US 2003/0171309 A1 · Pharmaceutically active pyrrolidine derivatives as bax inhibitors

Abstract

The present invention is related to new substituted pyrrolidine derivatives of formula (I). Said compounds are preferably for use as pharmaceutically active compounds. Specifically, pyrrolidine derivatives of formula (I) are useful in the treatment and/or prevention of neurodegenerative disorders, diseases associated with polygultamine tracts, epilepsy, ischemia, infertility, cardiovascular disorders renal hypoxia, hepatitis and AIDS. Said pyrrolidine derivatives display a modulatory and most notably a down-regulating-up to an inhibitory-activity with respect to the cellular death agonist Bax and/or the activation pathways leading to Bax and allows therefore to block the release of cytochrome (c). The present invention is furthermore related to novel pharmaceutically activity substituted pyrrolidine derivatives as well as to methods of their preparation, wherein X is selected from the group consisting of O, S, CR<6>R<7>, NOR<6>, NNR<6>R<7>; A is selected from the group consisting of —(C═O)—, —(C═O)—O—, —C(═NH)—, —(C═O)—NH—, —(C═S)—NH, —SO2-, —SO2NH—; —CH2-; B is either a group —(C═O)—NR<8>R<9> or represents a heterocyclic residue having the formula (II) wherein Q is NR<10>, O or S; n is an integer selected of 0, 1 or 2; Y, Z and E form together with the 2 carbons to which they are attached a 5-6 membered aryl or heteroaryl ring.

Pyrrolidine derivatives according to formula I

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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, NNR6R7;
A is selected from the group consisting of —(C═O)—, —(CO)—O—, —C(═NH)—, —(C═O)—NH—, —(C═S)—NH, —SO2—, —SO2NH—, —CH2—,
B is either a group —(C═O)—NR8R9 or represents a heterocyclic residue having the formula
19
wherein Q is NR10, O or S;
n is an integer selected of 0, 1 or 2;
Y, Z and E form together with the 2 carbons to which they are attached a 5-6 membered aryl or heteroaryl ring,
R1 is selected from the group comprising or 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, 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 R5 are independently selected from each other from the group consisting of hydrogen, halogen, C1-C6-alkyl, C1-C6-alkoxy,
R6 and R7 are independently selected from the group comprising or 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 heteroary], unsubstituted or substituted C1-C6-alkyl aryl, unsubstituted or substituted C1-C6-alkyl heteroaryl;
R8, R9 and R10 are independently selected from the group comprising or 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, unsubstituted or substituted heteroaryl, or
each pair R6, R7 and/or R8, R9 could 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 comprising or 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, unsubstituted or substituted saturated or unsaturated 3-8-membered cyclo-alkyl,
with the proviso that if X is (═CH2), A is —(C—O)—O—, R1 is a t-butyl group, B could not be —(C═O)—NMe2, —(C═O)—NHMe, —(C═O)—NH—CH(Me)-(C—O)—NH—CH(Me)—COOH, —(C═O)—NH—CH(COOCH2-Ph)—CH2—COOPh;
with the further proviso that if X is (═CHR6) with R6 being cyclohexylmethyl, A is —(C═O)—O—, R1 is a t-butyl group, B could not be —(C═O)—NH-t-butyl;
with the flier proviso that if X is a C1-C20 alkylidene, A is —(C═O)—O—, R1 is a t-butyl, B could not be
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with R being C1-C12 alkyl and Hal being Cl, Br, J;
with the final proviso that if X is a C1-C20 alkylidene, A-R1 is a protective group, B could not be
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with R being H or C1-C12 alkyl
with the final proviso that the following compounds are excluded:
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22 more elements

Pharmaceutically active pyrrolidine derivatives as bax inhibitors

Life of this patent

Pharmaceutically active pyrrolidine derivatives as bax inhibitors

Life of this patent

Abstract

Claims30