US 5,686,459 AGranted

Dioxopyrrolo pyrrole derivatives

AssigneeHoffmann-La Roche Inc.

InventorsFrancois Diederich, Ulrike Obst, Sabine Wallbaum, Lutz Weber

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Abstract

Novel dioxopyrrolo-pyrrole derivatives of the formula ##STR1## as well as hydrates or solvates thereof, which inhibit thrombin-induced or Factor Xa-induced platelet aggregation and fibrinogen clotting in blood plasma. The derivatives can be manufactured from the corresponding maleimides which are N-substituted by .alpha.-amino carboxylic acids of the formula HN(R.sup.2)CH(R.sup.4)COOH, or functional derivatives thereof; and ketones or aldehydes of the formula R.sup.5 C(O)R.sup.6.

Claims31

Dependent claims

An octahydro-1,3-dioxo-pyrrolo3,4-c!pyrrole compound having the formula ##STR7## wherein R.sup.1 is selected from the group consisting of H, lower alkyl, aryl, heteroaryl, cycloalkyl and lower-alkyl which is substituted with a group R.sup.10 and optionally a group R.sup.11 or with a group R.sup.11 and optionally a group R.sup.10 ;

R.sup.2 is selected from the group consisting of lower-alkanoyl, H, lower-alkyl, aryl, heteroaryl, cycloalkyl and lower-alkyl which is substituted with a group R.sup.10 and optionally a group R.sup.11 or with a group R.sup.11 and optionally a group R.sup.10 ;
R.sup.10 is CONH.sub.2 or COO-lower-alkyl;
R.sup.11 is aryl, heteroaryl or cycloalkyl;
R.sup.3 is selected from the group consisting of H, COOH, CONH.sub.2, COO-lower-alkyl, CONH-lower-alkyl and CON(lower-alkyl).sub.2 ;
and
R.sup.4, R.sup.5 and R.sup.6 are each independently selected from the group consisting of H, lower alkyl, aryl, aralkyl or cycloalkyl, or
R.sup.4 and optionally R.sup.5 or R.sup.6 are a group R.sup.40, or
R.sup.5 or R.sup.6 and optionally R.sup.4 are a group R.sup.40 ;
R.sup.40 is heteroaryl, or lower-alkyl substituted with OH, SO.sub.2 H, SO.sub.3 H, guanidino, aryl-lower-alkoxy or lower-alkyl-(O or S);
or
R.sup.2 and R.sup.4 together form a group G, wherein G is a tri- or tetramethylene group (CH.sub.2).sub.3 or (CH.sub.2).sub.4 wherein one methylene group may be replaced by S, SO or SO.sub.2, or may be substituted with OH, lower-alkyl, lower-alkenyl or carboxy-lower-alkyl, or wherein one methylene group may be substituted with lower-alkenyl and another methylene group may be substituted with carboxy-lower-alkyl;
wherein lower alkyl and alkanoyl are a straight-chain or branched group having, from 1 to 6 carbon atoms;
cycloalkyl is a saturated group having from 3 to 7 carbon atoms;
and heteroaryl is an aromatic group having from 5 to 10 members, containing at least one N atom and which further can be substituted by at least one NH.sub.2 group;
with the proviso that at least one of R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.6 is a group substituted with amino, amidino, guanidino or N-hydroxyamidino;
and
hydrates or solvates and physiologically usable salts thereof.

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Dependencies are inferred from the claim text.

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Abstract

R.sup.2 is selected from the group consisting of lower-alkanoyl, H, lower-alkyl, aryl, heteroaryl, cycloalkyl and lower-alkyl which is substituted with a group R.sup.10 and optionally a group R.sup.11 or with a group R.sup.11 and optionally a group R.sup.10 ;
R.sup.10 is CONH.sub.2 or COO-lower-alkyl;
R.sup.11 is aryl, heteroaryl or cycloalkyl;
R.sup.3 is selected from the group consisting of H, COOH, CONH.sub.2, COO-lower-alkyl, CONH-lower-alkyl and CON(lower-alkyl).sub.2 ;
and
R.sup.4, R.sup.5 and R.sup.6 are each independently selected from the group consisting of H, lower alkyl, aryl, aralkyl or cycloalkyl, or
R.sup.4 and optionally R.sup.5 or R.sup.6 are a group R.sup.40, or
R.sup.5 or R.sup.6 and optionally R.sup.4 are a group R.sup.40 ;
R.sup.40 is heteroaryl, or lower-alkyl substituted with OH, SO.sub.2 H, SO.sub.3 H, guanidino, aryl-lower-alkoxy or lower-alkyl-(O or S);
or
R.sup.2 and R.sup.4 together form a group G, wherein G is a tri- or tetramethylene group (CH.sub.2).sub.3 or (CH.sub.2).sub.4 wherein one methylene group may be replaced by S, SO or SO.sub.2, or may be substituted with OH, lower-alkyl, lower-alkenyl or carboxy-lower-alkyl, or wherein one methylene group may be substituted with lower-alkenyl and another methylene group may be substituted with carboxy-lower-alkyl;
wherein lower alkyl and alkanoyl are a straight-chain or branched group having, from 1 to 6 carbon atoms;
cycloalkyl is a saturated group having from 3 to 7 carbon atoms;
and heteroaryl is an aromatic group having from 5 to 10 members, containing at least one N atom and which further can be substituted by at least one NH.sub.2 group;
with the proviso that at least one of R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.6 is a group substituted with amino, amidino, guanidino or N-hydroxyamidino;
and
hydrates or solvates and physiologically usable salts thereof.

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