Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-12-12
2002-09-17
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S364000, C514S381000, C548S131000, C548S254000, C548S306100
Reexamination Certificate
active
06451832
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel benzimidazoles, methods for making them, pharmaceutical compositions comprising them, and their use as, inter alia, antithrombotic agents.
DESCRIPTION OF THE INVENTION
The present invention relates to benzimidazoles of general formula
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.
The compounds of the above general formula I wherein R
a
denotes a straight-chained C
1-3
-alkyl group which is substituted in the 1 position by a pyrrolidinocarbonyl or 2,5-dihydropyrrolocarbonyl group optionally substituted by a C
1-3
-alkyl group and by an amino group monosubstituted by a cyano-C
1-4
-alkyl group, and/or R
c
denotes a cyano group or a 1,2,4-oxadiazol-3-yl group substituted in the 5 position by a C
1-3
-alkyl or phenyl group, while the phenyl substituent may be substituted by a fluorine, chlorine or bromine atom or by a C
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
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.
In the above general formula
R
a
denotes a straight-chained C
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
1-3
-alkyl group and
by an amino group which is monosubstituted by a carboxy-C
1-4
-alkyl, cyano-C
1-4
-alkyl or tetrazolyl-C
1-4
-alkyl group,
or by a C
1-3
-alkyl group which is terminally substituted by an N-(carboxy-C
1-3
-alkylaminocarbonyl)-amino group optionally substituted by a C
1-3
-alkyl group at one or both amino nitrogen atoms, by a carboxy-C
1-3
-alkoxy, N-(carboxy-C
1-3
-alkyl)-amino, N-(C
1-3
-alkyl)-N-(carboxy-C
1-3
-alkyl)-amino, N-(carboxy-C
1-3
-alkylsulphonyl)-amino, N-(C
1-3
-alkyl)-N-(carboxy-C
1-3
-alkylsulphonyl)-amino or tetrazolyl-C
1-3
-alkyl group,
R
b
denotes a C
1-3
-alkyl group and
R
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
1-3
-alkyl or phenyl group, while the phenyl substituent may be substituted by a fluorine, chlorine or bromine atom or by a C
1-3
-alkyl group.
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
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).
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
1-6
-alkanol, a phenyl-C
1-3
-alkanol, a C
3-9
-cycloalkanol, whilst a C
5-8
-cycloalkanol may additionally be substituted by one or two C
1-3
-alkyl groups, a C
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
1-3
-alkyl, phenyl-C
1-3
-alkyl, phenyl-C
1-3
-alkoxycarbonyl or C
2-6
-alkanoyl group and the cycloalkanol moiety may additionally be substituted by one or two C
1-3
-alkyl groups, a C
4-7
-cycloalkenol, a C
3-5
-alkenol, a phenyl-C
3-5
-alkenol, a C
3-5
-alkinol or phenyl-C
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
3-8
-cycloalkyl-C
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
1-3
-alkyl groups, a 1,3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of formula
R
d
-CO—O—(R
e
CR
f
)—OH,
wherein
R
d
denotes a C
1-8
-alkyl, C
5-7
-cycloalkyl, phenyl or phenyl-C
1-3
-alkyl group,
R
e
denotes a hydrogen atom, a C
1-3
-alkyl, C
5-7
-cycloalkyl or phenyl group and
R
f
denotes a hydrogen atom or a C
1-3
-alkyl group,
by a group which is negatively charged under physiological conditions is meant a group such as a tetrazol-5-yl, phenylcarbonylaminocarbonyl, trifluoromethylcarbonylaminocarbonyl, C
1-6
-alkylsulphonylamino, phenylsulphonylamino, benzylsulphonylamino, trifluoromethylsulphonylamino, C
1-6
-alkylsulphonylaminocarbonyl, phenylsulphonylaminocarbonyl, benzylsulphonylaminocarbonyl or perfluoro-C
1-6
-alkylsulphonylaminocarbonyl group
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
1-3
-alkyl or C
1-3
-alkoxy groups, whilst the substituents may be identical or different, a pyridinoyl group or a C
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
1-16
-alkoxycarbonyl or C
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
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
1-6
-alkyl or C
3-7
-cycloalkyl groups and the substituents may be identical or different, a C
1-3
-alkylsulphonyl-C
2-4
-alkoxycarbonyl, C
1-3
-alkoxy-C
2-4
-alkoxy-C
2-4
-alkoxycarbonyl, R
d
-CO—O-(R
d
CR
f
)-O—CO, C
1-6
-alkyl-CO—NH—(R
g
CR
h
)—O—CO or C
1-6
-alkyl-CO—O—(R
g
CR
h
)-(R
g
CR
h
)—O—CO group wherein R
d
to R
f
are as hereinbefore defined,
R
g
and R
h
, which may be identical or different, denote hydrogen atoms or C
1-3
-alkyl groups.
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.
Preferred compounds of general formula I mentioned above are those wherein
R
b
and R
c
are as hereinbefore defined and
R
a
is as hereinbefore defined, with the proviso that one substituent denotes an unbranched C
1-3
-alkyl group or a 2,5-dihydropyrrolocarbonyl group optionally substituted by a C
1-3
-alkyl group,
or R
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, dimethylam
Hauel Norbert
Kaufmann-Hefner Iris
Nar Herbert
Priepke Henning
Ries Uwe
Boehringer Ingelheim Pharma KG
Devlin Mary-Ellen M.
Raymond Robert P.
Stempel Alan R.
Stockton Laura L.
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