C.sub.26H.sub.33N.sub.7O.sub.3.times.2 HCl
(491.6/564.51)
[0533] Mass spectrum: (M+H).sup.+=492
[0534] (2)
2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamin-
o)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole-dihydrochloride
[0535] Yield: 100% of theory,
[0536] R.sub.f value: 0.5 (Reversed phase RP8; 5% saline
solution/methanol=1:1)
[0537] C.sub.25H.sub.29N.sub.7O.sub.3.times.2 HCl
(475.55/548.46)
[0538] Mass spectrum: (M+H).sup.+=476 (M-H).sup.-=474
[0539] (3)
(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl--
5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole
[0540] Yield: 67% of theory,
[0541] R.sub.f value: 0.46 (silica gel; 5% methylene
chloride/methanol/conc. ammonia=4:0.9:0.1)
[0542] C.sub.32H.sub.35N.sub.7O.sub.4 (581.67)
[0543] Mass spectrum: (M+H).sup.+=582 (M-H).sup.-=580
(M+Na).sup.+=604
[0544] (4)
2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethyloxym-
ethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-hydrochloride
[0545] Yield: 45% of theory,
[0546] R.sub.f value: 0.4 (Reversed phase RP8; 5% saline
solution/methanol=1:1)
[0547] C.sub.26H.sub.32N.sub.6O.sub.4.times.HCl (492.58/529.03)
[0548] Mass spectrum: (M+H).sup.+=493 (M-H).sup.-=491
[0549] (5)
2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-(2-carboxyethyl-
)-N-methyl-aminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole
[0550] (6)
2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-carboxymethylsu-
lphonyl-N-methyl-aminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole
[0551] (7)
2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-carboxymethyami-
nocarbonyl)-N-methyl-aminomethyl)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-be-
nzimidazole-hydrochloride
[0552] Yield: 15% of theory,
[0553] R.sub.f value: 0.5 (Reversed phase RP8; 5% saline
solution/methanol=1:1)
[0554] C.sub.28H.sub.34N.sub.8O.sub.4.times.HCl (546.62/583.09)
[0555] Mass spectrum: (M+H).sup.+=547 (M-H).sup.-=545
(M+Cl).sup.-=581/583 (Cl)
Example 9
[0556] Dry ampoule containing 75 mg of active substance per 10
ml
2 Composition: Active substance 75.0 mg Mannitol 50.0 mg water for
injections ad 10.0 ml
[0557] Preparation:
[0558] Active substance and mannitol are dissolved in water. After
packaging the solution is freeze-dried. To produce the solution
ready for use, the product is dissolved in water for
injections.
Example 10
[0559] Dry ampoule containing 35 mg of active substance per 2
ml
3 Composition: Active substance 35.0 mg Mannitol 100.0 mg water for
injections ad 2.0 ml
[0560] Preparation:
[0561] Active substance and mannitol are dissolved in water. After
packaging, the solution is freeze-dried.
[0562] To produce the solution ready for use, the product is
dissolved in water for injections.
Example 11
[0563] Tablet containing 50 mg of active substance
4 Composition: (1) Active substance 50.0 mg (2) Lactose 98.0 mg (3)
Maize starch 50.0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium
stearate 2.0 mg 215.0 mg
[0564] Preparation:
[0565] (1), (2) and (3) are mixed together and granulated with an
aqueous solution of (4). (5) is added to the dried granulated
material. From this mixture tablets are pressed, biplanar, faceted
on both sides and with a dividing notch on one side.
[0566] Diameter of the tablets: 9 mm.
Example 12
[0567] Tablet containing 350 mg of active substance
5 Preparation: (1) Active substance 350.0 mg (2) Lactose 136.0 mg
(3) Maize starch 80.0 mg (4) Polyvinylpyrrolidone 30.0 mg (5)
Magnesium stearate 4.0 mg 600.0 mg
[0568] (1), (2) and (3) are mixed together and granulated with an
aqueous solution of (4). (5) is added to the dried granulated
material. From this mixture tablets are pressed, biplanar, faceted
on both sides and with a dividing notch on one side.
[0569] Diameter of the tablets: 12 mm.
Example 13
[0570] Capsules containing 50 mg of active substance
6 Composition: (1) Active substance 50.0 mg (2) Dried maize starch
58.0 mg (3) Powdered lactose 50.0 mg (4) Magnesium stearate 2.0 mg
160.0 mg
[0571] Preparation:
[0572] (1) is triturated with (3). This trituration is added to the
mixture of (2) and (4) with vigorous mixing.
[0573] This powder mixture is packed into size 3 hard gelatin
capsules in a capsule filling machine.
Example 14
[0574] Capsules containing 350 mg of active substance
7 Composition: (1) Active substance 350.0 mg (2) Dried maize starch
46.0 mg (3) Powdered lactose 30.0 mg (4) Magnesium stear 4.0 mg
430.0 mg
[0575] Preparation:
[0576] (1) is triturated with (3). This trituration is added to the
mixture of (2) and (4) with vigorous mixing.
[0577] This powder mixture is packed into size 0 hard gelatin
capsules in a capsule filling machine.
Example 15
[0578]
8 Suppositories containing 100 mg of active substance 1 suppository
contains: Active substance 100.0 mg Polyethyleneglycol (M.W. 1500)
600.0 mg Polyethyleneglycol (M.W. 6000) 460.0 mg
Polyethylenesorbitan monostearate 840.0 mg 2,000.0 mg
[0579] Method:
[0580] The polyethyleneglycol is melted together with polyethylene
sorbitan monostearate. At 40.degree. C. the ground active substance
is homogeneously dispersed in the melt. It is cooled to 38.degree.
C. and poured into slightly chilled suppository moulds.
* * * * *