Organic compounds

Details Organic compounds Organic compounds

1997-01-24

2000-01-11

Davenport, Avis M.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

530317, A61K 3800, A61K 3812, C07K 500, C07K 700

Patent

active

060136278

DESCRIPTION:

BRIEF SUMMARY
This invention relates to cyclopeptolides and to their therapeutic use as inhibitors of adhesion molecule expression.
Cellular adhesion molecules such as ICAM-1, VCAM-1 and E-selectin are expressed on the surface of endothelial cells, as well as keratinocytes for ICAM-1, in response to pro-inflammatory mediators including TNF.alpha., IFN.gamma., IL1 and LPS. Corresponding counter-ligands, e.g. LFA-1, VLA-4 and SLE.sup.x, are expressed on the surfaces of circulating blood cells. Transendothelial migration of leucocytes during inflammatory processes, as well as extravascular cell-cell interactions, are regulated as a result of the interactions between these adhesion molecules and their counterligands. Consequently, inhibitors of adhesion molecule expression offer potential for the treatment of many disease states. However, no suitable low molecular weight inhibitors of adhesion molecule expression are currently available.
Cyclopeptolides are cyclic molecules comprising amino acid residues linked together by peptide bonds and at least one hydroxy substituted carboxylic acid residue which is linked through its hydroxyl substituent to the neighbouring acid residue by an ester linkage.
We have now discovered a new class of cyclopeptolides which are inhibitors of ICAM-1, VCAM-1 and E-selectin expression.
The present invention provides cycloheptapeptolides of formula I ##STR2## wherein: A is an .alpha.-hydroxy-substituted butyric acid residue optionally .gamma.-substituted by R.sub.6, which represents CN, COOR.sub.2, CONR.sub.3 R.sub.4, COR.sub.5, CSNH.sub.2 or alkyl, which may be substituted by azido, halogen, alkoxy, optionally protected hydroxy or amino, vinyl, which may be substituted by alkyl, halogen or CN, cycloalkyl, tetrazolyl or --C.tbd.CH, wherein R.sub.2 represents hydrogen or optionally aryisubstituted alkyl, R.sub.3 and R.sub.4 are the same or different and represent hydrogen or alkyl or form together with the nitrogen a 3- to 6-membered ring optionally containing a second heteroatom, and R.sub.5 represents hydrogen or lower alkyl, ##STR3## wherein R.sub.8 represents hydrogen, alkoxy, alkyl or benzyl, R.sub.9 represents hydrogen or halogen, R.sub.10 represents hydrogen or methyl and ---- represents a single or double bond, X is an .alpha.-amino-substituted (C.sub.2 to C.sub.14) carboxylic acid residue, and Y is an .alpha.-amino- or N-methyl-.alpha.-amino substituted (C.sub.2 to C.sub.10) carboxylic acid residue.
In formula I the C-terminal to N-terminal orientation of the amino acid residues is in the clockwise direction, and the peptolide ester bond is between residues A and Y. When R.sub.1 is methyl, the residues R.sub.1 -Leu and Leu are N-methyl-leucine and leucine residues respectively.
Preferably A is an .alpha.-hydroxybutyric acid residue, which is .gamma.-substituted by cyano, COOR.sub.2 ', whererby R.sub.2 ' represents hydrogen, lower alkyl with 1 to 4 carbon atoms or diphenylmethyl, CONR.sub.3 'R.sub.4 ', whereby R.sub.3 ' represents hydrogen or methyl and R.sub.4 ' represents hydrogen or alkyl or R.sub.3 ' and R.sub.4 ' form together with the nitrogen a 3- to 6-membered ring or a morpholinyl ring, CH.sub.2 OH, COR.sub.5 ', whereby R.sub.5 ' represents hydrogen or lower alkyl with 1 to 4 carbon atoms, vinyl optionally substituted by CN, Br or lower alkyl with 1 to 4 carbon atoms, alkyl optionally substituted by azido, amino, hydroxy, chloro or alkoxy, tetrazolyl, cyclopropyl, CSNH.sub.2 or --C.tbd.CH.
Preferably C is a N-methyltryptophan residue of formula VI, wherein R.sub.8 represents hydrogen, (C.sub.1 to C.sub.4)alkoxy, especially methoxy, or alkyl and R.sub.9 represents hydrogen or halogen.
Preferably X is an .alpha.-amino-substituted (C.sub.4 to C.sub.8) carboxylic acid residue, which is optionally .beta.- or .gamma.-(C.sub.1 to C.sub.4) alkyl substituted. Most preferably X is an .alpha.-amino-.beta.- or .gamma.-(C.sub.1 to C.sub.4) alkyl-, especially methyl-, substituted octanoic or a butyric acid residue.
Preferably Y is an N-methyl-.alpha.-amino-substituted (C.sub.2 to C.sub.4) carb

REFERENCES:
patent: 4425428 (1984-01-01), Weingarten
patent: 4443367 (1984-04-01), Weingarten
patent: 5116816 (1992-05-01), Dreyfuss et al.
patent: 5643869 (1997-07-01), Dreyfuss et al.
Derwent Abstract JP07109229-A + English Translation.

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