Malonamid and malonamic ester derivatives with antithrombotic activity, their preparation, and their use

A compound of formula I,

• wherein:
• A is a compound of formula II,
• wherein:
• R3 is hydrogen, —OH, or —(C1-C7)-alkyl;
• R4 and R5, independently of one another, are
• 1. hydrogen;
• 2. —(C1-C7)-alkyl;
• 3. —OH;
• 4. —O—(C1-C7)-alkyl;
• 5. halogen;
• 6. —NH2;
• or
• 7. —NO2;
• X1 and X2, are selected from a carbon substituted by R4, wherein R4 is as defined above;
• D1 and D2, independently of one another, are
• 1. hydrogen;
• 2. —C(O)—(C1-C7)-alkyl;
• 3. —C(O)-aryl;
• 4. —C(O)—(C1-C7)-alkyl-aryl;
• 5. —C(O)—O—(C1-C7)-alkyl;
• 6. —C(O)—O—(C1-C7)-alkyl-aryl;
• or
• 7. —C(O)—O—(C1-C6)-aryl;
• or
• D1 is hydrogen, when D2 is
• 1. —OH;
• 2. —O—C(O)—(C1-C7)-alkyl;
• 3. —O—C(O)-aryl;
• or
• 4. —O—C(O)—(C1-C7)-alkyl-aryl;
• or
• D1 and D2, together with the nitrogen to which they are attached, form a cycle of the formula VIII
• R1 is
• 1. hydrogen;
• 2. —(C1-C7)-alkyl;
• 3. —OH;
• 4. —O—(C1-C7)-alkyl;
• or
• 5. —N—(R6)2, wherein R6 is, independently of one another, hydrogen, —C(O)-aryl, —C(O)—(C1-C7)-alkyl-aryl, —C(O)—(C1-C7)-alkyl, —(C1-C7)-alkyl, —C(O)—N(H)-aryl, —C(O)—N(H)—(C1-C7)-alkyl-aryl, —(C1-C6)—N(H)-alkyl, —C(O)—O-aryl, —C(O)—O—(C1-C7)-alkyl-aryl, —C(O)—O—(C1-C7)-alkyl-, S(O2)-aryl, or —S(O2)—(C1-C7)-alkyl;
• R2 is 1. aryl, wherein aryl is unsubstituted or mono- to tri-substituted, independently of one another, by
• 1.1 —CF3;
• 1.2. halogen;
• 1.3 —OH;
• 1.4 —CN;
• 1.5 sulfo;
• 1.6 —NO2;
• 1.7 —NH2;
• 1.8 —O—(C1-C7)-alkyl;
• 1.9 substituted amino;
• 1.10 —COOH;
• 1.11 —(C1-C7)-alkyl;
• 1.12 carbamyl;
• 1.13 carbonyl;
• 1.14 alkoxycarbonyl;
• 1.15 methylendioxyl;
• 1.16 aryloxy, wherein aryloxy is unsubstituted or mono- to tri-substituted, independently of one another, by a substituent as defined by 1.1 to 1.15;
• 1.17 —O—(C1-C7)-alkyl-aryl, wherein aryl is unsubstituted or mono- to tri-substituted, independently of one another, by a substituent as defined by 1.1 to 1.15;
• 1.18 Het-group, wherein Het-group is unsubstituted or mono- to tri-substituted, independently of one another, by a substituent as defined by 1.1 to 1.15;
• or
• 1.19 —(C0-C4)-alkyl-aryl, wherein aryl is unsubstituted or mono- to tri-substituted, independently of one another, by a substituent as defined by 1.1 to 1.15;
• 2. hydrogen;
• 3. Het-group, wherein the Het-group is unsubstituted or mono- to tri-substituted, independently of one another, by a substituent as defined by 1.1 to 1.19 above;
• 4. —(CH2)m—Yn—(CH2)o-aryl, in which
• m, n, and o are, independently of one another, 0, 1, or 2, provided that at least one of m, n, and o is not 0;
• aryl is unsubstituted or mono- to tri-substituted, independently of one another, by a substituent as defined by 1.1 to 1.19 above;
• and
• Y is —O—, —S—, or —N—(R6) wherein R6 is hydrogen or —(C1-C7)-alkyl, provided n is 1, or Y is —N(R6)—N(R6)— wherein R6 is, independently of one another, hydrogen or —(C1-C7)-alkyl, or —N═N—, provided n is 2;
• or
• 5. —(CH2)m—Yn—(CH2)o-Het-group, in which
• m, n, and o are, independently of one another, 0, 1, or 2, provided that at least one of m, n, and o is not 0;
• Het-group is unsubstituted or mono- to tri-substituted, independently of one another, by a substituent as defined by 1.1 to 1.19 above;
• and
• Y is as defined above;
• or
• R1 and R2, together with the carbon to which they are bonded, form
• 1. a —(C3-C7)-cycloalkyl, wherein cycloalkyl is unsubstituted or mono- to tri-substituted, independently of one another, by a substituent as defined by 1.1 to 1.19 above;
• 2. a —(C3-C7)-cycloalkyl, wherein cycloalkyl is unsubstituted or mono- to disubstituted, independently of one another, and fused to an aryl- or Het-group-ring, which itself is unsubstituted or mono- to tri-substituted, independently of one another, by a substituent as defined by 1.1 to 1.19 above;
• 3. a Het-group, wherein the Het-group is unsubstituted or mono- to tri-substituted, independently of one another, by a substituent as defined by 1.1 to 1.19 above;
• or
• 4. a keto-group, which may partially or totally exist in a hydrated state;
• provided that, when R1 is as defined above under 3, 4, or 5, then R2 is not directly bonded to formula I via a oxygen-, sulfur- or nitrogen-;
• B is 1. —N(R7)—(CH—(R8))p-aryl, in which
• aryl is unsubstituted or mono- to tri-substituted, independently of one another, by a substituent as defined by 1.1 to 1.3 and 1.5 to 1.19 above;
• p is 0, 1, or 2;
• R7 is
• 1.1 hydrogen;
• 1.2 —(C1-C7)-alkyl;
• 1.3 —OH;
• or
• 1.4 —N—(R6)2, wherein R6 is, independently of one another, hydrogen or —(C1-C7)-alkyl;
• R8 is 1.1 hydrogen;
• 1.2 —(C1-C7)-alkyl;
• 1.3 —(C2-C7)-alkenyl;
• 1.4 —(C2-C7)-alkynyl;
• 1.5 —(C0-C3)-alkyl-(C3-C7)-cycloalkyl;
• 1.6 —CN;
• 1.7 aryl, aryl is unsubstituted or mono- or di-substituted, independently of one another, by a substituent as defined by 1.1 to 1.19 above;
• 1.8 a Het-group, wherein the Het-group is unsubstituted or mono- or di-substituted, independently of one another, by a substituent as defined by 1.1 to 1.19 above;
• 1.9 —(CH—(R8))— forms a —(C3-C7)-cycloalkyl derivative;
• or
• 1.10 —(C0-C4)-alkyl-O—(C1-C7)-alkyl;
• 2. —O—(CH—(R8))p-aryl, wherein aryl, R8, and p are as defined above;
• 3. —N(R7)—(CH—(R8))p-Het-group, wherein the Het-group is unsubstituted or mono- or di-substituted, independently of one another, by a substituent as defined by 1.1 to 1.19 above, and R7, R8, and p are as defined above;
• 4. —N(R9)—N(R9′)—(CH—(R8))q-aryl, in which aryl is unsubstituted or mono- to tri-substituted, independently of one another, by a substituent as defined by 1.1 to 1.19 above;
• q is 0, 1, or 2;
• R9 and R9′ are, independently of one another, hydrogen, —(C1-C7)-alkyl, or —(C1-C3)-alkyl-aryl;
• and
• R8 is as defined above;
• 5. —O—N(R9)—(CH—(R8))q-aryl, in which aryl is unsubstituted or mono- to tri-substituted, independently of one another, by a substituent as defined by 1.1 to 1.19 above;
• q is 0, 1, or 2;
• and
• R8 and R9 are as defined above;
• 6. —N(R9)—N(R9′)—(CH—(R8))q-Het-group, in which
• Het-group is unsubstituted or mono- to tri-substituted, independently of one another, by a substituent as defined by 1.1 to 1.19 above;
• q is 0, 1, or 2;
• and
• R8, R9′, and R9 are as defined above;
• or
• 7. —O—N(R9)—(CH—(R8))q-Het-group, in which
• Het-group is unsubstituted or mono- to tri-substituted, independently of one another, by a substituent as defined by 1.1 to 1.19 above;
• q is 0, 1, or 2;
• and
• R8 and R9 are as defined above;
• in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof.