Pyrrolidine derivatives

Details Pyrrolidine derivatives Pyrrolidine derivatives

1996-01-11

1998-05-26

Richter, Johann

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

544106, 546139, 546156, 546183, 546290, 5483001, C07D20714, C07D26530, C07D21704, C07D23324

Patent

active

057567638

DESCRIPTION:

BRIEF SUMMARY
This application is a .sctn.371 of Application No. PCT/JP94/01208, filed Jul. 22, 1994, published as WO95/03277 Feb. 2, 1995.


TECHNICAL FIELD

The present invention relates to a novel pyrrolidine derivative having an inhibitory action on a serine protease or a thiol protease, especially on prolyl endopeptidase, which is expected to be effective for the treatment of amnesia (Alzheimer disease) and autoimmune diseases, or a pharmaceutically acceptable salt thereof.


BACKGROUND ART

Low molecular protease inhibitors originating from natural sources such as leupeptin, chymostatin and elastatinal are known. Based on these compounds, a number of peptidyl aldehydes have been synthesized and provided as inhibitors. It is known that upon inhibition of serine protease or thiol protease, these peptidyl aldehydes are known to form a covalent bond to the hydroxy or thiol group of the enzyme, see Thompson, R. C., Biochemistry, 12, 47-51 (1973).
Peptidyl aldehydes contain an aldehyde group at the C terminus of peptide chain. Then, modification of their amino acid sequences to enhance the specificity or inhibitory activity is restricted to the N-terminal site. Compounds including Poststatin, that were found by the present inventors, contain also at the C terminus as the activity center such a structure that enhances the specificity and contain an .alpha.-keto acid moiety in peptide chain; it is thus considered that these compounds would inhibit the enzyme in the same mechanism as in the peptidyl aldehydes, cf. EP-A-0423358, EP-A-0468339 and U.S. Pat. No. 5,221,752. However, poststatin and the like might be degraded by various proteases in vivo since they have the peptide residue and amino acid residue bound to the .alpha.-keto acid structure at the C and N termini. It is therefore expected to develop compounds having other stable functional groups with less possibility of degradation.


DISCLOSURE OF INVENTION

The present inventors have made extensive studies to solve the foregoing problems. As a result, it has been found that novel pyrrolidine derivatives inhibit a serine protease or a thiol protease, especially prolyl endopeptidase and are expected to be an effective ingredient of drugs for the treatment of amnesia and autoimmune disease.
That is, a first aspect of the present invention relates to a novel pyrrolidine derivative represented by formula (Z) below, preferably formulae (1) through (4) below.
A pyrrolidine derivative represented by formula (Z): ##STR2## wherein R represents R1, R2 or R3; R1 represents (1) a lower alkyl group having 1 to 6 carbon atoms, or (2) a 3- to 15-membered mono- or fused cyclic hydrocarbon group which may contain a hetero atom on the ring, or which may be substituted with a substituent(s); which may contain a hetero atom on the ring, or which may be substituted with a substituent(s); of 0 to 2; alkyl group having 1 to 6 carbon atoms), sulfur, phenylene, CH.dbd.CH or CH.sub.2 ; imino acid residue which functional group may be optionally protected, or a glycine residue which may be substituted at the amino moiety thereof; carbon atoms and Y2 represents a 3- to 15-membered mono- or fused cyclic hydrocarbon group which may contain a hetero atom on the ring, or which may be substituted with a substituent(s); (except that (1) R2 is a phenyl group which may be substituted and both X and E are CH.sub.2, (2) n+m is 0; R2 is a cycloalkyl group which may be substituted or a phenyl group which may be substituted and (3) R2 is a phenyl group which may be substituted, X is CH.sub.2, E is 0 and both n and m are 1); and, is R2 or R3 and Y is Y2; ##STR3## wherein: R1 represents (1) a lower alkyl group having 1 to 6 carbon atoms, or (2) a 3- to 15-membered mono- or fused cyclic hydrocarbon group which may contain a hetero atom on the ring, or which may be substituted with a substituent(s); of 0 to 2; alkyl group having 1 to 6 carbon atoms), sulfur, phenylene, CH.dbd.CH or CH.sub.2 ; functional group may be optionally protected, or a glycine residue which may be substituted at the amino moiety thereof

REFERENCES:
Supplementary Partial European Search Report dated Aug. 13, 1996.

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