US 2003/0212012 A1 · Pharmaceutically active pyrrolidine derivatives

Abstract

The present invention is related to pyrrolidine derivatives of formula (I). Said 1 compounds are preferably for use as pharmaceutically active compounds. Specifically, pyrrolidine derivatives of formula (I) are useful in the treatment and/or prevention of premature labor, premature birth and dysmenorrhea. In particular, the present invention is related to pyrrolidine derivatives displaying a substantial modulatory, notably an antagonist activity of the oxytocin receptor. More preferably, said compounds are useful in the treatment and/or prevention of disease states mediated by oxytocin, including premature labor, premature birth and dysmenorrhea. The present invention is furthermore related to novel pyrrolidine derivatives as well as to methods of their preparation, wherein X is selected from the group consisting of CR6R7, NOR6, NNR6R7; A is selected from the group consisting of —(C═O)—, —(C═O)—O—, —C(═NH)—, —(C═O)—NH—, —(C═S)—NH, —SO22—, —SO2NH—, —CH2—,B is either a group —(C═O)—NR8R9 or represents a heterocyclic residue having the formula (a) 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.

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 CR6R7, NOR6, NNR6R7;
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)—NR8R9 or represents a heterocyclic residue having the formula
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wherein Q is N10, O or S;
n is ani 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 cycloallyl, 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 fom 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 heteroaryl, 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 substi-tuted 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)—NEMe, —(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 further 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 allyl 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.

20 more elements

Pharmaceutically active pyrrolidine derivatives

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Pharmaceutically active pyrrolidine derivatives

Life of this patent

Abstract

Claims28