Pharmaceutically active pyrrolidine derivatives as Bax inhibitors

A method for treating a neuronal disorder, comprising administering to a patient in need thereof a pyrrolidine derivative according to formula IA

• as well as its geometrical isomers, its optically active forms as enantiomers, diastereomers and its racemate forms, as well as pharmaceutically acceptable salts thereof, wherein
• X is selected from the group consisting of O, S, CR6R7, NOR6, and NNR6R7;
• A is selected from the group consisting of —(C═O)—, —(C═O)—O—, —C(═NH)—, —(C═O)—NH—, —(C═S)—NH, —SO2—, —SO2NH—, and —CH2—,
• R1 is selected from the group consisting of unsubstituted or substituted C1–C6-alkyl, unsubstituted or substituted C2–C6-alkenyl, unsubstituted or substituted C2–C6-alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted saturated or unsaturated 3–8-membered cycloalkyl, acyl, unsubstituted or substituted C1–C6-alkyl aryl, and unsubstituted or substituted C1–C6-alkyl heteroaryl, wherein said cycloalkyl or aryl or heteroaryl groups may be fused with 1–2 further cycloalkyl or aryl or heteroaryl group;
• R2, R3, R4 and R5 are independently selected from each other from the group consisting of hydrogen, halogen, C1–C6-alkyl, and C1–C6-alkoxy;
• R6 and R7 are independently selected from the group consisting of hydrogen, unsubstituted or substituted C1–C6 alkyl, unsubstituted or substituted C2–C6 alkenyl, unsubstituted or substituted C2–C6 alkynyl, unsubstituted or substituted alkoxy, unsubstituted or substituted thioalkoxy, halogen, cyano, nitro, acyl, alkoxycarbonyl, aminocarbonyl, unsubstituted or substituted saturated or unsaturated 3–8-membered cycloalkyl which may contain 1 to 3 heteroatoms selected of N, O, S, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C1–C6-alkyl aryl, and unsubstituted or substituted C1–C6-alkyl heteroaryl;
• R8, R9 are independently selected from the group consisting of hydrogen, unsubstituted or substituted C1–C6 alkyl, unsubstituted or substituted C2–C6 alkenyl, unsubstituted or substituted C2–C6 alkynyl, unsubstituted or substituted saturated or unsaturated 3–8-membered cycloalkyl which may contain 1 to 3 heteroatoms selected of N, O, S, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl, or
• each pair R6, R7 and/or R8, R9 can form together with the N atom to which they are attached a 3–8 membered substituted or unsubstituted, saturated or unsaturated hetero-cyclic ring which may contain 1–2 further heteroatoms selected from N, S and O and which is optionally fused with an aryl, heteroaryl or 3–8 membered saturated or unsaturated cycloalkyl ring;
• R11 is selected from the group consisting of hydrogen, unsubstituted or substituted C1–C6-alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, hydroxy, mercapto, alkoxy, thioalkoxy, aryl, heteroaryl, halogen, nitro, cyano, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, sulfonyl, sulfoxy, carboxyl, primary, secondary or tertiary amino groups or quarternary ammonium moieties, and unsubstituted or substituted saturated or unsaturated 3–8-membered cycloalkyl.

A method for treating an autoimmune disease, comprising administering to a patient in need thereof a pyrrolidine derivative according to Formula IA

• as well as its geometrical isomers, its optically active forms as enantiomers, diastereomers and its racemate forms, as well as pharmaceutically acceptable salts thereof, wherein
• X is selected from the group consisting of O, S, CR6R7, NOR6, and NNR6R7;
• A is selected from the group consisting of —(C═O)—, —(C═O)—O—, —C(═NH)—, —(C═O)—NH—, —(C═S)—NH, —SO2—, —SO2NH—, and —CH2—,
• R1 is selected from the group consisting of unsubstituted or substituted C1–C6-alkyl, unsubstituted or substituted C2–C6-alkenyl, unsubstituted or substituted C2–C6-alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted saturated or unsaturated 3–8-membered cycloalkyl, acyl, unsubstituted or substituted C1–C6-alkyl aryl, and unsubstituted or substituted C1–C6-alkyl heteroaryl, said cycloalkyl or aryl or heteroaryl groups may be fused with 1–2 further cycloalkyl or aryl or heteroaryl group;
• R2, R3, R4 and are R5 independently selected from each other from the group consisting of hydrogen, halogen, C1–C6-alkyl, and C1–C6-alkoxy;
• R6 and R7 are independently selected from the group consisting of hydrogen, unsubstituted or substituted C2–C6 alkyl, unsubstituted or substituted C2–C6 alkenyl, unsubstituted or substituted C2–C6 alkynyl, unsubstituted or substituted alkoxy, unsubstituted or substituted thioalkoxy, halogen, cyano, nitro, acyl, alkoxycarbonyl, aminocarbonyl, unsubstituted or substituted saturated or unsaturated 3–8-membered cycloalkyl which may contain 1 to 3 heteroatoms selected of N, O, S, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C1–C6-alkyl aryl, and unsubstituted or substituted C1–C6-alkyl heteroaryl;
• R8, R9 are independently selected from the group consisting of hydrogen, unsubstituted or substituted C1–C6 alkyl, unsubstituted or substituted C2–C6 alkenyl, unsubstituted or substituted C2–C6 alkynyl, unsubstituted or substituted saturated or unsaturated 3–8-membered cycloalkyl which may contain 1 to 3 heteroatoms selected of N, O, S, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl, or
• each pair R6, R7 and/or R8, R9 can form together with the N atom to which they are attached a 3–8 membered substituted or unsubstituted, saturated or unsaturated heterocyclic ring which may contain 1–2 further heteroatoms selected from N, S and O and which is optionally fused with an aryl, heteroaryl or 3–8 membered saturated or unsaturated cycloalkyl ring;
• R11 is selected from the group consisting of hydrogen, unsubstituted or substituted C1–C6-alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, hydroxy, mercapto, alkoxy, thioalkoxy, aryl, heteroaryl, halogen, nitro, cyano, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, sulfonyl, sulfoxy, carboxyl, primary, secondary or tertiary amino groups or quarternary ammonium moieties, and unsubstituted or substituted saturated or unsaturated 3–8-membered cycloalkyl.

A method for treating ischemia, comprising administering to a patient in need thereof a pyrrolidine derivative according to formula I

• as well as its geometrical isomers, its optically active forms as enantiomers, diastereomers and its racemate forms, as well as pharmaceutically acceptable salts thereof, wherein
• X is selected from the group consisting of O, S, CR6R7, NOR6, and NNR6R7;
• A is selected from the group consisting of —(C═O)—, —(C═O)—O—, —C(═NH)—, —(C═O)—NH—, —(C═S)—NH, —SO2—, —SO2NH—, and —CH2—,
• B is a group —(C═O)—NR8R9;
• R1 is selected from the group consisting of unsubstituted or substituted C1–C6-alkyl, unsubstituted or substituted C2–C6-alkenyl, unsubstituted or substituted C2–C6-alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted saturated or unsaturated 3–8-membered cycloalkyl, acyl, unsubstituted or substituted C1–C6-alkyl aryl, and unsubstituted or substituted C1–C6-alkyl heteroaryl, wherein said cycloalkyl or aryl or heteroaryl groups may be fused with 1–2 further cycloalkyl or aryl or heteroaryl group;
• R2, R3, R4 and R5 are independently selected from each other from the group consisting of hydrogen, halogen, C1–C6-alkyl, and C1–C6-alkoxy;
• R6 and R7 are independently selected from the group consisting of hydrogen, unsubstituted or substituted C1–C6 alkyl, unsubstituted or substituted C2–C6 alkenyl, unsubstituted or substituted C2–C6 alkynyl, unsubstituted or substituted alkoxy, unsubstituted or substituted thioalkoxy, halogen, cyano, nitro, acyl, alkoxycarbonyl, aminocarbonyl, unsubstituted or substituted saturated or unsaturated 3–8-membered cycloalkyl which may contain 1 to 3 heteroatoms selected of N, O, S, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C1–C6-alkyl aryl, and unsubstituted or substituted C1–C6-alkyl heteroaryl;
• R8, R9 are independently selected from the group consisting of hydrogen, unsubstituted or substituted C1–C6 alkyl, unsubstituted or substituted C2–C6 alkenyl, unsubstituted or substituted C2–C6 alkynyl, and unsubstituted or substituted saturated or unsaturated 3–8-membered cycloalkyl which may contain 1 to 3 heteroatoms selected of N, O, S, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, or
• each pair R6, R7 and/or R8, R9 can form together with the N atom to which they are attached a 3–8 membered substituted or unsubstituted, saturated or unsaturated hetero-cyclic ring which may contain 1–2 further heteroatoms selected from N, S and O and which is optionally fused with an aryl, heteroaryl or 3–8 membered saturated or unsaturated cycloalkyl ring;
• R11 is selected from the group consisting of hydrogen, unsubstituted or substituted C1–C6-alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, hydroxy, mercapto, alkoxy, thioalkoxy, aryl, heteroaryl, halogen, nitro, cyano, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, sulfonyl, sulfoxy, carboxyl, primary, secondary or tertiary amino groups or quarternary ammonium moieties, and unsubstituted or substituted saturated or unsaturated 3–8-membered cycloalkyl.

A method for treating an infertility related disorder, comprising administering to a patient in need thereof a pyrrolidine derivative according to formula I

• as well as its geometrical isomers, its optically active forms as enantiomers, diastereo-mers and its racemate forms, as well as pharmaceutically acceptable salts thereof, wherein
• X is selected from the group consisting of O, S, CR6R7, NOR6, and NNR6R7;
• A is selected from the group consisting of —(C═O)—, —(C═O)—O—, —C(═NH)—, —(C═O)—NH—, —(C═S)—NH, —SO2—, —SO2NH—, and —CH2—,
• B is a group —(C═O)—NR8R9;
• R1 is selected from the group consisting of unsubstituted or substituted C1–C6-alkyl, unsubstituted or substituted C2–C6-alkenyl, unsubstituted or substituted C2–C6-alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted saturated or unsaturated 3–8-membered cycloalkyl, acyl, unsubstituted or substituted C1–C6-alkyl aryl, and unsubstituted or substituted C1–C6-alkyl heteroaryl, wherein said cycloalkyl or aryl or heteroaryl groups may be fused with 1–2 further cycloalkyl or aryl or heteroaryl group;
• R2, R3, R4 and R5 are independently selected from each other from the group consisting of hydrogen, halogen, C1–C6-alkyl, and C1–C6-alkoxy;
• R6 and R7 are independently selected from the group consisting of hydrogen, unsubstituted or substituted C2–C6 alkyl, unsubstituted or substituted C2–C6 alkenyl, unsubstituted or substituted C2–C6 alkynyl, unsubstituted or substituted alkoxy, unsubstituted or substituted thioalkoxy, halogen, cyano, nitro, acyl, alkoxycarbonyl, aminocarbonyl, unsubstituted or substituted saturated or unsaturated 3–8-membered cycloalkyl which may contain 1 to 3 heteroatoms selected of N, O, S, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C1–C6-alkyl aryl, and unsubstituted or substituted C1–C6-alkyl heteroaryl;
• R8, R9 are independently selected from the group consisting of hydrogen, unsubstituted or substituted C1–C6 alkyl, unsubstituted or substituted C2–C6 alkenyl, unsubstituted or substituted C2–C6 alkynyl, unsubstituted or substituted saturated or unsaturated 3–8-membered cycloalkyl which may contain 1 to 3 heteroatoms selected of N, O, S, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl, or
• each pair R6, R7 and/or R8, R9 can form together with the N atom to which they are attached a 3–8 membered substituted or unsubstituted, saturated or unsaturated hetero-cyclic ring which may contain 1–2 further heteroatoms selected from N, S and O and which is optionally fused with an aryl, heteroaryl or 3–8 membered saturated or unsaturated cycloalkyl ring;
• R11 is selected from the group consisting of hydrogen, unsubstituted or substituted C1–C6-alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, hydroxy, mercapto, alkoxy, thioalkoxy, aryl, heteroaryl, halogen, nitro, cyano, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, sulfonyl, sulfoxy, carboxyl, primary, secondary or tertiary amino groups or quarternary ammonium moieties, and unsubstituted or substituted saturated or unsaturated 3–8-membered cycloalkyl.