Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-06
2002-10-22
Morris, Patricia L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S309400
Reexamination Certificate
active
06469039
ABSTRACT:
DESCRIPTION OF THE INVENTION
The present invention relates to new disubstituted bicyclic heterocycles of general formula
R
a
—A—Het—B—Ar—E, (I)
the tautomers, stereoisomers and mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases which have valuable properties.
The compounds of general formula I above wherein E denotes a cyano group are valuable intermediates for preparing the other compounds of general formula I, and the compounds of general formula I above wherein E denotes an R
b
NH—C(═NH)— group, and the tautomers and stereoisomers thereof have useful pharmacological properties, particularly a thrombin-inhibiting activity and the effect of extending thrombin time.
The present application thus relates to the new compounds of general formula I above and the preparation thereof, pharmaceutical compositions containing the pharmacologically active compounds and the use thereof.
In the above general formula
A denotes a carbonyl or sulphonyl group linked to the benzo, pyrido, pyrimido, pyrazino, pyridazino or thieno moiety of the group Het, whilst moreover the abovementioned moieties may not contain, an R
1
group,
B denotes an ethylene group, wherein a methylene group, linked either to the group Het or Ar, may be replaced by an oxygen or sulphur atom or by a sulphinyl, sulphonyl, carbonyl or —NR
1
group, wherein
R
1
denotes a hydrogen atom or a C
1-6
-alkyl group,
E denotes a cyano or R
b
NH—C(═NH)— group wherein
R
b
denotes a hydrogen atom, a hydroxy group, a C
1-3
-alkyl group or a group which may be cleaved in vivo,
Ar denotes a phenylene or naphthylene group optionally substituted by a fluorine, chlorine or bromine atom or by a trifluoromethyl, C
1-3
-alkyl or C
1-3
-alkoxy group,
a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally substituted in the carbon skeleton by a C
1-3
-alkyl group,
Het denotes a bicyclic heterocycle of formula
wherein
X is a nitrogen atom and
Y is an oxygen or sulphur atom or a nitrogen atom optionally substituted by a C
1-4
-alkyl or C
3-7
-cycloalkyl group, whilst additionally one or two non-angular methyne groups in the phenyl moiety of the above-mentioned bicyclic heterocycle may each be replaced by a nitrogen atom,
or X denotes a methyne group optionally substituted by the group R
1
, wherein R
1
is as hereinbefore defined, and
Y denotes a nitrogen atom optionally substituted by a C
1-6
-alkyl or C
3-7
-cycloalkyl group,
or Het denotes a group of the formula
wherein
R
1
is as hereinbefore defined,
Z denotes an oxygen or sulphur atom,
one of the groups D or G denotes a nitrogen atom and the other group D or G denotes a methyne group,
and R
a
denotes a C
1-6
-alkyl group, a C
3-7
-cycloalkyl group optionally substituted by a C
1-3
-alkyl group, wherein the C
1-3
-alkyl group may additionally be substituted by a carboxyl group or by a group which may be converted in vivo into a carboxy group,
or an R
2
NR
3
— group wherein
R
2
denotes a C
1-4
-alkyl group, which may be substituted by a carboxy, C
1-6
-alkyloxycarbonyl, benzyloxycarbonyl, C
1-3
-alkylsulphonylaminocarbonyl, phenylsulphonylaminocarbonyl, trifluorosulphonylamino, trifluorosulphonylaminocarbonyl or 1H-tetrazolyl group,
C
2-4
-alkyl group substituted by a hydroxy, phenyl-C
1-3
-alkoxy, carboxy-C
1-3
-alkylamino, C
1-3
-alkoxycarbonyl-C
1-3
-alkylamino, N—(C
1-3
-alkyl)-carboxy-C
1-3
-alkylamino or N—(C
1-3
-alkyl)-C
1-3
-alkoxycarbonyl-C
1-3
-alkylamino group, whilst in the abovementioned groups the carbon atom in the &agr;-position relative to the adjacent nitrogen atom may not be substituted, or
a piperidinyl group optionally substituted by a C
1-3-
alkyl group and
R
3
denotes a hydrogen atom, a C
1-6
-alkyl group, a C
3-7
-cycloalkyl group optionally substituted by a C
1-3
-alkyl group, a C
3-6
-alkenyl or alkynyl group, wherein the unsaturated part may not be linked directly to the nitrogen atom of the R
2
NR
3
— group,
a phenyl group optionally substituted by a fluorine, chlorine or bromine atom or by a C
1-3
-alkyl or C
1-3
-alkoxy group, a benzyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl or imidazolyl group or
R
2
and R
3
together with the nitrogen atom between them denote a 5- to 7-membered cycloalkyleneimino group, optionally substituted by a carboxymethyl or C
1-4
-alkoxycarbonyl group, onto which a phenyl ring may additionally be fused.
The compounds of the above general formula I which contain a group capable of being cleaved in vivo are thus prodrugs and compounds of general formula I which contain two groups capable of being cleaved in vivo are so-called double prodrugs.
The phrase “a group which may be converted in vivo into a carboxy group” denotes, for example, a hydroxymethyl group, a carboxy group esterified with an alcohol, in which the alcoholic moiety is preferably a C
1-6
-alkanol, a phenyl-C
1-3
-alkanol, a C
3-6
-cycloalkanol, wherein a C
5-8
-cycloalkanol may additionally be substituted by one or two C
1-3
-alkyl groups, a C
5-8
-cycloalkanol, in which 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
-alkynol or phenyl-C
3-5
-alkynol, with the proviso that no bond to the oxygen atom emanates 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
4
—CO—O—(R
5
CR
6
)—OH,
wherein
R
4
denotes a C
1-8
-alkyl, C
5-7
-cycloalkyl, phenyl or phenyl-C
1-3
-alkyl group,
R
5
denotes a hydrogen atom, a C
1-3
-alkyl, C
5-7
-cycloalkyl or phenyl group and
R
6
denotes a hydrogen atom or a C
1-3
-alkyl group,
or the phrase “a group which may be cleaved in vivo from an imino or amino group” denotes for example a hydroxy group, an acyl group such as a benzoyl- or pyridinoyl group or a C
1-16
-alkanoyl group such as the formyl-, acetyl-, propionyl-, butanoyl-, pentanoyl- or hexanoyl group, an allyloxycarbonyl group, a C
1-16
-alkoxycarbonyl group such as the methoxycarbonyl-, ethoxycarbonyl-, propoxycarbonyl-, isopropoxycarbonyl-, butoxycarbonyl-, tert.-butoxycarbonyl-, pentoxycarbonyl-, hexoxycarbonyl-, octyloxycarbonyl-, nonyloxycarbonyl-, decyloxycarbonyl-, undecyloxycarbonyl-, dodecyloxycarbonyl- or hexadecyloxycarbonyl group, a phenyl-C
1-6
-alkoxycarbonyl group such as the benzyloxycarbonyl-, phenylethoxycarbonyl- or phenylpropoxycarbonyl group, a C
1-3
-alkylsulphonyl- C
2-4
-alkoxycarbonyl-, C
1-3
-alkoxy-C
2-4
-alkoxy-C
2-4
-alkoxycarbonyl- or R
4
CO—O—(R
5
CR
6
)—O—CO— group, wherein R
4
to R
6
are as hereinbefore defined.
Examples of preferred prodrug groups for a carboxy group include a C
1-6
-alkoxycarbonyl group such as the methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl or cyclohexyloxycarbonyl group or phenyl-C
1-3
-alkoxycarbonyl group such as the benzyloxycarbonyl group and for an imino or amino group a C
1-9
-alkoxycarbonyl group such as the methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl, cyclohexyloxycarbonyl, n-heptyloxycarbonyl, n-octyloxycarbonyl or n-nonyloxycarbonyl group, a phenyl-C
1-3
-alkoxycarbonyl group such as the benzyloxycarbonyl group, a phenylcarbonyl group optionally substituted by a C
1-3
-alkyl group such as the benzoyl or 4-ethyl-benzoyl group, a pyridinoyl group such as the nicotinoyl group, a C
1-3
-alkylsulphonyl-n
Hauel Norbert
Priepke Henning
Ries Uwe
Stassen Jean Marie
Wienen Wolfgang
Boehringer Ingelheim Pharma KG
Devlin Mary-Ellen M.
Morris Patricia L.
Raymond Robert P.
Witkowski Timothy X.
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